Clinical Review

Artificial intelligence (AI) in medicine has shown significant promise, particularly in neuroimaging. AI refers to computer systems designed to perform tasks that normally require human intelligence.¹ Machine learning (ML), a field in which computers learn from data without being specifically programmed, is the AI subset responsible for its success in matching or even surpassing humans in certain tasks.²

Supervised learning, a subset of ML, uses an algorithm with annotated data from which to learn.³ The program will use the characteristics of a training data set to predict a specific outcome or target when exposed to a sample data set of the same type. Unsupervised learning finds naturally occurring patterns or groupings within the data.⁴ With deep learning (DL) algorithms, computers learn the features that optimally represent the data for the problem at hand.⁵ Both ML and DL are meant to emulate neural networks in the brain, giving rise to artificial neural networks composed of nodes structured within input, hidden, and output layers.

The DL neural network differs from a conventional one by having many hidden layers instead of just 1 layer that extracts patterns within the data.⁶ Convolutional neural networks (CNNs) are the most prevalent DL architecture used in medical imaging. CNN’s hidden layers apply convolution and pooling operations to break down an image into features containing the most valuable information. The connecting layer applies high-level reasoning before the output layer provides predictions for the image. This framework has applications within radiology, such as predicting a lesion category or condition from an image, determining whether a specific pixel belongs to background or a target class, and predicting the location of lesions.¹

AI promises to increase efficiency and reduces errors. With increased data processing and image interpretation, AI technology may help radiologists improve the quality of patient care.⁶ This article discusses the current applications and future integration of AI in neuroradiology.

Neuroimaging Applications

AI can improve the quality of neuroimaging and reduce the clinical and systemic loads of other imaging modalities. AI can predict patient wait times for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and X-ray imaging.⁷ A ML-based AI has detected the variables that most affected patient wait times, including proximity to federal holidays and severity of the patient’s condition, and calculated how long patients would be delayed after their scheduled appointment time. This AI modality could allow more efficient patient scheduling and reveal areas of patient processing that could be changed, potentially improving patient satisfaction and outcomes for time-sensitive neurologic conditions.

AI can save patient and health care practitioner time for repeat MRIs. An estimated 20% of MRI scans require a repeat series—a massive loss of time and funds for both patients and the health care system.⁸ A DL approach can determine whether an MRI is usable clinically or unclear enough to require repetition.⁹ This initial screening measure can prevent patients from making return visits and neuroradiologists from reading inconclusive images. AI offers the opportunity to reduce time and costs incurred by optimizing the health care process before imaging is obtained.

Speeding Up Neuroimaging

AI can reduce the time spent performing imaging. Because MRIs consume time and resources, compressed sensing (CS) is commonly used. CS preferentially maintains in-plane resolution at the expense of through-plane resolution to produce a scan with a single, usable viewpoint that preserves signal-to-noise ratio (SNR). CS, however, limits interpretation to single directions and can create aliasing artifacts. An AI algorithm known as synthetic multi-orientation resolution enhancement works in real time to reduce aliasing and improve resolution in these compressed scans.¹⁰ This AI improved resolution of white matter lesions in patients with multiple sclerosis (MS) on FLAIR (fluid-attenuated inversion recovery) images, and permitted multiview reconstruction from these limited scans.

Tasks of reconstructing and anti-aliasing come with high computational costs that vary inversely with the extent of scanning compression, potentially negating the time and resource savings of CS. DL AI modalities have been developed to reduce operational loads and further improve image resolution in several directions from CS. One such deep residual learning AI was trained with compressed MRIs and used the framelet method to create a CNN that could rapidly remove global and deeply coherent aliasing artifacts.¹¹ This system, compared with synthetic multi-orientation resolution enhancement, uses a pretrained, pretested AI that does not require additional time during scanning for computational analysis, thereby multiplying the time benefit of CS while retaining the benefits of multidirectional reconstruction and increased resolution. This methodology suffers from inherent degradation of perceptual image quality in its reconstructions because of the L2 loss function the CNN uses to reduce mean squared error, which causes blurring by averaging all possible outcomes of signal distribution during reconstruction. To combat this, researchers have developed another AI to reduce reconstruction times that uses a different loss function in a generative adversarial network to retain image quality, while offering reconstruction times several hundred times faster than current CS-MRI structures.¹² So-called sparse-coding methods promise further reduction in reconstruction times, with the possibility of processing completed online with a lightweight architecture rather than on a local system.¹³

Neuroimaging of acute cases benefits most directly from these technologies because MRIs and their high resolution and SNR begin to approach CT imaging time scales. This could have important implications in clinical care, particularly for stroke imaging and evaluating spinal cord compression. CS-MRI optimization represents one of the greatest areas of neuroimaging cost savings and neurologic care improvement in the modern radiology era.

Reducing Contrast and Radiation Doses

AI has the ability to read CT, MRI, and positron emission tomography (PET) with reduced or without contrast without significant loss in sensitivity for detecting lesions. With MRI, gadolinium-based contrast can cause injection site reactions, allergic reactions, metal deposition throughout the body, and nephrogenic systemic fibrosis in the most severe instances.¹⁴ DL has been applied to brain MRIs performed with 10% of a full dose of contrast without significant degradation of image quality. Neuroradiologists did not rate the AI-synthesized images for several MRI indications lower than their full-dose counterparts.¹⁵ Low-dose contrast imaging, regardless of modality, generates greater noise with a significantly reduced signal. However, with AI applied, researchers found that the software suppressed motion and aliasing artifacts and improved image quality, perhaps evidence that this low-dose modality is less vulnerable to the most common pitfalls of MRI.

Recently, low-dose MRI moved into the spotlight when Subtle Medical SubtleGAD software received a National Institutes of Health grant and an expedited pathway to phase 2 clinical trials.¹⁶ SubtleGAD, a DL AI that enables low-dose MRI interpretation, might allow contrast MRI for patients with advanced kidney disease or contrast allergies. At some point, contrast with MRI might not be necessary because DL AI applied to noncontrast MRs for detecting MS lesions was found to be preliminarily effective with 78% lesion detection sensitivity.¹⁷

PET-MRI combines simultaneous PET and MRI and has been used to evaluate neurologic disorders. PET-MRI can detect amyloid plaques in Alzheimer disease 10 to 20 years before clinical signs of dementia emerge.¹⁸ PET-MRI has sparked DL AI development to decrease the dose of the IV radioactive tracer 18F-florbetaben used in imaging to reduce radiation exposure and imaging costs.This reduction is critical if PET-MRI is to become used widely.^19-21

An initial CNN could reconstruct low-dose amyloid scans to full-dose resolution, albeit with a greater susceptibility to some artifacts and motion blurring.²² Similar to the synthetic multi-orientation resolution enhancement CNN, this program showed signal blurring from the L2 loss function, which was corrected in a later AI that used a generative adversarial network to minimize perceptual loss.²³ This new AI demonstrated greater image resolution, feature preservation, and radiologist rating over the previous AI and was capable of reconstructing low-dose PET scans to full-dose resolution without an accompanying MRI. Applications of this algorithm are far-reaching, potentially allowing neuroimaging of brain tumors at more frequent intervals with higher resolution and lower total radiation exposure.

AI also has been applied to neurologic CT to reduce radiation exposure.²⁴ Because it is critical to abide by the principles of ALARA (as low as reasonably achievable), the ability of AI to reduce radiation exposure holds significant promise. A CNN has been used to transform low-dose CTs of anthropomorphic models with calcium inserts and cardiac patients to normal-dose CTs, with the goal of improving the SNR.²⁵ By training a noise-discriminating CNN and a noise-generating CNN together in a generative adversarial network, the AI improved image feature preservation during transformation. This algorithm has a direct application in imaging cerebral vasculature, including calcification that can explain lacunar infarcts and tracking systemic atherosclerosis.²⁶

Another CNN has been applied to remove more complex noise patterns from the phenomena of beam hardening and photon starvation common in low-dose CT. This algorithm extracts the directional components of artifacts and compares them to known artifact patterns, allowing for highly specific suppression of unwanted signals.²⁷ In June 2019, the US Food and Drug Administration (FDA) approved ClariPi, a deep CNN program for advanced denoising and resolution improvement of low- and ultra low-dose CTs.²⁸ Aside from only low-dose settings, this AI could reduce artifacts in all CT imaging modalities and improve therapeutic value of procedures, including cerebral angiograms and emergency cranial scans. As the average CT radiation dose decreased from 12 mSv in 2009 to 1.5 mSv in 2014 and continues to fall, these algorithms will become increasingly necessary to retain the high resolution and diagnostic power expected of neurologic CTs.^29,30

Downstream Applications

Downstream applications refer to AI use after a radiologic study is acquired, mostly image interpretation. More than 70% of FDA-approved AI medical devices are in radiology, and many of these relate to image analysis.^6,31 Although AI is not limited to black-and-white image interpretation, it is hypothesized that one of the reasons radiology is inviting to AI is because gray-scale images lend themselves to standardization.³ Moreover, most radiology departments already use AI-friendly picture archiving and communication systems.^31,32

AI has been applied to a range of radiologic modalities, including MRI, CT, ultrasonography, PET, and mammography.^32-38 AI also has been specifically applied to radiography, including the interpretation of tuberculosis, pneumonia, lung lesions, and COVID-19.^33,39-45 AI also can assist triage, patient screening, providing a “second opinion” rapidly, shortening the time needed for attaining a diagnosis, monitoring disease progression, and predicting prognosis.^{37-39,43,45-47} Downstream applications of AI in neuroradiology and neurology include using CT to aid in detecting hemorrhage or ischemic stroke; using MRI to automatically segment lesions, such as tumors or MS lesions; assisting in early diagnosis and predicting prognosis in MS; assisting in treating paralysis, including from spinal cord injury; determining seizure type and localizing area of seizure onset; and using cameras, wearable devices, and smartphone applications to diagnose and assess treatment response in neurodegenerative disorders, such as Parkinson or Alzheimer diseases (Figure).^37,48-56

Practical and Ethical Considerations

In any discussion of the benefits of AI, it is prudent to address its shortcomings. Chief among these is overfitting, which occurs when an AI is too closely aligned with its training dataset and prone to error when applied to novel cases. Often this is a byproduct of a small training set.⁶⁰ Neuroradiology, particularly with uncommon, advanced imaging methods, has a smaller number of available studies.⁶¹ Even with more prevalent imaging modalities, such as head CT, the work of collecting training scans from patients with the prerequisite disease processes, particularly if these processes are rare, can limit the number of datapoints collected. Neuroradiologists should understand how an AI tool was generated, including the size and variety of the training dataset used, to best gauge the clinical applicability and fitness of the system.

Another point of concern for AI clinical decision support tools’ implementation is automation bias—the tendency for clinicians to favor machine-generated decisions and ignore contrary data or conflicting human decisions.⁶² This situation often arises when radiologists experience overwhelming patient loads or are in underresourced settings, where there is little ability to review every AI-based diagnosis. Although AI might be of benefit in such conditions by reducing physician workload and streamlining the diagnostic process, there is the propensity to improperly rely on a tool meant to augment, not replace, a radiologist’s judgment. Such cases have led to adverse outcomes for patients, and legal precedence shows that this constitutes negligence.⁶³ Maintaining awareness of each tool’s limitations and proper application is the only remedy for such situations.

Ethically, we must consider the opaqueness of ML-developed neuroimaging AIs. For many systems, the specific process by which an AI arrives at its conclusions is unknown. This AI “black box” can conceal potential errors and biases that are masked by overall positive performance metrics. The lack of understanding about how a tool functions in the zero-failure clinical setting understandably gives radiologists pause. The question must be asked: Is it ethical to use a system that is a relatively unknown quantity? Entities, including state governments, Canada, and the European Union, have produced an answer. Each of these governments have implemented policies requiring that health care AIs use some method to display to end users the process by which they arrive at conclusions.^64-68

The 21st Century Cures Act declares that to attain approval, clinical AIs must demonstrate this explainability to clinicians and patients.⁶⁹ The response has been an explosion in the development of explainable AI. Systems that visualize the areas where AI attention most often rests with heatmaps, generate labels for the most heavily weighted features of radiographic images, and create full diagnostic reports to justify AI conclusions aim to meet the goal of transparency and inspiring confidence in clinical end users.⁷⁰ The ability to understand the “thought process” of a system proves useful for error correction and retooling. A trend toward under- or overdetecting conditions, flagging seemingly irrelevant image regions, or low reproducibility can be better addressed when it is clear how the AI is drawing its false conclusions. With an iterative process of testing and redesigning, false positive and negative rates can be reduced, the need for human intervention can be lowered to an appropriate minimum, and patient outcomes can be improved.⁷¹

Data collection raises another ethical concern. To train functional clinical decision support tools, massive amounts of patient demographic, laboratory, and imaging data are required. With incentives to develop the most powerful AI systems, record collection can venture down a path where patient autonomy and privacy are threatened. Radiologists have a duty to ensure data mining serves patients and improves the practice of radiology while protecting patients’ personal information.⁶² Policies have placed similar limits on the access to and use of patient records.^64-69 Patients have the right to request explanation of the AI systems their data have been used to train. Approval for data acquisition requires the use of explainable AI, standardized data security protocol implementation, and adequate proof of communal benefit from the clinical decision support tool. Establishment of state-mandated protections bodes well for a future when developers can access enormous caches of data while patients and health care professionals are assured that no identifying information has escaped a well-regulated space. On the level of the individual radiologist, the knowledge that each datum represents a human life. These are people who has made themselves vulnerable by seeking relief for what ails them, which should serve as a lasting reminder to operate with utmost care when handling sensitive information.

Conclusions

The demonstrated applications of AI in neuroimaging are numerous and varied, and it is reasonable to assume that its implementation will increase as the technology matures. AI use for detecting important neurologic conditions holds promise in combatting ever greater imaging volumes and providing timely diagnoses. As medicine witnesses the continuing adoption of AI, it is important that practitioners possess an understanding of its current and emerging uses.

Artificial intelligence (AI) in medicine has shown significant promise, particularly in neuroimaging. AI refers to computer systems designed to perform tasks that normally require human intelligence.¹ Machine learning (ML), a field in which computers learn from data without being specifically programmed, is the AI subset responsible for its success in matching or even surpassing humans in certain tasks.²

Supervised learning, a subset of ML, uses an algorithm with annotated data from which to learn.³ The program will use the characteristics of a training data set to predict a specific outcome or target when exposed to a sample data set of the same type. Unsupervised learning finds naturally occurring patterns or groupings within the data.⁴ With deep learning (DL) algorithms, computers learn the features that optimally represent the data for the problem at hand.⁵ Both ML and DL are meant to emulate neural networks in the brain, giving rise to artificial neural networks composed of nodes structured within input, hidden, and output layers.

The DL neural network differs from a conventional one by having many hidden layers instead of just 1 layer that extracts patterns within the data.⁶ Convolutional neural networks (CNNs) are the most prevalent DL architecture used in medical imaging. CNN’s hidden layers apply convolution and pooling operations to break down an image into features containing the most valuable information. The connecting layer applies high-level reasoning before the output layer provides predictions for the image. This framework has applications within radiology, such as predicting a lesion category or condition from an image, determining whether a specific pixel belongs to background or a target class, and predicting the location of lesions.¹

AI promises to increase efficiency and reduces errors. With increased data processing and image interpretation, AI technology may help radiologists improve the quality of patient care.⁶ This article discusses the current applications and future integration of AI in neuroradiology.

Neuroimaging Applications

AI can improve the quality of neuroimaging and reduce the clinical and systemic loads of other imaging modalities. AI can predict patient wait times for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and X-ray imaging.⁷ A ML-based AI has detected the variables that most affected patient wait times, including proximity to federal holidays and severity of the patient’s condition, and calculated how long patients would be delayed after their scheduled appointment time. This AI modality could allow more efficient patient scheduling and reveal areas of patient processing that could be changed, potentially improving patient satisfaction and outcomes for time-sensitive neurologic conditions.

AI can save patient and health care practitioner time for repeat MRIs. An estimated 20% of MRI scans require a repeat series—a massive loss of time and funds for both patients and the health care system.⁸ A DL approach can determine whether an MRI is usable clinically or unclear enough to require repetition.⁹ This initial screening measure can prevent patients from making return visits and neuroradiologists from reading inconclusive images. AI offers the opportunity to reduce time and costs incurred by optimizing the health care process before imaging is obtained.

Speeding Up Neuroimaging

AI can reduce the time spent performing imaging. Because MRIs consume time and resources, compressed sensing (CS) is commonly used. CS preferentially maintains in-plane resolution at the expense of through-plane resolution to produce a scan with a single, usable viewpoint that preserves signal-to-noise ratio (SNR). CS, however, limits interpretation to single directions and can create aliasing artifacts. An AI algorithm known as synthetic multi-orientation resolution enhancement works in real time to reduce aliasing and improve resolution in these compressed scans.¹⁰ This AI improved resolution of white matter lesions in patients with multiple sclerosis (MS) on FLAIR (fluid-attenuated inversion recovery) images, and permitted multiview reconstruction from these limited scans.

Tasks of reconstructing and anti-aliasing come with high computational costs that vary inversely with the extent of scanning compression, potentially negating the time and resource savings of CS. DL AI modalities have been developed to reduce operational loads and further improve image resolution in several directions from CS. One such deep residual learning AI was trained with compressed MRIs and used the framelet method to create a CNN that could rapidly remove global and deeply coherent aliasing artifacts.¹¹ This system, compared with synthetic multi-orientation resolution enhancement, uses a pretrained, pretested AI that does not require additional time during scanning for computational analysis, thereby multiplying the time benefit of CS while retaining the benefits of multidirectional reconstruction and increased resolution. This methodology suffers from inherent degradation of perceptual image quality in its reconstructions because of the L2 loss function the CNN uses to reduce mean squared error, which causes blurring by averaging all possible outcomes of signal distribution during reconstruction. To combat this, researchers have developed another AI to reduce reconstruction times that uses a different loss function in a generative adversarial network to retain image quality, while offering reconstruction times several hundred times faster than current CS-MRI structures.¹² So-called sparse-coding methods promise further reduction in reconstruction times, with the possibility of processing completed online with a lightweight architecture rather than on a local system.¹³

Neuroimaging of acute cases benefits most directly from these technologies because MRIs and their high resolution and SNR begin to approach CT imaging time scales. This could have important implications in clinical care, particularly for stroke imaging and evaluating spinal cord compression. CS-MRI optimization represents one of the greatest areas of neuroimaging cost savings and neurologic care improvement in the modern radiology era.

Reducing Contrast and Radiation Doses

AI has the ability to read CT, MRI, and positron emission tomography (PET) with reduced or without contrast without significant loss in sensitivity for detecting lesions. With MRI, gadolinium-based contrast can cause injection site reactions, allergic reactions, metal deposition throughout the body, and nephrogenic systemic fibrosis in the most severe instances.¹⁴ DL has been applied to brain MRIs performed with 10% of a full dose of contrast without significant degradation of image quality. Neuroradiologists did not rate the AI-synthesized images for several MRI indications lower than their full-dose counterparts.¹⁵ Low-dose contrast imaging, regardless of modality, generates greater noise with a significantly reduced signal. However, with AI applied, researchers found that the software suppressed motion and aliasing artifacts and improved image quality, perhaps evidence that this low-dose modality is less vulnerable to the most common pitfalls of MRI.

Recently, low-dose MRI moved into the spotlight when Subtle Medical SubtleGAD software received a National Institutes of Health grant and an expedited pathway to phase 2 clinical trials.¹⁶ SubtleGAD, a DL AI that enables low-dose MRI interpretation, might allow contrast MRI for patients with advanced kidney disease or contrast allergies. At some point, contrast with MRI might not be necessary because DL AI applied to noncontrast MRs for detecting MS lesions was found to be preliminarily effective with 78% lesion detection sensitivity.¹⁷

PET-MRI combines simultaneous PET and MRI and has been used to evaluate neurologic disorders. PET-MRI can detect amyloid plaques in Alzheimer disease 10 to 20 years before clinical signs of dementia emerge.¹⁸ PET-MRI has sparked DL AI development to decrease the dose of the IV radioactive tracer 18F-florbetaben used in imaging to reduce radiation exposure and imaging costs.This reduction is critical if PET-MRI is to become used widely.^19-21

An initial CNN could reconstruct low-dose amyloid scans to full-dose resolution, albeit with a greater susceptibility to some artifacts and motion blurring.²² Similar to the synthetic multi-orientation resolution enhancement CNN, this program showed signal blurring from the L2 loss function, which was corrected in a later AI that used a generative adversarial network to minimize perceptual loss.²³ This new AI demonstrated greater image resolution, feature preservation, and radiologist rating over the previous AI and was capable of reconstructing low-dose PET scans to full-dose resolution without an accompanying MRI. Applications of this algorithm are far-reaching, potentially allowing neuroimaging of brain tumors at more frequent intervals with higher resolution and lower total radiation exposure.

