Clinical Review

Autoimmune bullous dermatoses (ABDs) develop due to antibodies directed against antigens within the epidermis or at the dermoepidermal junction. They are categorized histologically by the location of acantholysis (separation of keratinocytes), clinical presentation, and presence of autoantibodies. The most common ABDs include pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid (BP). These conditions present on a spectrum of symptoms and severity.¹

Although multiple studies have evaluated the impact of bullous dermatoses on mental health, most were designed with a small sample size, thus limiting the generalizability of each study. Sebaratnam et al² summarized several studies in 2012. In this review, we will analyze additional relevant literature and systematically combine the data to determine the psychological burden of disease of ABDs. We also will discuss the existing questionnaires frequently used in the dermatology setting to assess adverse psychosocial symptoms.

Methods

We searched PubMed, MEDLINE, and Google Scholar for articles published within the last 15 years using the terms bullous pemphigoid, pemphigus, quality of life, anxiety, and depression. We reviewed the citations in each article to further our search.

Criteria for Inclusion and Exclusion—Studies that utilized validated questionnaires to evaluate the effects of pemphigus vulgaris, pemphigus foliaceus, and/or BP on mental health were included. All research participants were 18 years and older. For the questionnaires administered, each study must have included numerical scores in the results. The studies all reported statistically significant results (P<.05), but no studies were excluded on the basis of statistical significance.

Studies were excluded if they did not use a validated questionnaire to examine quality of life (QOL) or psychological status. We also excluded database, retrospective, qualitative, and observational studies. We did not include studies with a sample size less than 20. Studies that administered questionnaires that were uncommon in this realm of research such as the Attitude to Appearance Scale or The Anxiety Questionnaire also were excluded. We did not exclude articles based on their primary language.

Results

A total of 13 studies met the inclusion criteria with a total of 1716 participants enrolled in the trials. The questionnaires most commonly used are summarized in Table 1. Tables 2 and 3 demonstrate the studies that evaluate QOL and psychological state in patients with bullous dermatoses, respectively.

The Dermatology Life Quality Index (DLQI) was the most utilized method for analyzing QOL followed by the Skindex-17, Skindex-29, and 36-Item Short Form Health Survey. The DLQI is a skin-specific measurement tool with higher scores translating to greater impairment in QOL. Healthy patients have an average score of 0.5.³ The mean DLQI scores for ABD patients as seen in Table 2 were 9.45, 10.18, 16, 10.9, and 10.1.^13-15,18,22 The most commonly reported concerns among patients included feelings about appearance and disturbances in daily activities.¹⁸ Symptoms of mucosal involvement, itching, and burning also were indicators of lower QOL.^15,18,20,22 Furthermore, women consistently had lower scores than men.^15,17,19,25 Multiple studies concluded that severity of the disease correlated with a lower QOL, though the subtype of pemphigus did not have an effect on QOL scores.^15,19,20,21 Lastly, recent onset of symptoms was associated with a worse QOL score.^15,18-20 Age, education level, and marital status did not have an effect on QOL.

To evaluate psychological state, the General Health Questionnaire (GHQ)-28 and -12 primarily were used, in addition to the Hospital Anxiety and Depression Scale; the International Classification of Diseases, Tenth Revision; the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; and the Beck Depression Inventory-II. As seen in Table 3, GHQ-12 positivity, reflecting probable minor nonpsychotic psychiatric disorders such as depression and anxiety, was identified in 47%, 39.7%, and 40% of patients with pemphigus^15,19,24; GHQ-28 positivity was seen in 77.5% of pemphigus patients.¹⁸ In the average population, GHQ positivity was found in up to 12% of patients.^26,27 Similar to the QOL scores, no significant differences were seen based on subtype of pemphigus for symptoms of depression or anxiety.^20,23

Comment

Mental Health of Patients With ABDs—Immunobullous diseases are painful, potentially lifelong conditions that have no definitive cure. These conditions are characterized by bullae and erosions of the skin and mucosae that physically are disabling and often create a stigma for patients. Across multiple different validated psychosocial assessments, the 13 studies included in this review consistently reported that ABDs have a negative effect on mental well-being of patients that is more pronounced in women and worse at the onset of symptoms.^13-25

QOL Scores in Patients With ABDs—Quality of life is a broad term that encompasses a general sense of psychological and overall well-being. A score of approximately 10 on the DLQI most often was reported in patients with ABDs, which translates to a moderate impact on QOL. Incomparison, a large cohort study reported the mean (SD) DLQI scores for patients with atopic dermatitis and psoriasis as 7.31 (5.98) and 5.93 (5.66), respectively.²⁸ In another study, Penha et al¹⁴ found that patients with psoriasis have a mean DLQI score of 10. Reasons for the similarly low QOL scores in patients with ABDs include long hospitalization periods, disease chronicity, social anxiety, inability to control symptoms, difficulty with activities of daily living, and the belief that the disease is incurable.^17,19,23 Although there is a need for increased family and social support with performing necessary daily tasks, personal relationships often are negatively affected, resulting in social isolation, loneliness, and worsening of cutaneous symptoms.

Severity of cutaneous disease and recent onset of symptoms correlated with worse QOL scores. Tabolli et al²⁰ proposed the reason for this relates to not having had enough time to find the best treatment regimen. We believe there also may be an element of habituation involved, whereby patients become accustomed to the appearance of the lesions over time and therefore they become less distressing. Interestingly, Tabolli et al¹⁷ determined that patients in the quiescent phase of the disease—without any mucosal or cutaneous lesions—still maintained lower QOL scores than the average population, particularly on the psychosocial section of the 36-Item Short Form Health Survey, which may be due to a concern of disease relapse or from adverse effects of treatment. Providers should monitor patients for mental health complications not only in the disease infancy but throughout the disease course.

Future Directions—Cause and effect of the relationship between the psychosocial variables and ABD disease state has yet to be determined. Most studies included in this review were cross-sectional in design. Although many studies concluded that bullous dermatoses were the cause of impaired QOL, Ren and colleagues²⁹ proposed that medications used to treat neuropsychiatric disorders may trigger the autoimmune antigens of BP. Possible triggers for BP have been reported including hydrochlorothiazide, ciprofloxacin, and dipeptidyl peptidase-4 inhibitors.^27,30-32 A longitudinal study design would better evaluate the causal relationship.

The effects of the medications were included in 2 cases, one in which the steroid dose was not found to have a significant impact on rates of depression²³ and another in which patients treated with a higher dose of corticosteroids (>10 mg) had worse QOL scores.¹⁷ Sung et al¹⁵ suggested this may be because patients who took higher doses of steroids had worse symptoms and therefore also had a worse QOL. It also is possible that those patients taking higher doses had increased side effects.¹⁷ Further studies that evaluate treatment modalities and timing in relation to the disease onset would be helpful.

Study Limitations—There are potential barriers to combining these data. Multiple different questionnaires were used, and it was difficult to ascertain if all the participants were experiencing active disease. Additionally, questionnaires are not always the best proxy for what is happening in everyday life. Lastly, the sample size of each individual study was small, and the studies only included adults.

Conclusion

As demonstrated by the 13 studies in this review, patients with ABDs have lower QOL scores and higher numbers of psychological symptoms. Clinicians should be mindful of this at-risk population and create opportunities in clinic to discuss personal hardship associated with the disease process and recommend psychiatric intervention if indicated. Additionally, family members often are overburdened with the chronicity of ABDs, and they should not be forgotten. Using one of the aforementioned questionnaires is a practical way to screen patients for lower QOL scores. We agree with Paradisi and colleagues¹⁹ that although these questionnaires may be helpful, clinicians still need to determine if the use of a dermatologic QOL evaluation tool in clinical practice improves patient satisfaction.

Autoimmune bullous dermatoses (ABDs) develop due to antibodies directed against antigens within the epidermis or at the dermoepidermal junction. They are categorized histologically by the location of acantholysis (separation of keratinocytes), clinical presentation, and presence of autoantibodies. The most common ABDs include pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid (BP). These conditions present on a spectrum of symptoms and severity.¹

Although multiple studies have evaluated the impact of bullous dermatoses on mental health, most were designed with a small sample size, thus limiting the generalizability of each study. Sebaratnam et al² summarized several studies in 2012. In this review, we will analyze additional relevant literature and systematically combine the data to determine the psychological burden of disease of ABDs. We also will discuss the existing questionnaires frequently used in the dermatology setting to assess adverse psychosocial symptoms.

Methods

We searched PubMed, MEDLINE, and Google Scholar for articles published within the last 15 years using the terms bullous pemphigoid, pemphigus, quality of life, anxiety, and depression. We reviewed the citations in each article to further our search.

Criteria for Inclusion and Exclusion—Studies that utilized validated questionnaires to evaluate the effects of pemphigus vulgaris, pemphigus foliaceus, and/or BP on mental health were included. All research participants were 18 years and older. For the questionnaires administered, each study must have included numerical scores in the results. The studies all reported statistically significant results (P<.05), but no studies were excluded on the basis of statistical significance.

Studies were excluded if they did not use a validated questionnaire to examine quality of life (QOL) or psychological status. We also excluded database, retrospective, qualitative, and observational studies. We did not include studies with a sample size less than 20. Studies that administered questionnaires that were uncommon in this realm of research such as the Attitude to Appearance Scale or The Anxiety Questionnaire also were excluded. We did not exclude articles based on their primary language.

Results

A total of 13 studies met the inclusion criteria with a total of 1716 participants enrolled in the trials. The questionnaires most commonly used are summarized in Table 1. Tables 2 and 3 demonstrate the studies that evaluate QOL and psychological state in patients with bullous dermatoses, respectively.

The Dermatology Life Quality Index (DLQI) was the most utilized method for analyzing QOL followed by the Skindex-17, Skindex-29, and 36-Item Short Form Health Survey. The DLQI is a skin-specific measurement tool with higher scores translating to greater impairment in QOL. Healthy patients have an average score of 0.5.³ The mean DLQI scores for ABD patients as seen in Table 2 were 9.45, 10.18, 16, 10.9, and 10.1.^13-15,18,22 The most commonly reported concerns among patients included feelings about appearance and disturbances in daily activities.¹⁸ Symptoms of mucosal involvement, itching, and burning also were indicators of lower QOL.^15,18,20,22 Furthermore, women consistently had lower scores than men.^15,17,19,25 Multiple studies concluded that severity of the disease correlated with a lower QOL, though the subtype of pemphigus did not have an effect on QOL scores.^15,19,20,21 Lastly, recent onset of symptoms was associated with a worse QOL score.^15,18-20 Age, education level, and marital status did not have an effect on QOL.

To evaluate psychological state, the General Health Questionnaire (GHQ)-28 and -12 primarily were used, in addition to the Hospital Anxiety and Depression Scale; the International Classification of Diseases, Tenth Revision; the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; and the Beck Depression Inventory-II. As seen in Table 3, GHQ-12 positivity, reflecting probable minor nonpsychotic psychiatric disorders such as depression and anxiety, was identified in 47%, 39.7%, and 40% of patients with pemphigus^15,19,24; GHQ-28 positivity was seen in 77.5% of pemphigus patients.¹⁸ In the average population, GHQ positivity was found in up to 12% of patients.^26,27 Similar to the QOL scores, no significant differences were seen based on subtype of pemphigus for symptoms of depression or anxiety.^20,23

Comment

Mental Health of Patients With ABDs—Immunobullous diseases are painful, potentially lifelong conditions that have no definitive cure. These conditions are characterized by bullae and erosions of the skin and mucosae that physically are disabling and often create a stigma for patients. Across multiple different validated psychosocial assessments, the 13 studies included in this review consistently reported that ABDs have a negative effect on mental well-being of patients that is more pronounced in women and worse at the onset of symptoms.^13-25

QOL Scores in Patients With ABDs—Quality of life is a broad term that encompasses a general sense of psychological and overall well-being. A score of approximately 10 on the DLQI most often was reported in patients with ABDs, which translates to a moderate impact on QOL. Incomparison, a large cohort study reported the mean (SD) DLQI scores for patients with atopic dermatitis and psoriasis as 7.31 (5.98) and 5.93 (5.66), respectively.²⁸ In another study, Penha et al¹⁴ found that patients with psoriasis have a mean DLQI score of 10. Reasons for the similarly low QOL scores in patients with ABDs include long hospitalization periods, disease chronicity, social anxiety, inability to control symptoms, difficulty with activities of daily living, and the belief that the disease is incurable.^17,19,23 Although there is a need for increased family and social support with performing necessary daily tasks, personal relationships often are negatively affected, resulting in social isolation, loneliness, and worsening of cutaneous symptoms.

Severity of cutaneous disease and recent onset of symptoms correlated with worse QOL scores. Tabolli et al²⁰ proposed the reason for this relates to not having had enough time to find the best treatment regimen. We believe there also may be an element of habituation involved, whereby patients become accustomed to the appearance of the lesions over time and therefore they become less distressing. Interestingly, Tabolli et al¹⁷ determined that patients in the quiescent phase of the disease—without any mucosal or cutaneous lesions—still maintained lower QOL scores than the average population, particularly on the psychosocial section of the 36-Item Short Form Health Survey, which may be due to a concern of disease relapse or from adverse effects of treatment. Providers should monitor patients for mental health complications not only in the disease infancy but throughout the disease course.

Future Directions—Cause and effect of the relationship between the psychosocial variables and ABD disease state has yet to be determined. Most studies included in this review were cross-sectional in design. Although many studies concluded that bullous dermatoses were the cause of impaired QOL, Ren and colleagues²⁹ proposed that medications used to treat neuropsychiatric disorders may trigger the autoimmune antigens of BP. Possible triggers for BP have been reported including hydrochlorothiazide, ciprofloxacin, and dipeptidyl peptidase-4 inhibitors.^27,30-32 A longitudinal study design would better evaluate the causal relationship.

The effects of the medications were included in 2 cases, one in which the steroid dose was not found to have a significant impact on rates of depression²³ and another in which patients treated with a higher dose of corticosteroids (>10 mg) had worse QOL scores.¹⁷ Sung et al¹⁵ suggested this may be because patients who took higher doses of steroids had worse symptoms and therefore also had a worse QOL. It also is possible that those patients taking higher doses had increased side effects.¹⁷ Further studies that evaluate treatment modalities and timing in relation to the disease onset would be helpful.

Study Limitations—There are potential barriers to combining these data. Multiple different questionnaires were used, and it was difficult to ascertain if all the participants were experiencing active disease. Additionally, questionnaires are not always the best proxy for what is happening in everyday life. Lastly, the sample size of each individual study was small, and the studies only included adults.

Conclusion

As demonstrated by the 13 studies in this review, patients with ABDs have lower QOL scores and higher numbers of psychological symptoms. Clinicians should be mindful of this at-risk population and create opportunities in clinic to discuss personal hardship associated with the disease process and recommend psychiatric intervention if indicated. Additionally, family members often are overburdened with the chronicity of ABDs, and they should not be forgotten. Using one of the aforementioned questionnaires is a practical way to screen patients for lower QOL scores. We agree with Paradisi and colleagues¹⁹ that although these questionnaires may be helpful, clinicians still need to determine if the use of a dermatologic QOL evaluation tool in clinical practice improves patient satisfaction.

Autoimmune bullous dermatoses (ABDs) develop due to antibodies directed against antigens within the epidermis or at the dermoepidermal junction. They are categorized histologically by the location of acantholysis (separation of keratinocytes), clinical presentation, and presence of autoantibodies. The most common ABDs include pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid (BP). These conditions present on a spectrum of symptoms and severity.¹

Although multiple studies have evaluated the impact of bullous dermatoses on mental health, most were designed with a small sample size, thus limiting the generalizability of each study. Sebaratnam et al² summarized several studies in 2012. In this review, we will analyze additional relevant literature and systematically combine the data to determine the psychological burden of disease of ABDs. We also will discuss the existing questionnaires frequently used in the dermatology setting to assess adverse psychosocial symptoms.

Methods

We searched PubMed, MEDLINE, and Google Scholar for articles published within the last 15 years using the terms bullous pemphigoid, pemphigus, quality of life, anxiety, and depression. We reviewed the citations in each article to further our search.

Criteria for Inclusion and Exclusion—Studies that utilized validated questionnaires to evaluate the effects of pemphigus vulgaris, pemphigus foliaceus, and/or BP on mental health were included. All research participants were 18 years and older. For the questionnaires administered, each study must have included numerical scores in the results. The studies all reported statistically significant results (P<.05), but no studies were excluded on the basis of statistical significance.

Studies were excluded if they did not use a validated questionnaire to examine quality of life (QOL) or psychological status. We also excluded database, retrospective, qualitative, and observational studies. We did not include studies with a sample size less than 20. Studies that administered questionnaires that were uncommon in this realm of research such as the Attitude to Appearance Scale or The Anxiety Questionnaire also were excluded. We did not exclude articles based on their primary language.

Results

A total of 13 studies met the inclusion criteria with a total of 1716 participants enrolled in the trials. The questionnaires most commonly used are summarized in Table 1. Tables 2 and 3 demonstrate the studies that evaluate QOL and psychological state in patients with bullous dermatoses, respectively.

The Dermatology Life Quality Index (DLQI) was the most utilized method for analyzing QOL followed by the Skindex-17, Skindex-29, and 36-Item Short Form Health Survey. The DLQI is a skin-specific measurement tool with higher scores translating to greater impairment in QOL. Healthy patients have an average score of 0.5.³ The mean DLQI scores for ABD patients as seen in Table 2 were 9.45, 10.18, 16, 10.9, and 10.1.^13-15,18,22 The most commonly reported concerns among patients included feelings about appearance and disturbances in daily activities.¹⁸ Symptoms of mucosal involvement, itching, and burning also were indicators of lower QOL.^15,18,20,22 Furthermore, women consistently had lower scores than men.^15,17,19,25 Multiple studies concluded that severity of the disease correlated with a lower QOL, though the subtype of pemphigus did not have an effect on QOL scores.^15,19,20,21 Lastly, recent onset of symptoms was associated with a worse QOL score.^15,18-20 Age, education level, and marital status did not have an effect on QOL.

To evaluate psychological state, the General Health Questionnaire (GHQ)-28 and -12 primarily were used, in addition to the Hospital Anxiety and Depression Scale; the International Classification of Diseases, Tenth Revision; the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; and the Beck Depression Inventory-II. As seen in Table 3, GHQ-12 positivity, reflecting probable minor nonpsychotic psychiatric disorders such as depression and anxiety, was identified in 47%, 39.7%, and 40% of patients with pemphigus^15,19,24; GHQ-28 positivity was seen in 77.5% of pemphigus patients.¹⁸ In the average population, GHQ positivity was found in up to 12% of patients.^26,27 Similar to the QOL scores, no significant differences were seen based on subtype of pemphigus for symptoms of depression or anxiety.^20,23

Comment

Mental Health of Patients With ABDs—Immunobullous diseases are painful, potentially lifelong conditions that have no definitive cure. These conditions are characterized by bullae and erosions of the skin and mucosae that physically are disabling and often create a stigma for patients. Across multiple different validated psychosocial assessments, the 13 studies included in this review consistently reported that ABDs have a negative effect on mental well-being of patients that is more pronounced in women and worse at the onset of symptoms.^13-25

QOL Scores in Patients With ABDs—Quality of life is a broad term that encompasses a general sense of psychological and overall well-being. A score of approximately 10 on the DLQI most often was reported in patients with ABDs, which translates to a moderate impact on QOL. Incomparison, a large cohort study reported the mean (SD) DLQI scores for patients with atopic dermatitis and psoriasis as 7.31 (5.98) and 5.93 (5.66), respectively.²⁸ In another study, Penha et al¹⁴ found that patients with psoriasis have a mean DLQI score of 10. Reasons for the similarly low QOL scores in patients with ABDs include long hospitalization periods, disease chronicity, social anxiety, inability to control symptoms, difficulty with activities of daily living, and the belief that the disease is incurable.^17,19,23 Although there is a need for increased family and social support with performing necessary daily tasks, personal relationships often are negatively affected, resulting in social isolation, loneliness, and worsening of cutaneous symptoms.

Severity of cutaneous disease and recent onset of symptoms correlated with worse QOL scores. Tabolli et al²⁰ proposed the reason for this relates to not having had enough time to find the best treatment regimen. We believe there also may be an element of habituation involved, whereby patients become accustomed to the appearance of the lesions over time and therefore they become less distressing. Interestingly, Tabolli et al¹⁷ determined that patients in the quiescent phase of the disease—without any mucosal or cutaneous lesions—still maintained lower QOL scores than the average population, particularly on the psychosocial section of the 36-Item Short Form Health Survey, which may be due to a concern of disease relapse or from adverse effects of treatment. Providers should monitor patients for mental health complications not only in the disease infancy but throughout the disease course.

Future Directions—Cause and effect of the relationship between the psychosocial variables and ABD disease state has yet to be determined. Most studies included in this review were cross-sectional in design. Although many studies concluded that bullous dermatoses were the cause of impaired QOL, Ren and colleagues²⁹ proposed that medications used to treat neuropsychiatric disorders may trigger the autoimmune antigens of BP. Possible triggers for BP have been reported including hydrochlorothiazide, ciprofloxacin, and dipeptidyl peptidase-4 inhibitors.^27,30-32 A longitudinal study design would better evaluate the causal relationship.

The effects of the medications were included in 2 cases, one in which the steroid dose was not found to have a significant impact on rates of depression²³ and another in which patients treated with a higher dose of corticosteroids (>10 mg) had worse QOL scores.¹⁷ Sung et al¹⁵ suggested this may be because patients who took higher doses of steroids had worse symptoms and therefore also had a worse QOL. It also is possible that those patients taking higher doses had increased side effects.¹⁷ Further studies that evaluate treatment modalities and timing in relation to the disease onset would be helpful.