AI also has been applied to neurologic CT to reduce radiation exposure.²⁴ Because it is critical to abide by the principles of ALARA (as low as reasonably achievable), the ability of AI to reduce radiation exposure holds significant promise. A CNN has been used to transform low-dose CTs of anthropomorphic models with calcium inserts and cardiac patients to normal-dose CTs, with the goal of improving the SNR.²⁵ By training a noise-discriminating CNN and a noise-generating CNN together in a generative adversarial network, the AI improved image feature preservation during transformation. This algorithm has a direct application in imaging cerebral vasculature, including calcification that can explain lacunar infarcts and tracking systemic atherosclerosis.²⁶

Another CNN has been applied to remove more complex noise patterns from the phenomena of beam hardening and photon starvation common in low-dose CT. This algorithm extracts the directional components of artifacts and compares them to known artifact patterns, allowing for highly specific suppression of unwanted signals.²⁷ In June 2019, the US Food and Drug Administration (FDA) approved ClariPi, a deep CNN program for advanced denoising and resolution improvement of low- and ultra low-dose CTs.²⁸ Aside from only low-dose settings, this AI could reduce artifacts in all CT imaging modalities and improve therapeutic value of procedures, including cerebral angiograms and emergency cranial scans. As the average CT radiation dose decreased from 12 mSv in 2009 to 1.5 mSv in 2014 and continues to fall, these algorithms will become increasingly necessary to retain the high resolution and diagnostic power expected of neurologic CTs.^29,30

Downstream Applications

Downstream applications refer to AI use after a radiologic study is acquired, mostly image interpretation. More than 70% of FDA-approved AI medical devices are in radiology, and many of these relate to image analysis.^6,31 Although AI is not limited to black-and-white image interpretation, it is hypothesized that one of the reasons radiology is inviting to AI is because gray-scale images lend themselves to standardization.³ Moreover, most radiology departments already use AI-friendly picture archiving and communication systems.^31,32

AI has been applied to a range of radiologic modalities, including MRI, CT, ultrasonography, PET, and mammography.^32-38 AI also has been specifically applied to radiography, including the interpretation of tuberculosis, pneumonia, lung lesions, and COVID-19.^33,39-45 AI also can assist triage, patient screening, providing a “second opinion” rapidly, shortening the time needed for attaining a diagnosis, monitoring disease progression, and predicting prognosis.^{37-39,43,45-47} Downstream applications of AI in neuroradiology and neurology include using CT to aid in detecting hemorrhage or ischemic stroke; using MRI to automatically segment lesions, such as tumors or MS lesions; assisting in early diagnosis and predicting prognosis in MS; assisting in treating paralysis, including from spinal cord injury; determining seizure type and localizing area of seizure onset; and using cameras, wearable devices, and smartphone applications to diagnose and assess treatment response in neurodegenerative disorders, such as Parkinson or Alzheimer diseases (Figure).^37,48-56

Practical and Ethical Considerations

In any discussion of the benefits of AI, it is prudent to address its shortcomings. Chief among these is overfitting, which occurs when an AI is too closely aligned with its training dataset and prone to error when applied to novel cases. Often this is a byproduct of a small training set.⁶⁰ Neuroradiology, particularly with uncommon, advanced imaging methods, has a smaller number of available studies.⁶¹ Even with more prevalent imaging modalities, such as head CT, the work of collecting training scans from patients with the prerequisite disease processes, particularly if these processes are rare, can limit the number of datapoints collected. Neuroradiologists should understand how an AI tool was generated, including the size and variety of the training dataset used, to best gauge the clinical applicability and fitness of the system.

Another point of concern for AI clinical decision support tools’ implementation is automation bias—the tendency for clinicians to favor machine-generated decisions and ignore contrary data or conflicting human decisions.⁶² This situation often arises when radiologists experience overwhelming patient loads or are in underresourced settings, where there is little ability to review every AI-based diagnosis. Although AI might be of benefit in such conditions by reducing physician workload and streamlining the diagnostic process, there is the propensity to improperly rely on a tool meant to augment, not replace, a radiologist’s judgment. Such cases have led to adverse outcomes for patients, and legal precedence shows that this constitutes negligence.⁶³ Maintaining awareness of each tool’s limitations and proper application is the only remedy for such situations.

Ethically, we must consider the opaqueness of ML-developed neuroimaging AIs. For many systems, the specific process by which an AI arrives at its conclusions is unknown. This AI “black box” can conceal potential errors and biases that are masked by overall positive performance metrics. The lack of understanding about how a tool functions in the zero-failure clinical setting understandably gives radiologists pause. The question must be asked: Is it ethical to use a system that is a relatively unknown quantity? Entities, including state governments, Canada, and the European Union, have produced an answer. Each of these governments have implemented policies requiring that health care AIs use some method to display to end users the process by which they arrive at conclusions.^64-68

The 21st Century Cures Act declares that to attain approval, clinical AIs must demonstrate this explainability to clinicians and patients.⁶⁹ The response has been an explosion in the development of explainable AI. Systems that visualize the areas where AI attention most often rests with heatmaps, generate labels for the most heavily weighted features of radiographic images, and create full diagnostic reports to justify AI conclusions aim to meet the goal of transparency and inspiring confidence in clinical end users.⁷⁰ The ability to understand the “thought process” of a system proves useful for error correction and retooling. A trend toward under- or overdetecting conditions, flagging seemingly irrelevant image regions, or low reproducibility can be better addressed when it is clear how the AI is drawing its false conclusions. With an iterative process of testing and redesigning, false positive and negative rates can be reduced, the need for human intervention can be lowered to an appropriate minimum, and patient outcomes can be improved.⁷¹

Data collection raises another ethical concern. To train functional clinical decision support tools, massive amounts of patient demographic, laboratory, and imaging data are required. With incentives to develop the most powerful AI systems, record collection can venture down a path where patient autonomy and privacy are threatened. Radiologists have a duty to ensure data mining serves patients and improves the practice of radiology while protecting patients’ personal information.⁶² Policies have placed similar limits on the access to and use of patient records.^64-69 Patients have the right to request explanation of the AI systems their data have been used to train. Approval for data acquisition requires the use of explainable AI, standardized data security protocol implementation, and adequate proof of communal benefit from the clinical decision support tool. Establishment of state-mandated protections bodes well for a future when developers can access enormous caches of data while patients and health care professionals are assured that no identifying information has escaped a well-regulated space. On the level of the individual radiologist, the knowledge that each datum represents a human life. These are people who has made themselves vulnerable by seeking relief for what ails them, which should serve as a lasting reminder to operate with utmost care when handling sensitive information.

Conclusions

The demonstrated applications of AI in neuroimaging are numerous and varied, and it is reasonable to assume that its implementation will increase as the technology matures. AI use for detecting important neurologic conditions holds promise in combatting ever greater imaging volumes and providing timely diagnoses. As medicine witnesses the continuing adoption of AI, it is important that practitioners possess an understanding of its current and emerging uses.

Artificial intelligence (AI) in medicine has shown significant promise, particularly in neuroimaging. AI refers to computer systems designed to perform tasks that normally require human intelligence.¹ Machine learning (ML), a field in which computers learn from data without being specifically programmed, is the AI subset responsible for its success in matching or even surpassing humans in certain tasks.²

Supervised learning, a subset of ML, uses an algorithm with annotated data from which to learn.³ The program will use the characteristics of a training data set to predict a specific outcome or target when exposed to a sample data set of the same type. Unsupervised learning finds naturally occurring patterns or groupings within the data.⁴ With deep learning (DL) algorithms, computers learn the features that optimally represent the data for the problem at hand.⁵ Both ML and DL are meant to emulate neural networks in the brain, giving rise to artificial neural networks composed of nodes structured within input, hidden, and output layers.

The DL neural network differs from a conventional one by having many hidden layers instead of just 1 layer that extracts patterns within the data.⁶ Convolutional neural networks (CNNs) are the most prevalent DL architecture used in medical imaging. CNN’s hidden layers apply convolution and pooling operations to break down an image into features containing the most valuable information. The connecting layer applies high-level reasoning before the output layer provides predictions for the image. This framework has applications within radiology, such as predicting a lesion category or condition from an image, determining whether a specific pixel belongs to background or a target class, and predicting the location of lesions.¹

AI promises to increase efficiency and reduces errors. With increased data processing and image interpretation, AI technology may help radiologists improve the quality of patient care.⁶ This article discusses the current applications and future integration of AI in neuroradiology.

Neuroimaging Applications

AI can improve the quality of neuroimaging and reduce the clinical and systemic loads of other imaging modalities. AI can predict patient wait times for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and X-ray imaging.⁷ A ML-based AI has detected the variables that most affected patient wait times, including proximity to federal holidays and severity of the patient’s condition, and calculated how long patients would be delayed after their scheduled appointment time. This AI modality could allow more efficient patient scheduling and reveal areas of patient processing that could be changed, potentially improving patient satisfaction and outcomes for time-sensitive neurologic conditions.

AI can save patient and health care practitioner time for repeat MRIs. An estimated 20% of MRI scans require a repeat series—a massive loss of time and funds for both patients and the health care system.⁸ A DL approach can determine whether an MRI is usable clinically or unclear enough to require repetition.⁹ This initial screening measure can prevent patients from making return visits and neuroradiologists from reading inconclusive images. AI offers the opportunity to reduce time and costs incurred by optimizing the health care process before imaging is obtained.

Speeding Up Neuroimaging

AI can reduce the time spent performing imaging. Because MRIs consume time and resources, compressed sensing (CS) is commonly used. CS preferentially maintains in-plane resolution at the expense of through-plane resolution to produce a scan with a single, usable viewpoint that preserves signal-to-noise ratio (SNR). CS, however, limits interpretation to single directions and can create aliasing artifacts. An AI algorithm known as synthetic multi-orientation resolution enhancement works in real time to reduce aliasing and improve resolution in these compressed scans.¹⁰ This AI improved resolution of white matter lesions in patients with multiple sclerosis (MS) on FLAIR (fluid-attenuated inversion recovery) images, and permitted multiview reconstruction from these limited scans.

Tasks of reconstructing and anti-aliasing come with high computational costs that vary inversely with the extent of scanning compression, potentially negating the time and resource savings of CS. DL AI modalities have been developed to reduce operational loads and further improve image resolution in several directions from CS. One such deep residual learning AI was trained with compressed MRIs and used the framelet method to create a CNN that could rapidly remove global and deeply coherent aliasing artifacts.¹¹ This system, compared with synthetic multi-orientation resolution enhancement, uses a pretrained, pretested AI that does not require additional time during scanning for computational analysis, thereby multiplying the time benefit of CS while retaining the benefits of multidirectional reconstruction and increased resolution. This methodology suffers from inherent degradation of perceptual image quality in its reconstructions because of the L2 loss function the CNN uses to reduce mean squared error, which causes blurring by averaging all possible outcomes of signal distribution during reconstruction. To combat this, researchers have developed another AI to reduce reconstruction times that uses a different loss function in a generative adversarial network to retain image quality, while offering reconstruction times several hundred times faster than current CS-MRI structures.¹² So-called sparse-coding methods promise further reduction in reconstruction times, with the possibility of processing completed online with a lightweight architecture rather than on a local system.¹³

Neuroimaging of acute cases benefits most directly from these technologies because MRIs and their high resolution and SNR begin to approach CT imaging time scales. This could have important implications in clinical care, particularly for stroke imaging and evaluating spinal cord compression. CS-MRI optimization represents one of the greatest areas of neuroimaging cost savings and neurologic care improvement in the modern radiology era.

Reducing Contrast and Radiation Doses

AI has the ability to read CT, MRI, and positron emission tomography (PET) with reduced or without contrast without significant loss in sensitivity for detecting lesions. With MRI, gadolinium-based contrast can cause injection site reactions, allergic reactions, metal deposition throughout the body, and nephrogenic systemic fibrosis in the most severe instances.¹⁴ DL has been applied to brain MRIs performed with 10% of a full dose of contrast without significant degradation of image quality. Neuroradiologists did not rate the AI-synthesized images for several MRI indications lower than their full-dose counterparts.¹⁵ Low-dose contrast imaging, regardless of modality, generates greater noise with a significantly reduced signal. However, with AI applied, researchers found that the software suppressed motion and aliasing artifacts and improved image quality, perhaps evidence that this low-dose modality is less vulnerable to the most common pitfalls of MRI.

Recently, low-dose MRI moved into the spotlight when Subtle Medical SubtleGAD software received a National Institutes of Health grant and an expedited pathway to phase 2 clinical trials.¹⁶ SubtleGAD, a DL AI that enables low-dose MRI interpretation, might allow contrast MRI for patients with advanced kidney disease or contrast allergies. At some point, contrast with MRI might not be necessary because DL AI applied to noncontrast MRs for detecting MS lesions was found to be preliminarily effective with 78% lesion detection sensitivity.¹⁷

PET-MRI combines simultaneous PET and MRI and has been used to evaluate neurologic disorders. PET-MRI can detect amyloid plaques in Alzheimer disease 10 to 20 years before clinical signs of dementia emerge.¹⁸ PET-MRI has sparked DL AI development to decrease the dose of the IV radioactive tracer 18F-florbetaben used in imaging to reduce radiation exposure and imaging costs.This reduction is critical if PET-MRI is to become used widely.^19-21

An initial CNN could reconstruct low-dose amyloid scans to full-dose resolution, albeit with a greater susceptibility to some artifacts and motion blurring.²² Similar to the synthetic multi-orientation resolution enhancement CNN, this program showed signal blurring from the L2 loss function, which was corrected in a later AI that used a generative adversarial network to minimize perceptual loss.²³ This new AI demonstrated greater image resolution, feature preservation, and radiologist rating over the previous AI and was capable of reconstructing low-dose PET scans to full-dose resolution without an accompanying MRI. Applications of this algorithm are far-reaching, potentially allowing neuroimaging of brain tumors at more frequent intervals with higher resolution and lower total radiation exposure.

AI also has been applied to neurologic CT to reduce radiation exposure.²⁴ Because it is critical to abide by the principles of ALARA (as low as reasonably achievable), the ability of AI to reduce radiation exposure holds significant promise. A CNN has been used to transform low-dose CTs of anthropomorphic models with calcium inserts and cardiac patients to normal-dose CTs, with the goal of improving the SNR.²⁵ By training a noise-discriminating CNN and a noise-generating CNN together in a generative adversarial network, the AI improved image feature preservation during transformation. This algorithm has a direct application in imaging cerebral vasculature, including calcification that can explain lacunar infarcts and tracking systemic atherosclerosis.²⁶

Another CNN has been applied to remove more complex noise patterns from the phenomena of beam hardening and photon starvation common in low-dose CT. This algorithm extracts the directional components of artifacts and compares them to known artifact patterns, allowing for highly specific suppression of unwanted signals.²⁷ In June 2019, the US Food and Drug Administration (FDA) approved ClariPi, a deep CNN program for advanced denoising and resolution improvement of low- and ultra low-dose CTs.²⁸ Aside from only low-dose settings, this AI could reduce artifacts in all CT imaging modalities and improve therapeutic value of procedures, including cerebral angiograms and emergency cranial scans. As the average CT radiation dose decreased from 12 mSv in 2009 to 1.5 mSv in 2014 and continues to fall, these algorithms will become increasingly necessary to retain the high resolution and diagnostic power expected of neurologic CTs.^29,30

Downstream Applications

Downstream applications refer to AI use after a radiologic study is acquired, mostly image interpretation. More than 70% of FDA-approved AI medical devices are in radiology, and many of these relate to image analysis.^6,31 Although AI is not limited to black-and-white image interpretation, it is hypothesized that one of the reasons radiology is inviting to AI is because gray-scale images lend themselves to standardization.³ Moreover, most radiology departments already use AI-friendly picture archiving and communication systems.^31,32

AI has been applied to a range of radiologic modalities, including MRI, CT, ultrasonography, PET, and mammography.^32-38 AI also has been specifically applied to radiography, including the interpretation of tuberculosis, pneumonia, lung lesions, and COVID-19.^33,39-45 AI also can assist triage, patient screening, providing a “second opinion” rapidly, shortening the time needed for attaining a diagnosis, monitoring disease progression, and predicting prognosis.^{37-39,43,45-47} Downstream applications of AI in neuroradiology and neurology include using CT to aid in detecting hemorrhage or ischemic stroke; using MRI to automatically segment lesions, such as tumors or MS lesions; assisting in early diagnosis and predicting prognosis in MS; assisting in treating paralysis, including from spinal cord injury; determining seizure type and localizing area of seizure onset; and using cameras, wearable devices, and smartphone applications to diagnose and assess treatment response in neurodegenerative disorders, such as Parkinson or Alzheimer diseases (Figure).^37,48-56

Practical and Ethical Considerations

In any discussion of the benefits of AI, it is prudent to address its shortcomings. Chief among these is overfitting, which occurs when an AI is too closely aligned with its training dataset and prone to error when applied to novel cases. Often this is a byproduct of a small training set.⁶⁰ Neuroradiology, particularly with uncommon, advanced imaging methods, has a smaller number of available studies.⁶¹ Even with more prevalent imaging modalities, such as head CT, the work of collecting training scans from patients with the prerequisite disease processes, particularly if these processes are rare, can limit the number of datapoints collected. Neuroradiologists should understand how an AI tool was generated, including the size and variety of the training dataset used, to best gauge the clinical applicability and fitness of the system.

Another point of concern for AI clinical decision support tools’ implementation is automation bias—the tendency for clinicians to favor machine-generated decisions and ignore contrary data or conflicting human decisions.⁶² This situation often arises when radiologists experience overwhelming patient loads or are in underresourced settings, where there is little ability to review every AI-based diagnosis. Although AI might be of benefit in such conditions by reducing physician workload and streamlining the diagnostic process, there is the propensity to improperly rely on a tool meant to augment, not replace, a radiologist’s judgment. Such cases have led to adverse outcomes for patients, and legal precedence shows that this constitutes negligence.⁶³ Maintaining awareness of each tool’s limitations and proper application is the only remedy for such situations.

Ethically, we must consider the opaqueness of ML-developed neuroimaging AIs. For many systems, the specific process by which an AI arrives at its conclusions is unknown. This AI “black box” can conceal potential errors and biases that are masked by overall positive performance metrics. The lack of understanding about how a tool functions in the zero-failure clinical setting understandably gives radiologists pause. The question must be asked: Is it ethical to use a system that is a relatively unknown quantity? Entities, including state governments, Canada, and the European Union, have produced an answer. Each of these governments have implemented policies requiring that health care AIs use some method to display to end users the process by which they arrive at conclusions.^64-68

The 21st Century Cures Act declares that to attain approval, clinical AIs must demonstrate this explainability to clinicians and patients.⁶⁹ The response has been an explosion in the development of explainable AI. Systems that visualize the areas where AI attention most often rests with heatmaps, generate labels for the most heavily weighted features of radiographic images, and create full diagnostic reports to justify AI conclusions aim to meet the goal of transparency and inspiring confidence in clinical end users.⁷⁰ The ability to understand the “thought process” of a system proves useful for error correction and retooling. A trend toward under- or overdetecting conditions, flagging seemingly irrelevant image regions, or low reproducibility can be better addressed when it is clear how the AI is drawing its false conclusions. With an iterative process of testing and redesigning, false positive and negative rates can be reduced, the need for human intervention can be lowered to an appropriate minimum, and patient outcomes can be improved.⁷¹

Data collection raises another ethical concern. To train functional clinical decision support tools, massive amounts of patient demographic, laboratory, and imaging data are required. With incentives to develop the most powerful AI systems, record collection can venture down a path where patient autonomy and privacy are threatened. Radiologists have a duty to ensure data mining serves patients and improves the practice of radiology while protecting patients’ personal information.⁶² Policies have placed similar limits on the access to and use of patient records.^64-69 Patients have the right to request explanation of the AI systems their data have been used to train. Approval for data acquisition requires the use of explainable AI, standardized data security protocol implementation, and adequate proof of communal benefit from the clinical decision support tool. Establishment of state-mandated protections bodes well for a future when developers can access enormous caches of data while patients and health care professionals are assured that no identifying information has escaped a well-regulated space. On the level of the individual radiologist, the knowledge that each datum represents a human life. These are people who has made themselves vulnerable by seeking relief for what ails them, which should serve as a lasting reminder to operate with utmost care when handling sensitive information.

Conclusions

The demonstrated applications of AI in neuroimaging are numerous and varied, and it is reasonable to assume that its implementation will increase as the technology matures. AI use for detecting important neurologic conditions holds promise in combatting ever greater imaging volumes and providing timely diagnoses. As medicine witnesses the continuing adoption of AI, it is important that practitioners possess an understanding of its current and emerging uses.

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

In recent years, direct-to-consumer (DTC) teledermatology platforms have gained popularity as telehealth business models, allowing patients to directly initiate visits with physicians and purchase medications from single platforms. A shortage of dermatologists, improved technology, drug patent expirations, and rising health care costs accelerated the growth of DTC dermatology.¹ During the COVID-19 pandemic, teledermatology adoption surged due to the need to provide care while social distancing and minimizing viral exposure. These needs prompted additional federal funding and loosened regulatory provisions.² As the userbase of these companies has grown, so have their valuations.³ Although the DTC model has attracted the attention of patients and investors, its rise provokes many questions about patients acting as consumers in health care. Indeed, DTC telemedicine offers greater autonomy and convenience for patients, but it may impact the quality of care and the nature of physician-patient relationships, perhaps making them more transactional.

Evolution of DTC in Health Care

The DTC model emphasizes individual choice and accessible health care. Although the definition has evolved, the core idea is not new.⁴ Over decades, pharmaceutical companies have spent billions of dollars on DTC advertising, circumventing physicians by directly reaching patients with campaigns on prescription drugs and laboratory tests and shaping public definitions of diseases.⁵

The DTC model of care is fundamentally different from traditional care models in that it changes the roles of the patient and physician. Whereas early telehealth models required a health care provider to initiate teleconsultations with specialists, DTC telemedicine bypasses this step (eg, the patient can consult a dermatologist without needing a primary care provider’s input first). This care can then be provided by dermatologists with whom patients may or may not have pre-established relationships.^4,6

Dermatology was an early adopter of DTC telemedicine. The shortage of dermatologists in the United States created demand for increasing accessibility to dermatologic care. Additionally, the visual nature of diagnosing dermatologic disease was ideal for platforms supporting image sharing.⁷ Early DTC providers were primarily individual companies offering teledermatology. However, many dermatologists can now offer DTC capabilities via companies such as Amwell and Teladoc Health.⁸

Over the last 2 decades, start-ups such as Warby Parker (eyeglasses) and Casper (mattresses) defined the DTC industry using borrowed supply chains, cohesive branding, heavy social media marketing, and web-only retail. Scalability, lack of competition, and abundant venture capital created competition across numerous markets.⁹ Health care capitalized on this DTC model, creating a $700 billion market for products ranging from hearing aids to over-the-counter medications.¹⁰

Borrowing from this DTC playbook, platforms were created to offer delivery of generic prescription drugs to patients’ doorsteps. However, unlike with other products bought online, a consumer cannot simply add prescription drugs to their shopping cart and check out. In all models of American medical practice, physicians still serve as gatekeepers, providing a safeguard for patients to ensure appropriate prescription and avoid negative consequences of unnecessary drug use. This new model effectively streamlines diagnosis, prescription, and drug delivery without the patient ever having to leave home. Combining the prescribing and selling of medications (2 tasks that traditionally have been separated) potentially creates financial conflicts of interest (COIs). Additionally, high utilization of health care, including more prescriptions and visits, does not necessarily equal high quality of care. The companies stand to benefit from extra care regardless of need, and thus these models must be scrutinized for any incentives driving unnecessary care and prescriptions.