Study Limitations—There are potential barriers to combining these data. Multiple different questionnaires were used, and it was difficult to ascertain if all the participants were experiencing active disease. Additionally, questionnaires are not always the best proxy for what is happening in everyday life. Lastly, the sample size of each individual study was small, and the studies only included adults.

Conclusion

As demonstrated by the 13 studies in this review, patients with ABDs have lower QOL scores and higher numbers of psychological symptoms. Clinicians should be mindful of this at-risk population and create opportunities in clinic to discuss personal hardship associated with the disease process and recommend psychiatric intervention if indicated. Additionally, family members often are overburdened with the chronicity of ABDs, and they should not be forgotten. Using one of the aforementioned questionnaires is a practical way to screen patients for lower QOL scores. We agree with Paradisi and colleagues¹⁹ that although these questionnaires may be helpful, clinicians still need to determine if the use of a dermatologic QOL evaluation tool in clinical practice improves patient satisfaction.

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

Women who undergo bilateral salpingo-oophorectomy (BSO) for various indications prior to menopause experience a rapid decline in ovarian hormone levels and consequent vasomotor and other menopausal symptoms. In addition, the resulting estrogen deprivation is associated with such long-term adverse outcomes as osteoporosis and cardiovascular morbidity.

OBG Management convened a roundtable with 3 experts who discussed health considerations in women who have undergone BSO prior to the age of natural menopause¹ to further explore the issues involved in managing hormone therapy (HT) in these patients. Stephanie Faubion, MD, MBA, NCMP, moderated the exchange.

Surgical vs natural menopause

Stephanie Faubion, MD, MBA, NCMP: Since the Women’s Health Initiative study was published in 2002,² many clinicians have been fearful of using systemic HT in menopausal women, and HT use has declined dramatically such that only about 4% to 6% of menopausal women are now receiving systemic HT. Importantly, however, a group of younger menopausal women also are not receiving HT, and that is women who undergo BSO before they reach the average age of menopause, which in the United States is about age 52; this is sometimes referred to as surgical menopause or early surgical menopause. Early surgical menopause has different connotations for long-term health risks than natural menopause at the average age, and we are here to discuss these health effects and their management.

My name is Stephanie Faubion, and I am a women’s health internist and the Chair of the Department of Medicine at Mayo Clinic in Jacksonville, Florida, and Director of Mayo Clinic Women’s Health. I am here with 2 of my esteemed colleagues, Dr. Andrew Kaunitz and Dr. Ekta Kapoor.

Andrew M. Kaunitz, MD, NCMP: Hello, I am an ObGyn with the University of Florida College of Medicine in Jacksonville, with particular interests in contraception, menopause, and gynecologic ultrasonography.

Ekta Kapoor, MBBS, NCMP: And I am an endocrinologist at Mayo Clinic in Rochester with a specific interest in menopause and hormone therapy. I am also the Assistant Director for Mayo Clinic Women’s Health.

Higher-than-standard estrogen doses needed in younger menopausal women

Dr. Faubion: Let’s consider a couple of cases so that we can illustrate some important points regarding hormone management in women who have undergone BSO before the age of natural menopause.

Our first case patient is a woman who is 41 years of age and, because of adenomyosis, she will undergo a hysterectomy. She tells her clinician that she is very concerned about ovarian cancer risk because one of her good friends recently was diagnosed with ovarian cancer, and together they decide to remove her ovaries at the time of hysterectomy. Notably, her ovaries were healthy.

The patient is now menopausal postsurgery, and she is having significant hot flashes and night sweats. She visits her local internist, who is concerned about initiating HT. She is otherwise a healthy woman and does not have any contraindications to HT. Dr. Kaunitz, what would you tell her internist?

Dr. Kaunitz: We are dealing with 2 different issues in terms of decision making about systemic HT for this 41-year-old who has undergone BSO. First, as you mentioned, Dr. Faubion, she has bothersome hot flashes, or vasomotor symptoms. Unless there are contraindications, systemic HT would be appropriate. Although I might start treatment at standard doses, and the accompanying TABLE depicts standard doses for the 2 most common oral estrogen formulations as well as transdermal estradiol, it’s important to recognize that younger menopausal women often will need to use higher-than-standard doses.

For example, for a 53-year-old woman who has been menopausal for a year or 2 and now has bothersome symptoms, I might start her on estradiol 1 mg tablets with progestin if a uterus is present. However, in this 41-year-old case patient, while I might start treatment at a standard dose, I would anticipate increasing to higher doses, such as 1.5 or 2 mg of daily estradiol until she feels her menopausal symptoms are adequately addressed.

Dr. Faubion: It is important to note that sometimes women with early BSO tend to have more severe vasomotor symptoms. Do you find that sometimes a higher dose is required just to manage symptoms, Dr. Kaunitz?

Dr. Kaunitz: Absolutely, yes. The decision whether or not to use systemic HT might be considered discretionary or elective in the classic 53-year-old woman recently menopausal with hot flashes, a so-called spontaneously or naturally menopausal woman. But my perspective is that unless there are clear contraindications, the decision to start systemic HT in the 41-year-old BSO case patient is actually not discretionary. Unless contraindications are present, it is important not only to treat symptoms but also to prevent an array of chronic major health concerns that are more likely if we don’t prescribe systemic HT.

Continue to: Health effects of not using HT...

Dr. Faubion: Dr. Kapoor, can you describe the potential long-term adverse health consequences of not using estrogen therapy? Say the same 41-year-old woman does not have many bothersome symptoms. What would you do?

Dr. Kapoor: Thank you for that important question. Building on what Dr. Kaunitz said, in these patients there are really 2 issues that can seem to be independent but are not: The first relates to the immediate consequences of lack of estrogen, ie, the menopause-related symptoms, but the second and perhaps the bigger issue is the long-term risk associated with estrogen deprivation.

The symptoms in these women are often obvious as they can be quite severe and abrupt; one day these women have normal hormone levels and the next day, after BSO, suddenly their hormones are very low. So if symptoms occur, they are usually hard to miss, simply because they are very drastic and very severe.

Historically, patients and their clinicians have targeted these symptoms. Patients experience menopausal symptoms, they seek treatment, and then the clinicians basically titrate the treatment to manage these symptoms. That misses the bigger issue, however, which is that premature estrogen deprivation leads to a host of chronic health conditions, as Dr. Kaunitz mentioned. These mainly include increased risk for cardiovascular disease, diabetes, hypertension, dyslipidemia, increased risk of mortality, dementia, and osteoporosis.

Fairly strong observational evidence suggests that use of estrogen therapy given in replacement doses—doses higher than those typically used in women after natural menopause, therefore considered replacement doses—helps mitigate the risk of some of these adverse health conditions.

In these women, the bigger goal really is to reinstate the hormonal milieu that exists prior to menopause. To your point, Dr. Faubion, if I have a patient who is younger than 46 years, who has her ovaries taken out, and even if she has zero symptoms (and sometimes that does happen), I would still make a case for this patient to utilize hormone therapy unless there is a contraindication such as breast cancer or other estrogen-sensitive cancers.

Dr. Faubion: Again, would you aim for those higher doses rather than treat with the “lowest dose”?

Dr. Kapoor: Absolutely. My punchline to the patients and clinicians in these discussions is that the rules of the game are different for these women. We cannot extrapolate the risks and benefits of HT use in women after natural menopause to younger women who have surgical menopause. Those rules just do not apply with respect to both benefits and risks.

Dr. Faubion: I think it’s important to say that these same “rules” would apply if the women were to go through premature menopause for any other reason, too, such as chemotherapy, radiation therapy, or premature ovarian insufficiency for any number of reasons, including toxic, metabolic, or genetic causes and so on. Would that be true?

Dr. Kapoor: Yes, absolutely so.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: In terms of practical or clinical issues regarding systemic HT management, for the woman in her early 50s who has experienced normal or natural spontaneous menopause, a starting dose of transdermal estradiol would be, for instance, a 0.05-mg patch, which is a patch that over 24 hours releases 0.05 mg of estradiol daily; or standard oral estrogen, including conjugated equine estrogen, a 0.625-mg tablet daily, or estradiol, a 1-mg tablet daily.

But in younger patients, we want to use higher doses. For a patch, for instance, I would aim for a 0.075- or 0.1-mg estradiol patch, which releases a higher daily dose of estradiol than the standard dose. For oral estrogen, the dose would be 0.9- or even 1.25-mg tablets of conjugated equine estrogen or 1.5 mg, which is a 1-mg plus a 0.5-mg estradiol tablet, or a 2-mg estradiol tablet. Estradiol does come in a 2-mg strength.

For oral estrogen, I prefer estradiol because it’s available as a generic medication and often available at a very low cost, sometimes as low as $4 a month from chain pharmacies.

Continue to: Usefulness of monitoring estradiol levels for dosage adjustment...

Dr. Faubion: That’s a great point, and again it is important to emphasize that we are aiming to recreate the premenopausal hormonal milieu. If you were to check estradiol levels, that would be aiming for a premenopausal range of approximately 80 to 120 pg per mL. Dr. Kapoor, is there utility in monitoring estrogen levels?

Dr. Kapoor: Great question, Dr. Faubion, and as you know it’s a loaded one. We base this on empiric evidence. We know that if the hormonal milieu in a young patient is changed to a postmenopausal one, her risk for many chronic conditions is increased. So if we were to reinstate a premenopausal hormonal milieu, that risk would probably be reduced. It makes good sense to target an empiric goal of 80 to 120 pg per mL of estradiol, which is the average estradiol level in a premenopausal woman. If you were to ask me, however, are there randomized, controlled trial data to support this practice—that is, if you target that level, can you make sure that the risk of diabetes is lower or that the risk of heart disease is lower—that study has yet to be done, and it may not ever be done on a large scale. However, it intuitively makes good sense to target premenopausal estradiol levels.

Dr. Faubion: When might you check an estradiol level in this population? For example, if you are treating a patient with a 0.1-mg estradiol patch and she still has significant hot flashes, would it be useful to check the level?

Dr. Kapoor: It would. In my practice, I check estradiol levels on these patients on an annual basis, regardless of symptoms, but definitely in the patient who has symptoms. It makes good sense, because sometimes these patients don’t absorb the estrogen well, particularly if administered by the transdermal route.

A general rule of thumb is that in the average population, if a patient is on the 0.1-mg patch, for example, you would expect her level to be around 100. If it is much lower than that, which sometimes happens, that speaks for poor absorption. Options at that point would be to treat her with a higher dose patch, depending on what the level is, or switch to a different formulation, such as oral.

In instances in which I have treated patients with a 0.1-mg patch for example, and their estradiol levels are undetectable, that speaks for very poor absorption. For such patients I make a case for switching them to oral therapy. Most definitely that makes sense in a patient who is symptomatic despite treatment. But even for patients who don’t have symptoms, I like to target that level, acknowledging that there is no evidence as such to support this practice.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: Yes, a few practical points. Although patches are available in a wider array of doses than oral estrogen formulations, the highest dose available is 0.1 mg. It’s important for clinicians to recognize that while checking serum levels when indicated can be performed in women using transdermal estradiol or patches, in women who are using oral estrogen, checking blood levels is not going to work well because serum estrogen levels have a daily peak and valley in women who use oral versus transdermal estradiol.

I also wanted to talk about progestins. Although many patients who have had a BSO prior to spontaneous menopause also have had a hysterectomy, others have an intact uterus associated with their BSO, so progestins must be used along with estrogen. And if we are using higher-than-standard doses of estrogen, we also need to use higher-than-standard doses of progestin.

In that classic 53-year-old woman I referred to who had spontaneous normal menopause, if she is taking 1 mg of estradiol daily, or a 0.05-mg patch, or 0.625 mg of conjugated equine estrogen, 2.5 mg of medroxyprogesterone is fine. In fact, that showed excellent progestational protection of the endometrium in the Women’s Health Initiative and in other studies.

However, if we are going to use double the estrogen dose, we should increase the progestin dose too. In some of my patients on higher estrogen doses who have an intact uterus, I’ll use 5 or even 10 mg of daily medroxyprogesterone acetate to ensure adequate progestational suppression.

Dr. Faubion: Another practical tip is that if one is using conjugated equine estrogens, measuring the serum estradiol levels is not useful either.

Dr. Kaunitz: I agree.

Continue to: Oral contraceptives as replacement HT...

Dr. Faubion: Would you comment on use of a birth control pill in this circumstance? Would it be optimal to use a postmenopausal HT regimen as opposed to a birth control pill or combined hormonal contraception?

Dr. Kapoor: In this younger population, sometimes it seems like a more socially acceptable decision to be on a birth control option than on menopausal HT. But there are some issues with being on a contraceptive regimen. One is that we end up using estrogen doses much higher than what is really needed for replacement purposes. It is also a nonphysiologic way of replacement in another sense—as opposed to estradiol, which is the main hormone made by the ovaries, the hormonal contraceptive regimens contain the synthetic estrogen ethinyl estradiol for the most part.

The other issue that is based on some weak evidence is that it appears that the bone health outcomes are probably inferior with combined hormonal contraception. For these reasons, regimens that are based on replacement doses of estradiol are preferred.

Dr. Faubion: Right, although the data are somewhat weak, I agree that thus far it seems optimal to utilize a postmenopausal regimen for various reasons. Dr. Kaunitz, anything to add?

Dr. Kaunitz: Yes, to underscore Dr. Kapoor’s point, a common oral contraceptive that contains 20 µg of ethinyl estradiol is substantially more estrogenic than 1.0 or 2.0 mg of micronized oral estradiol.

Also consider that a 20-µg ethinyl estradiol oral contraceptive may increase the risk of venous thromboembolism more than menopausal doses of oral estradiol, whether it be a micronized estradiol or conjugated equine estrogen.

Dr. Faubion: So the risk may be greater with oral combined hormonal contraception as well?

Dr. Kaunitz: One thing we can do is explain to our patients that their ovaries, prior to surgery or prior to induced menopause, were making substantial quantities of estradiol. Whether we prescribe a patch or oral micronized estradiol, this estrogen is identical to the hormone that their ovaries were making prior to surgery or induced menopause.

Breast cancer concerns

Dr. Faubion: Let’s consider a more complicated case. A 35-year-old woman has an identified BRCA1 mutation; she has not had any cancers but has undergone risk-reducing BSO and her uterus remains. Is this woman a candidate for HT? At what dose, and for how long? Dr. Kaunitz, why don’t you start.

Dr. Kaunitz: That is a challenging case but one that I think our readers will find interesting and maybe even provocative.

We know that women with BRCA1 mutations, the more common of the 2 BRCA mutations, have a very high risk of developing epithelial ovarian cancer at a young age. For this reason, our colleagues in medical oncology who specialize in hereditary ovarian/breast cancer syndromes recommend prophylactic risk-reducing—and I would also say lifesaving—BSO with or without hysterectomy for women with BRCA1 mutations.

However, over the years there has been tremendous reluctance among physicians caring for BRCA patients and the women themselves—I use the term “previvors” to describe BRCA carriers who have not been diagnosed with breast or ovarian cancer—to use HT after BSO because of concerns that HT might increase breast cancer risk in women who are already at high risk for breast cancer.

I assume, Dr. Faubion, that in this case the woman had gynecologic surgery but continues to have intact breasts. Is that correct?

Dr. Faubion: That is correct.

Dr. Kaunitz: Although the assumption has been that it is not safe to prescribe HT in this setting, in fact, the reported cohort studies that have looked at this issue have not found an elevated risk of breast cancer when replacement estrogen, with or without progestin, is prescribed to BRCA1 previvors with intact breasts.

Given what Dr. Kapoor said regarding the morbidity that is associated with BSO without replacement of physiologic estrogen, and also given the severe symptoms that so many of these young menopausal women experience, in my practice I do prescribe estrogen or estrogen-progestin therapy and focus on the higher target doses that we discussed for the earlier case patient who had a hysterectomy for abnormal uterine bleeding with adenomyosis.

Dr. Faubion: Dr. Kapoor, do you agree with this approach? How long would you continue therapy?

Dr. Kapoor: First, in this BRCA1 case we need to appreciate that the indication for the BSO is a legitimate one, in contrast to the first case in which the ovaries were removed in a patient whose average risk of ovarian cancer was low. It is important to recognize that surgery performed in this context is the right thing to do because it does significantly reduce the risk of ovarian cancer.

The second thing to appreciate is that while we reduce the risk of ovarian cancer significantly and make sure that these patients survive longer, it’s striking a fine balance in that you want to make sure that their morbidity is not increased as a result of premature estrogen deprivation.

As Dr. Kaunitz told us, the evidence that we have so far, which granted is not very robust but is fairly strong observational evidence, suggests that the risk of breast cancer is not elevated when these patients are treated with replacement doses of HT.

Having said that, I do have very strong discussions with my patients in this category about having the risk-reducing bilateral mastectomy also, because if they were to get breast cancer because of their increased genetic predisposition, the cancer is likely to grow faster if the patient is on HT. So one of my counseling points to patients is that they strongly consider bilateral mastectomy, which reduces their breast cancer risk by more than 90%. At the same time, I also strongly endorse using HT in replacement doses for the reasons that we have already stated.

Dr. Faubion: Continue HT until age 50 or 52?

Dr. Kapoor: Definitely until that age, and possibly longer, depending on their symptoms. The indications for treating beyond the age of natural menopause are much the same as for women who experience natural menopause.

Dr. Faubion: That is assuming they had a bilateral mastectomy?

Dr. Kapoor: Yes.

Continue to: Continuing HT until the age of natural menopause...

Dr. Kaunitz: Dr. Kapoor brings up the important point of duration of systemic HT. I agree that similar considerations apply both to the healthy 41-year-old who had a hysterectomy for abnormal uterine bleeding and to the 35-year-old who had risk-reducing surgery because of her BRCA1 mutation.

In the 2 cases, both to treat symptoms and to prevent chronic diseases, it makes sense to continue HT at least until the age of natural menopause. That is consistent with 2017 guidance from The North American Menopause Society (NAMS) position statement on the use of systemic HT, that is, continuing systemic HT at least until the age of natural menopause.³ Then at that point, continuing or discontinuing systemic HT becomes discretionary, and that would be true for both cases. If the patient is slender or has a strong family history of osteoporosis, that tends to push the patient more in terms of continuing systemic HT. Those are just some examples, and Dr. Kapoor may want to detail other relevant considerations.

Dr. Kapoor: I completely agree. The decision is driven by symptoms that are not otherwise well managed, for example, with nonhormone strategies. If we have any concerns utilizing HT beyond the age of natural menopause, then nonhormonal options can be considered; but sometimes those are not as effective. And bone health is very important. You want to avoid using bisphosphonates in younger women and reserve them for older patients in their late 60s and 70s. Hormone therapy use is a very reasonable strategy to prevent bone loss.

Dr. Kaunitz: It is also worth mentioning that sometimes the woman involved in shared decision making with her clinician decides to stop systemic HT. In that setting, should the patient start developing new-onset dyspareunia, vaginal dryness, or other genital or sexuality-related concerns, it takes very little for me to advise that she start low-dose local vaginal estrogen therapy.

Dr. Faubion: In either scenario, if a woman were to develop symptoms consistent with genitourinary syndrome of menopause (GSM), would you use vaginal estrogen in addition to the systemic estrogen or alone after the woman elected to discontinue systemic therapy?

Dr. Kapoor: Yes to both, I would say.

Dr. Kaunitz: As my patients using systemic HT age, often I will lower the dose. For instance, the dose I use in a 53-year-old will be higher than when she is 59 or 62. At the same time, as we lower the dose of systemic estrogen therapy, symptoms of vaginal atrophy or GSM often will appear, and these can be effectively treated by adding low-dose vaginal estrogen therapy. A number of my patients, particularly those who are on lower-than-standard doses of systemic HT, are also using low-dose vaginal estrogen therapy.

There is a “hybrid” product available: the 90-day estradiol vaginal ring. Estring is a low-dose, 2-mg, 90-day estradiol ring that is very useful, but it is effective only for treating GSM or vaginal atrophy. A second menopausal vaginal estradiol ring, Femring, is available in 2 doses: 0.05 mg/day and 0.1 mg/day. These are very effective in treating both systemic issues, such as vasomotor symptoms or prevention of osteoporosis, and very effective in treating GSM or vaginal atrophy. One problem is that Femring, depending on insurance coverage, can be very expensive. It’s not available as a generic, so for insurance or financial reasons I don’t often prescribe it. If I could remove those financial barriers, I would prescribe Femring more often because it is very useful.

Dr. Faubion: You raise an important point, and that is, for women who have been on HT for some time, clinicians often feel the need to slowly reduce the dose. Would you do that same thing, Dr. Kapoor, for a 40-year-old woman? Would you reduce the dose as she approaches age 50? Is there pressure that “she shouldn’t be on that much estrogen”?

Dr. Kapoor: No, I would not feel pressured until the patient turns at least 46. I bring up age 46 because the average age range for menopause is 46 to 55. After that, if there is any concern, we can decrease the dose to half and keep the patient on that until she turns 50 or 51. But most of my patients are on replacement doses until the average age of menopause, which is around 51 years, and that’s when you reduce the dose to that of the typical HT regimens used after natural menopause.

Sometimes patients are told something by a friend or they have read something and they worry about the risk of 2 things. One is breast cancer and the other is venous thromboembolism (VTE), and that may be why they want to be on a lower dose. I counsel patients that while the risk of VTE is real with HT, it is the women after natural menopause who are at risk—because age itself is a risk for VTE—and it also has to do with the kind of HT regimen that a patient is on. High doses of oral estrogens and certain progestogens increase the risk. But again, for estradiol used in replacement doses and the more common progestogens that we now use in practice, such as micronized progesterone, the risk is not the same. The same goes for breast cancer. My biggest message to patients and clinicians who take care of these patients is that the rules that apply to women after natural menopause just do not apply to this very different patient population.