Ultimately, DTC has evolved to encompass multiple definitions in health care (Table 1). Although all models provide health care, each offers a different modality of delivery. The primary service may be the sale of prescription drugs or simply telemedicine visits. This review primarily discusses DTC pharmaceutical telemedicine platforms that sell private-label drugs and also offer telemedicine services to streamline care. However, the history, risks, and benefits discussed may apply to all models.

The DTC Landscape

Most DTC companies employ variations on a model with the same 3 main components: a triage questionnaire, telehealth services, and prescription/drug delivery (Figure). The triage questionnaire elicits a history of the patient’s presentation and medical history. Some companies may use artificial intelligence (AI) algorithms to tailor questions to patient needs. There are 2 modalities for patient-provider communication: synchronous and asynchronous. Synchronous communication entails real-time patient-physician conversations via audio only or video call. Asynchronous (or store-and-forward) communication refers to consultations provided via messaging or text-based modality, where a provider may respond to a patient within 24 hours.⁶ Direct-to-consumer platforms primarily use asynchronous visits (Table 2). However, some also use synchronous modalities if the provider deems it necessary or if state laws require it.

Once a provider has consulted with the patient, they can prescribe medication as needed. In certain cases, with adequate history, a prescription may be issued without a full physician visit. Furthermore, DTC companies require purchase of their custom-branded generic drugs. Prescriptions are fulfilled by the company’s pharmacy network and directly shipped to patients; few will allow patients to transfer a prescription to a pharmacy of their choice. Some platforms also sell supplements and over-the-counter medications.

Payment models vary among these companies, and most do not accept insurance (Table 2). Select models may provide free consultations and only require payment for pharmaceuticals. Others charge for consultations but reallocate payment to the cost of medication if prescribed. Another model involves flat rates for consultations and additional charges for drugs but unlimited messaging with providers for the duration of the prescription. Moreover, patients can subscribe to monthly deliveries of their medications.

Foundation of DTC

Technological advances have enabled patients to receive remote treatment from a single platform offering video calls, AI, electronic medical record interoperability, and integration of drug supply chains. Even in its simplest form, AI is increasingly used, as it allows for programs and chatbots to screen and triage patients.¹¹ Technology also has improved at targeted mass marketing through social media platforms and search engines (eg, companies can use age, interests, location, and other parameters to target individuals likely needing acne treatment).

Drug patent expirations are a key catalyst for the rise of DTC companies, creating an attractive business model with generic drugs as the core product. Since 2008, patents for medications treating chronic conditions, such as erectile dysfunction, have expired. These patent expirations are responsible for $198 billion in projected prescription sales between 2019 and 2024.¹ Thus, it follows that DTC companies have seized this opportunity to act as middlemen, taking advantage of these generic medications’ lower costs to create platforms focused on personalization and accessibility.

Rising deductibles have led patients to consider cheaper out-of-pocket alternatives that are not covered by insurance.¹ For example, insurers typically do not cover finasteride treatment for conditions deemed cosmetic, such as androgenetic alopecia.¹² The low cost of generic drugs creates an attractive business model for patients and investors. According to GoodRx, the average retail price for a 30-day supply of brand-name finasteride (Propecia [Merck]) is $135.92, whereas generic finasteride is $75.24.¹³ Direct-to-consumer pharmaceutical companies offer a 30-day supply of generic finasteride ranging from $8.33 to $30.¹⁴ The average wholesale cost for retailers is an estimated $2.31 for 30 days.¹⁵ Although profit margins on generic medications may be lower, more affordable drugs increase the size of the total market. These prescriptions are available as subscription plans, resulting in recurring revenue.

Lax US pharmaceutical marketing regulations allow direct advertising to the general public.¹⁶ In 1997, the US Food and Drug Administration allowed DTC advertisements to replace summaries of serious and common adverse effects with short statements covering important risks or referrals to other sources for complete information. In 2015, the US Food and Drug Administration guidelines preventing encouragement of self-diagnosis and self-treatment were withdrawn.⁵ These changes enable DTC companies to launch large advertising campaigns and to accelerate customer acquisition, as the industry often describes it, with ease.

Rapid Growth and Implications

Increasing generic drug availability and improving telemedicine capabilities have the potential to reduce costs and barriers but also have the potential for financial gain. Venture capital funds have recognized this opportunity, reflected by millions of dollars of investments, and accelerated the growth of DTC health care start-ups. For example, Ro has raised $376 million from venture capital, valuing the company at $1.5 billion.³

Direct-to-consumer companies require a heavy focus on marketing campaigns for customer acquisition. Their aesthetically pleasing websites and aggressive campaigns target specific audiences based on demographics, digital use habits, and purchasing behavior.⁴ Some campaigns celebrate the ease of obtaining prescriptions.¹⁷ Companies have been effective in recruiting so-called millennial and Generation Z patients, known to search the internet for remedies prior to seeking physician consultations.¹⁸ Recognizing these needs, some platforms offer guides on diseases they treat, creating effective customer-acquisition funnels. Recruitment of these technology-friendly patients has proven effective, especially given the largely positive media coverage of DTC platforms––potentially serving as a surrogate for medical credibility for patients.¹⁸

Some DTC companies also market physically; skin care ads may be strategically placed in social media feeds, or even found near mirrors in public bathrooms.¹⁹ Marketing campaigns also involve disease awareness; such efforts serve to increase diagnoses and prescribed treatments while destigmatizing diseases. Although DTC companies argue this strategy empowers patients, these marketing habits have the potential to take advantage of uninformed patients. Campaigns could potentially medicalize normal experiences and expand disease definitions resulting in overdiagnosis, overtreatment, and wasted resources.⁵ For example, off-label propranolol use has been advertised to attract patients who might have “nerves that come creeping before an important presentation.”¹⁷ Disease awareness campaigns also may lead people to falsely believe unproven drug benefits.⁵ According to studies, DTC pharmaceutical advertisements are low in informational quality and result in increased patient visits and prescriptions despite cost-effective alternatives.^5,20-22

Fragmentation of the health care system is another possible complication of DTC teledermatology. These companies operate as for-profit organizations separated from the rest of the health care system, raising concerns about care coordination.⁸ Vital health data may not be conveyed as patients move among different providers and pharmacies. One study found DTC teledermatology rarely offered to provide medical records or facilitate a referral to a local physician.²³ Such a lack of communication is concerning, as medication errors are the leading cause of avoidable harm in health care.²⁴

Direct-to-consumer care models also seemingly redefine the physician-patient relationship by turning patients into consumers. Patient interactions may seem transactional and streamlined toward sales. For these platforms, a visit often is set up as an evaluation of a patient’s suitability for a prescription, not necessarily for the best treatment modality for the problem. These companies primarily make money through the sale of prescription drugs, creating a potential COI that may undermine the patient-physician relationship. Although some companies have made it clear that medical care and pharmaceutical sales are provided by legally separate business entities and that they do not pay physicians on commission, a conflict may still exist given the financial importance of physicians prescribing medication to the success of the business.¹⁶

Even as DTC models advertise upon expanded access and choice, the companies largely prohibit patients from choosing their own pharmacy. Instead, they encourage patients to fill prescriptions with the company’s pharmacy network by claiming lower costs compared with competitors. One DTC company, Hims, is launching a prescription-fulfillment center to further consolidate their business.^17,19,25 The inherent COI of issuing and fulfilling prescriptions raises concerns of patient harm.²⁶ For example, when Dermatology.com launched as a DTC prescription skin medication shop backed by Bausch Health Companies Inc, its model included telemedicine consultation. Although consultations were provided by RxDefine, a third party, only Dermatology.com drugs were prescribed. Given the poor quality of care and obvious financial COI, an uproar in the dermatology community and advocacy by the American Academy of Dermatology led to the shutdown of Dermatology.com’s online prescription services.²⁶

The quality of care among DTC telemedicine platforms has been equivocal. Some studies have reported equivalent care in person and online, while others have reported poor adherence to guidelines, overuse of antibiotics, and misdiagnosis.^8,23 A vital portion of the DTC experience is the history questionnaire, which is geared to diagnosis and risk assessment.²⁵ Resneck et al²³ found diagnostic quality to be adequate for simple dermatologic clinical scenarios but poor for scenarios requiring more than basic histories. Although Ro has reported leveraging data from millions of interactions to ask the right questions and streamline visits, it is still unclear whether history questionnaires are adequate.^17,27 Additionally, consultations may lack sufficient counseling on adverse effects, risks, or pregnancy warnings, as well as discussions on alternative treatments and preventative care.^17,23 Finally, patients often are limited in their choice of dermatologist; the lack of a fully developed relationship increases concerns of follow-up and monitoring practices. Although some DTC platforms offer unlimited interactions with physicians for the duration of a prescription, it is unknown how often these services are utilized or how adequate the quality of these interactions is. This potential for lax follow-up is especially concerning for prescriptions that autorenew on a monthly basis and could result in unnecessary overtreatment.

Postpandemic and Future Outlook

The COVID-19 pandemic dramatically impacted the use of telemedicine. To minimize COVID-19 transmission, the Centers for Medicare & Medicaid Services and private payers expanded telehealth coverage and eliminated reimbursement and licensing barriers.²⁸ A decade’s worth of regulatory changes and consumer adoption was accelerated to weeks, resulting in telemedicine companies reaching record-high visit numbers.²⁹ McKinsey & Company estimated that telehealth visit numbers surged 50- to 175-fold compared with pre–COVID-19 numbers. Additionally, 76% of patients were interested in future telehealth use, and 64% of providers were more comfortable using telehealth than before the pandemic.³⁰ For their part, US dermatologists reported an increase in telemedicine use from 14.1% to 96.9% since COVID-19.³¹

Exactly how much DTC pharmaceutical telemedicine companies are growing is unclear, but private investments may be an indication. A record $14.7 billion was invested in the digital health sector in the first half of 2021; the majority went to telehealth companies.³⁰ Ro, which reported $230 million in revenue in 2020 and has served 6 million visits, raised $200 milllion in July 2020 and $500 million in March 2021.³² Although post–COVID-19 health care will certainly involve increased telemedicine, the extent remains unclear, as telehealth vendors saw decreased usage upon reopening of state economies. Ultimately, the postpandemic regulatory landscape is hard to predict.³⁰

Although COVID-19 appears to have caused rapid growth for DTC platforms, it also may have spurred competition. Telemedicine providers have given independent dermatologists and health care systems the infrastructure to implement custom DTC services.³³ Although systems do not directly sell prescription drugs, the target market is essentially the same: patients looking for instant virtual dermatologic care. Therefore, sustained telemedicine services offered by traditional practices and systems may prove detrimental to DTC companies. However, unlike most telemedicine services, DTC models are less affected by certain changes in regulation since they do not rely on insurance. If regulations are tightened and reimbursements for telehealth are not attractive for dermatologists, teledermatology services may see an overall decrease. If so, patients who appreciate teledermatology may shift to using DTC platforms, even if their insurance does not cover them. Still, a nationwide survey found 56% of respondents felt an established relationship with a physician prior to a telemedicine visit is important, which may create a barrier for DTC adoption.³⁴

Conclusion

Direct-to-consumer teledermatology represents a growing for-profit model of health care that provides patients with seemingly affordable and convenient care. However, there is potential for overtreatment, misdiagnosis, and fragmentation of health care. It will be important to monitor and evaluate the quality of care that DTC teledermatology offers and advocate for appropriate regulations and oversight. Eventually, more patients will have medications prescribed and dermatologic care administered through DTC companies. Dermatologists will benefit from this knowledge of DTC models to properly counsel patients on the risks and benefits of their use.

In recent years, direct-to-consumer (DTC) teledermatology platforms have gained popularity as telehealth business models, allowing patients to directly initiate visits with physicians and purchase medications from single platforms. A shortage of dermatologists, improved technology, drug patent expirations, and rising health care costs accelerated the growth of DTC dermatology.¹ During the COVID-19 pandemic, teledermatology adoption surged due to the need to provide care while social distancing and minimizing viral exposure. These needs prompted additional federal funding and loosened regulatory provisions.² As the userbase of these companies has grown, so have their valuations.³ Although the DTC model has attracted the attention of patients and investors, its rise provokes many questions about patients acting as consumers in health care. Indeed, DTC telemedicine offers greater autonomy and convenience for patients, but it may impact the quality of care and the nature of physician-patient relationships, perhaps making them more transactional.

Evolution of DTC in Health Care

The DTC model emphasizes individual choice and accessible health care. Although the definition has evolved, the core idea is not new.⁴ Over decades, pharmaceutical companies have spent billions of dollars on DTC advertising, circumventing physicians by directly reaching patients with campaigns on prescription drugs and laboratory tests and shaping public definitions of diseases.⁵

The DTC model of care is fundamentally different from traditional care models in that it changes the roles of the patient and physician. Whereas early telehealth models required a health care provider to initiate teleconsultations with specialists, DTC telemedicine bypasses this step (eg, the patient can consult a dermatologist without needing a primary care provider’s input first). This care can then be provided by dermatologists with whom patients may or may not have pre-established relationships.^4,6

Dermatology was an early adopter of DTC telemedicine. The shortage of dermatologists in the United States created demand for increasing accessibility to dermatologic care. Additionally, the visual nature of diagnosing dermatologic disease was ideal for platforms supporting image sharing.⁷ Early DTC providers were primarily individual companies offering teledermatology. However, many dermatologists can now offer DTC capabilities via companies such as Amwell and Teladoc Health.⁸

Over the last 2 decades, start-ups such as Warby Parker (eyeglasses) and Casper (mattresses) defined the DTC industry using borrowed supply chains, cohesive branding, heavy social media marketing, and web-only retail. Scalability, lack of competition, and abundant venture capital created competition across numerous markets.⁹ Health care capitalized on this DTC model, creating a $700 billion market for products ranging from hearing aids to over-the-counter medications.¹⁰

Borrowing from this DTC playbook, platforms were created to offer delivery of generic prescription drugs to patients’ doorsteps. However, unlike with other products bought online, a consumer cannot simply add prescription drugs to their shopping cart and check out. In all models of American medical practice, physicians still serve as gatekeepers, providing a safeguard for patients to ensure appropriate prescription and avoid negative consequences of unnecessary drug use. This new model effectively streamlines diagnosis, prescription, and drug delivery without the patient ever having to leave home. Combining the prescribing and selling of medications (2 tasks that traditionally have been separated) potentially creates financial conflicts of interest (COIs). Additionally, high utilization of health care, including more prescriptions and visits, does not necessarily equal high quality of care. The companies stand to benefit from extra care regardless of need, and thus these models must be scrutinized for any incentives driving unnecessary care and prescriptions.

Ultimately, DTC has evolved to encompass multiple definitions in health care (Table 1). Although all models provide health care, each offers a different modality of delivery. The primary service may be the sale of prescription drugs or simply telemedicine visits. This review primarily discusses DTC pharmaceutical telemedicine platforms that sell private-label drugs and also offer telemedicine services to streamline care. However, the history, risks, and benefits discussed may apply to all models.

The DTC Landscape

Most DTC companies employ variations on a model with the same 3 main components: a triage questionnaire, telehealth services, and prescription/drug delivery (Figure). The triage questionnaire elicits a history of the patient’s presentation and medical history. Some companies may use artificial intelligence (AI) algorithms to tailor questions to patient needs. There are 2 modalities for patient-provider communication: synchronous and asynchronous. Synchronous communication entails real-time patient-physician conversations via audio only or video call. Asynchronous (or store-and-forward) communication refers to consultations provided via messaging or text-based modality, where a provider may respond to a patient within 24 hours.⁶ Direct-to-consumer platforms primarily use asynchronous visits (Table 2). However, some also use synchronous modalities if the provider deems it necessary or if state laws require it.

Once a provider has consulted with the patient, they can prescribe medication as needed. In certain cases, with adequate history, a prescription may be issued without a full physician visit. Furthermore, DTC companies require purchase of their custom-branded generic drugs. Prescriptions are fulfilled by the company’s pharmacy network and directly shipped to patients; few will allow patients to transfer a prescription to a pharmacy of their choice. Some platforms also sell supplements and over-the-counter medications.

Payment models vary among these companies, and most do not accept insurance (Table 2). Select models may provide free consultations and only require payment for pharmaceuticals. Others charge for consultations but reallocate payment to the cost of medication if prescribed. Another model involves flat rates for consultations and additional charges for drugs but unlimited messaging with providers for the duration of the prescription. Moreover, patients can subscribe to monthly deliveries of their medications.

Foundation of DTC

Technological advances have enabled patients to receive remote treatment from a single platform offering video calls, AI, electronic medical record interoperability, and integration of drug supply chains. Even in its simplest form, AI is increasingly used, as it allows for programs and chatbots to screen and triage patients.¹¹ Technology also has improved at targeted mass marketing through social media platforms and search engines (eg, companies can use age, interests, location, and other parameters to target individuals likely needing acne treatment).

Drug patent expirations are a key catalyst for the rise of DTC companies, creating an attractive business model with generic drugs as the core product. Since 2008, patents for medications treating chronic conditions, such as erectile dysfunction, have expired. These patent expirations are responsible for $198 billion in projected prescription sales between 2019 and 2024.¹ Thus, it follows that DTC companies have seized this opportunity to act as middlemen, taking advantage of these generic medications’ lower costs to create platforms focused on personalization and accessibility.

Rising deductibles have led patients to consider cheaper out-of-pocket alternatives that are not covered by insurance.¹ For example, insurers typically do not cover finasteride treatment for conditions deemed cosmetic, such as androgenetic alopecia.¹² The low cost of generic drugs creates an attractive business model for patients and investors. According to GoodRx, the average retail price for a 30-day supply of brand-name finasteride (Propecia [Merck]) is $135.92, whereas generic finasteride is $75.24.¹³ Direct-to-consumer pharmaceutical companies offer a 30-day supply of generic finasteride ranging from $8.33 to $30.¹⁴ The average wholesale cost for retailers is an estimated $2.31 for 30 days.¹⁵ Although profit margins on generic medications may be lower, more affordable drugs increase the size of the total market. These prescriptions are available as subscription plans, resulting in recurring revenue.

Lax US pharmaceutical marketing regulations allow direct advertising to the general public.¹⁶ In 1997, the US Food and Drug Administration allowed DTC advertisements to replace summaries of serious and common adverse effects with short statements covering important risks or referrals to other sources for complete information. In 2015, the US Food and Drug Administration guidelines preventing encouragement of self-diagnosis and self-treatment were withdrawn.⁵ These changes enable DTC companies to launch large advertising campaigns and to accelerate customer acquisition, as the industry often describes it, with ease.

Rapid Growth and Implications

Increasing generic drug availability and improving telemedicine capabilities have the potential to reduce costs and barriers but also have the potential for financial gain. Venture capital funds have recognized this opportunity, reflected by millions of dollars of investments, and accelerated the growth of DTC health care start-ups. For example, Ro has raised $376 million from venture capital, valuing the company at $1.5 billion.³

Direct-to-consumer companies require a heavy focus on marketing campaigns for customer acquisition. Their aesthetically pleasing websites and aggressive campaigns target specific audiences based on demographics, digital use habits, and purchasing behavior.⁴ Some campaigns celebrate the ease of obtaining prescriptions.¹⁷ Companies have been effective in recruiting so-called millennial and Generation Z patients, known to search the internet for remedies prior to seeking physician consultations.¹⁸ Recognizing these needs, some platforms offer guides on diseases they treat, creating effective customer-acquisition funnels. Recruitment of these technology-friendly patients has proven effective, especially given the largely positive media coverage of DTC platforms––potentially serving as a surrogate for medical credibility for patients.¹⁸

Some DTC companies also market physically; skin care ads may be strategically placed in social media feeds, or even found near mirrors in public bathrooms.¹⁹ Marketing campaigns also involve disease awareness; such efforts serve to increase diagnoses and prescribed treatments while destigmatizing diseases. Although DTC companies argue this strategy empowers patients, these marketing habits have the potential to take advantage of uninformed patients. Campaigns could potentially medicalize normal experiences and expand disease definitions resulting in overdiagnosis, overtreatment, and wasted resources.⁵ For example, off-label propranolol use has been advertised to attract patients who might have “nerves that come creeping before an important presentation.”¹⁷ Disease awareness campaigns also may lead people to falsely believe unproven drug benefits.⁵ According to studies, DTC pharmaceutical advertisements are low in informational quality and result in increased patient visits and prescriptions despite cost-effective alternatives.^5,20-22

Fragmentation of the health care system is another possible complication of DTC teledermatology. These companies operate as for-profit organizations separated from the rest of the health care system, raising concerns about care coordination.⁸ Vital health data may not be conveyed as patients move among different providers and pharmacies. One study found DTC teledermatology rarely offered to provide medical records or facilitate a referral to a local physician.²³ Such a lack of communication is concerning, as medication errors are the leading cause of avoidable harm in health care.²⁴

Direct-to-consumer care models also seemingly redefine the physician-patient relationship by turning patients into consumers. Patient interactions may seem transactional and streamlined toward sales. For these platforms, a visit often is set up as an evaluation of a patient’s suitability for a prescription, not necessarily for the best treatment modality for the problem. These companies primarily make money through the sale of prescription drugs, creating a potential COI that may undermine the patient-physician relationship. Although some companies have made it clear that medical care and pharmaceutical sales are provided by legally separate business entities and that they do not pay physicians on commission, a conflict may still exist given the financial importance of physicians prescribing medication to the success of the business.¹⁶

Even as DTC models advertise upon expanded access and choice, the companies largely prohibit patients from choosing their own pharmacy. Instead, they encourage patients to fill prescriptions with the company’s pharmacy network by claiming lower costs compared with competitors. One DTC company, Hims, is launching a prescription-fulfillment center to further consolidate their business.^17,19,25 The inherent COI of issuing and fulfilling prescriptions raises concerns of patient harm.²⁶ For example, when Dermatology.com launched as a DTC prescription skin medication shop backed by Bausch Health Companies Inc, its model included telemedicine consultation. Although consultations were provided by RxDefine, a third party, only Dermatology.com drugs were prescribed. Given the poor quality of care and obvious financial COI, an uproar in the dermatology community and advocacy by the American Academy of Dermatology led to the shutdown of Dermatology.com’s online prescription services.²⁶

The quality of care among DTC telemedicine platforms has been equivocal. Some studies have reported equivalent care in person and online, while others have reported poor adherence to guidelines, overuse of antibiotics, and misdiagnosis.^8,23 A vital portion of the DTC experience is the history questionnaire, which is geared to diagnosis and risk assessment.²⁵ Resneck et al²³ found diagnostic quality to be adequate for simple dermatologic clinical scenarios but poor for scenarios requiring more than basic histories. Although Ro has reported leveraging data from millions of interactions to ask the right questions and streamline visits, it is still unclear whether history questionnaires are adequate.^17,27 Additionally, consultations may lack sufficient counseling on adverse effects, risks, or pregnancy warnings, as well as discussions on alternative treatments and preventative care.^17,23 Finally, patients often are limited in their choice of dermatologist; the lack of a fully developed relationship increases concerns of follow-up and monitoring practices. Although some DTC platforms offer unlimited interactions with physicians for the duration of a prescription, it is unknown how often these services are utilized or how adequate the quality of these interactions is. This potential for lax follow-up is especially concerning for prescriptions that autorenew on a monthly basis and could result in unnecessary overtreatment.

Postpandemic and Future Outlook

The COVID-19 pandemic dramatically impacted the use of telemedicine. To minimize COVID-19 transmission, the Centers for Medicare & Medicaid Services and private payers expanded telehealth coverage and eliminated reimbursement and licensing barriers.²⁸ A decade’s worth of regulatory changes and consumer adoption was accelerated to weeks, resulting in telemedicine companies reaching record-high visit numbers.²⁹ McKinsey & Company estimated that telehealth visit numbers surged 50- to 175-fold compared with pre–COVID-19 numbers. Additionally, 76% of patients were interested in future telehealth use, and 64% of providers were more comfortable using telehealth than before the pandemic.³⁰ For their part, US dermatologists reported an increase in telemedicine use from 14.1% to 96.9% since COVID-19.³¹

Exactly how much DTC pharmaceutical telemedicine companies are growing is unclear, but private investments may be an indication. A record $14.7 billion was invested in the digital health sector in the first half of 2021; the majority went to telehealth companies.³⁰ Ro, which reported $230 million in revenue in 2020 and has served 6 million visits, raised $200 milllion in July 2020 and $500 million in March 2021.³² Although post–COVID-19 health care will certainly involve increased telemedicine, the extent remains unclear, as telehealth vendors saw decreased usage upon reopening of state economies. Ultimately, the postpandemic regulatory landscape is hard to predict.³⁰

Although COVID-19 appears to have caused rapid growth for DTC platforms, it also may have spurred competition. Telemedicine providers have given independent dermatologists and health care systems the infrastructure to implement custom DTC services.³³ Although systems do not directly sell prescription drugs, the target market is essentially the same: patients looking for instant virtual dermatologic care. Therefore, sustained telemedicine services offered by traditional practices and systems may prove detrimental to DTC companies. However, unlike most telemedicine services, DTC models are less affected by certain changes in regulation since they do not rely on insurance. If regulations are tightened and reimbursements for telehealth are not attractive for dermatologists, teledermatology services may see an overall decrease. If so, patients who appreciate teledermatology may shift to using DTC platforms, even if their insurance does not cover them. Still, a nationwide survey found 56% of respondents felt an established relationship with a physician prior to a telemedicine visit is important, which may create a barrier for DTC adoption.³⁴

Conclusion

Direct-to-consumer teledermatology represents a growing for-profit model of health care that provides patients with seemingly affordable and convenient care. However, there is potential for overtreatment, misdiagnosis, and fragmentation of health care. It will be important to monitor and evaluate the quality of care that DTC teledermatology offers and advocate for appropriate regulations and oversight. Eventually, more patients will have medications prescribed and dermatologic care administered through DTC companies. Dermatologists will benefit from this knowledge of DTC models to properly counsel patients on the risks and benefits of their use.

In recent years, direct-to-consumer (DTC) teledermatology platforms have gained popularity as telehealth business models, allowing patients to directly initiate visits with physicians and purchase medications from single platforms. A shortage of dermatologists, improved technology, drug patent expirations, and rising health care costs accelerated the growth of DTC dermatology.¹ During the COVID-19 pandemic, teledermatology adoption surged due to the need to provide care while social distancing and minimizing viral exposure. These needs prompted additional federal funding and loosened regulatory provisions.² As the userbase of these companies has grown, so have their valuations.³ Although the DTC model has attracted the attention of patients and investors, its rise provokes many questions about patients acting as consumers in health care. Indeed, DTC telemedicine offers greater autonomy and convenience for patients, but it may impact the quality of care and the nature of physician-patient relationships, perhaps making them more transactional.

Evolution of DTC in Health Care

The DTC model emphasizes individual choice and accessible health care. Although the definition has evolved, the core idea is not new.⁴ Over decades, pharmaceutical companies have spent billions of dollars on DTC advertising, circumventing physicians by directly reaching patients with campaigns on prescription drugs and laboratory tests and shaping public definitions of diseases.⁵

The DTC model of care is fundamentally different from traditional care models in that it changes the roles of the patient and physician. Whereas early telehealth models required a health care provider to initiate teleconsultations with specialists, DTC telemedicine bypasses this step (eg, the patient can consult a dermatologist without needing a primary care provider’s input first). This care can then be provided by dermatologists with whom patients may or may not have pre-established relationships.^4,6

Dermatology was an early adopter of DTC telemedicine. The shortage of dermatologists in the United States created demand for increasing accessibility to dermatologic care. Additionally, the visual nature of diagnosing dermatologic disease was ideal for platforms supporting image sharing.⁷ Early DTC providers were primarily individual companies offering teledermatology. However, many dermatologists can now offer DTC capabilities via companies such as Amwell and Teladoc Health.⁸

Over the last 2 decades, start-ups such as Warby Parker (eyeglasses) and Casper (mattresses) defined the DTC industry using borrowed supply chains, cohesive branding, heavy social media marketing, and web-only retail. Scalability, lack of competition, and abundant venture capital created competition across numerous markets.⁹ Health care capitalized on this DTC model, creating a $700 billion market for products ranging from hearing aids to over-the-counter medications.¹⁰

Borrowing from this DTC playbook, platforms were created to offer delivery of generic prescription drugs to patients’ doorsteps. However, unlike with other products bought online, a consumer cannot simply add prescription drugs to their shopping cart and check out. In all models of American medical practice, physicians still serve as gatekeepers, providing a safeguard for patients to ensure appropriate prescription and avoid negative consequences of unnecessary drug use. This new model effectively streamlines diagnosis, prescription, and drug delivery without the patient ever having to leave home. Combining the prescribing and selling of medications (2 tasks that traditionally have been separated) potentially creates financial conflicts of interest (COIs). Additionally, high utilization of health care, including more prescriptions and visits, does not necessarily equal high quality of care. The companies stand to benefit from extra care regardless of need, and thus these models must be scrutinized for any incentives driving unnecessary care and prescriptions.

Ultimately, DTC has evolved to encompass multiple definitions in health care (Table 1). Although all models provide health care, each offers a different modality of delivery. The primary service may be the sale of prescription drugs or simply telemedicine visits. This review primarily discusses DTC pharmaceutical telemedicine platforms that sell private-label drugs and also offer telemedicine services to streamline care. However, the history, risks, and benefits discussed may apply to all models.

The DTC Landscape

Most DTC companies employ variations on a model with the same 3 main components: a triage questionnaire, telehealth services, and prescription/drug delivery (Figure). The triage questionnaire elicits a history of the patient’s presentation and medical history. Some companies may use artificial intelligence (AI) algorithms to tailor questions to patient needs. There are 2 modalities for patient-provider communication: synchronous and asynchronous. Synchronous communication entails real-time patient-physician conversations via audio only or video call. Asynchronous (or store-and-forward) communication refers to consultations provided via messaging or text-based modality, where a provider may respond to a patient within 24 hours.⁶ Direct-to-consumer platforms primarily use asynchronous visits (Table 2). However, some also use synchronous modalities if the provider deems it necessary or if state laws require it.

Once a provider has consulted with the patient, they can prescribe medication as needed. In certain cases, with adequate history, a prescription may be issued without a full physician visit. Furthermore, DTC companies require purchase of their custom-branded generic drugs. Prescriptions are fulfilled by the company’s pharmacy network and directly shipped to patients; few will allow patients to transfer a prescription to a pharmacy of their choice. Some platforms also sell supplements and over-the-counter medications.

Payment models vary among these companies, and most do not accept insurance (Table 2). Select models may provide free consultations and only require payment for pharmaceuticals. Others charge for consultations but reallocate payment to the cost of medication if prescribed. Another model involves flat rates for consultations and additional charges for drugs but unlimited messaging with providers for the duration of the prescription. Moreover, patients can subscribe to monthly deliveries of their medications.

Foundation of DTC

Technological advances have enabled patients to receive remote treatment from a single platform offering video calls, AI, electronic medical record interoperability, and integration of drug supply chains. Even in its simplest form, AI is increasingly used, as it allows for programs and chatbots to screen and triage patients.¹¹ Technology also has improved at targeted mass marketing through social media platforms and search engines (eg, companies can use age, interests, location, and other parameters to target individuals likely needing acne treatment).

Drug patent expirations are a key catalyst for the rise of DTC companies, creating an attractive business model with generic drugs as the core product. Since 2008, patents for medications treating chronic conditions, such as erectile dysfunction, have expired. These patent expirations are responsible for $198 billion in projected prescription sales between 2019 and 2024.¹ Thus, it follows that DTC companies have seized this opportunity to act as middlemen, taking advantage of these generic medications’ lower costs to create platforms focused on personalization and accessibility.

Rising deductibles have led patients to consider cheaper out-of-pocket alternatives that are not covered by insurance.¹ For example, insurers typically do not cover finasteride treatment for conditions deemed cosmetic, such as androgenetic alopecia.¹² The low cost of generic drugs creates an attractive business model for patients and investors. According to GoodRx, the average retail price for a 30-day supply of brand-name finasteride (Propecia [Merck]) is $135.92, whereas generic finasteride is $75.24.¹³ Direct-to-consumer pharmaceutical companies offer a 30-day supply of generic finasteride ranging from $8.33 to $30.¹⁴ The average wholesale cost for retailers is an estimated $2.31 for 30 days.¹⁵ Although profit margins on generic medications may be lower, more affordable drugs increase the size of the total market. These prescriptions are available as subscription plans, resulting in recurring revenue.

Lax US pharmaceutical marketing regulations allow direct advertising to the general public.¹⁶ In 1997, the US Food and Drug Administration allowed DTC advertisements to replace summaries of serious and common adverse effects with short statements covering important risks or referrals to other sources for complete information. In 2015, the US Food and Drug Administration guidelines preventing encouragement of self-diagnosis and self-treatment were withdrawn.⁵ These changes enable DTC companies to launch large advertising campaigns and to accelerate customer acquisition, as the industry often describes it, with ease.

Rapid Growth and Implications

Increasing generic drug availability and improving telemedicine capabilities have the potential to reduce costs and barriers but also have the potential for financial gain. Venture capital funds have recognized this opportunity, reflected by millions of dollars of investments, and accelerated the growth of DTC health care start-ups. For example, Ro has raised $376 million from venture capital, valuing the company at $1.5 billion.³

Direct-to-consumer companies require a heavy focus on marketing campaigns for customer acquisition. Their aesthetically pleasing websites and aggressive campaigns target specific audiences based on demographics, digital use habits, and purchasing behavior.⁴ Some campaigns celebrate the ease of obtaining prescriptions.¹⁷ Companies have been effective in recruiting so-called millennial and Generation Z patients, known to search the internet for remedies prior to seeking physician consultations.¹⁸ Recognizing these needs, some platforms offer guides on diseases they treat, creating effective customer-acquisition funnels. Recruitment of these technology-friendly patients has proven effective, especially given the largely positive media coverage of DTC platforms––potentially serving as a surrogate for medical credibility for patients.¹⁸

Some DTC companies also market physically; skin care ads may be strategically placed in social media feeds, or even found near mirrors in public bathrooms.¹⁹ Marketing campaigns also involve disease awareness; such efforts serve to increase diagnoses and prescribed treatments while destigmatizing diseases. Although DTC companies argue this strategy empowers patients, these marketing habits have the potential to take advantage of uninformed patients. Campaigns could potentially medicalize normal experiences and expand disease definitions resulting in overdiagnosis, overtreatment, and wasted resources.⁵ For example, off-label propranolol use has been advertised to attract patients who might have “nerves that come creeping before an important presentation.”¹⁷ Disease awareness campaigns also may lead people to falsely believe unproven drug benefits.⁵ According to studies, DTC pharmaceutical advertisements are low in informational quality and result in increased patient visits and prescriptions despite cost-effective alternatives.^5,20-22

Fragmentation of the health care system is another possible complication of DTC teledermatology. These companies operate as for-profit organizations separated from the rest of the health care system, raising concerns about care coordination.⁸ Vital health data may not be conveyed as patients move among different providers and pharmacies. One study found DTC teledermatology rarely offered to provide medical records or facilitate a referral to a local physician.²³ Such a lack of communication is concerning, as medication errors are the leading cause of avoidable harm in health care.²⁴

Direct-to-consumer care models also seemingly redefine the physician-patient relationship by turning patients into consumers. Patient interactions may seem transactional and streamlined toward sales. For these platforms, a visit often is set up as an evaluation of a patient’s suitability for a prescription, not necessarily for the best treatment modality for the problem. These companies primarily make money through the sale of prescription drugs, creating a potential COI that may undermine the patient-physician relationship. Although some companies have made it clear that medical care and pharmaceutical sales are provided by legally separate business entities and that they do not pay physicians on commission, a conflict may still exist given the financial importance of physicians prescribing medication to the success of the business.¹⁶

Even as DTC models advertise upon expanded access and choice, the companies largely prohibit patients from choosing their own pharmacy. Instead, they encourage patients to fill prescriptions with the company’s pharmacy network by claiming lower costs compared with competitors. One DTC company, Hims, is launching a prescription-fulfillment center to further consolidate their business.^17,19,25 The inherent COI of issuing and fulfilling prescriptions raises concerns of patient harm.²⁶ For example, when Dermatology.com launched as a DTC prescription skin medication shop backed by Bausch Health Companies Inc, its model included telemedicine consultation. Although consultations were provided by RxDefine, a third party, only Dermatology.com drugs were prescribed. Given the poor quality of care and obvious financial COI, an uproar in the dermatology community and advocacy by the American Academy of Dermatology led to the shutdown of Dermatology.com’s online prescription services.²⁶

The quality of care among DTC telemedicine platforms has been equivocal. Some studies have reported equivalent care in person and online, while others have reported poor adherence to guidelines, overuse of antibiotics, and misdiagnosis.^8,23 A vital portion of the DTC experience is the history questionnaire, which is geared to diagnosis and risk assessment.²⁵ Resneck et al²³ found diagnostic quality to be adequate for simple dermatologic clinical scenarios but poor for scenarios requiring more than basic histories. Although Ro has reported leveraging data from millions of interactions to ask the right questions and streamline visits, it is still unclear whether history questionnaires are adequate.^17,27 Additionally, consultations may lack sufficient counseling on adverse effects, risks, or pregnancy warnings, as well as discussions on alternative treatments and preventative care.^17,23 Finally, patients often are limited in their choice of dermatologist; the lack of a fully developed relationship increases concerns of follow-up and monitoring practices. Although some DTC platforms offer unlimited interactions with physicians for the duration of a prescription, it is unknown how often these services are utilized or how adequate the quality of these interactions is. This potential for lax follow-up is especially concerning for prescriptions that autorenew on a monthly basis and could result in unnecessary overtreatment.

Postpandemic and Future Outlook

The COVID-19 pandemic dramatically impacted the use of telemedicine. To minimize COVID-19 transmission, the Centers for Medicare & Medicaid Services and private payers expanded telehealth coverage and eliminated reimbursement and licensing barriers.²⁸ A decade’s worth of regulatory changes and consumer adoption was accelerated to weeks, resulting in telemedicine companies reaching record-high visit numbers.²⁹ McKinsey & Company estimated that telehealth visit numbers surged 50- to 175-fold compared with pre–COVID-19 numbers. Additionally, 76% of patients were interested in future telehealth use, and 64% of providers were more comfortable using telehealth than before the pandemic.³⁰ For their part, US dermatologists reported an increase in telemedicine use from 14.1% to 96.9% since COVID-19.³¹

Exactly how much DTC pharmaceutical telemedicine companies are growing is unclear, but private investments may be an indication. A record $14.7 billion was invested in the digital health sector in the first half of 2021; the majority went to telehealth companies.³⁰ Ro, which reported $230 million in revenue in 2020 and has served 6 million visits, raised $200 milllion in July 2020 and $500 million in March 2021.³² Although post–COVID-19 health care will certainly involve increased telemedicine, the extent remains unclear, as telehealth vendors saw decreased usage upon reopening of state economies. Ultimately, the postpandemic regulatory landscape is hard to predict.³⁰

Although COVID-19 appears to have caused rapid growth for DTC platforms, it also may have spurred competition. Telemedicine providers have given independent dermatologists and health care systems the infrastructure to implement custom DTC services.³³ Although systems do not directly sell prescription drugs, the target market is essentially the same: patients looking for instant virtual dermatologic care. Therefore, sustained telemedicine services offered by traditional practices and systems may prove detrimental to DTC companies. However, unlike most telemedicine services, DTC models are less affected by certain changes in regulation since they do not rely on insurance. If regulations are tightened and reimbursements for telehealth are not attractive for dermatologists, teledermatology services may see an overall decrease. If so, patients who appreciate teledermatology may shift to using DTC platforms, even if their insurance does not cover them. Still, a nationwide survey found 56% of respondents felt an established relationship with a physician prior to a telemedicine visit is important, which may create a barrier for DTC adoption.³⁴

Conclusion

Direct-to-consumer teledermatology represents a growing for-profit model of health care that provides patients with seemingly affordable and convenient care. However, there is potential for overtreatment, misdiagnosis, and fragmentation of health care. It will be important to monitor and evaluate the quality of care that DTC teledermatology offers and advocate for appropriate regulations and oversight. Eventually, more patients will have medications prescribed and dermatologic care administered through DTC companies. Dermatologists will benefit from this knowledge of DTC models to properly counsel patients on the risks and benefits of their use.

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Despite the challenges of an ongoing COVID-19 pandemic, researchers in 2021 delivered practice-changing studies in gynecologic oncology. In this cancer Update, we highlight 4 studies that shed light on the surgical and systemic therapies that may improve outcomes for patients with cancers of the ovary, endometrium, and cervix. We review DESKTOP III, a trial that investigated the role of cytoreductive surgery in patients with recurrent ovarian cancer, and SENTOR, a study that evaluated the performance of sentinel lymph node biopsy in patients with high-grade endometrial cancers. Additionally, we examine 2 studies of systemic therapy that reveal the growing role of targeted therapies and immuno-oncology in the treatment of gynecologic malignancies.

A new era for patients with BRCA mutation–associated ovarian cancer

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.

Ovarian cancer remains the most lethal gynecologic malignancy due to the frequency of advanced-stage diagnosis and frequent relapse after primary therapy. But for ovarian cancer patients with inherited mutations of the BRCA1 or BRCA2 genes, poly(ADP-ribose) polymerase (PARP) inhibitors, a class of oral anticancer medicines that target DNA repair, have ushered in a new era in which the possibility of long-term remission, and even cure, is more likely than at any other time.

Olaparib trial details

The SOLO1 study was a double-blind, placebo-controlled, phase 3 trial that investigated the role of PARP inhibitor maintenance therapy with olaparib in patients with pathologic BRCA1 or BRCA2 mutations who responded to platinum-based chemotherapy administered for a newly diagnosed, advanced-stage ovarian cancer.¹ The study enrolled 391 patients, with 260 randomly assigned to receive olaparib for 24 months and 131 patients randomly assigned to receive placebo tablets. Most patients in the study had a mutation in the BRCA1 gene (72%), 27% had a BRCA2 mutation, and 1% had mutations in both genes.

The primary analysis of SOLO1 was published in 2018 and was based on a median follow-up of 3.4 years.¹ That study showed that olaparib maintenance therapy resulted in a large progression-free survival benefit and led to its approval by the US Food and Drug Administration (FDA) as a maintenance therapy for patients with BRCA-mutated advanced ovarian cancer who responded to first-line platinum-based chemotherapy.