Dr. Faubion: Thank you, Dr. Kaunitz and Dr. Kapoor, for sharing your knowledge and experience. ●

Women who undergo bilateral salpingo-oophorectomy (BSO) for various indications prior to menopause experience a rapid decline in ovarian hormone levels and consequent vasomotor and other menopausal symptoms. In addition, the resulting estrogen deprivation is associated with such long-term adverse outcomes as osteoporosis and cardiovascular morbidity.

OBG Management convened a roundtable with 3 experts who discussed health considerations in women who have undergone BSO prior to the age of natural menopause¹ to further explore the issues involved in managing hormone therapy (HT) in these patients. Stephanie Faubion, MD, MBA, NCMP, moderated the exchange.

Surgical vs natural menopause

Stephanie Faubion, MD, MBA, NCMP: Since the Women’s Health Initiative study was published in 2002,² many clinicians have been fearful of using systemic HT in menopausal women, and HT use has declined dramatically such that only about 4% to 6% of menopausal women are now receiving systemic HT. Importantly, however, a group of younger menopausal women also are not receiving HT, and that is women who undergo BSO before they reach the average age of menopause, which in the United States is about age 52; this is sometimes referred to as surgical menopause or early surgical menopause. Early surgical menopause has different connotations for long-term health risks than natural menopause at the average age, and we are here to discuss these health effects and their management.

My name is Stephanie Faubion, and I am a women’s health internist and the Chair of the Department of Medicine at Mayo Clinic in Jacksonville, Florida, and Director of Mayo Clinic Women’s Health. I am here with 2 of my esteemed colleagues, Dr. Andrew Kaunitz and Dr. Ekta Kapoor.

Andrew M. Kaunitz, MD, NCMP: Hello, I am an ObGyn with the University of Florida College of Medicine in Jacksonville, with particular interests in contraception, menopause, and gynecologic ultrasonography.

Ekta Kapoor, MBBS, NCMP: And I am an endocrinologist at Mayo Clinic in Rochester with a specific interest in menopause and hormone therapy. I am also the Assistant Director for Mayo Clinic Women’s Health.

Higher-than-standard estrogen doses needed in younger menopausal women

Dr. Faubion: Let’s consider a couple of cases so that we can illustrate some important points regarding hormone management in women who have undergone BSO before the age of natural menopause.

Our first case patient is a woman who is 41 years of age and, because of adenomyosis, she will undergo a hysterectomy. She tells her clinician that she is very concerned about ovarian cancer risk because one of her good friends recently was diagnosed with ovarian cancer, and together they decide to remove her ovaries at the time of hysterectomy. Notably, her ovaries were healthy.

The patient is now menopausal postsurgery, and she is having significant hot flashes and night sweats. She visits her local internist, who is concerned about initiating HT. She is otherwise a healthy woman and does not have any contraindications to HT. Dr. Kaunitz, what would you tell her internist?

Dr. Kaunitz: We are dealing with 2 different issues in terms of decision making about systemic HT for this 41-year-old who has undergone BSO. First, as you mentioned, Dr. Faubion, she has bothersome hot flashes, or vasomotor symptoms. Unless there are contraindications, systemic HT would be appropriate. Although I might start treatment at standard doses, and the accompanying TABLE depicts standard doses for the 2 most common oral estrogen formulations as well as transdermal estradiol, it’s important to recognize that younger menopausal women often will need to use higher-than-standard doses.

For example, for a 53-year-old woman who has been menopausal for a year or 2 and now has bothersome symptoms, I might start her on estradiol 1 mg tablets with progestin if a uterus is present. However, in this 41-year-old case patient, while I might start treatment at a standard dose, I would anticipate increasing to higher doses, such as 1.5 or 2 mg of daily estradiol until she feels her menopausal symptoms are adequately addressed.

Dr. Faubion: It is important to note that sometimes women with early BSO tend to have more severe vasomotor symptoms. Do you find that sometimes a higher dose is required just to manage symptoms, Dr. Kaunitz?

Dr. Kaunitz: Absolutely, yes. The decision whether or not to use systemic HT might be considered discretionary or elective in the classic 53-year-old woman recently menopausal with hot flashes, a so-called spontaneously or naturally menopausal woman. But my perspective is that unless there are clear contraindications, the decision to start systemic HT in the 41-year-old BSO case patient is actually not discretionary. Unless contraindications are present, it is important not only to treat symptoms but also to prevent an array of chronic major health concerns that are more likely if we don’t prescribe systemic HT.

Continue to: Health effects of not using HT...

Dr. Faubion: Dr. Kapoor, can you describe the potential long-term adverse health consequences of not using estrogen therapy? Say the same 41-year-old woman does not have many bothersome symptoms. What would you do?

Dr. Kapoor: Thank you for that important question. Building on what Dr. Kaunitz said, in these patients there are really 2 issues that can seem to be independent but are not: The first relates to the immediate consequences of lack of estrogen, ie, the menopause-related symptoms, but the second and perhaps the bigger issue is the long-term risk associated with estrogen deprivation.

The symptoms in these women are often obvious as they can be quite severe and abrupt; one day these women have normal hormone levels and the next day, after BSO, suddenly their hormones are very low. So if symptoms occur, they are usually hard to miss, simply because they are very drastic and very severe.

Historically, patients and their clinicians have targeted these symptoms. Patients experience menopausal symptoms, they seek treatment, and then the clinicians basically titrate the treatment to manage these symptoms. That misses the bigger issue, however, which is that premature estrogen deprivation leads to a host of chronic health conditions, as Dr. Kaunitz mentioned. These mainly include increased risk for cardiovascular disease, diabetes, hypertension, dyslipidemia, increased risk of mortality, dementia, and osteoporosis.

Fairly strong observational evidence suggests that use of estrogen therapy given in replacement doses—doses higher than those typically used in women after natural menopause, therefore considered replacement doses—helps mitigate the risk of some of these adverse health conditions.

In these women, the bigger goal really is to reinstate the hormonal milieu that exists prior to menopause. To your point, Dr. Faubion, if I have a patient who is younger than 46 years, who has her ovaries taken out, and even if she has zero symptoms (and sometimes that does happen), I would still make a case for this patient to utilize hormone therapy unless there is a contraindication such as breast cancer or other estrogen-sensitive cancers.

Dr. Faubion: Again, would you aim for those higher doses rather than treat with the “lowest dose”?

Dr. Kapoor: Absolutely. My punchline to the patients and clinicians in these discussions is that the rules of the game are different for these women. We cannot extrapolate the risks and benefits of HT use in women after natural menopause to younger women who have surgical menopause. Those rules just do not apply with respect to both benefits and risks.

Dr. Faubion: I think it’s important to say that these same “rules” would apply if the women were to go through premature menopause for any other reason, too, such as chemotherapy, radiation therapy, or premature ovarian insufficiency for any number of reasons, including toxic, metabolic, or genetic causes and so on. Would that be true?

Dr. Kapoor: Yes, absolutely so.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: In terms of practical or clinical issues regarding systemic HT management, for the woman in her early 50s who has experienced normal or natural spontaneous menopause, a starting dose of transdermal estradiol would be, for instance, a 0.05-mg patch, which is a patch that over 24 hours releases 0.05 mg of estradiol daily; or standard oral estrogen, including conjugated equine estrogen, a 0.625-mg tablet daily, or estradiol, a 1-mg tablet daily.

But in younger patients, we want to use higher doses. For a patch, for instance, I would aim for a 0.075- or 0.1-mg estradiol patch, which releases a higher daily dose of estradiol than the standard dose. For oral estrogen, the dose would be 0.9- or even 1.25-mg tablets of conjugated equine estrogen or 1.5 mg, which is a 1-mg plus a 0.5-mg estradiol tablet, or a 2-mg estradiol tablet. Estradiol does come in a 2-mg strength.

For oral estrogen, I prefer estradiol because it’s available as a generic medication and often available at a very low cost, sometimes as low as $4 a month from chain pharmacies.

Continue to: Usefulness of monitoring estradiol levels for dosage adjustment...

Dr. Faubion: That’s a great point, and again it is important to emphasize that we are aiming to recreate the premenopausal hormonal milieu. If you were to check estradiol levels, that would be aiming for a premenopausal range of approximately 80 to 120 pg per mL. Dr. Kapoor, is there utility in monitoring estrogen levels?

Dr. Kapoor: Great question, Dr. Faubion, and as you know it’s a loaded one. We base this on empiric evidence. We know that if the hormonal milieu in a young patient is changed to a postmenopausal one, her risk for many chronic conditions is increased. So if we were to reinstate a premenopausal hormonal milieu, that risk would probably be reduced. It makes good sense to target an empiric goal of 80 to 120 pg per mL of estradiol, which is the average estradiol level in a premenopausal woman. If you were to ask me, however, are there randomized, controlled trial data to support this practice—that is, if you target that level, can you make sure that the risk of diabetes is lower or that the risk of heart disease is lower—that study has yet to be done, and it may not ever be done on a large scale. However, it intuitively makes good sense to target premenopausal estradiol levels.

Dr. Faubion: When might you check an estradiol level in this population? For example, if you are treating a patient with a 0.1-mg estradiol patch and she still has significant hot flashes, would it be useful to check the level?

Dr. Kapoor: It would. In my practice, I check estradiol levels on these patients on an annual basis, regardless of symptoms, but definitely in the patient who has symptoms. It makes good sense, because sometimes these patients don’t absorb the estrogen well, particularly if administered by the transdermal route.

A general rule of thumb is that in the average population, if a patient is on the 0.1-mg patch, for example, you would expect her level to be around 100. If it is much lower than that, which sometimes happens, that speaks for poor absorption. Options at that point would be to treat her with a higher dose patch, depending on what the level is, or switch to a different formulation, such as oral.

In instances in which I have treated patients with a 0.1-mg patch for example, and their estradiol levels are undetectable, that speaks for very poor absorption. For such patients I make a case for switching them to oral therapy. Most definitely that makes sense in a patient who is symptomatic despite treatment. But even for patients who don’t have symptoms, I like to target that level, acknowledging that there is no evidence as such to support this practice.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: Yes, a few practical points. Although patches are available in a wider array of doses than oral estrogen formulations, the highest dose available is 0.1 mg. It’s important for clinicians to recognize that while checking serum levels when indicated can be performed in women using transdermal estradiol or patches, in women who are using oral estrogen, checking blood levels is not going to work well because serum estrogen levels have a daily peak and valley in women who use oral versus transdermal estradiol.

I also wanted to talk about progestins. Although many patients who have had a BSO prior to spontaneous menopause also have had a hysterectomy, others have an intact uterus associated with their BSO, so progestins must be used along with estrogen. And if we are using higher-than-standard doses of estrogen, we also need to use higher-than-standard doses of progestin.

In that classic 53-year-old woman I referred to who had spontaneous normal menopause, if she is taking 1 mg of estradiol daily, or a 0.05-mg patch, or 0.625 mg of conjugated equine estrogen, 2.5 mg of medroxyprogesterone is fine. In fact, that showed excellent progestational protection of the endometrium in the Women’s Health Initiative and in other studies.

However, if we are going to use double the estrogen dose, we should increase the progestin dose too. In some of my patients on higher estrogen doses who have an intact uterus, I’ll use 5 or even 10 mg of daily medroxyprogesterone acetate to ensure adequate progestational suppression.

Dr. Faubion: Another practical tip is that if one is using conjugated equine estrogens, measuring the serum estradiol levels is not useful either.

Dr. Kaunitz: I agree.

Continue to: Oral contraceptives as replacement HT...

Dr. Faubion: Would you comment on use of a birth control pill in this circumstance? Would it be optimal to use a postmenopausal HT regimen as opposed to a birth control pill or combined hormonal contraception?

Dr. Kapoor: In this younger population, sometimes it seems like a more socially acceptable decision to be on a birth control option than on menopausal HT. But there are some issues with being on a contraceptive regimen. One is that we end up using estrogen doses much higher than what is really needed for replacement purposes. It is also a nonphysiologic way of replacement in another sense—as opposed to estradiol, which is the main hormone made by the ovaries, the hormonal contraceptive regimens contain the synthetic estrogen ethinyl estradiol for the most part.

The other issue that is based on some weak evidence is that it appears that the bone health outcomes are probably inferior with combined hormonal contraception. For these reasons, regimens that are based on replacement doses of estradiol are preferred.

Dr. Faubion: Right, although the data are somewhat weak, I agree that thus far it seems optimal to utilize a postmenopausal regimen for various reasons. Dr. Kaunitz, anything to add?

Dr. Kaunitz: Yes, to underscore Dr. Kapoor’s point, a common oral contraceptive that contains 20 µg of ethinyl estradiol is substantially more estrogenic than 1.0 or 2.0 mg of micronized oral estradiol.

Also consider that a 20-µg ethinyl estradiol oral contraceptive may increase the risk of venous thromboembolism more than menopausal doses of oral estradiol, whether it be a micronized estradiol or conjugated equine estrogen.

Dr. Faubion: So the risk may be greater with oral combined hormonal contraception as well?

Dr. Kaunitz: One thing we can do is explain to our patients that their ovaries, prior to surgery or prior to induced menopause, were making substantial quantities of estradiol. Whether we prescribe a patch or oral micronized estradiol, this estrogen is identical to the hormone that their ovaries were making prior to surgery or induced menopause.

Breast cancer concerns

Dr. Faubion: Let’s consider a more complicated case. A 35-year-old woman has an identified BRCA1 mutation; she has not had any cancers but has undergone risk-reducing BSO and her uterus remains. Is this woman a candidate for HT? At what dose, and for how long? Dr. Kaunitz, why don’t you start.

Dr. Kaunitz: That is a challenging case but one that I think our readers will find interesting and maybe even provocative.

We know that women with BRCA1 mutations, the more common of the 2 BRCA mutations, have a very high risk of developing epithelial ovarian cancer at a young age. For this reason, our colleagues in medical oncology who specialize in hereditary ovarian/breast cancer syndromes recommend prophylactic risk-reducing—and I would also say lifesaving—BSO with or without hysterectomy for women with BRCA1 mutations.

However, over the years there has been tremendous reluctance among physicians caring for BRCA patients and the women themselves—I use the term “previvors” to describe BRCA carriers who have not been diagnosed with breast or ovarian cancer—to use HT after BSO because of concerns that HT might increase breast cancer risk in women who are already at high risk for breast cancer.

I assume, Dr. Faubion, that in this case the woman had gynecologic surgery but continues to have intact breasts. Is that correct?

Dr. Faubion: That is correct.

Dr. Kaunitz: Although the assumption has been that it is not safe to prescribe HT in this setting, in fact, the reported cohort studies that have looked at this issue have not found an elevated risk of breast cancer when replacement estrogen, with or without progestin, is prescribed to BRCA1 previvors with intact breasts.

Given what Dr. Kapoor said regarding the morbidity that is associated with BSO without replacement of physiologic estrogen, and also given the severe symptoms that so many of these young menopausal women experience, in my practice I do prescribe estrogen or estrogen-progestin therapy and focus on the higher target doses that we discussed for the earlier case patient who had a hysterectomy for abnormal uterine bleeding with adenomyosis.

Dr. Faubion: Dr. Kapoor, do you agree with this approach? How long would you continue therapy?

Dr. Kapoor: First, in this BRCA1 case we need to appreciate that the indication for the BSO is a legitimate one, in contrast to the first case in which the ovaries were removed in a patient whose average risk of ovarian cancer was low. It is important to recognize that surgery performed in this context is the right thing to do because it does significantly reduce the risk of ovarian cancer.

The second thing to appreciate is that while we reduce the risk of ovarian cancer significantly and make sure that these patients survive longer, it’s striking a fine balance in that you want to make sure that their morbidity is not increased as a result of premature estrogen deprivation.

As Dr. Kaunitz told us, the evidence that we have so far, which granted is not very robust but is fairly strong observational evidence, suggests that the risk of breast cancer is not elevated when these patients are treated with replacement doses of HT.

Having said that, I do have very strong discussions with my patients in this category about having the risk-reducing bilateral mastectomy also, because if they were to get breast cancer because of their increased genetic predisposition, the cancer is likely to grow faster if the patient is on HT. So one of my counseling points to patients is that they strongly consider bilateral mastectomy, which reduces their breast cancer risk by more than 90%. At the same time, I also strongly endorse using HT in replacement doses for the reasons that we have already stated.

Dr. Faubion: Continue HT until age 50 or 52?

Dr. Kapoor: Definitely until that age, and possibly longer, depending on their symptoms. The indications for treating beyond the age of natural menopause are much the same as for women who experience natural menopause.

Dr. Faubion: That is assuming they had a bilateral mastectomy?

Dr. Kapoor: Yes.

Continue to: Continuing HT until the age of natural menopause...

Dr. Kaunitz: Dr. Kapoor brings up the important point of duration of systemic HT. I agree that similar considerations apply both to the healthy 41-year-old who had a hysterectomy for abnormal uterine bleeding and to the 35-year-old who had risk-reducing surgery because of her BRCA1 mutation.

In the 2 cases, both to treat symptoms and to prevent chronic diseases, it makes sense to continue HT at least until the age of natural menopause. That is consistent with 2017 guidance from The North American Menopause Society (NAMS) position statement on the use of systemic HT, that is, continuing systemic HT at least until the age of natural menopause.³ Then at that point, continuing or discontinuing systemic HT becomes discretionary, and that would be true for both cases. If the patient is slender or has a strong family history of osteoporosis, that tends to push the patient more in terms of continuing systemic HT. Those are just some examples, and Dr. Kapoor may want to detail other relevant considerations.

Dr. Kapoor: I completely agree. The decision is driven by symptoms that are not otherwise well managed, for example, with nonhormone strategies. If we have any concerns utilizing HT beyond the age of natural menopause, then nonhormonal options can be considered; but sometimes those are not as effective. And bone health is very important. You want to avoid using bisphosphonates in younger women and reserve them for older patients in their late 60s and 70s. Hormone therapy use is a very reasonable strategy to prevent bone loss.

Dr. Kaunitz: It is also worth mentioning that sometimes the woman involved in shared decision making with her clinician decides to stop systemic HT. In that setting, should the patient start developing new-onset dyspareunia, vaginal dryness, or other genital or sexuality-related concerns, it takes very little for me to advise that she start low-dose local vaginal estrogen therapy.

Dr. Faubion: In either scenario, if a woman were to develop symptoms consistent with genitourinary syndrome of menopause (GSM), would you use vaginal estrogen in addition to the systemic estrogen or alone after the woman elected to discontinue systemic therapy?

Dr. Kapoor: Yes to both, I would say.

Dr. Kaunitz: As my patients using systemic HT age, often I will lower the dose. For instance, the dose I use in a 53-year-old will be higher than when she is 59 or 62. At the same time, as we lower the dose of systemic estrogen therapy, symptoms of vaginal atrophy or GSM often will appear, and these can be effectively treated by adding low-dose vaginal estrogen therapy. A number of my patients, particularly those who are on lower-than-standard doses of systemic HT, are also using low-dose vaginal estrogen therapy.

There is a “hybrid” product available: the 90-day estradiol vaginal ring. Estring is a low-dose, 2-mg, 90-day estradiol ring that is very useful, but it is effective only for treating GSM or vaginal atrophy. A second menopausal vaginal estradiol ring, Femring, is available in 2 doses: 0.05 mg/day and 0.1 mg/day. These are very effective in treating both systemic issues, such as vasomotor symptoms or prevention of osteoporosis, and very effective in treating GSM or vaginal atrophy. One problem is that Femring, depending on insurance coverage, can be very expensive. It’s not available as a generic, so for insurance or financial reasons I don’t often prescribe it. If I could remove those financial barriers, I would prescribe Femring more often because it is very useful.

Dr. Faubion: You raise an important point, and that is, for women who have been on HT for some time, clinicians often feel the need to slowly reduce the dose. Would you do that same thing, Dr. Kapoor, for a 40-year-old woman? Would you reduce the dose as she approaches age 50? Is there pressure that “she shouldn’t be on that much estrogen”?

Dr. Kapoor: No, I would not feel pressured until the patient turns at least 46. I bring up age 46 because the average age range for menopause is 46 to 55. After that, if there is any concern, we can decrease the dose to half and keep the patient on that until she turns 50 or 51. But most of my patients are on replacement doses until the average age of menopause, which is around 51 years, and that’s when you reduce the dose to that of the typical HT regimens used after natural menopause.

Sometimes patients are told something by a friend or they have read something and they worry about the risk of 2 things. One is breast cancer and the other is venous thromboembolism (VTE), and that may be why they want to be on a lower dose. I counsel patients that while the risk of VTE is real with HT, it is the women after natural menopause who are at risk—because age itself is a risk for VTE—and it also has to do with the kind of HT regimen that a patient is on. High doses of oral estrogens and certain progestogens increase the risk. But again, for estradiol used in replacement doses and the more common progestogens that we now use in practice, such as micronized progesterone, the risk is not the same. The same goes for breast cancer. My biggest message to patients and clinicians who take care of these patients is that the rules that apply to women after natural menopause just do not apply to this very different patient population.

Dr. Faubion: Thank you, Dr. Kaunitz and Dr. Kapoor, for sharing your knowledge and experience. ●

Women who undergo bilateral salpingo-oophorectomy (BSO) for various indications prior to menopause experience a rapid decline in ovarian hormone levels and consequent vasomotor and other menopausal symptoms. In addition, the resulting estrogen deprivation is associated with such long-term adverse outcomes as osteoporosis and cardiovascular morbidity.