In 2021, Banerjee and colleagues updated the progression-free survival results for the SOLO1 trial after 5 years of follow-up.² In this study, the patients randomly assigned to olaparib maintenance therapy had a persistent and statistically significant progression-free survival benefit, with the median progression-free survival reaching 56 months among the olaparib group compared with 13.8 months in the placebo group (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.43).² Olaparib maintenance therapy resulted in more clinically significant adverse events, including anemia and neutropenia. Serious adverse events occurred in 55 (21%) of the olaparib-treated patients and 17 (13%) of the placebo-treated patients, but no treatment-related adverse events were fatal.

Continue to: Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients...

Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients

Harter P, Sehouli J, Vergote I, et al; DESKTOP III Investigators. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021;385:2123- 2131.

In the DESKTOP III trial, Harter and colleagues contribute results to the ongoing discourse surrounding treatment options for patients with recurrent, platinum-sensitive ovarian cancer.³ Systemic therapies continue to be the mainstay of treatment in this setting; however, several groups have attempted to evaluate the role of secondary cytoreductive surgery in this setting.^4,5

Specific inclusion criteria employed

The DESKTOP III investigators randomly assigned 407 patients with platinum-sensitive recurrent ovarian cancer to secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) or platinum-based chemotherapy alone (n = 201).³ An essential aspect of the study’s design was the use of specific inclusion criteria known to identify patients with a high likelihood of complete resection at the time of secondary cytoreduction.^6,7 Patients were eligible only if they had at least a 6-month remission following platinum-based chemotherapy, had a complete resection at their previous surgery, had no restriction on physical activity, and had ascites of no more than 500 mL.

Surgery group had superior overall and progression-free survival

After a median follow-up of approximately 70 months, patients randomly assigned to surgery had superior overall survival (53.7 months) compared with those assigned to chemotherapy alone (46.0 months; HR, 0.75; 95% CI, 0.59–0.96).³ Progression-free survival also was improved among patients who underwent surgery (median 18.4 vs 12.7 months; HR, 0.66; 95% CI, 0.54–0.82). Subgroup analyses did not identify any subset of patients who did not benefit from surgery. Whether a complete resection was achieved at secondary cytoreduction was highly prognostic: Patients who had a complete resection had a median overall survival of 61.9 months compared with 27.7 months in patients with residual disease. There were no deaths within 90 days of surgery.

Continue to: Immunotherapy enters first-line treatment regimen for advanced cervical cancer...

Immunotherapy enters first-line treatment regimen for advanced cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Persistent, recurrent, and metastatic cervical cancer carries a very poor prognosis: Most patients progress less than a year after starting treatment, and fewer than half survive for 2 years. First-line treatment in this setting has been platinum-based chemotherapy, often given with bevacizumab, a humanized monoclonal antibody that inhibits tumor growth by blocking angiogenesis.⁸ Pembrolizumab, an immune checkpoint inhibitor, targets cancer cells by blocking their ability to evade the immune system, and it is FDA approved and widely administered to patients with advanced cervical cancer who progress after first-line treatment.⁹

Addition of pembrolizumab extended survival

In the KEYNOTE-826 trial, Colombo and colleagues investigated the efficacy of incorporating an immune checkpoint inhibitor into the first-line treatment regimen for patients with persistent, recurrent, and metastatic cervical cancer.¹⁰ Researchers in this double-blinded, phase 3, randomized controlled trial assigned 617 patients to receive pembrolizumab or placebo concurrently with the investigator’s choice platinum-based chemotherapy. Bevacizumab was administered at the discretion of the treating oncologist.

The proportion of patients who survived at least 2 years following randomization was significantly higher among those assigned to pembrolizumab compared with placebo (53% vs 42%; HR, 0.67, 95% CI, 0.54–0.84).¹⁰ Similarly, median progression-free survival was superior among patients who received pembrolizumab compared with those who received placebo (10.4 months vs 8.2 months; HR, 0.65; 95% CI, 0.53–0.79). The role of bevacizumab in conjunction with pembrolizumab and platinum-based chemotherapy was not elucidated in this study because bevacizumab administration was not randomly assigned.

Anemia and neutropenia were the most common adverse events and were more frequent in the pembrolizumab group, but there were no new safety concerns related to concurrent use of pembrolizumab with cytotoxic chemotherapy and bevacizumab. Importantly, subgroup analysis results suggested that pembrolizumab was effective only in patients whose tumors expressed PD-L1 (programmed death ligand 1), a biomarker of pembrolizumab sensitivity in cervical cancer.

Continue to: Endometrial cancer surgical staging...

Endometrial cancer surgical staging: Is sentinel lymph node biopsy a viable option for high-risk histologies?

Cusimano MC, Vicus D, Pulman K, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156:157-164.

The use of intraoperative sentinel lymph node mapping and biopsy to identify lymph node metastases among patients undergoing surgical staging for endometrial cancer has become increasingly common. Lymph node status is an important prognostic factor, and it guides adjuvant treatment decisions in endometrial cancer. However, traditional pelvic and para-aortic lymphadenectomy is associated with increased risk of lower-extremity lymphedema, postoperative complications, and intraoperative injury.

Sentinel lymph node biopsy seeks to identify lymph node metastases while minimizing surgical morbidity by identifying and excising only lymph nodes that directly receive lymphatic drainage from the uterus. The combination of a fluorescent dye (indocyanine green) and near infrared cameras have led to the broad adoption of sentinel lymph node biopsy in endometrial cancer staging surgery. This practice is supported by prospective studies that demonstrate the high diagnostic accuracy of this approach.^11,12 However, because most patients included in prior studies had low-grade endometrial cancer, the utility of sentinel lymph node biopsy in cases of high-grade histology has been less clear.

Sentinel lymph node biopsy vs lymphadenectomy for staging

In the SENTOR trial, Cusimano and colleagues examined the diagnostic accuracy of sentinel lymph node mapping and biopsy, using indocyanine green, in patients with intermediate- or high-grade early-stage endometrial cancer.¹³

All eligible patients (N = 156) underwent traditional or robot-assisted laparoscopic hysterectomy with sentinel lymph node biopsy. Subsequently, patients with grade 2 endometrioid carcinoma underwent bilateral pelvic lymphadenectomy, and those with high-grade histology (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high grade) underwent bilateral pelvic and para-aortic lymphadenectomy. The investigators evaluated the diagnostic characteristics of sentinel lymph node biopsy, treating complete lymphadenectomy as the gold standard.

Of the 156 patients enrolled, the median age was 65.5 and median body mass index was 27.5; 126 patients (81%) had high-grade histology. The sentinel lymph node biopsy had a sensitivity of 96% (95% CI, 81%–100%), identifying 26 of the 27 patients with nodal metastases. The false-negative rate was 4% (95% CI, 0%–9%) and the negative predictive value was 99% (95% CI, 96%–100%). Intraoperative adverse events occurred in 5 patients (3%), but none occurred during the sentinel lymph node biopsy. ●

Despite the challenges of an ongoing COVID-19 pandemic, researchers in 2021 delivered practice-changing studies in gynecologic oncology. In this cancer Update, we highlight 4 studies that shed light on the surgical and systemic therapies that may improve outcomes for patients with cancers of the ovary, endometrium, and cervix. We review DESKTOP III, a trial that investigated the role of cytoreductive surgery in patients with recurrent ovarian cancer, and SENTOR, a study that evaluated the performance of sentinel lymph node biopsy in patients with high-grade endometrial cancers. Additionally, we examine 2 studies of systemic therapy that reveal the growing role of targeted therapies and immuno-oncology in the treatment of gynecologic malignancies.

A new era for patients with BRCA mutation–associated ovarian cancer

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.

Ovarian cancer remains the most lethal gynecologic malignancy due to the frequency of advanced-stage diagnosis and frequent relapse after primary therapy. But for ovarian cancer patients with inherited mutations of the BRCA1 or BRCA2 genes, poly(ADP-ribose) polymerase (PARP) inhibitors, a class of oral anticancer medicines that target DNA repair, have ushered in a new era in which the possibility of long-term remission, and even cure, is more likely than at any other time.

Olaparib trial details

The SOLO1 study was a double-blind, placebo-controlled, phase 3 trial that investigated the role of PARP inhibitor maintenance therapy with olaparib in patients with pathologic BRCA1 or BRCA2 mutations who responded to platinum-based chemotherapy administered for a newly diagnosed, advanced-stage ovarian cancer.¹ The study enrolled 391 patients, with 260 randomly assigned to receive olaparib for 24 months and 131 patients randomly assigned to receive placebo tablets. Most patients in the study had a mutation in the BRCA1 gene (72%), 27% had a BRCA2 mutation, and 1% had mutations in both genes.

The primary analysis of SOLO1 was published in 2018 and was based on a median follow-up of 3.4 years.¹ That study showed that olaparib maintenance therapy resulted in a large progression-free survival benefit and led to its approval by the US Food and Drug Administration (FDA) as a maintenance therapy for patients with BRCA-mutated advanced ovarian cancer who responded to first-line platinum-based chemotherapy.

In 2021, Banerjee and colleagues updated the progression-free survival results for the SOLO1 trial after 5 years of follow-up.² In this study, the patients randomly assigned to olaparib maintenance therapy had a persistent and statistically significant progression-free survival benefit, with the median progression-free survival reaching 56 months among the olaparib group compared with 13.8 months in the placebo group (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.43).² Olaparib maintenance therapy resulted in more clinically significant adverse events, including anemia and neutropenia. Serious adverse events occurred in 55 (21%) of the olaparib-treated patients and 17 (13%) of the placebo-treated patients, but no treatment-related adverse events were fatal.

Continue to: Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients...

Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients

Harter P, Sehouli J, Vergote I, et al; DESKTOP III Investigators. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021;385:2123- 2131.

In the DESKTOP III trial, Harter and colleagues contribute results to the ongoing discourse surrounding treatment options for patients with recurrent, platinum-sensitive ovarian cancer.³ Systemic therapies continue to be the mainstay of treatment in this setting; however, several groups have attempted to evaluate the role of secondary cytoreductive surgery in this setting.^4,5

Specific inclusion criteria employed

The DESKTOP III investigators randomly assigned 407 patients with platinum-sensitive recurrent ovarian cancer to secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) or platinum-based chemotherapy alone (n = 201).³ An essential aspect of the study’s design was the use of specific inclusion criteria known to identify patients with a high likelihood of complete resection at the time of secondary cytoreduction.^6,7 Patients were eligible only if they had at least a 6-month remission following platinum-based chemotherapy, had a complete resection at their previous surgery, had no restriction on physical activity, and had ascites of no more than 500 mL.

Surgery group had superior overall and progression-free survival

After a median follow-up of approximately 70 months, patients randomly assigned to surgery had superior overall survival (53.7 months) compared with those assigned to chemotherapy alone (46.0 months; HR, 0.75; 95% CI, 0.59–0.96).³ Progression-free survival also was improved among patients who underwent surgery (median 18.4 vs 12.7 months; HR, 0.66; 95% CI, 0.54–0.82). Subgroup analyses did not identify any subset of patients who did not benefit from surgery. Whether a complete resection was achieved at secondary cytoreduction was highly prognostic: Patients who had a complete resection had a median overall survival of 61.9 months compared with 27.7 months in patients with residual disease. There were no deaths within 90 days of surgery.

Continue to: Immunotherapy enters first-line treatment regimen for advanced cervical cancer...

Immunotherapy enters first-line treatment regimen for advanced cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Persistent, recurrent, and metastatic cervical cancer carries a very poor prognosis: Most patients progress less than a year after starting treatment, and fewer than half survive for 2 years. First-line treatment in this setting has been platinum-based chemotherapy, often given with bevacizumab, a humanized monoclonal antibody that inhibits tumor growth by blocking angiogenesis.⁸ Pembrolizumab, an immune checkpoint inhibitor, targets cancer cells by blocking their ability to evade the immune system, and it is FDA approved and widely administered to patients with advanced cervical cancer who progress after first-line treatment.⁹

Addition of pembrolizumab extended survival

In the KEYNOTE-826 trial, Colombo and colleagues investigated the efficacy of incorporating an immune checkpoint inhibitor into the first-line treatment regimen for patients with persistent, recurrent, and metastatic cervical cancer.¹⁰ Researchers in this double-blinded, phase 3, randomized controlled trial assigned 617 patients to receive pembrolizumab or placebo concurrently with the investigator’s choice platinum-based chemotherapy. Bevacizumab was administered at the discretion of the treating oncologist.

The proportion of patients who survived at least 2 years following randomization was significantly higher among those assigned to pembrolizumab compared with placebo (53% vs 42%; HR, 0.67, 95% CI, 0.54–0.84).¹⁰ Similarly, median progression-free survival was superior among patients who received pembrolizumab compared with those who received placebo (10.4 months vs 8.2 months; HR, 0.65; 95% CI, 0.53–0.79). The role of bevacizumab in conjunction with pembrolizumab and platinum-based chemotherapy was not elucidated in this study because bevacizumab administration was not randomly assigned.

Anemia and neutropenia were the most common adverse events and were more frequent in the pembrolizumab group, but there were no new safety concerns related to concurrent use of pembrolizumab with cytotoxic chemotherapy and bevacizumab. Importantly, subgroup analysis results suggested that pembrolizumab was effective only in patients whose tumors expressed PD-L1 (programmed death ligand 1), a biomarker of pembrolizumab sensitivity in cervical cancer.

Continue to: Endometrial cancer surgical staging...

Endometrial cancer surgical staging: Is sentinel lymph node biopsy a viable option for high-risk histologies?

Cusimano MC, Vicus D, Pulman K, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156:157-164.

The use of intraoperative sentinel lymph node mapping and biopsy to identify lymph node metastases among patients undergoing surgical staging for endometrial cancer has become increasingly common. Lymph node status is an important prognostic factor, and it guides adjuvant treatment decisions in endometrial cancer. However, traditional pelvic and para-aortic lymphadenectomy is associated with increased risk of lower-extremity lymphedema, postoperative complications, and intraoperative injury.

Sentinel lymph node biopsy seeks to identify lymph node metastases while minimizing surgical morbidity by identifying and excising only lymph nodes that directly receive lymphatic drainage from the uterus. The combination of a fluorescent dye (indocyanine green) and near infrared cameras have led to the broad adoption of sentinel lymph node biopsy in endometrial cancer staging surgery. This practice is supported by prospective studies that demonstrate the high diagnostic accuracy of this approach.^11,12 However, because most patients included in prior studies had low-grade endometrial cancer, the utility of sentinel lymph node biopsy in cases of high-grade histology has been less clear.

Sentinel lymph node biopsy vs lymphadenectomy for staging

In the SENTOR trial, Cusimano and colleagues examined the diagnostic accuracy of sentinel lymph node mapping and biopsy, using indocyanine green, in patients with intermediate- or high-grade early-stage endometrial cancer.¹³

All eligible patients (N = 156) underwent traditional or robot-assisted laparoscopic hysterectomy with sentinel lymph node biopsy. Subsequently, patients with grade 2 endometrioid carcinoma underwent bilateral pelvic lymphadenectomy, and those with high-grade histology (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high grade) underwent bilateral pelvic and para-aortic lymphadenectomy. The investigators evaluated the diagnostic characteristics of sentinel lymph node biopsy, treating complete lymphadenectomy as the gold standard.

Of the 156 patients enrolled, the median age was 65.5 and median body mass index was 27.5; 126 patients (81%) had high-grade histology. The sentinel lymph node biopsy had a sensitivity of 96% (95% CI, 81%–100%), identifying 26 of the 27 patients with nodal metastases. The false-negative rate was 4% (95% CI, 0%–9%) and the negative predictive value was 99% (95% CI, 96%–100%). Intraoperative adverse events occurred in 5 patients (3%), but none occurred during the sentinel lymph node biopsy. ●

Despite the challenges of an ongoing COVID-19 pandemic, researchers in 2021 delivered practice-changing studies in gynecologic oncology. In this cancer Update, we highlight 4 studies that shed light on the surgical and systemic therapies that may improve outcomes for patients with cancers of the ovary, endometrium, and cervix. We review DESKTOP III, a trial that investigated the role of cytoreductive surgery in patients with recurrent ovarian cancer, and SENTOR, a study that evaluated the performance of sentinel lymph node biopsy in patients with high-grade endometrial cancers. Additionally, we examine 2 studies of systemic therapy that reveal the growing role of targeted therapies and immuno-oncology in the treatment of gynecologic malignancies.

A new era for patients with BRCA mutation–associated ovarian cancer

Banerjee S, Moore KN, Colombo N, et al. Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.

Ovarian cancer remains the most lethal gynecologic malignancy due to the frequency of advanced-stage diagnosis and frequent relapse after primary therapy. But for ovarian cancer patients with inherited mutations of the BRCA1 or BRCA2 genes, poly(ADP-ribose) polymerase (PARP) inhibitors, a class of oral anticancer medicines that target DNA repair, have ushered in a new era in which the possibility of long-term remission, and even cure, is more likely than at any other time.

Olaparib trial details

The SOLO1 study was a double-blind, placebo-controlled, phase 3 trial that investigated the role of PARP inhibitor maintenance therapy with olaparib in patients with pathologic BRCA1 or BRCA2 mutations who responded to platinum-based chemotherapy administered for a newly diagnosed, advanced-stage ovarian cancer.¹ The study enrolled 391 patients, with 260 randomly assigned to receive olaparib for 24 months and 131 patients randomly assigned to receive placebo tablets. Most patients in the study had a mutation in the BRCA1 gene (72%), 27% had a BRCA2 mutation, and 1% had mutations in both genes.

The primary analysis of SOLO1 was published in 2018 and was based on a median follow-up of 3.4 years.¹ That study showed that olaparib maintenance therapy resulted in a large progression-free survival benefit and led to its approval by the US Food and Drug Administration (FDA) as a maintenance therapy for patients with BRCA-mutated advanced ovarian cancer who responded to first-line platinum-based chemotherapy.

In 2021, Banerjee and colleagues updated the progression-free survival results for the SOLO1 trial after 5 years of follow-up.² In this study, the patients randomly assigned to olaparib maintenance therapy had a persistent and statistically significant progression-free survival benefit, with the median progression-free survival reaching 56 months among the olaparib group compared with 13.8 months in the placebo group (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.25–0.43).² Olaparib maintenance therapy resulted in more clinically significant adverse events, including anemia and neutropenia. Serious adverse events occurred in 55 (21%) of the olaparib-treated patients and 17 (13%) of the placebo-treated patients, but no treatment-related adverse events were fatal.

Continue to: Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients...

Cytoreductive surgery for recurrent ovarian cancer improves survival in well-selected patients

Harter P, Sehouli J, Vergote I, et al; DESKTOP III Investigators. Randomized trial of cytoreductive surgery for relapsed ovarian cancer. N Engl J Med. 2021;385:2123- 2131.

In the DESKTOP III trial, Harter and colleagues contribute results to the ongoing discourse surrounding treatment options for patients with recurrent, platinum-sensitive ovarian cancer.³ Systemic therapies continue to be the mainstay of treatment in this setting; however, several groups have attempted to evaluate the role of secondary cytoreductive surgery in this setting.^4,5

Specific inclusion criteria employed

The DESKTOP III investigators randomly assigned 407 patients with platinum-sensitive recurrent ovarian cancer to secondary cytoreductive surgery followed by platinum-based chemotherapy (n = 206) or platinum-based chemotherapy alone (n = 201).³ An essential aspect of the study’s design was the use of specific inclusion criteria known to identify patients with a high likelihood of complete resection at the time of secondary cytoreduction.^6,7 Patients were eligible only if they had at least a 6-month remission following platinum-based chemotherapy, had a complete resection at their previous surgery, had no restriction on physical activity, and had ascites of no more than 500 mL.

Surgery group had superior overall and progression-free survival

After a median follow-up of approximately 70 months, patients randomly assigned to surgery had superior overall survival (53.7 months) compared with those assigned to chemotherapy alone (46.0 months; HR, 0.75; 95% CI, 0.59–0.96).³ Progression-free survival also was improved among patients who underwent surgery (median 18.4 vs 12.7 months; HR, 0.66; 95% CI, 0.54–0.82). Subgroup analyses did not identify any subset of patients who did not benefit from surgery. Whether a complete resection was achieved at secondary cytoreduction was highly prognostic: Patients who had a complete resection had a median overall survival of 61.9 months compared with 27.7 months in patients with residual disease. There were no deaths within 90 days of surgery.

Continue to: Immunotherapy enters first-line treatment regimen for advanced cervical cancer...

Immunotherapy enters first-line treatment regimen for advanced cervical cancer

Colombo N, Dubot C, Lorusso D, et al; KEYNOTE-826 Investigators. Pembrolizumab for persistent, recurrent, or metastatic cervical cancer. N Engl J Med. 2021;385:1856-1867.

Persistent, recurrent, and metastatic cervical cancer carries a very poor prognosis: Most patients progress less than a year after starting treatment, and fewer than half survive for 2 years. First-line treatment in this setting has been platinum-based chemotherapy, often given with bevacizumab, a humanized monoclonal antibody that inhibits tumor growth by blocking angiogenesis.⁸ Pembrolizumab, an immune checkpoint inhibitor, targets cancer cells by blocking their ability to evade the immune system, and it is FDA approved and widely administered to patients with advanced cervical cancer who progress after first-line treatment.⁹

Addition of pembrolizumab extended survival

In the KEYNOTE-826 trial, Colombo and colleagues investigated the efficacy of incorporating an immune checkpoint inhibitor into the first-line treatment regimen for patients with persistent, recurrent, and metastatic cervical cancer.¹⁰ Researchers in this double-blinded, phase 3, randomized controlled trial assigned 617 patients to receive pembrolizumab or placebo concurrently with the investigator’s choice platinum-based chemotherapy. Bevacizumab was administered at the discretion of the treating oncologist.

The proportion of patients who survived at least 2 years following randomization was significantly higher among those assigned to pembrolizumab compared with placebo (53% vs 42%; HR, 0.67, 95% CI, 0.54–0.84).¹⁰ Similarly, median progression-free survival was superior among patients who received pembrolizumab compared with those who received placebo (10.4 months vs 8.2 months; HR, 0.65; 95% CI, 0.53–0.79). The role of bevacizumab in conjunction with pembrolizumab and platinum-based chemotherapy was not elucidated in this study because bevacizumab administration was not randomly assigned.

Anemia and neutropenia were the most common adverse events and were more frequent in the pembrolizumab group, but there were no new safety concerns related to concurrent use of pembrolizumab with cytotoxic chemotherapy and bevacizumab. Importantly, subgroup analysis results suggested that pembrolizumab was effective only in patients whose tumors expressed PD-L1 (programmed death ligand 1), a biomarker of pembrolizumab sensitivity in cervical cancer.

Continue to: Endometrial cancer surgical staging...

Endometrial cancer surgical staging: Is sentinel lymph node biopsy a viable option for high-risk histologies?

Cusimano MC, Vicus D, Pulman K, et al. Assessment of sentinel lymph node biopsy vs lymphadenectomy for intermediate- and high-grade endometrial cancer staging. JAMA Surg. 2021;156:157-164.

The use of intraoperative sentinel lymph node mapping and biopsy to identify lymph node metastases among patients undergoing surgical staging for endometrial cancer has become increasingly common. Lymph node status is an important prognostic factor, and it guides adjuvant treatment decisions in endometrial cancer. However, traditional pelvic and para-aortic lymphadenectomy is associated with increased risk of lower-extremity lymphedema, postoperative complications, and intraoperative injury.

Sentinel lymph node biopsy seeks to identify lymph node metastases while minimizing surgical morbidity by identifying and excising only lymph nodes that directly receive lymphatic drainage from the uterus. The combination of a fluorescent dye (indocyanine green) and near infrared cameras have led to the broad adoption of sentinel lymph node biopsy in endometrial cancer staging surgery. This practice is supported by prospective studies that demonstrate the high diagnostic accuracy of this approach.^11,12 However, because most patients included in prior studies had low-grade endometrial cancer, the utility of sentinel lymph node biopsy in cases of high-grade histology has been less clear.

Sentinel lymph node biopsy vs lymphadenectomy for staging

In the SENTOR trial, Cusimano and colleagues examined the diagnostic accuracy of sentinel lymph node mapping and biopsy, using indocyanine green, in patients with intermediate- or high-grade early-stage endometrial cancer.¹³

All eligible patients (N = 156) underwent traditional or robot-assisted laparoscopic hysterectomy with sentinel lymph node biopsy. Subsequently, patients with grade 2 endometrioid carcinoma underwent bilateral pelvic lymphadenectomy, and those with high-grade histology (grade 3 endometrioid, serous, carcinosarcoma, clear cell, undifferentiated or dedifferentiated, and mixed high grade) underwent bilateral pelvic and para-aortic lymphadenectomy. The investigators evaluated the diagnostic characteristics of sentinel lymph node biopsy, treating complete lymphadenectomy as the gold standard.

Of the 156 patients enrolled, the median age was 65.5 and median body mass index was 27.5; 126 patients (81%) had high-grade histology. The sentinel lymph node biopsy had a sensitivity of 96% (95% CI, 81%–100%), identifying 26 of the 27 patients with nodal metastases. The false-negative rate was 4% (95% CI, 0%–9%) and the negative predictive value was 99% (95% CI, 96%–100%). Intraoperative adverse events occurred in 5 patients (3%), but none occurred during the sentinel lymph node biopsy. ●

CASE 1 Pregnant patient endures extensive wait and travel times to have antenatal testing

Pregnant at age 35 without comorbidities, Ms. H was instructed to schedule weekly biophysical profiles (BPP) after 36 weeks’ gestation for advanced maternal age. She receives care at a community office 25 miles from the hospital where she will deliver. Ms. H must complete her antenatal testing at the hospital where the sonographer performs BPPs. She sees her physician at the nearby clinic and then takes public transit to the hospital. She waits 2 hours to be seen then makes her way back home. Her prenatal care visit, which usually takes 30 minutes, turns into a 5-hour ordeal. Ms. H delivered a healthy baby at 39 weeks. Unfortunately, she was fired from her job for missing too many workdays.

Antenatal testing has become routine, and it is costly

For the prescriber, antenatal testing is simple: Order a weekly ultrasound exam to reduce the risk of stillbirth, decrease litigation, generate income, and maximize patient satisfaction (with the assumption that everyone likes to peek at their baby). Recommending antenatal testing has—with the best intentions—become a habit and therefore is difficult to break. However, the American College of Obstetricians and Gynecologists (ACOG) recognizes that “there is a paucity of evidenced-based recommendations on the timing and frequency of antenatal fetal surveillance because of the challenges of conducting prospective trials in pregnancies complicated by stillbirths and the varying conditions that place pregnancies at high risk for stillbirth. As a result, evidence for the efficacy of antenatal fetal surveillance, when available, is largely circumstantial.”¹

Antenatal testing without an evidence-based indication can be costly for the health care system, insurance companies, and patients. Many clinics, especially those in rural communities, do not have the equipment or personnel to complete antenatal testing on site. Asking a pregnant patient to travel repeatedly to another location for antenatal testing can increase her time off from work, complicate childcare, pose a financial burden, and lead to nonadherence. As clinicians, it is imperative that we work with our patients to create an individualized care plan to minimize these burdens and increase adherence.

Antenatal fetal surveillance can be considered for conditions in which stillbirth is reported more frequently than 0.8 per 1,000.

Advanced maternal age and stillbirth risk

One of the most common reasons for antenatal testing is advanced maternal age, that is, age older than 35. According to the Centers for Disease Control and Prevention and the National Vital Statistics System, from 2000 to 2012, 46 states and the District of Columbia (DC) reported an increase in first birth rates for women aged 35 to 39. Thirty-one states and DC saw a rise among women aged 40 to 44 in the same period (FIGURE).²

Advanced maternal age is an independent risk factor for stillbirth, with women aged 35 to 39 at 1.9-fold increased risk and women older than age 40 with a 2.4-fold higher risk compared with women younger than age 30.³ In a review of 44 studies including nearly 45,000,000 births, case-control studies, versus cohort studies, demonstrated a higher odds for stillbirth among women aged 35 and older (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.57-3.66 vs OR, 1.73; 95% CI, 1.6-1.87).⁴ Now, many women older than age 35 may have a concomitant risk factor, such as diabetes or hypertension, that requires antenatal testing. However, for those without other risk factors, nearly 863 antenatal tests and 71 inductions would need to be completed to reduce the number of stillbirths by 1. Antenatal testing for women older than age 35 without other risk factors should be individualized through shared decision making.⁵ See the ACOG committee opinion for a table that outlines factors associated with an increased risk of stillbirth and suggested strategies for antenatal surveillance after viability.¹

Continue to: CASE 2 Patient with high BPP score and altered...

CASE 2 Patient with high BPP score and altered fetal movements delivered for nonreassuring fetal heart rate

Ms. Q was undergoing weekly BPPs for diet-controlled gestational diabetes and a prepregnancy body mass index (BMI) of 52. At 37 weeks’ gestation, she had a BPP score of 8/8. However, it took almost 30 minutes to see 2 discrete body or limb movements. Ms. Q mentioned to the nurse taking her vitals after the BPP that the baby’s movements had changed over the previous few days, especially after contractions. Ms. Q then completed a nonstress test (NST); she had 2 contractions and 2 fetal heart rate decelerations, each lasting approximately 60 seconds. Ms. Q was sent to labor and delivery for prolonged monitoring, and she was delivered that day for a nonreassuring fetal heart rate tracing. Meconium-stained amniotic fluid and a tight triple nuchal cord were noted at delivery.

BPP considerations

While considered an in-depth look at the fetal status, BPPs may not predict overall fetal well-being during acute changes, such as umbilical cord compression or placental abruption. BPPs take longer to complete, require a trained sonographer, and include components like fetal breathing that may be influenced by such factors as nicotine,^6-8 labor,⁹ rupture of membranes,¹⁰ magnesium sulfate,¹¹ and infection.¹²

If medically indicated, which antenatal surveillance technique is right for your patient?

Frequently used antepartum fetal surveillance techniques include maternal perception of fetal movement or “kick counting,” NST, BPP, modified BPP, contraction stress test (CST), and umbilical artery Doppler velocimetry.

Worldwide, the most common form of antenatal surveillance is fetal kick counting. It is noninvasive, can be completed frequently, may decrease maternal anxiety, may improve maternal-fetal bonding, and is free.¹³ According to the results of a 2020 meta-analysis of 468,601 fetuses, however, there was no difference in perinatal death among patients who assessed fetal movements (0.54%) and those who did not (0.59%).¹⁴ There was a statistically significant increase in induction of labor, cesarean delivery, and preterm delivery among patients who counted fetal movements. Women who perceive a decrease in fetal movement should seek medical attention from a health care provider.

An evaluation for decreased fetal movement typically includes taking a history that focuses on risk factors that may increase stillbirth, including hypertension, growth restriction, fetal anomalies, diabetes, and substance use, and auscultation with a fetal Doppler. In the absence of risk factors and the presence of a normal fetal heartbeat, pregnant women should be reassured of fetal well-being. In a pregnancy at greater than 28 weeks, a 20-minute NST can be completed as well; this has become part of the standard workup of decreased fetal movement in developed countries. A reactive NST indicates normal fetal autonomic function in real time and a low incidence of stillbirth (1.9/1,000) within 1 week.¹⁵

Additionally, by measuring the amniotic fluid volume using the largest maximal vertical pocket (MVP), clinicians can gain insight into overall uteroplacental function. The combination of the NST and the MVP—otherwise known as a modified BPP—provides both short-term acid-base status and long-term uteroplacental function. The incidence of stillbirth in the 1 week after a modified BPP has been reported to be 0.8/1,000, which is equivalent to stillbirth incidence using a full BPP (0.8/1,000).¹⁶ The negative predictive value for both the modified BPP and the BPP is 99.9%—equivalent.

The case for modified BPP use

The modified BPP requires less time, is less costly (cost savings of approximately 50%), does not require a specialized sonographer, and can be performed in local community clinics.

Perhaps the initial antepartum surveillance test of choice should be the modified BPP, with the BPP used in cases in which the results of a modified BPP are abnormal. ●

CASE 1 Pregnant patient endures extensive wait and travel times to have antenatal testing

Pregnant at age 35 without comorbidities, Ms. H was instructed to schedule weekly biophysical profiles (BPP) after 36 weeks’ gestation for advanced maternal age. She receives care at a community office 25 miles from the hospital where she will deliver. Ms. H must complete her antenatal testing at the hospital where the sonographer performs BPPs. She sees her physician at the nearby clinic and then takes public transit to the hospital. She waits 2 hours to be seen then makes her way back home. Her prenatal care visit, which usually takes 30 minutes, turns into a 5-hour ordeal. Ms. H delivered a healthy baby at 39 weeks. Unfortunately, she was fired from her job for missing too many workdays.

Antenatal testing has become routine, and it is costly

For the prescriber, antenatal testing is simple: Order a weekly ultrasound exam to reduce the risk of stillbirth, decrease litigation, generate income, and maximize patient satisfaction (with the assumption that everyone likes to peek at their baby). Recommending antenatal testing has—with the best intentions—become a habit and therefore is difficult to break. However, the American College of Obstetricians and Gynecologists (ACOG) recognizes that “there is a paucity of evidenced-based recommendations on the timing and frequency of antenatal fetal surveillance because of the challenges of conducting prospective trials in pregnancies complicated by stillbirths and the varying conditions that place pregnancies at high risk for stillbirth. As a result, evidence for the efficacy of antenatal fetal surveillance, when available, is largely circumstantial.”¹

Antenatal testing without an evidence-based indication can be costly for the health care system, insurance companies, and patients. Many clinics, especially those in rural communities, do not have the equipment or personnel to complete antenatal testing on site. Asking a pregnant patient to travel repeatedly to another location for antenatal testing can increase her time off from work, complicate childcare, pose a financial burden, and lead to nonadherence. As clinicians, it is imperative that we work with our patients to create an individualized care plan to minimize these burdens and increase adherence.

Antenatal fetal surveillance can be considered for conditions in which stillbirth is reported more frequently than 0.8 per 1,000.

Advanced maternal age and stillbirth risk

One of the most common reasons for antenatal testing is advanced maternal age, that is, age older than 35. According to the Centers for Disease Control and Prevention and the National Vital Statistics System, from 2000 to 2012, 46 states and the District of Columbia (DC) reported an increase in first birth rates for women aged 35 to 39. Thirty-one states and DC saw a rise among women aged 40 to 44 in the same period (FIGURE).²

Advanced maternal age is an independent risk factor for stillbirth, with women aged 35 to 39 at 1.9-fold increased risk and women older than age 40 with a 2.4-fold higher risk compared with women younger than age 30.³ In a review of 44 studies including nearly 45,000,000 births, case-control studies, versus cohort studies, demonstrated a higher odds for stillbirth among women aged 35 and older (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.57-3.66 vs OR, 1.73; 95% CI, 1.6-1.87).⁴ Now, many women older than age 35 may have a concomitant risk factor, such as diabetes or hypertension, that requires antenatal testing. However, for those without other risk factors, nearly 863 antenatal tests and 71 inductions would need to be completed to reduce the number of stillbirths by 1. Antenatal testing for women older than age 35 without other risk factors should be individualized through shared decision making.⁵ See the ACOG committee opinion for a table that outlines factors associated with an increased risk of stillbirth and suggested strategies for antenatal surveillance after viability.¹

Continue to: CASE 2 Patient with high BPP score and altered...

CASE 2 Patient with high BPP score and altered fetal movements delivered for nonreassuring fetal heart rate

Ms. Q was undergoing weekly BPPs for diet-controlled gestational diabetes and a prepregnancy body mass index (BMI) of 52. At 37 weeks’ gestation, she had a BPP score of 8/8. However, it took almost 30 minutes to see 2 discrete body or limb movements. Ms. Q mentioned to the nurse taking her vitals after the BPP that the baby’s movements had changed over the previous few days, especially after contractions. Ms. Q then completed a nonstress test (NST); she had 2 contractions and 2 fetal heart rate decelerations, each lasting approximately 60 seconds. Ms. Q was sent to labor and delivery for prolonged monitoring, and she was delivered that day for a nonreassuring fetal heart rate tracing. Meconium-stained amniotic fluid and a tight triple nuchal cord were noted at delivery.

BPP considerations

While considered an in-depth look at the fetal status, BPPs may not predict overall fetal well-being during acute changes, such as umbilical cord compression or placental abruption. BPPs take longer to complete, require a trained sonographer, and include components like fetal breathing that may be influenced by such factors as nicotine,^6-8 labor,⁹ rupture of membranes,¹⁰ magnesium sulfate,¹¹ and infection.¹²

If medically indicated, which antenatal surveillance technique is right for your patient?

Frequently used antepartum fetal surveillance techniques include maternal perception of fetal movement or “kick counting,” NST, BPP, modified BPP, contraction stress test (CST), and umbilical artery Doppler velocimetry.

Worldwide, the most common form of antenatal surveillance is fetal kick counting. It is noninvasive, can be completed frequently, may decrease maternal anxiety, may improve maternal-fetal bonding, and is free.¹³ According to the results of a 2020 meta-analysis of 468,601 fetuses, however, there was no difference in perinatal death among patients who assessed fetal movements (0.54%) and those who did not (0.59%).¹⁴ There was a statistically significant increase in induction of labor, cesarean delivery, and preterm delivery among patients who counted fetal movements. Women who perceive a decrease in fetal movement should seek medical attention from a health care provider.

An evaluation for decreased fetal movement typically includes taking a history that focuses on risk factors that may increase stillbirth, including hypertension, growth restriction, fetal anomalies, diabetes, and substance use, and auscultation with a fetal Doppler. In the absence of risk factors and the presence of a normal fetal heartbeat, pregnant women should be reassured of fetal well-being. In a pregnancy at greater than 28 weeks, a 20-minute NST can be completed as well; this has become part of the standard workup of decreased fetal movement in developed countries. A reactive NST indicates normal fetal autonomic function in real time and a low incidence of stillbirth (1.9/1,000) within 1 week.¹⁵

Additionally, by measuring the amniotic fluid volume using the largest maximal vertical pocket (MVP), clinicians can gain insight into overall uteroplacental function. The combination of the NST and the MVP—otherwise known as a modified BPP—provides both short-term acid-base status and long-term uteroplacental function. The incidence of stillbirth in the 1 week after a modified BPP has been reported to be 0.8/1,000, which is equivalent to stillbirth incidence using a full BPP (0.8/1,000).¹⁶ The negative predictive value for both the modified BPP and the BPP is 99.9%—equivalent.

The case for modified BPP use

The modified BPP requires less time, is less costly (cost savings of approximately 50%), does not require a specialized sonographer, and can be performed in local community clinics.

Perhaps the initial antepartum surveillance test of choice should be the modified BPP, with the BPP used in cases in which the results of a modified BPP are abnormal. ●

CASE 1 Pregnant patient endures extensive wait and travel times to have antenatal testing

Pregnant at age 35 without comorbidities, Ms. H was instructed to schedule weekly biophysical profiles (BPP) after 36 weeks’ gestation for advanced maternal age. She receives care at a community office 25 miles from the hospital where she will deliver. Ms. H must complete her antenatal testing at the hospital where the sonographer performs BPPs. She sees her physician at the nearby clinic and then takes public transit to the hospital. She waits 2 hours to be seen then makes her way back home. Her prenatal care visit, which usually takes 30 minutes, turns into a 5-hour ordeal. Ms. H delivered a healthy baby at 39 weeks. Unfortunately, she was fired from her job for missing too many workdays.

Antenatal testing has become routine, and it is costly

For the prescriber, antenatal testing is simple: Order a weekly ultrasound exam to reduce the risk of stillbirth, decrease litigation, generate income, and maximize patient satisfaction (with the assumption that everyone likes to peek at their baby). Recommending antenatal testing has—with the best intentions—become a habit and therefore is difficult to break. However, the American College of Obstetricians and Gynecologists (ACOG) recognizes that “there is a paucity of evidenced-based recommendations on the timing and frequency of antenatal fetal surveillance because of the challenges of conducting prospective trials in pregnancies complicated by stillbirths and the varying conditions that place pregnancies at high risk for stillbirth. As a result, evidence for the efficacy of antenatal fetal surveillance, when available, is largely circumstantial.”¹

Antenatal testing without an evidence-based indication can be costly for the health care system, insurance companies, and patients. Many clinics, especially those in rural communities, do not have the equipment or personnel to complete antenatal testing on site. Asking a pregnant patient to travel repeatedly to another location for antenatal testing can increase her time off from work, complicate childcare, pose a financial burden, and lead to nonadherence. As clinicians, it is imperative that we work with our patients to create an individualized care plan to minimize these burdens and increase adherence.

Antenatal fetal surveillance can be considered for conditions in which stillbirth is reported more frequently than 0.8 per 1,000.

Advanced maternal age and stillbirth risk

One of the most common reasons for antenatal testing is advanced maternal age, that is, age older than 35. According to the Centers for Disease Control and Prevention and the National Vital Statistics System, from 2000 to 2012, 46 states and the District of Columbia (DC) reported an increase in first birth rates for women aged 35 to 39. Thirty-one states and DC saw a rise among women aged 40 to 44 in the same period (FIGURE).²

Advanced maternal age is an independent risk factor for stillbirth, with women aged 35 to 39 at 1.9-fold increased risk and women older than age 40 with a 2.4-fold higher risk compared with women younger than age 30.³ In a review of 44 studies including nearly 45,000,000 births, case-control studies, versus cohort studies, demonstrated a higher odds for stillbirth among women aged 35 and older (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.57-3.66 vs OR, 1.73; 95% CI, 1.6-1.87).⁴ Now, many women older than age 35 may have a concomitant risk factor, such as diabetes or hypertension, that requires antenatal testing. However, for those without other risk factors, nearly 863 antenatal tests and 71 inductions would need to be completed to reduce the number of stillbirths by 1. Antenatal testing for women older than age 35 without other risk factors should be individualized through shared decision making.⁵ See the ACOG committee opinion for a table that outlines factors associated with an increased risk of stillbirth and suggested strategies for antenatal surveillance after viability.¹

Continue to: CASE 2 Patient with high BPP score and altered...

CASE 2 Patient with high BPP score and altered fetal movements delivered for nonreassuring fetal heart rate

Ms. Q was undergoing weekly BPPs for diet-controlled gestational diabetes and a prepregnancy body mass index (BMI) of 52. At 37 weeks’ gestation, she had a BPP score of 8/8. However, it took almost 30 minutes to see 2 discrete body or limb movements. Ms. Q mentioned to the nurse taking her vitals after the BPP that the baby’s movements had changed over the previous few days, especially after contractions. Ms. Q then completed a nonstress test (NST); she had 2 contractions and 2 fetal heart rate decelerations, each lasting approximately 60 seconds. Ms. Q was sent to labor and delivery for prolonged monitoring, and she was delivered that day for a nonreassuring fetal heart rate tracing. Meconium-stained amniotic fluid and a tight triple nuchal cord were noted at delivery.

BPP considerations

While considered an in-depth look at the fetal status, BPPs may not predict overall fetal well-being during acute changes, such as umbilical cord compression or placental abruption. BPPs take longer to complete, require a trained sonographer, and include components like fetal breathing that may be influenced by such factors as nicotine,^6-8 labor,⁹ rupture of membranes,¹⁰ magnesium sulfate,¹¹ and infection.¹²

If medically indicated, which antenatal surveillance technique is right for your patient?