OBG Management convened a roundtable with 3 experts who discussed health considerations in women who have undergone BSO prior to the age of natural menopause¹ to further explore the issues involved in managing hormone therapy (HT) in these patients. Stephanie Faubion, MD, MBA, NCMP, moderated the exchange.

Surgical vs natural menopause

Stephanie Faubion, MD, MBA, NCMP: Since the Women’s Health Initiative study was published in 2002,² many clinicians have been fearful of using systemic HT in menopausal women, and HT use has declined dramatically such that only about 4% to 6% of menopausal women are now receiving systemic HT. Importantly, however, a group of younger menopausal women also are not receiving HT, and that is women who undergo BSO before they reach the average age of menopause, which in the United States is about age 52; this is sometimes referred to as surgical menopause or early surgical menopause. Early surgical menopause has different connotations for long-term health risks than natural menopause at the average age, and we are here to discuss these health effects and their management.

My name is Stephanie Faubion, and I am a women’s health internist and the Chair of the Department of Medicine at Mayo Clinic in Jacksonville, Florida, and Director of Mayo Clinic Women’s Health. I am here with 2 of my esteemed colleagues, Dr. Andrew Kaunitz and Dr. Ekta Kapoor.

Andrew M. Kaunitz, MD, NCMP: Hello, I am an ObGyn with the University of Florida College of Medicine in Jacksonville, with particular interests in contraception, menopause, and gynecologic ultrasonography.

Ekta Kapoor, MBBS, NCMP: And I am an endocrinologist at Mayo Clinic in Rochester with a specific interest in menopause and hormone therapy. I am also the Assistant Director for Mayo Clinic Women’s Health.

Higher-than-standard estrogen doses needed in younger menopausal women

Dr. Faubion: Let’s consider a couple of cases so that we can illustrate some important points regarding hormone management in women who have undergone BSO before the age of natural menopause.

Our first case patient is a woman who is 41 years of age and, because of adenomyosis, she will undergo a hysterectomy. She tells her clinician that she is very concerned about ovarian cancer risk because one of her good friends recently was diagnosed with ovarian cancer, and together they decide to remove her ovaries at the time of hysterectomy. Notably, her ovaries were healthy.

The patient is now menopausal postsurgery, and she is having significant hot flashes and night sweats. She visits her local internist, who is concerned about initiating HT. She is otherwise a healthy woman and does not have any contraindications to HT. Dr. Kaunitz, what would you tell her internist?

Dr. Kaunitz: We are dealing with 2 different issues in terms of decision making about systemic HT for this 41-year-old who has undergone BSO. First, as you mentioned, Dr. Faubion, she has bothersome hot flashes, or vasomotor symptoms. Unless there are contraindications, systemic HT would be appropriate. Although I might start treatment at standard doses, and the accompanying TABLE depicts standard doses for the 2 most common oral estrogen formulations as well as transdermal estradiol, it’s important to recognize that younger menopausal women often will need to use higher-than-standard doses.

For example, for a 53-year-old woman who has been menopausal for a year or 2 and now has bothersome symptoms, I might start her on estradiol 1 mg tablets with progestin if a uterus is present. However, in this 41-year-old case patient, while I might start treatment at a standard dose, I would anticipate increasing to higher doses, such as 1.5 or 2 mg of daily estradiol until she feels her menopausal symptoms are adequately addressed.

Dr. Faubion: It is important to note that sometimes women with early BSO tend to have more severe vasomotor symptoms. Do you find that sometimes a higher dose is required just to manage symptoms, Dr. Kaunitz?

Dr. Kaunitz: Absolutely, yes. The decision whether or not to use systemic HT might be considered discretionary or elective in the classic 53-year-old woman recently menopausal with hot flashes, a so-called spontaneously or naturally menopausal woman. But my perspective is that unless there are clear contraindications, the decision to start systemic HT in the 41-year-old BSO case patient is actually not discretionary. Unless contraindications are present, it is important not only to treat symptoms but also to prevent an array of chronic major health concerns that are more likely if we don’t prescribe systemic HT.

Continue to: Health effects of not using HT...

Dr. Faubion: Dr. Kapoor, can you describe the potential long-term adverse health consequences of not using estrogen therapy? Say the same 41-year-old woman does not have many bothersome symptoms. What would you do?

Dr. Kapoor: Thank you for that important question. Building on what Dr. Kaunitz said, in these patients there are really 2 issues that can seem to be independent but are not: The first relates to the immediate consequences of lack of estrogen, ie, the menopause-related symptoms, but the second and perhaps the bigger issue is the long-term risk associated with estrogen deprivation.

The symptoms in these women are often obvious as they can be quite severe and abrupt; one day these women have normal hormone levels and the next day, after BSO, suddenly their hormones are very low. So if symptoms occur, they are usually hard to miss, simply because they are very drastic and very severe.

Historically, patients and their clinicians have targeted these symptoms. Patients experience menopausal symptoms, they seek treatment, and then the clinicians basically titrate the treatment to manage these symptoms. That misses the bigger issue, however, which is that premature estrogen deprivation leads to a host of chronic health conditions, as Dr. Kaunitz mentioned. These mainly include increased risk for cardiovascular disease, diabetes, hypertension, dyslipidemia, increased risk of mortality, dementia, and osteoporosis.

Fairly strong observational evidence suggests that use of estrogen therapy given in replacement doses—doses higher than those typically used in women after natural menopause, therefore considered replacement doses—helps mitigate the risk of some of these adverse health conditions.

In these women, the bigger goal really is to reinstate the hormonal milieu that exists prior to menopause. To your point, Dr. Faubion, if I have a patient who is younger than 46 years, who has her ovaries taken out, and even if she has zero symptoms (and sometimes that does happen), I would still make a case for this patient to utilize hormone therapy unless there is a contraindication such as breast cancer or other estrogen-sensitive cancers.

Dr. Faubion: Again, would you aim for those higher doses rather than treat with the “lowest dose”?

Dr. Kapoor: Absolutely. My punchline to the patients and clinicians in these discussions is that the rules of the game are different for these women. We cannot extrapolate the risks and benefits of HT use in women after natural menopause to younger women who have surgical menopause. Those rules just do not apply with respect to both benefits and risks.

Dr. Faubion: I think it’s important to say that these same “rules” would apply if the women were to go through premature menopause for any other reason, too, such as chemotherapy, radiation therapy, or premature ovarian insufficiency for any number of reasons, including toxic, metabolic, or genetic causes and so on. Would that be true?

Dr. Kapoor: Yes, absolutely so.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: In terms of practical or clinical issues regarding systemic HT management, for the woman in her early 50s who has experienced normal or natural spontaneous menopause, a starting dose of transdermal estradiol would be, for instance, a 0.05-mg patch, which is a patch that over 24 hours releases 0.05 mg of estradiol daily; or standard oral estrogen, including conjugated equine estrogen, a 0.625-mg tablet daily, or estradiol, a 1-mg tablet daily.

But in younger patients, we want to use higher doses. For a patch, for instance, I would aim for a 0.075- or 0.1-mg estradiol patch, which releases a higher daily dose of estradiol than the standard dose. For oral estrogen, the dose would be 0.9- or even 1.25-mg tablets of conjugated equine estrogen or 1.5 mg, which is a 1-mg plus a 0.5-mg estradiol tablet, or a 2-mg estradiol tablet. Estradiol does come in a 2-mg strength.

For oral estrogen, I prefer estradiol because it’s available as a generic medication and often available at a very low cost, sometimes as low as $4 a month from chain pharmacies.

Continue to: Usefulness of monitoring estradiol levels for dosage adjustment...

Dr. Faubion: That’s a great point, and again it is important to emphasize that we are aiming to recreate the premenopausal hormonal milieu. If you were to check estradiol levels, that would be aiming for a premenopausal range of approximately 80 to 120 pg per mL. Dr. Kapoor, is there utility in monitoring estrogen levels?

Dr. Kapoor: Great question, Dr. Faubion, and as you know it’s a loaded one. We base this on empiric evidence. We know that if the hormonal milieu in a young patient is changed to a postmenopausal one, her risk for many chronic conditions is increased. So if we were to reinstate a premenopausal hormonal milieu, that risk would probably be reduced. It makes good sense to target an empiric goal of 80 to 120 pg per mL of estradiol, which is the average estradiol level in a premenopausal woman. If you were to ask me, however, are there randomized, controlled trial data to support this practice—that is, if you target that level, can you make sure that the risk of diabetes is lower or that the risk of heart disease is lower—that study has yet to be done, and it may not ever be done on a large scale. However, it intuitively makes good sense to target premenopausal estradiol levels.

Dr. Faubion: When might you check an estradiol level in this population? For example, if you are treating a patient with a 0.1-mg estradiol patch and she still has significant hot flashes, would it be useful to check the level?

Dr. Kapoor: It would. In my practice, I check estradiol levels on these patients on an annual basis, regardless of symptoms, but definitely in the patient who has symptoms. It makes good sense, because sometimes these patients don’t absorb the estrogen well, particularly if administered by the transdermal route.

A general rule of thumb is that in the average population, if a patient is on the 0.1-mg patch, for example, you would expect her level to be around 100. If it is much lower than that, which sometimes happens, that speaks for poor absorption. Options at that point would be to treat her with a higher dose patch, depending on what the level is, or switch to a different formulation, such as oral.

In instances in which I have treated patients with a 0.1-mg patch for example, and their estradiol levels are undetectable, that speaks for very poor absorption. For such patients I make a case for switching them to oral therapy. Most definitely that makes sense in a patient who is symptomatic despite treatment. But even for patients who don’t have symptoms, I like to target that level, acknowledging that there is no evidence as such to support this practice.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: Yes, a few practical points. Although patches are available in a wider array of doses than oral estrogen formulations, the highest dose available is 0.1 mg. It’s important for clinicians to recognize that while checking serum levels when indicated can be performed in women using transdermal estradiol or patches, in women who are using oral estrogen, checking blood levels is not going to work well because serum estrogen levels have a daily peak and valley in women who use oral versus transdermal estradiol.

I also wanted to talk about progestins. Although many patients who have had a BSO prior to spontaneous menopause also have had a hysterectomy, others have an intact uterus associated with their BSO, so progestins must be used along with estrogen. And if we are using higher-than-standard doses of estrogen, we also need to use higher-than-standard doses of progestin.

In that classic 53-year-old woman I referred to who had spontaneous normal menopause, if she is taking 1 mg of estradiol daily, or a 0.05-mg patch, or 0.625 mg of conjugated equine estrogen, 2.5 mg of medroxyprogesterone is fine. In fact, that showed excellent progestational protection of the endometrium in the Women’s Health Initiative and in other studies.

However, if we are going to use double the estrogen dose, we should increase the progestin dose too. In some of my patients on higher estrogen doses who have an intact uterus, I’ll use 5 or even 10 mg of daily medroxyprogesterone acetate to ensure adequate progestational suppression.

Dr. Faubion: Another practical tip is that if one is using conjugated equine estrogens, measuring the serum estradiol levels is not useful either.

Dr. Kaunitz: I agree.

Continue to: Oral contraceptives as replacement HT...

Dr. Faubion: Would you comment on use of a birth control pill in this circumstance? Would it be optimal to use a postmenopausal HT regimen as opposed to a birth control pill or combined hormonal contraception?

Dr. Kapoor: In this younger population, sometimes it seems like a more socially acceptable decision to be on a birth control option than on menopausal HT. But there are some issues with being on a contraceptive regimen. One is that we end up using estrogen doses much higher than what is really needed for replacement purposes. It is also a nonphysiologic way of replacement in another sense—as opposed to estradiol, which is the main hormone made by the ovaries, the hormonal contraceptive regimens contain the synthetic estrogen ethinyl estradiol for the most part.

The other issue that is based on some weak evidence is that it appears that the bone health outcomes are probably inferior with combined hormonal contraception. For these reasons, regimens that are based on replacement doses of estradiol are preferred.

Dr. Faubion: Right, although the data are somewhat weak, I agree that thus far it seems optimal to utilize a postmenopausal regimen for various reasons. Dr. Kaunitz, anything to add?

Dr. Kaunitz: Yes, to underscore Dr. Kapoor’s point, a common oral contraceptive that contains 20 µg of ethinyl estradiol is substantially more estrogenic than 1.0 or 2.0 mg of micronized oral estradiol.

Also consider that a 20-µg ethinyl estradiol oral contraceptive may increase the risk of venous thromboembolism more than menopausal doses of oral estradiol, whether it be a micronized estradiol or conjugated equine estrogen.

Dr. Faubion: So the risk may be greater with oral combined hormonal contraception as well?

Dr. Kaunitz: One thing we can do is explain to our patients that their ovaries, prior to surgery or prior to induced menopause, were making substantial quantities of estradiol. Whether we prescribe a patch or oral micronized estradiol, this estrogen is identical to the hormone that their ovaries were making prior to surgery or induced menopause.

Breast cancer concerns

Dr. Faubion: Let’s consider a more complicated case. A 35-year-old woman has an identified BRCA1 mutation; she has not had any cancers but has undergone risk-reducing BSO and her uterus remains. Is this woman a candidate for HT? At what dose, and for how long? Dr. Kaunitz, why don’t you start.

Dr. Kaunitz: That is a challenging case but one that I think our readers will find interesting and maybe even provocative.

We know that women with BRCA1 mutations, the more common of the 2 BRCA mutations, have a very high risk of developing epithelial ovarian cancer at a young age. For this reason, our colleagues in medical oncology who specialize in hereditary ovarian/breast cancer syndromes recommend prophylactic risk-reducing—and I would also say lifesaving—BSO with or without hysterectomy for women with BRCA1 mutations.

However, over the years there has been tremendous reluctance among physicians caring for BRCA patients and the women themselves—I use the term “previvors” to describe BRCA carriers who have not been diagnosed with breast or ovarian cancer—to use HT after BSO because of concerns that HT might increase breast cancer risk in women who are already at high risk for breast cancer.

I assume, Dr. Faubion, that in this case the woman had gynecologic surgery but continues to have intact breasts. Is that correct?

Dr. Faubion: That is correct.

Dr. Kaunitz: Although the assumption has been that it is not safe to prescribe HT in this setting, in fact, the reported cohort studies that have looked at this issue have not found an elevated risk of breast cancer when replacement estrogen, with or without progestin, is prescribed to BRCA1 previvors with intact breasts.

Given what Dr. Kapoor said regarding the morbidity that is associated with BSO without replacement of physiologic estrogen, and also given the severe symptoms that so many of these young menopausal women experience, in my practice I do prescribe estrogen or estrogen-progestin therapy and focus on the higher target doses that we discussed for the earlier case patient who had a hysterectomy for abnormal uterine bleeding with adenomyosis.

Dr. Faubion: Dr. Kapoor, do you agree with this approach? How long would you continue therapy?

Dr. Kapoor: First, in this BRCA1 case we need to appreciate that the indication for the BSO is a legitimate one, in contrast to the first case in which the ovaries were removed in a patient whose average risk of ovarian cancer was low. It is important to recognize that surgery performed in this context is the right thing to do because it does significantly reduce the risk of ovarian cancer.

The second thing to appreciate is that while we reduce the risk of ovarian cancer significantly and make sure that these patients survive longer, it’s striking a fine balance in that you want to make sure that their morbidity is not increased as a result of premature estrogen deprivation.

As Dr. Kaunitz told us, the evidence that we have so far, which granted is not very robust but is fairly strong observational evidence, suggests that the risk of breast cancer is not elevated when these patients are treated with replacement doses of HT.

Having said that, I do have very strong discussions with my patients in this category about having the risk-reducing bilateral mastectomy also, because if they were to get breast cancer because of their increased genetic predisposition, the cancer is likely to grow faster if the patient is on HT. So one of my counseling points to patients is that they strongly consider bilateral mastectomy, which reduces their breast cancer risk by more than 90%. At the same time, I also strongly endorse using HT in replacement doses for the reasons that we have already stated.

Dr. Faubion: Continue HT until age 50 or 52?

Dr. Kapoor: Definitely until that age, and possibly longer, depending on their symptoms. The indications for treating beyond the age of natural menopause are much the same as for women who experience natural menopause.

Dr. Faubion: That is assuming they had a bilateral mastectomy?

Dr. Kapoor: Yes.

Continue to: Continuing HT until the age of natural menopause...

Dr. Kaunitz: Dr. Kapoor brings up the important point of duration of systemic HT. I agree that similar considerations apply both to the healthy 41-year-old who had a hysterectomy for abnormal uterine bleeding and to the 35-year-old who had risk-reducing surgery because of her BRCA1 mutation.

In the 2 cases, both to treat symptoms and to prevent chronic diseases, it makes sense to continue HT at least until the age of natural menopause. That is consistent with 2017 guidance from The North American Menopause Society (NAMS) position statement on the use of systemic HT, that is, continuing systemic HT at least until the age of natural menopause.³ Then at that point, continuing or discontinuing systemic HT becomes discretionary, and that would be true for both cases. If the patient is slender or has a strong family history of osteoporosis, that tends to push the patient more in terms of continuing systemic HT. Those are just some examples, and Dr. Kapoor may want to detail other relevant considerations.

Dr. Kapoor: I completely agree. The decision is driven by symptoms that are not otherwise well managed, for example, with nonhormone strategies. If we have any concerns utilizing HT beyond the age of natural menopause, then nonhormonal options can be considered; but sometimes those are not as effective. And bone health is very important. You want to avoid using bisphosphonates in younger women and reserve them for older patients in their late 60s and 70s. Hormone therapy use is a very reasonable strategy to prevent bone loss.

Dr. Kaunitz: It is also worth mentioning that sometimes the woman involved in shared decision making with her clinician decides to stop systemic HT. In that setting, should the patient start developing new-onset dyspareunia, vaginal dryness, or other genital or sexuality-related concerns, it takes very little for me to advise that she start low-dose local vaginal estrogen therapy.

Dr. Faubion: In either scenario, if a woman were to develop symptoms consistent with genitourinary syndrome of menopause (GSM), would you use vaginal estrogen in addition to the systemic estrogen or alone after the woman elected to discontinue systemic therapy?

Dr. Kapoor: Yes to both, I would say.

Dr. Kaunitz: As my patients using systemic HT age, often I will lower the dose. For instance, the dose I use in a 53-year-old will be higher than when she is 59 or 62. At the same time, as we lower the dose of systemic estrogen therapy, symptoms of vaginal atrophy or GSM often will appear, and these can be effectively treated by adding low-dose vaginal estrogen therapy. A number of my patients, particularly those who are on lower-than-standard doses of systemic HT, are also using low-dose vaginal estrogen therapy.

There is a “hybrid” product available: the 90-day estradiol vaginal ring. Estring is a low-dose, 2-mg, 90-day estradiol ring that is very useful, but it is effective only for treating GSM or vaginal atrophy. A second menopausal vaginal estradiol ring, Femring, is available in 2 doses: 0.05 mg/day and 0.1 mg/day. These are very effective in treating both systemic issues, such as vasomotor symptoms or prevention of osteoporosis, and very effective in treating GSM or vaginal atrophy. One problem is that Femring, depending on insurance coverage, can be very expensive. It’s not available as a generic, so for insurance or financial reasons I don’t often prescribe it. If I could remove those financial barriers, I would prescribe Femring more often because it is very useful.

Dr. Faubion: You raise an important point, and that is, for women who have been on HT for some time, clinicians often feel the need to slowly reduce the dose. Would you do that same thing, Dr. Kapoor, for a 40-year-old woman? Would you reduce the dose as she approaches age 50? Is there pressure that “she shouldn’t be on that much estrogen”?

Dr. Kapoor: No, I would not feel pressured until the patient turns at least 46. I bring up age 46 because the average age range for menopause is 46 to 55. After that, if there is any concern, we can decrease the dose to half and keep the patient on that until she turns 50 or 51. But most of my patients are on replacement doses until the average age of menopause, which is around 51 years, and that’s when you reduce the dose to that of the typical HT regimens used after natural menopause.

Sometimes patients are told something by a friend or they have read something and they worry about the risk of 2 things. One is breast cancer and the other is venous thromboembolism (VTE), and that may be why they want to be on a lower dose. I counsel patients that while the risk of VTE is real with HT, it is the women after natural menopause who are at risk—because age itself is a risk for VTE—and it also has to do with the kind of HT regimen that a patient is on. High doses of oral estrogens and certain progestogens increase the risk. But again, for estradiol used in replacement doses and the more common progestogens that we now use in practice, such as micronized progesterone, the risk is not the same. The same goes for breast cancer. My biggest message to patients and clinicians who take care of these patients is that the rules that apply to women after natural menopause just do not apply to this very different patient population.

Dr. Faubion: Thank you, Dr. Kaunitz and Dr. Kapoor, for sharing your knowledge and experience. ●

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Obstetrical practice saw updates in 2021 to 3 major areas of pregnancy management: preterm birth prevention, antepartum fetal surveillance, and the use of antenatal corticosteroids.

Updated guidance on predicting and preventing spontaneous PTB

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin, number 234. Obstet Gynecol. 2021;138:e65-e90.

Preterm birth (PTB) continues to pose a challenge in clinical obstetrics, with the most recently reported rate of 10.2% in the United States.¹ This accounts for almost 75% of perinatal mortality and more than half of neonatal morbidity, in which effects last well past the neonatal period. PTB is classified as spontaneous (following preterm labor, preterm prelabor rupture of membranes, or cervical insufficiency) or iatrogenic (indicated due to maternal and/or fetal complications).

Assessing risk for PTB

The single strongest predictor of subsequent PTB is a history of spontaneous PTB. Recurrence risk is further increased by the number of prior PTBs and the gestational age at prior PTB. Identification of and intervention for a short cervix has been shown to prolong gestation. Transvaginal ultrasonography of the cervix is the most accurate method for evaluating cervical length (CL). Specific examination criteria exist to ensure that CL measurements are reproducible and reliable.² A short CL is generally defined as a measurement of less than 25 mm between 16 and 24 weeks’ gestation.

Screening strategies

The American College of Obstetricians and Gynecologists (ACOG), with an endorsement from the Society for Maternal-Fetal Medicine (SMFM), recommends cervical evaluation during the anatomy ultrasound exam between 18 0/7 and 22 6/7 weeks’ gestation in all pregnant patients regardless of prior PTB.³ If transabdominal imaging is concerning for a shortened cervix, transvaginal ultrasonography should be performed to assess the CL.

Serial transvaginal CL measurements are recommended between 16 0/7 and 24 0/7 weeks’ gestation for patients with a current singleton pregnancy and history of a spontaneous PTB, but not for patients with a history of iatrogenic or indicated PTB.

Interventions: Mind your p’s and c’s

Interventions to reduce the risk of spontaneous PTB depend on whether the current pregnancy is a singleton, twins, or higher-order multiples; CL measurement; and history of spontaneous PTB. Preconception optimization of underlying medical conditions also is important to reduce the risk of recurrent indicated PTB.

Continue to: Progesterone...

Progesterone

Vaginal administration. Several trials have shown that vaginal progesterone can be used to reduce the risk of spontaneous PTB in asymptomatic patients with a singleton pregnancy, incidental finding of a short cervix (<25 mm), and no history of spontaneous PTB. This is a change from the prior recommendation of CL of less than 20 mm. In the setting of a twin pregnancy, regardless of CL, data do not definitively support the use of vaginal progesterone.

Intramuscular administration.^4,5 The popularity of intramuscular progesterone has waxed and waned. At present, ACOG recommends that all patients with a singleton pregnancy and history of spontaneous PTB be offered progesterone beginning at 16 0/7 weeks’ gestation following a shared decision-making process that includes the limited data of efficacy noted in existing studies.

In a twin pregnancy with no history of spontaneous PTB, the use of intramuscular progesterone has been shown to potentially increase the risk of PTB and admission to the neonatal intensive care unit. As such, intramuscular progesterone in the setting of a twin gestation without a history of spontaneous PTB is not recommended. When a prior spontaneous PTB has occurred, there may be some benefit to intramuscular progesterone in twin gestations.

Cerclage

Ultrasound indicated. In a singleton pregnancy with an incidental finding of short cervix (<25 mm) and no history of PTB, the use of cerclage is of uncertain benefit. Effectiveness may be seen if the cervix is less than 10 mm. Ultrasound-indicated cerclage should be considered in a singleton pregnancy with a CL less than 25 mm and a history of spontaneous PTB.

Possibly one of the most controversial topics is ultrasound-indicated cerclage placement in twin gestation. As with many situations in obstetrics, data regarding ultrasound-indicated cerclage in twin gestation is based on small retrospective studies fraught with bias. Results from these studies range from no benefit, to potential benefit, to even possible increased risk of PTB. Since data are limited, as we await more evidence, it is recommended that the clinician and patient use shared decision making to decide on cerclage placement in a twin gestation.

Exam indicated. In a singleton pregnancy with a dilated cervix on digital or speculum exam between 16 0/7 to 23 6/7 weeks’ gestation, a physical exam–indicated cerclage should be offered. Exam-indicated cerclage also may reduce the incidence of PTB in twin gestations with cervical dilation between 16 0/7 and 23 6/7 weeks’ gestation. Indomethacin tocolysis and perioperative antibiotics should be considered when an exam-indicated cerclage is placed.

As the limits of viability are continually pushed earlier, more in-depth conversation is needed with patients who are considering an exam-indicated cerclage. The nuances of periviability and the likelihood that an exam-indicated cerclage will commit a pregnancy to a periviable or extremely preterm birth should be discussed in detail using a shared decision making model.

Regardless of whether the cerclage is ultrasound or exam indicated, once it is placed there is no utility in additional CL ultrasound monitoring.

Pessary

Vaginal pessaries for prevention of PTB have not gained popularity in the United States as they have in other countries. Trials are being conducted to determine the utility of vaginal pessary, but current data have not proven its effectiveness in preventing PTB in the setting of singleton pregnancy, short cervix, and no history of spontaneous PTB. So for now, pessary is not recommended. The same can be said for use in the twin gestation.

Which patients may benefit from antepartum fetal surveillance and when to initiate it

American College of Obstetricians and Gynecologists’ Committee on Obstetrics Practice, Society for Maternal-Fetal Medicine. Indications for outpatient antenatal surveillance: ACOG committee opinion, number 828. Obstet Gynecol. 2021;137:e177-e197.

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Antepartum fetal surveillance: ACOG practice bulletin, number 229. Obstet Gynecol. 2021;137:e116-e127.

The ultimate purpose of antenatal fetal surveillance is to prevent stillbirth. However, stillbirth has multiple etiologies, not all of which are preventable with testing. In June 2021, ACOG released a new Committee Opinion containing guidelines for fetal surveillance, including suggested gestational age at initiation and frequency of testing, for the most common high-risk conditions. ACOG also released an update to the Practice Bulletin on antepartum fetal surveillance; additions include randomized controlled trial level data on the utility of fetal kick counts (FKCs) and recommendations that align with the new Committee Opinion.

Data for the efficacy of antepartum fetal surveillance are lacking, mainly due to the difficulty of performing prospective studies in stillbirth. The existing evidence is subject to intervention bias, as deliveries increase in tested patients, and recommendations rely heavily on expert consensus and nonrandomized studies. Antenatal testing is also time, cost, and labor intensive, with the risk of intervention for a false-positive result. Despite these limitations, obstetrical practices routinely perform antenatal fetal surveillance.

The new guidelines: The why, when, and how often

Why. Antepartum fetal surveillance is suggested for conditions that have a risk of stillbirth greater than 0.8 per 1,000 (that is, the false-negative rate of a biophysical profile or a modified biophysical profile) and the relative risk or odds ratio is greater than 2.0 for stillbirth compared with unaffected pregnancies.

When. For most conditions, ACOG recommends initiation of testing at 32 weeks or later, with notable earlier exceptions for some of the highest-risk patients. For certain conditions, such as fetal growth restriction and hypertensive disorders of pregnancy, the recommendation is to start “at diagnosis,” with the corollary “or at a gestational age when delivery would be considered because of abnormal results.” Shared decision making with the patient about pregnancy goals therefore is required, particularly in cases of fetal anomalies, genetic conditions, or at very early gestational ages.

How often. The recommended frequency of testing is at least weekly. Testing frequency should be increased to twice-weekly outpatient or daily inpatient for the most complicated pregnancies (for example, fetal growth restriction with abnormal umbilical artery Doppler studies, preeclampsia with severe features).

Once or twice weekly is an option for many conditions, which gives the clinician the opportunity to assess clinical stability as well as the patient’s input in terms of logistics and anxiety.

Patients with multiple conditions may fall into the “individualized” category, as do patients with suboptimal control of conditions (for example, diabetes, hypertension) that may affect the fetus as the pregnancy progresses.

New diagnoses included for surveillance

Several diagnoses not previously included now qualify for antepartum fetal surveillance under the new guidelines, most notably:

• history of obstetrical complications in the immediate preceding pregnancy

—history of prior fetal growth restriction requiring preterm delivery

—history of prior preeclampsia requiring delivery

• alcohol use of 5 or more drinks per day
• in vitro fertilization
• abnormal serum markers

—pregnancy-associated plasma protein A (PAPP-A) in the fifth or lower percentile or 0.4 multiples of the median (MoM)

—second trimester inhibin A of 2 or greater MoM

• prepregnancy body mass index (BMI)

—this is divided into 2 categories for timing of initiation of testing:

1.  37 weeks for BMI of 35 to 39.9 kg/m²
2.  34 weeks for BMI of or greater than 40 kg/m².

Fetal kick counts

The major change to the updated Practice Bulletin on antenatal surveillance is the inclusion of data on FKCs, a simple modality of fetal surveillance that does not require a clinical visit. For FKCs, a meta-analysis of more than 450,000 patients did not demonstrate a difference in perinatal death between the FKC intervention group (0.54%) and the control group (0.59%). Of note, there were small but statistically significant increases in the rates of induction of labor, cesarean delivery, and preterm delivery in the FKC intervention group. Therefore, this update does not recommend a formal program of FKCs for all patients.

Continue to: Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation...

Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation

American College of Obstetricians and Gynecologists. Use of antenatal corticosteroids at 22 weeks of gestation: ACOG practice advisory. September 2021. https://www .acog.org/clinical/clinical-guidance/practice-advisory /articles/2021/09/use-of-antenatal-corticosteroids-at -22-weeks-of-gestation. Accessed December 11, 2021.

In September 2021, ACOG and SMFM released a Practice Advisory updating the current recommendations for the administration of antenatal corticosteroids in the periviable period (22 to 25 6/7 weeks’ gestation). Whereas the prior lower limit of gestational age for consideration of steroids was 23 weeks, the new recommendation now extends this consideration down to 22 weeks.

The cited data include a meta-analysis of more than 2,200 patients in which the survival rate of infants born between 22 and 22 6/7 weeks who were exposed to antenatal steroids was 39% compared with 19.5% in the unexposed group. Another study of more than 1,000 patients demonstrated a statistically significant increase in overall survival in patients treated with antenatal steroids plus life support compared with life support only (38.5% vs 17.7%). Survival without major morbidity in this study, although increased from 1% to 4.4%, was still low.

Recommendation carries caveats

Given this information, the Practice Advisory offers a 2C level recommendation (weak recommendation, low quality of evidence) for antenatal steroids at 22 to 22 6/7 weeks’ gestation if neonatal resuscitation is planned, acknowledging the limitations and potential bias of the available data.

The Practice Advisory emphasizes the importance of counseling and patient involvement in the decision making. This requires a multidisciplinary collaboration among the neonatology and obstetrical teams, flexibility in the plan after birth depending on the infant’s condition, and redirection of care if appropriate. Estimated fetal weight, the presence of multiple gestations, fetal biologic sex, and any anomalies are also important in helping families make an informed decision for their particular pregnancy. As described in the Obstetric Care Consensus on periviable birth,⁶ it is important to remember that considerations and recommendations are not the same as requirements, and redirection of care to comfort and family memory making is not the same as withholding care.

The rest of the recommendations for the administration of antenatal steroids remain the same: Antenatal steroids are not recommended at less than 22 weeks due to lack of evidence of benefit, and they continue to be recommended at 24 weeks and beyond. ●

Obstetrical practice saw updates in 2021 to 3 major areas of pregnancy management: preterm birth prevention, antepartum fetal surveillance, and the use of antenatal corticosteroids.

Updated guidance on predicting and preventing spontaneous PTB

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin, number 234. Obstet Gynecol. 2021;138:e65-e90.

Preterm birth (PTB) continues to pose a challenge in clinical obstetrics, with the most recently reported rate of 10.2% in the United States.¹ This accounts for almost 75% of perinatal mortality and more than half of neonatal morbidity, in which effects last well past the neonatal period. PTB is classified as spontaneous (following preterm labor, preterm prelabor rupture of membranes, or cervical insufficiency) or iatrogenic (indicated due to maternal and/or fetal complications).

Assessing risk for PTB

The single strongest predictor of subsequent PTB is a history of spontaneous PTB. Recurrence risk is further increased by the number of prior PTBs and the gestational age at prior PTB. Identification of and intervention for a short cervix has been shown to prolong gestation. Transvaginal ultrasonography of the cervix is the most accurate method for evaluating cervical length (CL). Specific examination criteria exist to ensure that CL measurements are reproducible and reliable.² A short CL is generally defined as a measurement of less than 25 mm between 16 and 24 weeks’ gestation.

Screening strategies

The American College of Obstetricians and Gynecologists (ACOG), with an endorsement from the Society for Maternal-Fetal Medicine (SMFM), recommends cervical evaluation during the anatomy ultrasound exam between 18 0/7 and 22 6/7 weeks’ gestation in all pregnant patients regardless of prior PTB.³ If transabdominal imaging is concerning for a shortened cervix, transvaginal ultrasonography should be performed to assess the CL.

Serial transvaginal CL measurements are recommended between 16 0/7 and 24 0/7 weeks’ gestation for patients with a current singleton pregnancy and history of a spontaneous PTB, but not for patients with a history of iatrogenic or indicated PTB.

Interventions: Mind your p’s and c’s

Interventions to reduce the risk of spontaneous PTB depend on whether the current pregnancy is a singleton, twins, or higher-order multiples; CL measurement; and history of spontaneous PTB. Preconception optimization of underlying medical conditions also is important to reduce the risk of recurrent indicated PTB.

Continue to: Progesterone...

Progesterone

Vaginal administration. Several trials have shown that vaginal progesterone can be used to reduce the risk of spontaneous PTB in asymptomatic patients with a singleton pregnancy, incidental finding of a short cervix (<25 mm), and no history of spontaneous PTB. This is a change from the prior recommendation of CL of less than 20 mm. In the setting of a twin pregnancy, regardless of CL, data do not definitively support the use of vaginal progesterone.

Intramuscular administration.^4,5 The popularity of intramuscular progesterone has waxed and waned. At present, ACOG recommends that all patients with a singleton pregnancy and history of spontaneous PTB be offered progesterone beginning at 16 0/7 weeks’ gestation following a shared decision-making process that includes the limited data of efficacy noted in existing studies.

In a twin pregnancy with no history of spontaneous PTB, the use of intramuscular progesterone has been shown to potentially increase the risk of PTB and admission to the neonatal intensive care unit. As such, intramuscular progesterone in the setting of a twin gestation without a history of spontaneous PTB is not recommended. When a prior spontaneous PTB has occurred, there may be some benefit to intramuscular progesterone in twin gestations.

Cerclage

Ultrasound indicated. In a singleton pregnancy with an incidental finding of short cervix (<25 mm) and no history of PTB, the use of cerclage is of uncertain benefit. Effectiveness may be seen if the cervix is less than 10 mm. Ultrasound-indicated cerclage should be considered in a singleton pregnancy with a CL less than 25 mm and a history of spontaneous PTB.

Possibly one of the most controversial topics is ultrasound-indicated cerclage placement in twin gestation. As with many situations in obstetrics, data regarding ultrasound-indicated cerclage in twin gestation is based on small retrospective studies fraught with bias. Results from these studies range from no benefit, to potential benefit, to even possible increased risk of PTB. Since data are limited, as we await more evidence, it is recommended that the clinician and patient use shared decision making to decide on cerclage placement in a twin gestation.

Exam indicated. In a singleton pregnancy with a dilated cervix on digital or speculum exam between 16 0/7 to 23 6/7 weeks’ gestation, a physical exam–indicated cerclage should be offered. Exam-indicated cerclage also may reduce the incidence of PTB in twin gestations with cervical dilation between 16 0/7 and 23 6/7 weeks’ gestation. Indomethacin tocolysis and perioperative antibiotics should be considered when an exam-indicated cerclage is placed.

As the limits of viability are continually pushed earlier, more in-depth conversation is needed with patients who are considering an exam-indicated cerclage. The nuances of periviability and the likelihood that an exam-indicated cerclage will commit a pregnancy to a periviable or extremely preterm birth should be discussed in detail using a shared decision making model.

Regardless of whether the cerclage is ultrasound or exam indicated, once it is placed there is no utility in additional CL ultrasound monitoring.

Pessary

Vaginal pessaries for prevention of PTB have not gained popularity in the United States as they have in other countries. Trials are being conducted to determine the utility of vaginal pessary, but current data have not proven its effectiveness in preventing PTB in the setting of singleton pregnancy, short cervix, and no history of spontaneous PTB. So for now, pessary is not recommended. The same can be said for use in the twin gestation.

Which patients may benefit from antepartum fetal surveillance and when to initiate it

American College of Obstetricians and Gynecologists’ Committee on Obstetrics Practice, Society for Maternal-Fetal Medicine. Indications for outpatient antenatal surveillance: ACOG committee opinion, number 828. Obstet Gynecol. 2021;137:e177-e197.

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Antepartum fetal surveillance: ACOG practice bulletin, number 229. Obstet Gynecol. 2021;137:e116-e127.

The ultimate purpose of antenatal fetal surveillance is to prevent stillbirth. However, stillbirth has multiple etiologies, not all of which are preventable with testing. In June 2021, ACOG released a new Committee Opinion containing guidelines for fetal surveillance, including suggested gestational age at initiation and frequency of testing, for the most common high-risk conditions. ACOG also released an update to the Practice Bulletin on antepartum fetal surveillance; additions include randomized controlled trial level data on the utility of fetal kick counts (FKCs) and recommendations that align with the new Committee Opinion.

Data for the efficacy of antepartum fetal surveillance are lacking, mainly due to the difficulty of performing prospective studies in stillbirth. The existing evidence is subject to intervention bias, as deliveries increase in tested patients, and recommendations rely heavily on expert consensus and nonrandomized studies. Antenatal testing is also time, cost, and labor intensive, with the risk of intervention for a false-positive result. Despite these limitations, obstetrical practices routinely perform antenatal fetal surveillance.

The new guidelines: The why, when, and how often

Why. Antepartum fetal surveillance is suggested for conditions that have a risk of stillbirth greater than 0.8 per 1,000 (that is, the false-negative rate of a biophysical profile or a modified biophysical profile) and the relative risk or odds ratio is greater than 2.0 for stillbirth compared with unaffected pregnancies.

When. For most conditions, ACOG recommends initiation of testing at 32 weeks or later, with notable earlier exceptions for some of the highest-risk patients. For certain conditions, such as fetal growth restriction and hypertensive disorders of pregnancy, the recommendation is to start “at diagnosis,” with the corollary “or at a gestational age when delivery would be considered because of abnormal results.” Shared decision making with the patient about pregnancy goals therefore is required, particularly in cases of fetal anomalies, genetic conditions, or at very early gestational ages.

How often. The recommended frequency of testing is at least weekly. Testing frequency should be increased to twice-weekly outpatient or daily inpatient for the most complicated pregnancies (for example, fetal growth restriction with abnormal umbilical artery Doppler studies, preeclampsia with severe features).

Once or twice weekly is an option for many conditions, which gives the clinician the opportunity to assess clinical stability as well as the patient’s input in terms of logistics and anxiety.

Patients with multiple conditions may fall into the “individualized” category, as do patients with suboptimal control of conditions (for example, diabetes, hypertension) that may affect the fetus as the pregnancy progresses.

New diagnoses included for surveillance

Several diagnoses not previously included now qualify for antepartum fetal surveillance under the new guidelines, most notably:

• history of obstetrical complications in the immediate preceding pregnancy

—history of prior fetal growth restriction requiring preterm delivery

—history of prior preeclampsia requiring delivery

• alcohol use of 5 or more drinks per day
• in vitro fertilization
• abnormal serum markers

—pregnancy-associated plasma protein A (PAPP-A) in the fifth or lower percentile or 0.4 multiples of the median (MoM)

—second trimester inhibin A of 2 or greater MoM

• prepregnancy body mass index (BMI)

—this is divided into 2 categories for timing of initiation of testing:

1.  37 weeks for BMI of 35 to 39.9 kg/m²
2.  34 weeks for BMI of or greater than 40 kg/m².

Fetal kick counts

The major change to the updated Practice Bulletin on antenatal surveillance is the inclusion of data on FKCs, a simple modality of fetal surveillance that does not require a clinical visit. For FKCs, a meta-analysis of more than 450,000 patients did not demonstrate a difference in perinatal death between the FKC intervention group (0.54%) and the control group (0.59%). Of note, there were small but statistically significant increases in the rates of induction of labor, cesarean delivery, and preterm delivery in the FKC intervention group. Therefore, this update does not recommend a formal program of FKCs for all patients.

Continue to: Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation...

Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation

American College of Obstetricians and Gynecologists. Use of antenatal corticosteroids at 22 weeks of gestation: ACOG practice advisory. September 2021. https://www .acog.org/clinical/clinical-guidance/practice-advisory /articles/2021/09/use-of-antenatal-corticosteroids-at -22-weeks-of-gestation. Accessed December 11, 2021.

In September 2021, ACOG and SMFM released a Practice Advisory updating the current recommendations for the administration of antenatal corticosteroids in the periviable period (22 to 25 6/7 weeks’ gestation). Whereas the prior lower limit of gestational age for consideration of steroids was 23 weeks, the new recommendation now extends this consideration down to 22 weeks.

The cited data include a meta-analysis of more than 2,200 patients in which the survival rate of infants born between 22 and 22 6/7 weeks who were exposed to antenatal steroids was 39% compared with 19.5% in the unexposed group. Another study of more than 1,000 patients demonstrated a statistically significant increase in overall survival in patients treated with antenatal steroids plus life support compared with life support only (38.5% vs 17.7%). Survival without major morbidity in this study, although increased from 1% to 4.4%, was still low.

Recommendation carries caveats

Given this information, the Practice Advisory offers a 2C level recommendation (weak recommendation, low quality of evidence) for antenatal steroids at 22 to 22 6/7 weeks’ gestation if neonatal resuscitation is planned, acknowledging the limitations and potential bias of the available data.

The Practice Advisory emphasizes the importance of counseling and patient involvement in the decision making. This requires a multidisciplinary collaboration among the neonatology and obstetrical teams, flexibility in the plan after birth depending on the infant’s condition, and redirection of care if appropriate. Estimated fetal weight, the presence of multiple gestations, fetal biologic sex, and any anomalies are also important in helping families make an informed decision for their particular pregnancy. As described in the Obstetric Care Consensus on periviable birth,⁶ it is important to remember that considerations and recommendations are not the same as requirements, and redirection of care to comfort and family memory making is not the same as withholding care.