Frequently used antepartum fetal surveillance techniques include maternal perception of fetal movement or “kick counting,” NST, BPP, modified BPP, contraction stress test (CST), and umbilical artery Doppler velocimetry.

Worldwide, the most common form of antenatal surveillance is fetal kick counting. It is noninvasive, can be completed frequently, may decrease maternal anxiety, may improve maternal-fetal bonding, and is free.¹³ According to the results of a 2020 meta-analysis of 468,601 fetuses, however, there was no difference in perinatal death among patients who assessed fetal movements (0.54%) and those who did not (0.59%).¹⁴ There was a statistically significant increase in induction of labor, cesarean delivery, and preterm delivery among patients who counted fetal movements. Women who perceive a decrease in fetal movement should seek medical attention from a health care provider.

An evaluation for decreased fetal movement typically includes taking a history that focuses on risk factors that may increase stillbirth, including hypertension, growth restriction, fetal anomalies, diabetes, and substance use, and auscultation with a fetal Doppler. In the absence of risk factors and the presence of a normal fetal heartbeat, pregnant women should be reassured of fetal well-being. In a pregnancy at greater than 28 weeks, a 20-minute NST can be completed as well; this has become part of the standard workup of decreased fetal movement in developed countries. A reactive NST indicates normal fetal autonomic function in real time and a low incidence of stillbirth (1.9/1,000) within 1 week.¹⁵

Additionally, by measuring the amniotic fluid volume using the largest maximal vertical pocket (MVP), clinicians can gain insight into overall uteroplacental function. The combination of the NST and the MVP—otherwise known as a modified BPP—provides both short-term acid-base status and long-term uteroplacental function. The incidence of stillbirth in the 1 week after a modified BPP has been reported to be 0.8/1,000, which is equivalent to stillbirth incidence using a full BPP (0.8/1,000).¹⁶ The negative predictive value for both the modified BPP and the BPP is 99.9%—equivalent.

The case for modified BPP use

The modified BPP requires less time, is less costly (cost savings of approximately 50%), does not require a specialized sonographer, and can be performed in local community clinics.

Perhaps the initial antepartum surveillance test of choice should be the modified BPP, with the BPP used in cases in which the results of a modified BPP are abnormal. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Copyright: Digital illustrations by John J. DeNapoli/Cristian Storto Fotografia/IStock/Getty Images Plus/Prostock-Studio/IStock/Getty Images Plus/ClaudioVentrella/IStock Getty Images Plus

COVID-19 vaccination is recommended for all reproductive-aged women, regardless of pregnancy status.¹ Yet, national vaccination rates in pregnancy remain woefully low—lower than vaccine coverage rates for other recommended vaccines during pregnancy.^2,3 COVID-19 infection has clearly documented risks for maternal and fetal health, and data continue to accumulate on the maternal and neonatal benefits of COVID-19 vaccination in pregnancy, as well as the safety of vaccination during pregnancy.

Maternal and neonatal benefits of COVID-19 vaccination

Does vaccination in pregnancy result in decreased rates of severe COVID-19 infection? Results from a study from a Louisiana health system comparing maternal outcomes between fully vaccinated (defined as 2 weeks after the final vaccine dose) and unvaccinated or partially vaccinated pregnant women during the delta variant—predominant COVID-19 surge clearly answer this question. Vaccination in pregnancy resulted in a 90% risk reduction in severe or critical COVID-19 infection and a 70% risk reduction in COVID-19 infection of any severity among fully vaccinated women. The study also provides some useful absolute numbers for patient counseling: Although none of the 1,332 vaccinated pregnant women in the study required supplemental oxygen or intensive care unit (ICU) admission, there was 1 maternal death, 5 ICU admissions, and 6 stillbirths among the 8,760 unvaccinated pregnant women.⁴

A larger population-based data set from Scotland and Israel demonstrated similar findings.⁵ Most importantly, the Scotland data, with most patients having had an mRNA-based vaccine, showed that, while 77% of all COVID-19 infections occurred in unvaccinated pregnant women, 91% of all hospital admissions occurred in unvaccinated women, and 98% of all critical care admissions occurred in unvaccinated women. Furthermore, although 13% of all COVID-19 hospitalizations in pregnancy occurred among vaccinated women, only 2% of critical care admissions occurred among vaccinated women. The Israeli experience (which identified nearly 30,000 eligible pregnancies from 1 of 4 state-mandated health funds in the country), demonstrated that the efficacy of the Pfizer/BioNTech vaccine to prevent a SARS-CoV-2 infection of any severity once fully vaccinated is more than 80%.⁶

Breakthrough infections, which were more prevalent during the omicron surge, have caused some patients to question the utility of COVID-19 vaccination. Recent data from South Africa, where the omicron variant was first identified, noted that efficacy of the Pfizer/ BioNTech vaccine to prevent hospitalization with COVID-19 infection during an omicron-predominant period was 70%—versus 93% efficacy in a delta-predominant period.⁷ These data, however, were in the absence of a booster dose, and in vitro studies suggest increased vaccine efficacy with a booster dose.⁸

Continue to: Counseling women on vaccination benefits and risks...

Counseling women on vaccination benefits and risks. No matter the specific numeric rate of efficacy against a COVID-19 infection, it is important to counsel women that the goal of vaccination is to prevent severe or critical COVID-19 infections, and these data all demonstrate that COVID-19 vaccination meets this goal. However, women may have additional questions regarding both fetal/neonatal benefits and safety with immunization in pregnancy.

Let us address the question of benefit first. In a large cohort of more than 1,300 women vaccinated during pregnancy and delivering at >34 weeks’ gestation, a few observations are worth noting.⁹ The first is that women who were fully vaccinated by the time of delivery had detectable antibodies at birth, even with first trimester vaccination, and these antibodies did cross the placenta to the neonate. Although higher maternal and neonatal antibody levels are achieved with early third trimester vaccination, it is key that women interpret this finding in light of 2 important points:

1. women cannot know what gestational age they will deliver, thus waiting until the early third trimester for vaccination to optimize neonatal antibody levels could result in delivery prior to planned vaccination, with benefit for neither the woman nor the baby
2. partial vaccination in the early third trimester resulted in lower maternal and neonatal antibody levels than full vaccination in the first trimester.

In addition, while the data were limited, a booster dose in the third trimester results in the highest antibody levels at delivery. Given the recommendation to initiate a booster dose 5 months after the completion of the primary vaccine series,¹⁰ many women will be eligible for a booster prior to delivery and thus can achieve the goals of high maternal and neonatal antibody levels simultaneously. One caveat to these data is that, while higher antibody levels seem comforting and may be better, we do not yet know the level of neonatal antibody necessary to decrease risks of COVID-19 infection in early newborn life.⁹ Recent data from the Centers for Disease Control and Prevention provide real-world evidence that maternal vaccination decreases the risk of hospitalization from COVID-19 for infants aged <6 months, with vaccine efficacy estimated to be 61% during a period of both Delta and Omicron predominance.¹¹

The evidence is clear—the time for COVID-19 vaccination is now. There is no “optimal” time of vaccination in pregnancy for neonatal benefit that would be worth risking any amount of time a woman is susceptible to COVID-19, especially given the promising data regarding maternal and neonatal antibody levels achieved after a booster dose.

Safety of COVID-19 vaccination: Current data

Risks for pregnancy loss, birth defects, and preterm delivery often are concerns of pregnant women considering a COVID-19 vaccination. Data from more than 2,400 women who submitted their information to the v-SAFE registry demonstrated a 14% risk for pregnancy loss between 6 and 20 weeks’ gestation—well within the expected rate of pregnancy loss in this gestational age range.¹²

Data from more than 46,000 pregnancies included in the Vaccine Safety Datalink, which includes data from health care organizations in 6 states, demonstrated a preterm birth rate of 6.6% and a small-for-gestational-age rate of 8.2% among fully vaccinated women, rates that were no different among unvaccinated women. There were no differences in the outcomes by trimester of vaccination, and these rates are comparable to the expected rates of these outcomes.¹³

Women also worry about the risks of vaccine side effects, such as fever or rare adverse events. Although all adverse events (ie, Guillain-Barre syndrome, pericarditis/myocarditis, thrombosis with thrombocytopenia syndrome [TTS]) are very rare, the American College of Obstetricians and Gynecologists does recommend that women get an mRNA COVID-19 vaccine, as the Johnson & Johnson/Janssen vaccine is associated with TTS, which occurred more commonly (although still rare) in women of reproductive age.¹⁴

Two large studies of typical side effects experienced after COVID-19 vaccination in pregnancy are incredibly reassuring. In the first, authors of a large study of more than 12,000 pregnant women enrolled in the v-SAFE registry reported that the most common side effect after each mRNA dose was injection site pain (88% after dose 1, 92% after dose 2).¹⁵ Self-reported fever occurred in 4% of women after dose 1 and 35% after dose 2. Although this frequency may seem high, a fever of 38.0°C (100.4°F) or higher only occurred among 8% of all participants.

In another study of almost 8,000 women self-reporting side effects (some of whom also may have contributed data to the v-SAFE study), fever occurred in approximately 5% after dose 1 and in about 20% after dose 2.¹⁶ In this study, the highest mean temperature was 38.1°C (100.6°F) after dose 1 and 38.2°C (100.7°F) after dose 2. Although it is a reasonable expectation for fever to follow COVID-19 vaccination, particularly after the second dose, the typical fever is a low-grade temperature that will not harm a developing fetus and will be responsive to acetaminophen administration. Moreover, if the fever were the harbinger of harm, then it might stand to reason that an increased signal of preterm delivery may be observed, but data from nearly 10,000 pregnant women vaccinated during the second or third trimesters showed no association with preterm birth (adjusted hazard ratio, 0.91; 95% confidence interval, 0.82–1.01).¹³

The bottom line

The data are clear. COVID-19 vaccination decreases the risks of severe infection in pregnancy, confers antibodies to neonates with at least some level of protection, and has no demonstrated harmful side effects in pregnancy. ●

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with hyperandrogenism and is caused by occlusion or rupture of follicular units and inflammation of the apocrine glands.^1-3 The disease most commonly affects women (female to male ratio of 3:1) of childbearing age.^1,2,4,5 Body areas affected include the axillae and groin, and less commonly the perineum; perianal region; and skin folds, such as gluteal, inframammary, and infraumbilical folds.^1,2 Symptoms manifest as painful subcutaneous nodules with possible accompanying purulent drainage, sinus tracts, and/or dermal contractures. Although the pathophysiology is unclear, androgens affect the course of HS during pregnancy by stimulating the affected glands and altering cytokines.^1,2,6

During pregnancy, maternal immune function switches from cell-mediated T helper cell (T_H1) to humoral T_H2 cytokine production. The activity of sebaceous and eccrine glands increases while the activity of apocrine glands decreases, thus changing the inflammatory course of HS during pregnancy.³ Approximately 20% of women with HS experience improvement of symptoms during pregnancy, while the remainder either experience no relief or deterioration of symptoms.¹ Improvement in symptoms during pregnancy was found to occur more frequently in those who had worsening symptoms during menses owing to the possible hormonal effect estrogen has on inhibiting T_H1 and T_H17 proinflammatory cytokines, which promotes an immunosuppressive environment.⁴

Lactation and breastfeeding abilities may be hindered if a woman has HS affecting the apocrine glands of breast tissue and a symptom flare in the postpartum period. If HS causes notable inflammation in the nipple-areolar complex during pregnancy, the patient may experience difficulties with lactation and milk fistula formation, leading to inability to breastfeed.² Another reason why mothers with HS may not be able to breastfeed is that the medications required to treat the disease are unsafe if passed to the infant via breast milk. In addition, the teratogenic effects of HS medications may necessitate therapy adjustments in pregnancy.¹ Here, we provide a brief overview of the medical management considerations of HS in the setting of pregnancy and the impact on breastfeeding.

MEDICAL MANAGEMENT AND DRUG SAFETY

Dermatologists prescribe a myriad of topical and systemic medications to ameliorate symptoms of HS. Therapy regimens often are multimodal and include antibiotics, biologics, and immunosuppressants.^1,3

Antibiotics

First-line antibiotics include clindamycin, metronidazole, tetracyclines, erythromycin, rifampin, dapsone, and fluoroquinolones. Topical clindamycin 1%, metronidazole 0.75%, and erythromycin 2% are used for open or active HS lesions and are all safe to use in pregnancy since there is minimal systemic absorption and minimal excretion into breast milk.¹ Topical antimicrobial washes such as benzoyl peroxide and chlorhexidine often are used in combination with systemic medications to treat HS. These washes are safe during pregnancy and lactation, as they have minimal systemic absorption.⁷

Of these first-line antibiotics, only tetracyclines are contraindicated during pregnancy and lactation, as they are deemed to be in category D by the US Food and Drug Administration (FDA).¹ Aside from tetracyclines, these antibiotics do not cause birth defects and are safe for nursing infants.^1,8 Systemic clindamycin is safe during pregnancy and breastfeeding. Systemic metronidazole also is safe for use in pregnant patients but needs to be discontinued 12 to 24 hours prior to breastfeeding, which often prohibits appropriate dosing.¹

Systemic Erythromycin—There are several forms of systemic erythromycin, including erythromycin base, erythromycin estolate, erythromycin ethylsuccinate (EES), and erythromycin stearate. Erythromycin estolate is contraindicated in pregnancy because it is associated with reversible maternal hepatoxicity and jaundice.^9-11 Erythromycin ethylsuccinate is the preferred form for pregnant patients. Providers should exercise caution when prescribing EES to lactating mothers, as small amounts are still secreted through breast milk.¹¹ Some studies have shown an increased risk for development of infantile hypertrophic pyloric stenosis with systemic erythromycin use, especially if a neonate is exposed in the first 14 days of life. Thus, we recommend withholding EES for 2 weeks after delivery if the patient is breastfeeding. A follow-up study did not find any association between erythromycin and infantile hypertrophic pyloric stenosis; however, the American Academy of Pediatrics still recommends short-term use only of erythromycin if it is to be used in the systemic form.⁸

Rifampin—Rifampin is excreted into breast milk but without adverse effects to the infant. Rifampin also is safe in pregnancy but should be used on a case-by-case basis in pregnant or nursing women because it is a cytochrome P450 inducer.

Dapsone—Dapsone has no increased risk for congenital anomalies. However, it is associated with hemolytic anemia and neonatal hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹² Newborns exposed to dapsone are at an increased risk for methemoglobinemia owing to increased sensitivity of fetal erythrocytes to oxidizing agents.¹³ If dapsone use is necessary, stopping dapsone treatment in the last month of gestation is recommended to minimize risk for kernicterus.⁹ Dapsone can be found in high concentrations in breast milk at 14.3% of the maternal dose. It is still safe to use during breastfeeding, but there is a risk of the infant developing hyperbilirubinemia/G6PD deficiency.^1,8 Thus, physicians may consider performing a G6PD screen on infants to determine if breastfeeding is safe.¹²

Fluoroquinolones—Quinolones are not contraindicated during pregnancy, but they can damage fetal cartilage and thus should be reserved for use in complicated infections when the benefits outweigh the risks.¹² Quinolones are believed to increase risk for arthropathy but are safe for use in lactation. When quinolones are digested with milk, exposure decreases below pediatric doses because of the ionized property of calcium in milk.⁸

Tumor Necrosis Factor α Inhibitors—The safety of anti–tumor necrosis factor (TNF) α biologics in pregnancy is less certain when compared with antibiotics.¹ Anti–TNF-α inhibitors such as etanercept, adalimumab, and infliximab are all labeled as FDA category B, meaning there are no well-controlled human studies of the drugs.⁹ There are limited data that support safe use of TNF-α inhibitors prior to the third trimester before maternal IgG antibodies are transferred to the fetus via the placenta.^1,13 Anti–TNF-α inhibitors may be safe when breastfeeding because the drugs have large molecular weights that prevent them from entering breast milk in large amounts. Absorption also is limited due to the infant’s digestive acids and enzymes breaking down the protein structure of the medication.⁸ Overall, TNF-α inhibitor use is still controversial and only used if the benefits outweigh the risks during pregnancy or if there is no alternative treatment.^1,3,9

Ustekinumab and Anakinra—Ustekinumab (an IL-12/IL-23 inhibitor) and anakinra (an IL-1α and IL-1β inhibitor) also are FDA category B drugs and have limited data supporting their use as HS treatment in pregnancy. Anakinra may have evidence of compatibility with breastfeeding, as endogenous IL-1α inhibitor is found in colostrum and mature breast milk.¹

Immunosuppressants

Immunosuppressants that are used to treat HS include corticosteroids and cyclosporine.

Corticosteroids—Topical corticosteroids can be used safely in lactation if they are not applied directly to the nipple or any area that makes direct contact with the infant’s mouth. Intralesional corticosteroid injections are safe for use during both pregnancy and breastfeeding to decrease inflammation of acutely flaring lesions and can be considered first-line treatment.¹ Oral glucocorticoids also can be safely used for acute flares during pregnancy; however, prolonged use is associated with pregnancy complications such as preeclampsia, eclampsia, premature delivery, and gestational diabetes.¹² There also is a small risk of oral cleft deformity in the infant; thus, potent corticosteroids are recommended in short durations during pregnancy, and there are no adverse effects if the maternal dose is less than 10 mg daily.^8,12 Systemic steroids are safe to use with breastfeeding, but patients should be advised to wait 4 hours after ingesting medication before breastfeeding.^1,8

Cyclosporine—Topical and oral calcineurin inhibitors such as cyclosporine have low risk for transmission into breast milk; however, potential effects of exposure through breast milk are unknown. For that reason, manufacturers state that cyclosporine use is contraindicated during lactation.⁸ If cyclosporine is to be used by a breastfeeding woman, monitoring cyclosporine concentrations in the infant is suggested to ensure that the exposure is less than 5% to 10% of the therapeutic dose.¹³ The use of cyclosporine has been extensively studied in pregnant transplant patients and is considered relatively safe for use in pregnancy.¹⁴ Cyclosporine is lipid soluble and thus is quickly metabolized and spread throughout the body; it can easily cross the placenta.^9,13 Blood concentration in the fetus is 30% to 64% that of the maternal circulation. However, cyclosporine is only toxic to the fetus at maternally toxic doses, which can result in low birth weight and increased prenatal and postnatal mortality.¹³

Isotretinoin, Oral Contraceptive Pills, and Spironolactone

Isotretinoin and hormonal treatments such as oral contraceptive pills and spironolactone (an androgen receptor blocker) commonly are used to treat HS, but all are contraindicated in pregnancy and lactation. Isotretinoin is a well-established teratogen, but adverse effects on nursing babies have not been described. However, the manufacturer of isotretinoin advises against its use in lactation. Oral contraceptive pill use in early pregnancy is associated with increased risk for Down syndrome. Oral contraceptive pill use also is contraindicated in lactation for 2 reasons: decreased milk production and risk for fetal feminization. Antiandrogenic agents such as spironolactone have been shown to be associated with hypospadias and feminization of the male fetus.⁷

COMMENT

Women with HS usually require ongoing medical treatment during pregnancy and immediately postpartum; thus, it is important that treatments are proven to be safe for use in this specific population. Current management guidelines are not entirely suitable for pregnant and breastfeeding women given that many HS drugs have teratogenic effects and/or can be excreted into breast milk.¹ Several treatments have uncertain safety profiles in pregnancy and breastfeeding, which calls for dermatologists to change or create new regimens for their patients. Close management also is necessary to prevent excess inflammation of breast tissue and milk fistula formation, which would hinder normal breastfeeding.

The eTable lists medications used to treat HS. The FDA category is listed next to each drug. However, it should be noted that these FDA letter categories were replaced with the Pregnancy and Lactation Labeling Rule in 2015. The letter ratings were deemed overly simplistic and replaced with narrative-based labeling that provides more detailed adverse effects and clinical considerations.⁹

Risk Factors of HS—Predisposing risk factors for HS flares that are controllable include obesity and smoking.² Pregnancy weight gain may cause increased skin maceration at intertriginous sites, which can contribute to worsening HS symptoms.^1,5 Adipocytes play a role in HS exacerbation by promoting secretion of TNF-α, leading to increased inflammation.⁵ Dermatologists can help prevent postpartum HS flares by monitoring weight gain during pregnancy, encouraging smoking cessation, and promoting weight and nutrition goals as set by an obstetrician.¹ In addition to medications, management of HS should include emotional support and education on wearing loose-fitting clothing to avoid irritation of the affected areas.³ An emphasis on dermatologist counseling for all patients with HS, even for those with milder disease, can reduce exacerbations during pregnancy.⁵

CONCLUSION

The selection of dermatologic drugs for the treatment of HS in the setting of pregnancy involves complex decision-making. Dermatologists need more guidelines and proven safety data in human trials, especially regarding use of biologics and immunosuppressants to better treat HS in pregnancy. With more data, they can create more evidence-based treatment regimens to help prevent postpartum exacerbations of HS. Thus, patients can breastfeed their infants comfortably and without any risks of impaired child development. In the meantime, dermatologists can continue to work together with obstetricians and psychiatrists to decrease disease flares through counseling patients on nutrition and weight gain and providing emotional support.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with hyperandrogenism and is caused by occlusion or rupture of follicular units and inflammation of the apocrine glands.^1-3 The disease most commonly affects women (female to male ratio of 3:1) of childbearing age.^1,2,4,5 Body areas affected include the axillae and groin, and less commonly the perineum; perianal region; and skin folds, such as gluteal, inframammary, and infraumbilical folds.^1,2 Symptoms manifest as painful subcutaneous nodules with possible accompanying purulent drainage, sinus tracts, and/or dermal contractures. Although the pathophysiology is unclear, androgens affect the course of HS during pregnancy by stimulating the affected glands and altering cytokines.^1,2,6

During pregnancy, maternal immune function switches from cell-mediated T helper cell (T_H1) to humoral T_H2 cytokine production. The activity of sebaceous and eccrine glands increases while the activity of apocrine glands decreases, thus changing the inflammatory course of HS during pregnancy.³ Approximately 20% of women with HS experience improvement of symptoms during pregnancy, while the remainder either experience no relief or deterioration of symptoms.¹ Improvement in symptoms during pregnancy was found to occur more frequently in those who had worsening symptoms during menses owing to the possible hormonal effect estrogen has on inhibiting T_H1 and T_H17 proinflammatory cytokines, which promotes an immunosuppressive environment.⁴

Lactation and breastfeeding abilities may be hindered if a woman has HS affecting the apocrine glands of breast tissue and a symptom flare in the postpartum period. If HS causes notable inflammation in the nipple-areolar complex during pregnancy, the patient may experience difficulties with lactation and milk fistula formation, leading to inability to breastfeed.² Another reason why mothers with HS may not be able to breastfeed is that the medications required to treat the disease are unsafe if passed to the infant via breast milk. In addition, the teratogenic effects of HS medications may necessitate therapy adjustments in pregnancy.¹ Here, we provide a brief overview of the medical management considerations of HS in the setting of pregnancy and the impact on breastfeeding.