The rest of the recommendations for the administration of antenatal steroids remain the same: Antenatal steroids are not recommended at less than 22 weeks due to lack of evidence of benefit, and they continue to be recommended at 24 weeks and beyond. ●

Obstetrical practice saw updates in 2021 to 3 major areas of pregnancy management: preterm birth prevention, antepartum fetal surveillance, and the use of antenatal corticosteroids.

Updated guidance on predicting and preventing spontaneous PTB

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins–Obstetrics. Prediction and prevention of spontaneous preterm birth: ACOG practice bulletin, number 234. Obstet Gynecol. 2021;138:e65-e90.

Preterm birth (PTB) continues to pose a challenge in clinical obstetrics, with the most recently reported rate of 10.2% in the United States.¹ This accounts for almost 75% of perinatal mortality and more than half of neonatal morbidity, in which effects last well past the neonatal period. PTB is classified as spontaneous (following preterm labor, preterm prelabor rupture of membranes, or cervical insufficiency) or iatrogenic (indicated due to maternal and/or fetal complications).

Assessing risk for PTB

The single strongest predictor of subsequent PTB is a history of spontaneous PTB. Recurrence risk is further increased by the number of prior PTBs and the gestational age at prior PTB. Identification of and intervention for a short cervix has been shown to prolong gestation. Transvaginal ultrasonography of the cervix is the most accurate method for evaluating cervical length (CL). Specific examination criteria exist to ensure that CL measurements are reproducible and reliable.² A short CL is generally defined as a measurement of less than 25 mm between 16 and 24 weeks’ gestation.

Screening strategies

The American College of Obstetricians and Gynecologists (ACOG), with an endorsement from the Society for Maternal-Fetal Medicine (SMFM), recommends cervical evaluation during the anatomy ultrasound exam between 18 0/7 and 22 6/7 weeks’ gestation in all pregnant patients regardless of prior PTB.³ If transabdominal imaging is concerning for a shortened cervix, transvaginal ultrasonography should be performed to assess the CL.

Serial transvaginal CL measurements are recommended between 16 0/7 and 24 0/7 weeks’ gestation for patients with a current singleton pregnancy and history of a spontaneous PTB, but not for patients with a history of iatrogenic or indicated PTB.

Interventions: Mind your p’s and c’s

Interventions to reduce the risk of spontaneous PTB depend on whether the current pregnancy is a singleton, twins, or higher-order multiples; CL measurement; and history of spontaneous PTB. Preconception optimization of underlying medical conditions also is important to reduce the risk of recurrent indicated PTB.

Continue to: Progesterone...

Progesterone

Vaginal administration. Several trials have shown that vaginal progesterone can be used to reduce the risk of spontaneous PTB in asymptomatic patients with a singleton pregnancy, incidental finding of a short cervix (<25 mm), and no history of spontaneous PTB. This is a change from the prior recommendation of CL of less than 20 mm. In the setting of a twin pregnancy, regardless of CL, data do not definitively support the use of vaginal progesterone.

Intramuscular administration.^4,5 The popularity of intramuscular progesterone has waxed and waned. At present, ACOG recommends that all patients with a singleton pregnancy and history of spontaneous PTB be offered progesterone beginning at 16 0/7 weeks’ gestation following a shared decision-making process that includes the limited data of efficacy noted in existing studies.

In a twin pregnancy with no history of spontaneous PTB, the use of intramuscular progesterone has been shown to potentially increase the risk of PTB and admission to the neonatal intensive care unit. As such, intramuscular progesterone in the setting of a twin gestation without a history of spontaneous PTB is not recommended. When a prior spontaneous PTB has occurred, there may be some benefit to intramuscular progesterone in twin gestations.

Cerclage

Ultrasound indicated. In a singleton pregnancy with an incidental finding of short cervix (<25 mm) and no history of PTB, the use of cerclage is of uncertain benefit. Effectiveness may be seen if the cervix is less than 10 mm. Ultrasound-indicated cerclage should be considered in a singleton pregnancy with a CL less than 25 mm and a history of spontaneous PTB.

Possibly one of the most controversial topics is ultrasound-indicated cerclage placement in twin gestation. As with many situations in obstetrics, data regarding ultrasound-indicated cerclage in twin gestation is based on small retrospective studies fraught with bias. Results from these studies range from no benefit, to potential benefit, to even possible increased risk of PTB. Since data are limited, as we await more evidence, it is recommended that the clinician and patient use shared decision making to decide on cerclage placement in a twin gestation.

Exam indicated. In a singleton pregnancy with a dilated cervix on digital or speculum exam between 16 0/7 to 23 6/7 weeks’ gestation, a physical exam–indicated cerclage should be offered. Exam-indicated cerclage also may reduce the incidence of PTB in twin gestations with cervical dilation between 16 0/7 and 23 6/7 weeks’ gestation. Indomethacin tocolysis and perioperative antibiotics should be considered when an exam-indicated cerclage is placed.

As the limits of viability are continually pushed earlier, more in-depth conversation is needed with patients who are considering an exam-indicated cerclage. The nuances of periviability and the likelihood that an exam-indicated cerclage will commit a pregnancy to a periviable or extremely preterm birth should be discussed in detail using a shared decision making model.

Regardless of whether the cerclage is ultrasound or exam indicated, once it is placed there is no utility in additional CL ultrasound monitoring.

Pessary

Vaginal pessaries for prevention of PTB have not gained popularity in the United States as they have in other countries. Trials are being conducted to determine the utility of vaginal pessary, but current data have not proven its effectiveness in preventing PTB in the setting of singleton pregnancy, short cervix, and no history of spontaneous PTB. So for now, pessary is not recommended. The same can be said for use in the twin gestation.

Which patients may benefit from antepartum fetal surveillance and when to initiate it

American College of Obstetricians and Gynecologists’ Committee on Obstetrics Practice, Society for Maternal-Fetal Medicine. Indications for outpatient antenatal surveillance: ACOG committee opinion, number 828. Obstet Gynecol. 2021;137:e177-e197.

American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Antepartum fetal surveillance: ACOG practice bulletin, number 229. Obstet Gynecol. 2021;137:e116-e127.

The ultimate purpose of antenatal fetal surveillance is to prevent stillbirth. However, stillbirth has multiple etiologies, not all of which are preventable with testing. In June 2021, ACOG released a new Committee Opinion containing guidelines for fetal surveillance, including suggested gestational age at initiation and frequency of testing, for the most common high-risk conditions. ACOG also released an update to the Practice Bulletin on antepartum fetal surveillance; additions include randomized controlled trial level data on the utility of fetal kick counts (FKCs) and recommendations that align with the new Committee Opinion.

Data for the efficacy of antepartum fetal surveillance are lacking, mainly due to the difficulty of performing prospective studies in stillbirth. The existing evidence is subject to intervention bias, as deliveries increase in tested patients, and recommendations rely heavily on expert consensus and nonrandomized studies. Antenatal testing is also time, cost, and labor intensive, with the risk of intervention for a false-positive result. Despite these limitations, obstetrical practices routinely perform antenatal fetal surveillance.

The new guidelines: The why, when, and how often

Why. Antepartum fetal surveillance is suggested for conditions that have a risk of stillbirth greater than 0.8 per 1,000 (that is, the false-negative rate of a biophysical profile or a modified biophysical profile) and the relative risk or odds ratio is greater than 2.0 for stillbirth compared with unaffected pregnancies.

When. For most conditions, ACOG recommends initiation of testing at 32 weeks or later, with notable earlier exceptions for some of the highest-risk patients. For certain conditions, such as fetal growth restriction and hypertensive disorders of pregnancy, the recommendation is to start “at diagnosis,” with the corollary “or at a gestational age when delivery would be considered because of abnormal results.” Shared decision making with the patient about pregnancy goals therefore is required, particularly in cases of fetal anomalies, genetic conditions, or at very early gestational ages.

How often. The recommended frequency of testing is at least weekly. Testing frequency should be increased to twice-weekly outpatient or daily inpatient for the most complicated pregnancies (for example, fetal growth restriction with abnormal umbilical artery Doppler studies, preeclampsia with severe features).

Once or twice weekly is an option for many conditions, which gives the clinician the opportunity to assess clinical stability as well as the patient’s input in terms of logistics and anxiety.

Patients with multiple conditions may fall into the “individualized” category, as do patients with suboptimal control of conditions (for example, diabetes, hypertension) that may affect the fetus as the pregnancy progresses.

New diagnoses included for surveillance

Several diagnoses not previously included now qualify for antepartum fetal surveillance under the new guidelines, most notably:

• history of obstetrical complications in the immediate preceding pregnancy

—history of prior fetal growth restriction requiring preterm delivery

—history of prior preeclampsia requiring delivery

• alcohol use of 5 or more drinks per day
• in vitro fertilization
• abnormal serum markers

—pregnancy-associated plasma protein A (PAPP-A) in the fifth or lower percentile or 0.4 multiples of the median (MoM)

—second trimester inhibin A of 2 or greater MoM

• prepregnancy body mass index (BMI)

—this is divided into 2 categories for timing of initiation of testing:

1.  37 weeks for BMI of 35 to 39.9 kg/m²
2.  34 weeks for BMI of or greater than 40 kg/m².

Fetal kick counts

The major change to the updated Practice Bulletin on antenatal surveillance is the inclusion of data on FKCs, a simple modality of fetal surveillance that does not require a clinical visit. For FKCs, a meta-analysis of more than 450,000 patients did not demonstrate a difference in perinatal death between the FKC intervention group (0.54%) and the control group (0.59%). Of note, there were small but statistically significant increases in the rates of induction of labor, cesarean delivery, and preterm delivery in the FKC intervention group. Therefore, this update does not recommend a formal program of FKCs for all patients.

Continue to: Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation...

Use of antenatal corticosteroids now may be considered at 22 weeks’ gestation

American College of Obstetricians and Gynecologists. Use of antenatal corticosteroids at 22 weeks of gestation: ACOG practice advisory. September 2021. https://www .acog.org/clinical/clinical-guidance/practice-advisory /articles/2021/09/use-of-antenatal-corticosteroids-at -22-weeks-of-gestation. Accessed December 11, 2021.

In September 2021, ACOG and SMFM released a Practice Advisory updating the current recommendations for the administration of antenatal corticosteroids in the periviable period (22 to 25 6/7 weeks’ gestation). Whereas the prior lower limit of gestational age for consideration of steroids was 23 weeks, the new recommendation now extends this consideration down to 22 weeks.

The cited data include a meta-analysis of more than 2,200 patients in which the survival rate of infants born between 22 and 22 6/7 weeks who were exposed to antenatal steroids was 39% compared with 19.5% in the unexposed group. Another study of more than 1,000 patients demonstrated a statistically significant increase in overall survival in patients treated with antenatal steroids plus life support compared with life support only (38.5% vs 17.7%). Survival without major morbidity in this study, although increased from 1% to 4.4%, was still low.

Recommendation carries caveats

Given this information, the Practice Advisory offers a 2C level recommendation (weak recommendation, low quality of evidence) for antenatal steroids at 22 to 22 6/7 weeks’ gestation if neonatal resuscitation is planned, acknowledging the limitations and potential bias of the available data.

The Practice Advisory emphasizes the importance of counseling and patient involvement in the decision making. This requires a multidisciplinary collaboration among the neonatology and obstetrical teams, flexibility in the plan after birth depending on the infant’s condition, and redirection of care if appropriate. Estimated fetal weight, the presence of multiple gestations, fetal biologic sex, and any anomalies are also important in helping families make an informed decision for their particular pregnancy. As described in the Obstetric Care Consensus on periviable birth,⁶ it is important to remember that considerations and recommendations are not the same as requirements, and redirection of care to comfort and family memory making is not the same as withholding care.

The rest of the recommendations for the administration of antenatal steroids remain the same: Antenatal steroids are not recommended at less than 22 weeks due to lack of evidence of benefit, and they continue to be recommended at 24 weeks and beyond. ●

Feminine hygiene products have been commercially available for decades. They are commonly marketed to reduce odor or clean vaginal discharge and menses. Multiple formulas are available as topical washes, wipes, creams, sprays, powders, deodorants, and douches.¹ Products on the market range from those used externally on the vulva, such as wipes and sprays, to liquid solutions used intravaginally, such as washes and douches.

Who uses feminine hygiene products?

According to a 2006 study, the majority of women who use douches started using them between age 15 and 19 years, but some women initiate this practice habit as early as age 10 to 14.¹ Predictably, women who douche are more likely to perceive douche products as safe.¹

Demographic data on douche utilization are mixed: Some studies show that there are no significant racial differences in douching practices,² while others have found that Black and African American women are more likely to practice douching than White and Hispanic women.^1,3 Studies have shown a significant difference in attitudes toward douching and knowledge of normal vaginal symptoms among US racial demographics, although this must be examined through the historical context of racism and the lens of medical anthropology.⁴

Women cite that common reasons they use feminine hygiene products are to feel clean, to control odor, and to use after menses and intercourse.^1,2

Modern marketing approaches

From wipes to soaps to douches, feminine hygiene products often are advertised to promote “funk-free periods”⁵ and “freshness,” fostering an environment in which women and men develop unrealistic standards for what is considered normal genital odor and resulting in poor body image.⁶

Recently, Vagisil (Combe Incorporated) marketing efforts faced backlash from the ObGyn community for targeting younger populations with a specific product line for adolescents called OMV! In addition, attention has been drawn to VCF vaginal odor eliminating film (Apothecus Pharmaceutical Corp), small stamp-sized dissolving films that are placed in the vaginal canal in contact with the epithelium. This product has entered the market of feminine hygiene products accompanied by slogans of eliminating “feminine odor” and providing “confidence for women to be intimate.”

Continue to: Effects of feminine hygiene products on the vaginal microbiome...

Frequent use of feminine hygiene products has been associated with recurrent vaginitis, bacterial vaginosis, and general irritation/itch,^7,8 which can cause more discharge and odor. Ironically, this may result in women using the product more frequently since they often seek out these products to eliminate odor and discharge.^1,2

The pH of the vagina changes during a woman’s lifetime, but in the reproductive years, the normal pH range is typically 3.8 to 4.4.⁹ This range allows for a normal vaginal flora to form with bacteria such as Lactobacillus species and Gardnerella vaginalis, while feminine hygiene products have a wide range of pH.^9,10

Regardless of the formulation, most feminine hygiene products contain ingredients and compositions that potentially are detrimental to the health of the vulva and vagina. Many products contain acidic ingredients, such as citric acid, lactic acid, and dehydroacetic acid, that can alter the vaginal pH and weaken the vaginal barrier by wiping out normal vaginal flora¹⁰ despite being advertised for use on “sensitive areas” (TABLE). Lactic acid also has been found to increase diverse anaerobic bacteria in the vaginal microbiome.¹¹ Some feminine hygiene products have been shown to suppress Lactobacillus growth at 2 hours after use and to kill all lactobacilli at 24 hours.¹⁰ Shifts in microbiota numbers often occur when the vaginal pH has been altered, as is frequently the case with feminine hygiene products. In the absence of microbiome bacteria, the presence of vaginal hygiene products has been shown to increase interleukin-8 (IL-8), suggesting a proinflammatory reaction.¹⁰

A study in the United Kingdom found that women who used bubble bath, antiseptics, or douche products had a higher incidence of bacterial vaginosis compared with women who did not use such products.⁷ Women in Canada who used feminine hygiene products were more likely to report adverse conditions, including yeast infections, bacterial vaginosis, urinary tract infections, and sexually transmitted diseases.⁸ Furthermore, a significant association exists between vaginal douching and endometrial infection by bacterial vaginosis–associated organisms.¹²

Additionally, a study that analyzed volatile organic compound levels in the blood with the use of feminine hygiene products revealed a significant positive dose-exposure relationship between the frequency of vaginal douching in the last 6 months and concentrations of 1,4-dichloromethane, one of the volatile organic compounds.³ This points to the issue of not only disruption of pH and vaginal flora but also to the introduction of harmful substances that can further disrupt the vaginal barrier.

Understand the products to help educate patients

Use of feminine hygiene products is common among women. While women depend on the market to filter out products that are considered unsafe or may have harmful side effects,¹ unfortunately that is not necessarily the case. With increasingly more feminine products on the market and the target demographic becoming younger, women of all ages are susceptible to misinformation that could affect their vaginal health long term.

It is vital that clinicians understand the topical effects of these products in order to properly educate and counsel patients. Ultimately, research on feminine hygiene products is limited and, as more products come to market, we must continue to reassess the effects of topical products on the vaginal epithelium and vulvar tissues. ●

Feminine hygiene products have been commercially available for decades. They are commonly marketed to reduce odor or clean vaginal discharge and menses. Multiple formulas are available as topical washes, wipes, creams, sprays, powders, deodorants, and douches.¹ Products on the market range from those used externally on the vulva, such as wipes and sprays, to liquid solutions used intravaginally, such as washes and douches.

Who uses feminine hygiene products?

According to a 2006 study, the majority of women who use douches started using them between age 15 and 19 years, but some women initiate this practice habit as early as age 10 to 14.¹ Predictably, women who douche are more likely to perceive douche products as safe.¹

Demographic data on douche utilization are mixed: Some studies show that there are no significant racial differences in douching practices,² while others have found that Black and African American women are more likely to practice douching than White and Hispanic women.^1,3 Studies have shown a significant difference in attitudes toward douching and knowledge of normal vaginal symptoms among US racial demographics, although this must be examined through the historical context of racism and the lens of medical anthropology.⁴

Women cite that common reasons they use feminine hygiene products are to feel clean, to control odor, and to use after menses and intercourse.^1,2

Modern marketing approaches

From wipes to soaps to douches, feminine hygiene products often are advertised to promote “funk-free periods”⁵ and “freshness,” fostering an environment in which women and men develop unrealistic standards for what is considered normal genital odor and resulting in poor body image.⁶

Recently, Vagisil (Combe Incorporated) marketing efforts faced backlash from the ObGyn community for targeting younger populations with a specific product line for adolescents called OMV! In addition, attention has been drawn to VCF vaginal odor eliminating film (Apothecus Pharmaceutical Corp), small stamp-sized dissolving films that are placed in the vaginal canal in contact with the epithelium. This product has entered the market of feminine hygiene products accompanied by slogans of eliminating “feminine odor” and providing “confidence for women to be intimate.”

Continue to: Effects of feminine hygiene products on the vaginal microbiome...

Frequent use of feminine hygiene products has been associated with recurrent vaginitis, bacterial vaginosis, and general irritation/itch,^7,8 which can cause more discharge and odor. Ironically, this may result in women using the product more frequently since they often seek out these products to eliminate odor and discharge.^1,2

The pH of the vagina changes during a woman’s lifetime, but in the reproductive years, the normal pH range is typically 3.8 to 4.4.⁹ This range allows for a normal vaginal flora to form with bacteria such as Lactobacillus species and Gardnerella vaginalis, while feminine hygiene products have a wide range of pH.^9,10

Regardless of the formulation, most feminine hygiene products contain ingredients and compositions that potentially are detrimental to the health of the vulva and vagina. Many products contain acidic ingredients, such as citric acid, lactic acid, and dehydroacetic acid, that can alter the vaginal pH and weaken the vaginal barrier by wiping out normal vaginal flora¹⁰ despite being advertised for use on “sensitive areas” (TABLE). Lactic acid also has been found to increase diverse anaerobic bacteria in the vaginal microbiome.¹¹ Some feminine hygiene products have been shown to suppress Lactobacillus growth at 2 hours after use and to kill all lactobacilli at 24 hours.¹⁰ Shifts in microbiota numbers often occur when the vaginal pH has been altered, as is frequently the case with feminine hygiene products. In the absence of microbiome bacteria, the presence of vaginal hygiene products has been shown to increase interleukin-8 (IL-8), suggesting a proinflammatory reaction.¹⁰

A study in the United Kingdom found that women who used bubble bath, antiseptics, or douche products had a higher incidence of bacterial vaginosis compared with women who did not use such products.⁷ Women in Canada who used feminine hygiene products were more likely to report adverse conditions, including yeast infections, bacterial vaginosis, urinary tract infections, and sexually transmitted diseases.⁸ Furthermore, a significant association exists between vaginal douching and endometrial infection by bacterial vaginosis–associated organisms.¹²

Additionally, a study that analyzed volatile organic compound levels in the blood with the use of feminine hygiene products revealed a significant positive dose-exposure relationship between the frequency of vaginal douching in the last 6 months and concentrations of 1,4-dichloromethane, one of the volatile organic compounds.³ This points to the issue of not only disruption of pH and vaginal flora but also to the introduction of harmful substances that can further disrupt the vaginal barrier.

Understand the products to help educate patients

Use of feminine hygiene products is common among women. While women depend on the market to filter out products that are considered unsafe or may have harmful side effects,¹ unfortunately that is not necessarily the case. With increasingly more feminine products on the market and the target demographic becoming younger, women of all ages are susceptible to misinformation that could affect their vaginal health long term.

It is vital that clinicians understand the topical effects of these products in order to properly educate and counsel patients. Ultimately, research on feminine hygiene products is limited and, as more products come to market, we must continue to reassess the effects of topical products on the vaginal epithelium and vulvar tissues. ●

Feminine hygiene products have been commercially available for decades. They are commonly marketed to reduce odor or clean vaginal discharge and menses. Multiple formulas are available as topical washes, wipes, creams, sprays, powders, deodorants, and douches.¹ Products on the market range from those used externally on the vulva, such as wipes and sprays, to liquid solutions used intravaginally, such as washes and douches.

Who uses feminine hygiene products?

According to a 2006 study, the majority of women who use douches started using them between age 15 and 19 years, but some women initiate this practice habit as early as age 10 to 14.¹ Predictably, women who douche are more likely to perceive douche products as safe.¹

Demographic data on douche utilization are mixed: Some studies show that there are no significant racial differences in douching practices,² while others have found that Black and African American women are more likely to practice douching than White and Hispanic women.^1,3 Studies have shown a significant difference in attitudes toward douching and knowledge of normal vaginal symptoms among US racial demographics, although this must be examined through the historical context of racism and the lens of medical anthropology.⁴

Women cite that common reasons they use feminine hygiene products are to feel clean, to control odor, and to use after menses and intercourse.^1,2

Modern marketing approaches

From wipes to soaps to douches, feminine hygiene products often are advertised to promote “funk-free periods”⁵ and “freshness,” fostering an environment in which women and men develop unrealistic standards for what is considered normal genital odor and resulting in poor body image.⁶

Recently, Vagisil (Combe Incorporated) marketing efforts faced backlash from the ObGyn community for targeting younger populations with a specific product line for adolescents called OMV! In addition, attention has been drawn to VCF vaginal odor eliminating film (Apothecus Pharmaceutical Corp), small stamp-sized dissolving films that are placed in the vaginal canal in contact with the epithelium. This product has entered the market of feminine hygiene products accompanied by slogans of eliminating “feminine odor” and providing “confidence for women to be intimate.”

Continue to: Effects of feminine hygiene products on the vaginal microbiome...

Frequent use of feminine hygiene products has been associated with recurrent vaginitis, bacterial vaginosis, and general irritation/itch,^7,8 which can cause more discharge and odor. Ironically, this may result in women using the product more frequently since they often seek out these products to eliminate odor and discharge.^1,2

The pH of the vagina changes during a woman’s lifetime, but in the reproductive years, the normal pH range is typically 3.8 to 4.4.⁹ This range allows for a normal vaginal flora to form with bacteria such as Lactobacillus species and Gardnerella vaginalis, while feminine hygiene products have a wide range of pH.^9,10

Regardless of the formulation, most feminine hygiene products contain ingredients and compositions that potentially are detrimental to the health of the vulva and vagina. Many products contain acidic ingredients, such as citric acid, lactic acid, and dehydroacetic acid, that can alter the vaginal pH and weaken the vaginal barrier by wiping out normal vaginal flora¹⁰ despite being advertised for use on “sensitive areas” (TABLE). Lactic acid also has been found to increase diverse anaerobic bacteria in the vaginal microbiome.¹¹ Some feminine hygiene products have been shown to suppress Lactobacillus growth at 2 hours after use and to kill all lactobacilli at 24 hours.¹⁰ Shifts in microbiota numbers often occur when the vaginal pH has been altered, as is frequently the case with feminine hygiene products. In the absence of microbiome bacteria, the presence of vaginal hygiene products has been shown to increase interleukin-8 (IL-8), suggesting a proinflammatory reaction.¹⁰

A study in the United Kingdom found that women who used bubble bath, antiseptics, or douche products had a higher incidence of bacterial vaginosis compared with women who did not use such products.⁷ Women in Canada who used feminine hygiene products were more likely to report adverse conditions, including yeast infections, bacterial vaginosis, urinary tract infections, and sexually transmitted diseases.⁸ Furthermore, a significant association exists between vaginal douching and endometrial infection by bacterial vaginosis–associated organisms.¹²

Additionally, a study that analyzed volatile organic compound levels in the blood with the use of feminine hygiene products revealed a significant positive dose-exposure relationship between the frequency of vaginal douching in the last 6 months and concentrations of 1,4-dichloromethane, one of the volatile organic compounds.³ This points to the issue of not only disruption of pH and vaginal flora but also to the introduction of harmful substances that can further disrupt the vaginal barrier.

Understand the products to help educate patients

Use of feminine hygiene products is common among women. While women depend on the market to filter out products that are considered unsafe or may have harmful side effects,¹ unfortunately that is not necessarily the case. With increasingly more feminine products on the market and the target demographic becoming younger, women of all ages are susceptible to misinformation that could affect their vaginal health long term.

It is vital that clinicians understand the topical effects of these products in order to properly educate and counsel patients. Ultimately, research on feminine hygiene products is limited and, as more products come to market, we must continue to reassess the effects of topical products on the vaginal epithelium and vulvar tissues. ●

The buccal fat pad (Bichat fat pad) is a tubular-shaped collection of adipose tissue that occupies a prominent position in the midface. The buccal fat pad has been described as having 3 lobes: an anterior lobe, which is anterior to the masseter muscle; an intermediate lobe between the masseter and buccinator muscles; and a posterior lobe between the temporal masticatory space.¹ There are 4 extensions from the body of the buccal fat pad: the buccal, the sublevator, the melolabial, and the pterygoid. It is the buccal extension and main body that are removed intraorally to achieve midfacial and lower facial contouring, as these support the contours of the cheeks. The deep fat pad within the temporal fossa is a true extension of the buccal fat pad (Figure).² It has a complex relationship to the facial structures, with known variability in the positions of the buccal branch of the facial nerve and the parotid duct.³ The parotid duct travels over, superior to, or through the buccal extension 42%, 32%, and 26% of the time, respectively. The duct travels along the surface of the masseter, then pierces the buccinator to drain into the vestibule of the mouth at the second superior molar tooth. The buccal branch of the facial nerve travels on the surface of the buccal fat pad 73% of the time, whereas 27% of the time it travels deeper through the buccal extension.⁴ A study that used ultrasonography to map the surface anatomy path of the parotid duct in 50 healthy patients showed that the duct was within 1.5 cm of the middle half of a line between the lower border of the tragus and the oral commissure in 93% of individuals.⁵ We describe a technique in which part of the buccal fat pad is removed and the fat is transferred to the temple to achieve aesthetically pleasing facial contouring. We used a vertical line from the lateral canthus as a surface anatomy landmark to determine when the duct emerges from the gland and is most susceptible to injury.

Illustration by Ni-ka Ford, MS. Printed with permission from Mount Sinai Health System (New York, New York).

Operative Technique

Correct instrumentation is important to obtain appropriate anatomic exposure for this procedure. The surgical tray should include 4-0 poliglecaprone 25 suture, bite guards, a needle driver, a hemostat, surgical scissors, toothed forceps, a Beaver surgical handle with #15 blade, a protected diathermy needle, cotton tip applicators, and gauze.

Fat Harvest—With the patient supine, bite blocks are placed, and the buccal fat pad incision line is marked with a surgical marker. A 1-cm line is drawn approximately 4 cm posterior to the oral commissure by the buccal bite marks. The location is verified by balloting externally on the buccal fat pad on the cheek. The incision line is then anesthetized transorally with lidocaine and epinephrine-containing solution. The cheek is retracted laterally with Caldwell-Luc retractors, and a 1-cm incision is made and carried through the mucosa and superficial muscle using the Colorado needle. Scissors are then used to spread the deeper muscle fibers to expose the deeper fascia and fat pads. Metzenbaum scissors are used to gently spread the fat while the surgeon places pressure on the external cheek, manipulating the fat into the wound. Without excess traction, the walnut-sized portion of the fat pad that protrudes is grasped with Debakey forceps, gently teased into the field, clamped at its base with a curved hemostat, and excised. The stump is electrocoagulated with an extendable protected Colorado needle, with care to prevent inadvertent cauterization of the lips. The wound is closed with a single 4-0 poliglecaprone-25 suture.

A 5-cc Luer lock syringe is preloaded with 2 cc of normal saline and attached to another 5-cc Luer lock syringe via a female-female attachment. The excised fat is then placed in a 5-cc Luer lock syringe by removing the plunger. The plunger is then reinstalled, and the fat is injected back and forth approximately 30 times. The fat is centrifuged at 3500 rpm for 3 minutes. The purified fat is then transferred to a 1-cc Luer lock syringe attached to an 18-gauge needle.

Fat Injection—The authors use an 18-gauge needle to perform depot injections into the temporal fossae above the periosteum. This is a relatively safe area of the face to inject, but care must be taken to avoid injury to the superficial temporal artery. Between 1.5 and 3 cc of high-quality fat usually are administered to each temple.

Aftercare Instructions—The patient is instructed to have a soft diet for 24 to 48 hours and can return to work the next day. The patient also is given prophylactic antibiotics with Gram-negative coverage for 7 days (amoxicillin-clavulanate 875 mg/125 mg orally twice daily for 7 days).

Candidates for Buccal Fat Pad Reduction

Buccal fat pad reduction has become an increasingly popular technique for midface and lower face shaping to decrease the appearance of a round face. To achieve an aesthetically pleasing midface, surgeons should consider enhancing zygomatic eminences while emphasizing the border between the zygomatic prominence and cheek hollow.⁶ Selection criteria for buccal fat pad reduction are not well established. One study recommended avoiding the procedure in pregnant or lactating patients, patients with chronic illnesses, patients on blood-thinning agents, and patients younger than 18 years. In addition, this study suggested ensuring the malar fullness is in the anteromedial portion of the face, as posterolateral fullness may be due to masseter hypertrophy.⁶

Complications associated with buccal fat pad reduction include inadvertent damage to surrounding structures, including the buccal branch of the facial nerve and parotid duct. Because the location of the facial nerve in relation to the parotid duct is highly variable, surgeons must be aware of its anatomy to avoid unintentional damage. Hwang et al⁷ reported that the parotid duct and buccal branches of the facial nerves passed through the buccal extension in 26.3% of cadavers. The transbuccal approach is preferred over the sub–superficial muscular aponeurotic system approach largely because it avoids these structures. In addition, blunt dissection may further decrease chances of injury. Although the long-term effects are unknown, there is a potential risk for facial hollowing.³ The use of preprocedure ultrasonography to quantify the buccal fat pad may avoid overresection and enhanced potential for facial hollowing.⁶

Avoidance of Temporal Hollowing

Because the buccal fat pad extends into the temporal space, buccal fat pad reduction may lead to further temporal hollowing, contributing to an aged appearance. The authors’ technique addresses both midface and upper face contouring in one minimally invasive procedure. Temporal hollowing commonly has been corrected with autologous fat grafting from the thigh or abdomen, which leads to an additional scar at the donor site. Our technique relies on autologous adjacent fat transfer from previously removed buccal fat. In addition, compared with the use of hyaluronic acid fillers for temple reflation, fat transfer largely is safe and biocompatible. Major complications of autologous fat transfer to the temples include nodularity or fat clumping, fat necrosis, sensory or motor nerve damage, and edema or ecchymosis.⁴ Also, with time there will be ongoing hollowing of the temples as part of the aging process with soft tissue and bone resorption. Therefore, further volume restoration procedures may be required in the future to address these dynamic changes.

Conclusion

The buccal fat pad has been extensively used to reconstruct oral defects, including oroantral and cranial base defects, owing to its high vascularity.⁶ However, there also is great potential to utilize buccal fat for autologous fat transfer to improve temporal wasting. Further studies are needed to determine optimal technique as well as longer-term safety and efficacy of this procedure.

The buccal fat pad (Bichat fat pad) is a tubular-shaped collection of adipose tissue that occupies a prominent position in the midface. The buccal fat pad has been described as having 3 lobes: an anterior lobe, which is anterior to the masseter muscle; an intermediate lobe between the masseter and buccinator muscles; and a posterior lobe between the temporal masticatory space.¹ There are 4 extensions from the body of the buccal fat pad: the buccal, the sublevator, the melolabial, and the pterygoid. It is the buccal extension and main body that are removed intraorally to achieve midfacial and lower facial contouring, as these support the contours of the cheeks. The deep fat pad within the temporal fossa is a true extension of the buccal fat pad (Figure).² It has a complex relationship to the facial structures, with known variability in the positions of the buccal branch of the facial nerve and the parotid duct.³ The parotid duct travels over, superior to, or through the buccal extension 42%, 32%, and 26% of the time, respectively. The duct travels along the surface of the masseter, then pierces the buccinator to drain into the vestibule of the mouth at the second superior molar tooth. The buccal branch of the facial nerve travels on the surface of the buccal fat pad 73% of the time, whereas 27% of the time it travels deeper through the buccal extension.⁴ A study that used ultrasonography to map the surface anatomy path of the parotid duct in 50 healthy patients showed that the duct was within 1.5 cm of the middle half of a line between the lower border of the tragus and the oral commissure in 93% of individuals.⁵ We describe a technique in which part of the buccal fat pad is removed and the fat is transferred to the temple to achieve aesthetically pleasing facial contouring. We used a vertical line from the lateral canthus as a surface anatomy landmark to determine when the duct emerges from the gland and is most susceptible to injury.

Illustration by Ni-ka Ford, MS. Printed with permission from Mount Sinai Health System (New York, New York).

Operative Technique

Correct instrumentation is important to obtain appropriate anatomic exposure for this procedure. The surgical tray should include 4-0 poliglecaprone 25 suture, bite guards, a needle driver, a hemostat, surgical scissors, toothed forceps, a Beaver surgical handle with #15 blade, a protected diathermy needle, cotton tip applicators, and gauze.

Fat Harvest—With the patient supine, bite blocks are placed, and the buccal fat pad incision line is marked with a surgical marker. A 1-cm line is drawn approximately 4 cm posterior to the oral commissure by the buccal bite marks. The location is verified by balloting externally on the buccal fat pad on the cheek. The incision line is then anesthetized transorally with lidocaine and epinephrine-containing solution. The cheek is retracted laterally with Caldwell-Luc retractors, and a 1-cm incision is made and carried through the mucosa and superficial muscle using the Colorado needle. Scissors are then used to spread the deeper muscle fibers to expose the deeper fascia and fat pads. Metzenbaum scissors are used to gently spread the fat while the surgeon places pressure on the external cheek, manipulating the fat into the wound. Without excess traction, the walnut-sized portion of the fat pad that protrudes is grasped with Debakey forceps, gently teased into the field, clamped at its base with a curved hemostat, and excised. The stump is electrocoagulated with an extendable protected Colorado needle, with care to prevent inadvertent cauterization of the lips. The wound is closed with a single 4-0 poliglecaprone-25 suture.

A 5-cc Luer lock syringe is preloaded with 2 cc of normal saline and attached to another 5-cc Luer lock syringe via a female-female attachment. The excised fat is then placed in a 5-cc Luer lock syringe by removing the plunger. The plunger is then reinstalled, and the fat is injected back and forth approximately 30 times. The fat is centrifuged at 3500 rpm for 3 minutes. The purified fat is then transferred to a 1-cc Luer lock syringe attached to an 18-gauge needle.

Fat Injection—The authors use an 18-gauge needle to perform depot injections into the temporal fossae above the periosteum. This is a relatively safe area of the face to inject, but care must be taken to avoid injury to the superficial temporal artery. Between 1.5 and 3 cc of high-quality fat usually are administered to each temple.

Aftercare Instructions—The patient is instructed to have a soft diet for 24 to 48 hours and can return to work the next day. The patient also is given prophylactic antibiotics with Gram-negative coverage for 7 days (amoxicillin-clavulanate 875 mg/125 mg orally twice daily for 7 days).

Candidates for Buccal Fat Pad Reduction

Buccal fat pad reduction has become an increasingly popular technique for midface and lower face shaping to decrease the appearance of a round face. To achieve an aesthetically pleasing midface, surgeons should consider enhancing zygomatic eminences while emphasizing the border between the zygomatic prominence and cheek hollow.⁶ Selection criteria for buccal fat pad reduction are not well established. One study recommended avoiding the procedure in pregnant or lactating patients, patients with chronic illnesses, patients on blood-thinning agents, and patients younger than 18 years. In addition, this study suggested ensuring the malar fullness is in the anteromedial portion of the face, as posterolateral fullness may be due to masseter hypertrophy.⁶

Complications associated with buccal fat pad reduction include inadvertent damage to surrounding structures, including the buccal branch of the facial nerve and parotid duct. Because the location of the facial nerve in relation to the parotid duct is highly variable, surgeons must be aware of its anatomy to avoid unintentional damage. Hwang et al⁷ reported that the parotid duct and buccal branches of the facial nerves passed through the buccal extension in 26.3% of cadavers. The transbuccal approach is preferred over the sub–superficial muscular aponeurotic system approach largely because it avoids these structures. In addition, blunt dissection may further decrease chances of injury. Although the long-term effects are unknown, there is a potential risk for facial hollowing.³ The use of preprocedure ultrasonography to quantify the buccal fat pad may avoid overresection and enhanced potential for facial hollowing.⁶

Avoidance of Temporal Hollowing

Because the buccal fat pad extends into the temporal space, buccal fat pad reduction may lead to further temporal hollowing, contributing to an aged appearance. The authors’ technique addresses both midface and upper face contouring in one minimally invasive procedure. Temporal hollowing commonly has been corrected with autologous fat grafting from the thigh or abdomen, which leads to an additional scar at the donor site. Our technique relies on autologous adjacent fat transfer from previously removed buccal fat. In addition, compared with the use of hyaluronic acid fillers for temple reflation, fat transfer largely is safe and biocompatible. Major complications of autologous fat transfer to the temples include nodularity or fat clumping, fat necrosis, sensory or motor nerve damage, and edema or ecchymosis.⁴ Also, with time there will be ongoing hollowing of the temples as part of the aging process with soft tissue and bone resorption. Therefore, further volume restoration procedures may be required in the future to address these dynamic changes.

Conclusion

The buccal fat pad has been extensively used to reconstruct oral defects, including oroantral and cranial base defects, owing to its high vascularity.⁶ However, there also is great potential to utilize buccal fat for autologous fat transfer to improve temporal wasting. Further studies are needed to determine optimal technique as well as longer-term safety and efficacy of this procedure.

The buccal fat pad (Bichat fat pad) is a tubular-shaped collection of adipose tissue that occupies a prominent position in the midface. The buccal fat pad has been described as having 3 lobes: an anterior lobe, which is anterior to the masseter muscle; an intermediate lobe between the masseter and buccinator muscles; and a posterior lobe between the temporal masticatory space.¹ There are 4 extensions from the body of the buccal fat pad: the buccal, the sublevator, the melolabial, and the pterygoid. It is the buccal extension and main body that are removed intraorally to achieve midfacial and lower facial contouring, as these support the contours of the cheeks. The deep fat pad within the temporal fossa is a true extension of the buccal fat pad (Figure).² It has a complex relationship to the facial structures, with known variability in the positions of the buccal branch of the facial nerve and the parotid duct.³ The parotid duct travels over, superior to, or through the buccal extension 42%, 32%, and 26% of the time, respectively. The duct travels along the surface of the masseter, then pierces the buccinator to drain into the vestibule of the mouth at the second superior molar tooth. The buccal branch of the facial nerve travels on the surface of the buccal fat pad 73% of the time, whereas 27% of the time it travels deeper through the buccal extension.⁴ A study that used ultrasonography to map the surface anatomy path of the parotid duct in 50 healthy patients showed that the duct was within 1.5 cm of the middle half of a line between the lower border of the tragus and the oral commissure in 93% of individuals.⁵ We describe a technique in which part of the buccal fat pad is removed and the fat is transferred to the temple to achieve aesthetically pleasing facial contouring. We used a vertical line from the lateral canthus as a surface anatomy landmark to determine when the duct emerges from the gland and is most susceptible to injury.

Illustration by Ni-ka Ford, MS. Printed with permission from Mount Sinai Health System (New York, New York).

Operative Technique

Correct instrumentation is important to obtain appropriate anatomic exposure for this procedure. The surgical tray should include 4-0 poliglecaprone 25 suture, bite guards, a needle driver, a hemostat, surgical scissors, toothed forceps, a Beaver surgical handle with #15 blade, a protected diathermy needle, cotton tip applicators, and gauze.

Fat Harvest—With the patient supine, bite blocks are placed, and the buccal fat pad incision line is marked with a surgical marker. A 1-cm line is drawn approximately 4 cm posterior to the oral commissure by the buccal bite marks. The location is verified by balloting externally on the buccal fat pad on the cheek. The incision line is then anesthetized transorally with lidocaine and epinephrine-containing solution. The cheek is retracted laterally with Caldwell-Luc retractors, and a 1-cm incision is made and carried through the mucosa and superficial muscle using the Colorado needle. Scissors are then used to spread the deeper muscle fibers to expose the deeper fascia and fat pads. Metzenbaum scissors are used to gently spread the fat while the surgeon places pressure on the external cheek, manipulating the fat into the wound. Without excess traction, the walnut-sized portion of the fat pad that protrudes is grasped with Debakey forceps, gently teased into the field, clamped at its base with a curved hemostat, and excised. The stump is electrocoagulated with an extendable protected Colorado needle, with care to prevent inadvertent cauterization of the lips. The wound is closed with a single 4-0 poliglecaprone-25 suture.

A 5-cc Luer lock syringe is preloaded with 2 cc of normal saline and attached to another 5-cc Luer lock syringe via a female-female attachment. The excised fat is then placed in a 5-cc Luer lock syringe by removing the plunger. The plunger is then reinstalled, and the fat is injected back and forth approximately 30 times. The fat is centrifuged at 3500 rpm for 3 minutes. The purified fat is then transferred to a 1-cc Luer lock syringe attached to an 18-gauge needle.

Fat Injection—The authors use an 18-gauge needle to perform depot injections into the temporal fossae above the periosteum. This is a relatively safe area of the face to inject, but care must be taken to avoid injury to the superficial temporal artery. Between 1.5 and 3 cc of high-quality fat usually are administered to each temple.

Aftercare Instructions—The patient is instructed to have a soft diet for 24 to 48 hours and can return to work the next day. The patient also is given prophylactic antibiotics with Gram-negative coverage for 7 days (amoxicillin-clavulanate 875 mg/125 mg orally twice daily for 7 days).