MEDICAL MANAGEMENT AND DRUG SAFETY

Dermatologists prescribe a myriad of topical and systemic medications to ameliorate symptoms of HS. Therapy regimens often are multimodal and include antibiotics, biologics, and immunosuppressants.^1,3

Antibiotics

First-line antibiotics include clindamycin, metronidazole, tetracyclines, erythromycin, rifampin, dapsone, and fluoroquinolones. Topical clindamycin 1%, metronidazole 0.75%, and erythromycin 2% are used for open or active HS lesions and are all safe to use in pregnancy since there is minimal systemic absorption and minimal excretion into breast milk.¹ Topical antimicrobial washes such as benzoyl peroxide and chlorhexidine often are used in combination with systemic medications to treat HS. These washes are safe during pregnancy and lactation, as they have minimal systemic absorption.⁷

Of these first-line antibiotics, only tetracyclines are contraindicated during pregnancy and lactation, as they are deemed to be in category D by the US Food and Drug Administration (FDA).¹ Aside from tetracyclines, these antibiotics do not cause birth defects and are safe for nursing infants.^1,8 Systemic clindamycin is safe during pregnancy and breastfeeding. Systemic metronidazole also is safe for use in pregnant patients but needs to be discontinued 12 to 24 hours prior to breastfeeding, which often prohibits appropriate dosing.¹

Systemic Erythromycin—There are several forms of systemic erythromycin, including erythromycin base, erythromycin estolate, erythromycin ethylsuccinate (EES), and erythromycin stearate. Erythromycin estolate is contraindicated in pregnancy because it is associated with reversible maternal hepatoxicity and jaundice.^9-11 Erythromycin ethylsuccinate is the preferred form for pregnant patients. Providers should exercise caution when prescribing EES to lactating mothers, as small amounts are still secreted through breast milk.¹¹ Some studies have shown an increased risk for development of infantile hypertrophic pyloric stenosis with systemic erythromycin use, especially if a neonate is exposed in the first 14 days of life. Thus, we recommend withholding EES for 2 weeks after delivery if the patient is breastfeeding. A follow-up study did not find any association between erythromycin and infantile hypertrophic pyloric stenosis; however, the American Academy of Pediatrics still recommends short-term use only of erythromycin if it is to be used in the systemic form.⁸

Rifampin—Rifampin is excreted into breast milk but without adverse effects to the infant. Rifampin also is safe in pregnancy but should be used on a case-by-case basis in pregnant or nursing women because it is a cytochrome P450 inducer.

Dapsone—Dapsone has no increased risk for congenital anomalies. However, it is associated with hemolytic anemia and neonatal hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹² Newborns exposed to dapsone are at an increased risk for methemoglobinemia owing to increased sensitivity of fetal erythrocytes to oxidizing agents.¹³ If dapsone use is necessary, stopping dapsone treatment in the last month of gestation is recommended to minimize risk for kernicterus.⁹ Dapsone can be found in high concentrations in breast milk at 14.3% of the maternal dose. It is still safe to use during breastfeeding, but there is a risk of the infant developing hyperbilirubinemia/G6PD deficiency.^1,8 Thus, physicians may consider performing a G6PD screen on infants to determine if breastfeeding is safe.¹²

Fluoroquinolones—Quinolones are not contraindicated during pregnancy, but they can damage fetal cartilage and thus should be reserved for use in complicated infections when the benefits outweigh the risks.¹² Quinolones are believed to increase risk for arthropathy but are safe for use in lactation. When quinolones are digested with milk, exposure decreases below pediatric doses because of the ionized property of calcium in milk.⁸

Tumor Necrosis Factor α Inhibitors—The safety of anti–tumor necrosis factor (TNF) α biologics in pregnancy is less certain when compared with antibiotics.¹ Anti–TNF-α inhibitors such as etanercept, adalimumab, and infliximab are all labeled as FDA category B, meaning there are no well-controlled human studies of the drugs.⁹ There are limited data that support safe use of TNF-α inhibitors prior to the third trimester before maternal IgG antibodies are transferred to the fetus via the placenta.^1,13 Anti–TNF-α inhibitors may be safe when breastfeeding because the drugs have large molecular weights that prevent them from entering breast milk in large amounts. Absorption also is limited due to the infant’s digestive acids and enzymes breaking down the protein structure of the medication.⁸ Overall, TNF-α inhibitor use is still controversial and only used if the benefits outweigh the risks during pregnancy or if there is no alternative treatment.^1,3,9

Ustekinumab and Anakinra—Ustekinumab (an IL-12/IL-23 inhibitor) and anakinra (an IL-1α and IL-1β inhibitor) also are FDA category B drugs and have limited data supporting their use as HS treatment in pregnancy. Anakinra may have evidence of compatibility with breastfeeding, as endogenous IL-1α inhibitor is found in colostrum and mature breast milk.¹

Immunosuppressants

Immunosuppressants that are used to treat HS include corticosteroids and cyclosporine.

Corticosteroids—Topical corticosteroids can be used safely in lactation if they are not applied directly to the nipple or any area that makes direct contact with the infant’s mouth. Intralesional corticosteroid injections are safe for use during both pregnancy and breastfeeding to decrease inflammation of acutely flaring lesions and can be considered first-line treatment.¹ Oral glucocorticoids also can be safely used for acute flares during pregnancy; however, prolonged use is associated with pregnancy complications such as preeclampsia, eclampsia, premature delivery, and gestational diabetes.¹² There also is a small risk of oral cleft deformity in the infant; thus, potent corticosteroids are recommended in short durations during pregnancy, and there are no adverse effects if the maternal dose is less than 10 mg daily.^8,12 Systemic steroids are safe to use with breastfeeding, but patients should be advised to wait 4 hours after ingesting medication before breastfeeding.^1,8

Cyclosporine—Topical and oral calcineurin inhibitors such as cyclosporine have low risk for transmission into breast milk; however, potential effects of exposure through breast milk are unknown. For that reason, manufacturers state that cyclosporine use is contraindicated during lactation.⁸ If cyclosporine is to be used by a breastfeeding woman, monitoring cyclosporine concentrations in the infant is suggested to ensure that the exposure is less than 5% to 10% of the therapeutic dose.¹³ The use of cyclosporine has been extensively studied in pregnant transplant patients and is considered relatively safe for use in pregnancy.¹⁴ Cyclosporine is lipid soluble and thus is quickly metabolized and spread throughout the body; it can easily cross the placenta.^9,13 Blood concentration in the fetus is 30% to 64% that of the maternal circulation. However, cyclosporine is only toxic to the fetus at maternally toxic doses, which can result in low birth weight and increased prenatal and postnatal mortality.¹³

Isotretinoin, Oral Contraceptive Pills, and Spironolactone

Isotretinoin and hormonal treatments such as oral contraceptive pills and spironolactone (an androgen receptor blocker) commonly are used to treat HS, but all are contraindicated in pregnancy and lactation. Isotretinoin is a well-established teratogen, but adverse effects on nursing babies have not been described. However, the manufacturer of isotretinoin advises against its use in lactation. Oral contraceptive pill use in early pregnancy is associated with increased risk for Down syndrome. Oral contraceptive pill use also is contraindicated in lactation for 2 reasons: decreased milk production and risk for fetal feminization. Antiandrogenic agents such as spironolactone have been shown to be associated with hypospadias and feminization of the male fetus.⁷

COMMENT

Women with HS usually require ongoing medical treatment during pregnancy and immediately postpartum; thus, it is important that treatments are proven to be safe for use in this specific population. Current management guidelines are not entirely suitable for pregnant and breastfeeding women given that many HS drugs have teratogenic effects and/or can be excreted into breast milk.¹ Several treatments have uncertain safety profiles in pregnancy and breastfeeding, which calls for dermatologists to change or create new regimens for their patients. Close management also is necessary to prevent excess inflammation of breast tissue and milk fistula formation, which would hinder normal breastfeeding.

The eTable lists medications used to treat HS. The FDA category is listed next to each drug. However, it should be noted that these FDA letter categories were replaced with the Pregnancy and Lactation Labeling Rule in 2015. The letter ratings were deemed overly simplistic and replaced with narrative-based labeling that provides more detailed adverse effects and clinical considerations.⁹

Risk Factors of HS—Predisposing risk factors for HS flares that are controllable include obesity and smoking.² Pregnancy weight gain may cause increased skin maceration at intertriginous sites, which can contribute to worsening HS symptoms.^1,5 Adipocytes play a role in HS exacerbation by promoting secretion of TNF-α, leading to increased inflammation.⁵ Dermatologists can help prevent postpartum HS flares by monitoring weight gain during pregnancy, encouraging smoking cessation, and promoting weight and nutrition goals as set by an obstetrician.¹ In addition to medications, management of HS should include emotional support and education on wearing loose-fitting clothing to avoid irritation of the affected areas.³ An emphasis on dermatologist counseling for all patients with HS, even for those with milder disease, can reduce exacerbations during pregnancy.⁵

CONCLUSION

The selection of dermatologic drugs for the treatment of HS in the setting of pregnancy involves complex decision-making. Dermatologists need more guidelines and proven safety data in human trials, especially regarding use of biologics and immunosuppressants to better treat HS in pregnancy. With more data, they can create more evidence-based treatment regimens to help prevent postpartum exacerbations of HS. Thus, patients can breastfeed their infants comfortably and without any risks of impaired child development. In the meantime, dermatologists can continue to work together with obstetricians and psychiatrists to decrease disease flares through counseling patients on nutrition and weight gain and providing emotional support.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with hyperandrogenism and is caused by occlusion or rupture of follicular units and inflammation of the apocrine glands.^1-3 The disease most commonly affects women (female to male ratio of 3:1) of childbearing age.^1,2,4,5 Body areas affected include the axillae and groin, and less commonly the perineum; perianal region; and skin folds, such as gluteal, inframammary, and infraumbilical folds.^1,2 Symptoms manifest as painful subcutaneous nodules with possible accompanying purulent drainage, sinus tracts, and/or dermal contractures. Although the pathophysiology is unclear, androgens affect the course of HS during pregnancy by stimulating the affected glands and altering cytokines.^1,2,6

During pregnancy, maternal immune function switches from cell-mediated T helper cell (T_H1) to humoral T_H2 cytokine production. The activity of sebaceous and eccrine glands increases while the activity of apocrine glands decreases, thus changing the inflammatory course of HS during pregnancy.³ Approximately 20% of women with HS experience improvement of symptoms during pregnancy, while the remainder either experience no relief or deterioration of symptoms.¹ Improvement in symptoms during pregnancy was found to occur more frequently in those who had worsening symptoms during menses owing to the possible hormonal effect estrogen has on inhibiting T_H1 and T_H17 proinflammatory cytokines, which promotes an immunosuppressive environment.⁴

Lactation and breastfeeding abilities may be hindered if a woman has HS affecting the apocrine glands of breast tissue and a symptom flare in the postpartum period. If HS causes notable inflammation in the nipple-areolar complex during pregnancy, the patient may experience difficulties with lactation and milk fistula formation, leading to inability to breastfeed.² Another reason why mothers with HS may not be able to breastfeed is that the medications required to treat the disease are unsafe if passed to the infant via breast milk. In addition, the teratogenic effects of HS medications may necessitate therapy adjustments in pregnancy.¹ Here, we provide a brief overview of the medical management considerations of HS in the setting of pregnancy and the impact on breastfeeding.

MEDICAL MANAGEMENT AND DRUG SAFETY

Dermatologists prescribe a myriad of topical and systemic medications to ameliorate symptoms of HS. Therapy regimens often are multimodal and include antibiotics, biologics, and immunosuppressants.^1,3

Antibiotics

First-line antibiotics include clindamycin, metronidazole, tetracyclines, erythromycin, rifampin, dapsone, and fluoroquinolones. Topical clindamycin 1%, metronidazole 0.75%, and erythromycin 2% are used for open or active HS lesions and are all safe to use in pregnancy since there is minimal systemic absorption and minimal excretion into breast milk.¹ Topical antimicrobial washes such as benzoyl peroxide and chlorhexidine often are used in combination with systemic medications to treat HS. These washes are safe during pregnancy and lactation, as they have minimal systemic absorption.⁷

Of these first-line antibiotics, only tetracyclines are contraindicated during pregnancy and lactation, as they are deemed to be in category D by the US Food and Drug Administration (FDA).¹ Aside from tetracyclines, these antibiotics do not cause birth defects and are safe for nursing infants.^1,8 Systemic clindamycin is safe during pregnancy and breastfeeding. Systemic metronidazole also is safe for use in pregnant patients but needs to be discontinued 12 to 24 hours prior to breastfeeding, which often prohibits appropriate dosing.¹

Systemic Erythromycin—There are several forms of systemic erythromycin, including erythromycin base, erythromycin estolate, erythromycin ethylsuccinate (EES), and erythromycin stearate. Erythromycin estolate is contraindicated in pregnancy because it is associated with reversible maternal hepatoxicity and jaundice.^9-11 Erythromycin ethylsuccinate is the preferred form for pregnant patients. Providers should exercise caution when prescribing EES to lactating mothers, as small amounts are still secreted through breast milk.¹¹ Some studies have shown an increased risk for development of infantile hypertrophic pyloric stenosis with systemic erythromycin use, especially if a neonate is exposed in the first 14 days of life. Thus, we recommend withholding EES for 2 weeks after delivery if the patient is breastfeeding. A follow-up study did not find any association between erythromycin and infantile hypertrophic pyloric stenosis; however, the American Academy of Pediatrics still recommends short-term use only of erythromycin if it is to be used in the systemic form.⁸

Rifampin—Rifampin is excreted into breast milk but without adverse effects to the infant. Rifampin also is safe in pregnancy but should be used on a case-by-case basis in pregnant or nursing women because it is a cytochrome P450 inducer.

Dapsone—Dapsone has no increased risk for congenital anomalies. However, it is associated with hemolytic anemia and neonatal hyperbilirubinemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.¹² Newborns exposed to dapsone are at an increased risk for methemoglobinemia owing to increased sensitivity of fetal erythrocytes to oxidizing agents.¹³ If dapsone use is necessary, stopping dapsone treatment in the last month of gestation is recommended to minimize risk for kernicterus.⁹ Dapsone can be found in high concentrations in breast milk at 14.3% of the maternal dose. It is still safe to use during breastfeeding, but there is a risk of the infant developing hyperbilirubinemia/G6PD deficiency.^1,8 Thus, physicians may consider performing a G6PD screen on infants to determine if breastfeeding is safe.¹²

Fluoroquinolones—Quinolones are not contraindicated during pregnancy, but they can damage fetal cartilage and thus should be reserved for use in complicated infections when the benefits outweigh the risks.¹² Quinolones are believed to increase risk for arthropathy but are safe for use in lactation. When quinolones are digested with milk, exposure decreases below pediatric doses because of the ionized property of calcium in milk.⁸

Tumor Necrosis Factor α Inhibitors—The safety of anti–tumor necrosis factor (TNF) α biologics in pregnancy is less certain when compared with antibiotics.¹ Anti–TNF-α inhibitors such as etanercept, adalimumab, and infliximab are all labeled as FDA category B, meaning there are no well-controlled human studies of the drugs.⁹ There are limited data that support safe use of TNF-α inhibitors prior to the third trimester before maternal IgG antibodies are transferred to the fetus via the placenta.^1,13 Anti–TNF-α inhibitors may be safe when breastfeeding because the drugs have large molecular weights that prevent them from entering breast milk in large amounts. Absorption also is limited due to the infant’s digestive acids and enzymes breaking down the protein structure of the medication.⁸ Overall, TNF-α inhibitor use is still controversial and only used if the benefits outweigh the risks during pregnancy or if there is no alternative treatment.^1,3,9

Ustekinumab and Anakinra—Ustekinumab (an IL-12/IL-23 inhibitor) and anakinra (an IL-1α and IL-1β inhibitor) also are FDA category B drugs and have limited data supporting their use as HS treatment in pregnancy. Anakinra may have evidence of compatibility with breastfeeding, as endogenous IL-1α inhibitor is found in colostrum and mature breast milk.¹

Immunosuppressants

Immunosuppressants that are used to treat HS include corticosteroids and cyclosporine.

Corticosteroids—Topical corticosteroids can be used safely in lactation if they are not applied directly to the nipple or any area that makes direct contact with the infant’s mouth. Intralesional corticosteroid injections are safe for use during both pregnancy and breastfeeding to decrease inflammation of acutely flaring lesions and can be considered first-line treatment.¹ Oral glucocorticoids also can be safely used for acute flares during pregnancy; however, prolonged use is associated with pregnancy complications such as preeclampsia, eclampsia, premature delivery, and gestational diabetes.¹² There also is a small risk of oral cleft deformity in the infant; thus, potent corticosteroids are recommended in short durations during pregnancy, and there are no adverse effects if the maternal dose is less than 10 mg daily.^8,12 Systemic steroids are safe to use with breastfeeding, but patients should be advised to wait 4 hours after ingesting medication before breastfeeding.^1,8

Cyclosporine—Topical and oral calcineurin inhibitors such as cyclosporine have low risk for transmission into breast milk; however, potential effects of exposure through breast milk are unknown. For that reason, manufacturers state that cyclosporine use is contraindicated during lactation.⁸ If cyclosporine is to be used by a breastfeeding woman, monitoring cyclosporine concentrations in the infant is suggested to ensure that the exposure is less than 5% to 10% of the therapeutic dose.¹³ The use of cyclosporine has been extensively studied in pregnant transplant patients and is considered relatively safe for use in pregnancy.¹⁴ Cyclosporine is lipid soluble and thus is quickly metabolized and spread throughout the body; it can easily cross the placenta.^9,13 Blood concentration in the fetus is 30% to 64% that of the maternal circulation. However, cyclosporine is only toxic to the fetus at maternally toxic doses, which can result in low birth weight and increased prenatal and postnatal mortality.¹³

Isotretinoin, Oral Contraceptive Pills, and Spironolactone

Isotretinoin and hormonal treatments such as oral contraceptive pills and spironolactone (an androgen receptor blocker) commonly are used to treat HS, but all are contraindicated in pregnancy and lactation. Isotretinoin is a well-established teratogen, but adverse effects on nursing babies have not been described. However, the manufacturer of isotretinoin advises against its use in lactation. Oral contraceptive pill use in early pregnancy is associated with increased risk for Down syndrome. Oral contraceptive pill use also is contraindicated in lactation for 2 reasons: decreased milk production and risk for fetal feminization. Antiandrogenic agents such as spironolactone have been shown to be associated with hypospadias and feminization of the male fetus.⁷

COMMENT

Women with HS usually require ongoing medical treatment during pregnancy and immediately postpartum; thus, it is important that treatments are proven to be safe for use in this specific population. Current management guidelines are not entirely suitable for pregnant and breastfeeding women given that many HS drugs have teratogenic effects and/or can be excreted into breast milk.¹ Several treatments have uncertain safety profiles in pregnancy and breastfeeding, which calls for dermatologists to change or create new regimens for their patients. Close management also is necessary to prevent excess inflammation of breast tissue and milk fistula formation, which would hinder normal breastfeeding.

The eTable lists medications used to treat HS. The FDA category is listed next to each drug. However, it should be noted that these FDA letter categories were replaced with the Pregnancy and Lactation Labeling Rule in 2015. The letter ratings were deemed overly simplistic and replaced with narrative-based labeling that provides more detailed adverse effects and clinical considerations.⁹

Risk Factors of HS—Predisposing risk factors for HS flares that are controllable include obesity and smoking.² Pregnancy weight gain may cause increased skin maceration at intertriginous sites, which can contribute to worsening HS symptoms.^1,5 Adipocytes play a role in HS exacerbation by promoting secretion of TNF-α, leading to increased inflammation.⁵ Dermatologists can help prevent postpartum HS flares by monitoring weight gain during pregnancy, encouraging smoking cessation, and promoting weight and nutrition goals as set by an obstetrician.¹ In addition to medications, management of HS should include emotional support and education on wearing loose-fitting clothing to avoid irritation of the affected areas.³ An emphasis on dermatologist counseling for all patients with HS, even for those with milder disease, can reduce exacerbations during pregnancy.⁵

CONCLUSION

The selection of dermatologic drugs for the treatment of HS in the setting of pregnancy involves complex decision-making. Dermatologists need more guidelines and proven safety data in human trials, especially regarding use of biologics and immunosuppressants to better treat HS in pregnancy. With more data, they can create more evidence-based treatment regimens to help prevent postpartum exacerbations of HS. Thus, patients can breastfeed their infants comfortably and without any risks of impaired child development. In the meantime, dermatologists can continue to work together with obstetricians and psychiatrists to decrease disease flares through counseling patients on nutrition and weight gain and providing emotional support.