Candidates for Buccal Fat Pad Reduction

Buccal fat pad reduction has become an increasingly popular technique for midface and lower face shaping to decrease the appearance of a round face. To achieve an aesthetically pleasing midface, surgeons should consider enhancing zygomatic eminences while emphasizing the border between the zygomatic prominence and cheek hollow.⁶ Selection criteria for buccal fat pad reduction are not well established. One study recommended avoiding the procedure in pregnant or lactating patients, patients with chronic illnesses, patients on blood-thinning agents, and patients younger than 18 years. In addition, this study suggested ensuring the malar fullness is in the anteromedial portion of the face, as posterolateral fullness may be due to masseter hypertrophy.⁶

Complications associated with buccal fat pad reduction include inadvertent damage to surrounding structures, including the buccal branch of the facial nerve and parotid duct. Because the location of the facial nerve in relation to the parotid duct is highly variable, surgeons must be aware of its anatomy to avoid unintentional damage. Hwang et al⁷ reported that the parotid duct and buccal branches of the facial nerves passed through the buccal extension in 26.3% of cadavers. The transbuccal approach is preferred over the sub–superficial muscular aponeurotic system approach largely because it avoids these structures. In addition, blunt dissection may further decrease chances of injury. Although the long-term effects are unknown, there is a potential risk for facial hollowing.³ The use of preprocedure ultrasonography to quantify the buccal fat pad may avoid overresection and enhanced potential for facial hollowing.⁶

Avoidance of Temporal Hollowing

Because the buccal fat pad extends into the temporal space, buccal fat pad reduction may lead to further temporal hollowing, contributing to an aged appearance. The authors’ technique addresses both midface and upper face contouring in one minimally invasive procedure. Temporal hollowing commonly has been corrected with autologous fat grafting from the thigh or abdomen, which leads to an additional scar at the donor site. Our technique relies on autologous adjacent fat transfer from previously removed buccal fat. In addition, compared with the use of hyaluronic acid fillers for temple reflation, fat transfer largely is safe and biocompatible. Major complications of autologous fat transfer to the temples include nodularity or fat clumping, fat necrosis, sensory or motor nerve damage, and edema or ecchymosis.⁴ Also, with time there will be ongoing hollowing of the temples as part of the aging process with soft tissue and bone resorption. Therefore, further volume restoration procedures may be required in the future to address these dynamic changes.

Conclusion

The buccal fat pad has been extensively used to reconstruct oral defects, including oroantral and cranial base defects, owing to its high vascularity.⁶ However, there also is great potential to utilize buccal fat for autologous fat transfer to improve temporal wasting. Further studies are needed to determine optimal technique as well as longer-term safety and efficacy of this procedure.

Chest pain is one of the most common concerns in patients presenting to the emergency department in the United States, accounting for approximately 7.6 million visits annually.¹ Given the high mortality rate associated with acute coronary syndromes, prompt evaluation of chest pain is essential.² Even in mild cases, recognition of newly onset or worsening coronary artery disease (CAD) is crucial to ensure that patients receive optimal medication therapy.

In symptomatic patients with risk factors for CAD, such as advanced age, hypertension, hyperlipidemia, obesity, and diabetes mellitus, myocardial perfusion imaging (MPI) is frequently used as a modality to assess the presence, location, and severity of ischemic or infarcted myocardium.² MPI requires administration of a radiopharmaceutical before and after the patient undergoes a form of stress.² This radiopharmaceutical is then detected in the myocardium with a nuclear camera, and images are obtained of the heart to assess myocardial blood flow.²

MPI can be performed using exercise-induced stress via a treadmill, or medication-induced stress (Table 1). In both strategies, healthy coronary arteries dilate to provide the myocardium with more blood flow to meet the increasing myocardial oxygen demand during this period of stress. While healthy vessels are able to dilate appropriately, coronary arteries with flow-limiting stenoses are unable to dilate to the same extent in response to stress.² Because radioactive isotope uptake by the myocardium is directly related to arterial blood flow, MPI is able to demonstrate a mismatch in coronary blood flow between healthy and diseased coronary arteries indicated by differences in radioisotope uptake.² The presence of such a mismatch, in conjunction with clinical history, potentially suggests the presence of CAD.

Because nicotine and nicotine replacement therapy (NRT) may have substantial effects on coronary circulation, a current area of controversy is whether these should be stopped prior to the use of a stress-inducing medication during MPI. To date, no formal drug interaction studies have been conducted between nicotine and regadenoson.⁵ Similarly, the ADVANCE MPI 2 Trial, which led to the US Food and Drug Administration approval of regadenoson, did not specify restrictions on the use of nicotine prior to stress testing in the protocol.⁶ However, as this trial was multicenter, investigators admit that individual study sites could have had their own restrictions on the use of nicotine prior to stress testing with regadenoson, but this information was not collected.⁶ The current review focuses on how the simultaneous use of nicotine or NRT during MPI with pharmacologic agents, such as regadenoson, may affect the accuracy of imaging results and the clinical impact of this interaction.

Nicotine Coronary Artery Effect

It is well documented that long-term cigarette smoking is a major risk factor for CAD.⁷ Compared with nonsmokers, cigarette smokers experience 2 times greater risk of morbidity and mortality from ischemic heart disease.⁷ There are several mechanisms by which nicotine induces damage to the myocardium (Figure). Nicotine has direct effects on both the sympathetic nervous system (SNS) and myocardial endothelium.⁸ Together, these factors result in reduced coronary blood flow, leading to less oxygen supply to meet an increased oxygen demand, resulting in myocardial ischemia.

Nicotine’s effect on coronary vasomotor tone occurs primarily through noradrenergic stimulation of α and β receptors associated with coronary vasoconstriction or vasodilation, respectively.^9,10 These competing influences on coronary blood flow appear to manifest differently based on whether patients are at rest or in a stressed state. A study by Czerin and colleagues demonstrated that in healthy patients with relatively short smoking histories and in a healthy nonsmoker control group, coronary blood flow increased by 25% and 40%, respectively, with nicotine use at rest.⁹ However, when these patients were stressed with dipyramidole and while smoking during the examination, myocardial blood flow was reduced by 11% in the study group and 14% in the control group.⁹ This is likely because the patients studied had relatively healthy coronary arteries that were able to maximally dilate when stressed. In this scenario, nicotine’s dilatory effects are offset by nicotine’s α-receptor–mediated vasoconstriction effects.⁹ Of note, patients in the study group experienced a somewhat diminished increase in coronary blood flow at rest with nicotine use, suggesting that even a short smoking history may damage the myocardial endothelium, rendering it less responsive to nicotine’s vasodilatory effects.⁹

Nicotine Replacement Therapy and Stress Testing

Given the association between cigarette smoking and CAD, medical practitioners strongly encourage patients to quit smoking to reduce their risk of adverse cardiovascular outcomes. Various smoking cessation treatments are available for patients. Common, readily accessible forms of therapy include nicotine replacement products (Table 2).

Early studies of NRT in patients with underlying CVD found an increased risk of cardiovascular events, such as myocardial infarction, presumably due to the nicotine content of these products.^13,14 However, the concentration of nicotine in NRT is substantially lower than that found in cigarettes and in some formulations, such as transdermal patches, nicotine is delivered over a prolonged period of time.¹⁵ For this reason, NRT is thought to be safe in patients with underlying CVD and stable ischemic heart disease. A recent systematic review and meta-analysis found that while NRT may be associated with tachycardia, it did not increase the risk of more serious cardiovascular adverse effects (AEs).^16,17

Given the lower nicotine concentration in NRT products, the associated hemodynamic effect of nicotine also is thought to be less pronounced. In a study conducted by Tzivoni and colleagues in patients with CAD using transdermal nicotine patches, no differences in blood pressure, heart rate, ischemia, or arrhythmias were found from baseline to 2 weeks.¹⁸ These findings were further confirmed in a small study by Lucini and colleagues, which found that nicotine patches produced slight hemodynamic effects, but to a lesser extent than cigarette smoking.¹⁹ For the NRT gum formulation, while a small study found that 4 mg produced coronary vasoconstriction in patients with underlying CAD, a study by Nitenberg and Antony demonstrated that healthy and diseased coronary arteries did not significantly constrict while patients were using nicotine gum both before and after a cold pressor test, suggesting a lesser degree of coronary vasoconstriction than nicotine from cigarette smoking.^20,21 Similar findings have been described with the nicotine intranasal spray in a study by Keeley and colleagues, which showed no additional AEs on myocardial demand or vasoconstriction when an intranasal nicotine spray was added to cigarette smoking.²² Importantly, a review of the transdermal and gum formulations found that these less pronounced hemodynamic effects were observed across different doses of NRT; however, further studies are needed to clarify the relationship between NRT dose and cardiovascular effects.²³

Overall, NRT does not seem to activate the SNS to the same degree as nicotine obtained via cigarette smoking and likely does not increase the myocardial oxygen demand as much. Additionally, by containing a lower concentration of nicotine, NRT may not impair the myocardium’s ability to supply oxygen to coronary arteries to the same extent as nicotine from cigarette smoking. Therefore, the effects of NRT on MPI using a stress-inducing medication may not be as pronounced. However, due to study limitations, results should be interpreted cautiously.^18-23

Conclusions

Because of the close relationship between cigarette smoking and CAD, many patients with underlying CVD are either current smokers or may be using NRT for smoking cessation. Therefore, the question of whether to refrain from nicotine use prior to MPI is clinically relevant. Currently, there is a lack of high-quality studies demonstrating the effects of nicotine and NRT on coronary perfusion. Because of this, the impact of nicotine and NRT use on the accuracy of MPI using stress-inducing medications remains uncertain. Nevertheless, given that nicotine and NRT may largely affect the accuracy of imaging results, several institutions have adopted protocols that prohibit patients from using these drugs on the day of nuclear stress testing.

There are currently no data specifying the number of hours to hold nicotine products prior to cardiac stress testing. It is generally recommended that other medications that affect coronary blood flow be held for 5 half-lives before conducting MPI.⁴ Following the same guidance for nicotine and NRT may present a reasonable approach to ensure accurate imaging results. Based on the discussed literature, patients should be instructed to refrain from cigarette smoking for at least 5 to 10 hours prior to MPI, given nicotine’s half-life of about 1 to 2 hours.²⁴

The data for NRT are less clear. While use of NRT may not be an absolute contraindication to conducting MPI, it is important to consider that this may affect the accuracy of results. Given this uncertainty, it is likely ideal to hold NRT prior to MPI, based on the specific formulation of NRT and that product's half-life. Further robust studies are needed to analyze the impact of nicotine and NRT on the accuracy of nuclear stress testing using a medication.

Chest pain is one of the most common concerns in patients presenting to the emergency department in the United States, accounting for approximately 7.6 million visits annually.¹ Given the high mortality rate associated with acute coronary syndromes, prompt evaluation of chest pain is essential.² Even in mild cases, recognition of newly onset or worsening coronary artery disease (CAD) is crucial to ensure that patients receive optimal medication therapy.

In symptomatic patients with risk factors for CAD, such as advanced age, hypertension, hyperlipidemia, obesity, and diabetes mellitus, myocardial perfusion imaging (MPI) is frequently used as a modality to assess the presence, location, and severity of ischemic or infarcted myocardium.² MPI requires administration of a radiopharmaceutical before and after the patient undergoes a form of stress.² This radiopharmaceutical is then detected in the myocardium with a nuclear camera, and images are obtained of the heart to assess myocardial blood flow.²

MPI can be performed using exercise-induced stress via a treadmill, or medication-induced stress (Table 1). In both strategies, healthy coronary arteries dilate to provide the myocardium with more blood flow to meet the increasing myocardial oxygen demand during this period of stress. While healthy vessels are able to dilate appropriately, coronary arteries with flow-limiting stenoses are unable to dilate to the same extent in response to stress.² Because radioactive isotope uptake by the myocardium is directly related to arterial blood flow, MPI is able to demonstrate a mismatch in coronary blood flow between healthy and diseased coronary arteries indicated by differences in radioisotope uptake.² The presence of such a mismatch, in conjunction with clinical history, potentially suggests the presence of CAD.

Because nicotine and nicotine replacement therapy (NRT) may have substantial effects on coronary circulation, a current area of controversy is whether these should be stopped prior to the use of a stress-inducing medication during MPI. To date, no formal drug interaction studies have been conducted between nicotine and regadenoson.⁵ Similarly, the ADVANCE MPI 2 Trial, which led to the US Food and Drug Administration approval of regadenoson, did not specify restrictions on the use of nicotine prior to stress testing in the protocol.⁶ However, as this trial was multicenter, investigators admit that individual study sites could have had their own restrictions on the use of nicotine prior to stress testing with regadenoson, but this information was not collected.⁶ The current review focuses on how the simultaneous use of nicotine or NRT during MPI with pharmacologic agents, such as regadenoson, may affect the accuracy of imaging results and the clinical impact of this interaction.

Nicotine Coronary Artery Effect

It is well documented that long-term cigarette smoking is a major risk factor for CAD.⁷ Compared with nonsmokers, cigarette smokers experience 2 times greater risk of morbidity and mortality from ischemic heart disease.⁷ There are several mechanisms by which nicotine induces damage to the myocardium (Figure). Nicotine has direct effects on both the sympathetic nervous system (SNS) and myocardial endothelium.⁸ Together, these factors result in reduced coronary blood flow, leading to less oxygen supply to meet an increased oxygen demand, resulting in myocardial ischemia.

Nicotine’s effect on coronary vasomotor tone occurs primarily through noradrenergic stimulation of α and β receptors associated with coronary vasoconstriction or vasodilation, respectively.^9,10 These competing influences on coronary blood flow appear to manifest differently based on whether patients are at rest or in a stressed state. A study by Czerin and colleagues demonstrated that in healthy patients with relatively short smoking histories and in a healthy nonsmoker control group, coronary blood flow increased by 25% and 40%, respectively, with nicotine use at rest.⁹ However, when these patients were stressed with dipyramidole and while smoking during the examination, myocardial blood flow was reduced by 11% in the study group and 14% in the control group.⁹ This is likely because the patients studied had relatively healthy coronary arteries that were able to maximally dilate when stressed. In this scenario, nicotine’s dilatory effects are offset by nicotine’s α-receptor–mediated vasoconstriction effects.⁹ Of note, patients in the study group experienced a somewhat diminished increase in coronary blood flow at rest with nicotine use, suggesting that even a short smoking history may damage the myocardial endothelium, rendering it less responsive to nicotine’s vasodilatory effects.⁹

Nicotine Replacement Therapy and Stress Testing

Given the association between cigarette smoking and CAD, medical practitioners strongly encourage patients to quit smoking to reduce their risk of adverse cardiovascular outcomes. Various smoking cessation treatments are available for patients. Common, readily accessible forms of therapy include nicotine replacement products (Table 2).

Early studies of NRT in patients with underlying CVD found an increased risk of cardiovascular events, such as myocardial infarction, presumably due to the nicotine content of these products.^13,14 However, the concentration of nicotine in NRT is substantially lower than that found in cigarettes and in some formulations, such as transdermal patches, nicotine is delivered over a prolonged period of time.¹⁵ For this reason, NRT is thought to be safe in patients with underlying CVD and stable ischemic heart disease. A recent systematic review and meta-analysis found that while NRT may be associated with tachycardia, it did not increase the risk of more serious cardiovascular adverse effects (AEs).^16,17

Given the lower nicotine concentration in NRT products, the associated hemodynamic effect of nicotine also is thought to be less pronounced. In a study conducted by Tzivoni and colleagues in patients with CAD using transdermal nicotine patches, no differences in blood pressure, heart rate, ischemia, or arrhythmias were found from baseline to 2 weeks.¹⁸ These findings were further confirmed in a small study by Lucini and colleagues, which found that nicotine patches produced slight hemodynamic effects, but to a lesser extent than cigarette smoking.¹⁹ For the NRT gum formulation, while a small study found that 4 mg produced coronary vasoconstriction in patients with underlying CAD, a study by Nitenberg and Antony demonstrated that healthy and diseased coronary arteries did not significantly constrict while patients were using nicotine gum both before and after a cold pressor test, suggesting a lesser degree of coronary vasoconstriction than nicotine from cigarette smoking.^20,21 Similar findings have been described with the nicotine intranasal spray in a study by Keeley and colleagues, which showed no additional AEs on myocardial demand or vasoconstriction when an intranasal nicotine spray was added to cigarette smoking.²² Importantly, a review of the transdermal and gum formulations found that these less pronounced hemodynamic effects were observed across different doses of NRT; however, further studies are needed to clarify the relationship between NRT dose and cardiovascular effects.²³

Overall, NRT does not seem to activate the SNS to the same degree as nicotine obtained via cigarette smoking and likely does not increase the myocardial oxygen demand as much. Additionally, by containing a lower concentration of nicotine, NRT may not impair the myocardium’s ability to supply oxygen to coronary arteries to the same extent as nicotine from cigarette smoking. Therefore, the effects of NRT on MPI using a stress-inducing medication may not be as pronounced. However, due to study limitations, results should be interpreted cautiously.^18-23

Conclusions

Because of the close relationship between cigarette smoking and CAD, many patients with underlying CVD are either current smokers or may be using NRT for smoking cessation. Therefore, the question of whether to refrain from nicotine use prior to MPI is clinically relevant. Currently, there is a lack of high-quality studies demonstrating the effects of nicotine and NRT on coronary perfusion. Because of this, the impact of nicotine and NRT use on the accuracy of MPI using stress-inducing medications remains uncertain. Nevertheless, given that nicotine and NRT may largely affect the accuracy of imaging results, several institutions have adopted protocols that prohibit patients from using these drugs on the day of nuclear stress testing.

There are currently no data specifying the number of hours to hold nicotine products prior to cardiac stress testing. It is generally recommended that other medications that affect coronary blood flow be held for 5 half-lives before conducting MPI.⁴ Following the same guidance for nicotine and NRT may present a reasonable approach to ensure accurate imaging results. Based on the discussed literature, patients should be instructed to refrain from cigarette smoking for at least 5 to 10 hours prior to MPI, given nicotine’s half-life of about 1 to 2 hours.²⁴

The data for NRT are less clear. While use of NRT may not be an absolute contraindication to conducting MPI, it is important to consider that this may affect the accuracy of results. Given this uncertainty, it is likely ideal to hold NRT prior to MPI, based on the specific formulation of NRT and that product's half-life. Further robust studies are needed to analyze the impact of nicotine and NRT on the accuracy of nuclear stress testing using a medication.

Chest pain is one of the most common concerns in patients presenting to the emergency department in the United States, accounting for approximately 7.6 million visits annually.¹ Given the high mortality rate associated with acute coronary syndromes, prompt evaluation of chest pain is essential.² Even in mild cases, recognition of newly onset or worsening coronary artery disease (CAD) is crucial to ensure that patients receive optimal medication therapy.

In symptomatic patients with risk factors for CAD, such as advanced age, hypertension, hyperlipidemia, obesity, and diabetes mellitus, myocardial perfusion imaging (MPI) is frequently used as a modality to assess the presence, location, and severity of ischemic or infarcted myocardium.² MPI requires administration of a radiopharmaceutical before and after the patient undergoes a form of stress.² This radiopharmaceutical is then detected in the myocardium with a nuclear camera, and images are obtained of the heart to assess myocardial blood flow.²

MPI can be performed using exercise-induced stress via a treadmill, or medication-induced stress (Table 1). In both strategies, healthy coronary arteries dilate to provide the myocardium with more blood flow to meet the increasing myocardial oxygen demand during this period of stress. While healthy vessels are able to dilate appropriately, coronary arteries with flow-limiting stenoses are unable to dilate to the same extent in response to stress.² Because radioactive isotope uptake by the myocardium is directly related to arterial blood flow, MPI is able to demonstrate a mismatch in coronary blood flow between healthy and diseased coronary arteries indicated by differences in radioisotope uptake.² The presence of such a mismatch, in conjunction with clinical history, potentially suggests the presence of CAD.

Because nicotine and nicotine replacement therapy (NRT) may have substantial effects on coronary circulation, a current area of controversy is whether these should be stopped prior to the use of a stress-inducing medication during MPI. To date, no formal drug interaction studies have been conducted between nicotine and regadenoson.⁵ Similarly, the ADVANCE MPI 2 Trial, which led to the US Food and Drug Administration approval of regadenoson, did not specify restrictions on the use of nicotine prior to stress testing in the protocol.⁶ However, as this trial was multicenter, investigators admit that individual study sites could have had their own restrictions on the use of nicotine prior to stress testing with regadenoson, but this information was not collected.⁶ The current review focuses on how the simultaneous use of nicotine or NRT during MPI with pharmacologic agents, such as regadenoson, may affect the accuracy of imaging results and the clinical impact of this interaction.

Nicotine Coronary Artery Effect

It is well documented that long-term cigarette smoking is a major risk factor for CAD.⁷ Compared with nonsmokers, cigarette smokers experience 2 times greater risk of morbidity and mortality from ischemic heart disease.⁷ There are several mechanisms by which nicotine induces damage to the myocardium (Figure). Nicotine has direct effects on both the sympathetic nervous system (SNS) and myocardial endothelium.⁸ Together, these factors result in reduced coronary blood flow, leading to less oxygen supply to meet an increased oxygen demand, resulting in myocardial ischemia.

Nicotine’s effect on coronary vasomotor tone occurs primarily through noradrenergic stimulation of α and β receptors associated with coronary vasoconstriction or vasodilation, respectively.^9,10 These competing influences on coronary blood flow appear to manifest differently based on whether patients are at rest or in a stressed state. A study by Czerin and colleagues demonstrated that in healthy patients with relatively short smoking histories and in a healthy nonsmoker control group, coronary blood flow increased by 25% and 40%, respectively, with nicotine use at rest.⁹ However, when these patients were stressed with dipyramidole and while smoking during the examination, myocardial blood flow was reduced by 11% in the study group and 14% in the control group.⁹ This is likely because the patients studied had relatively healthy coronary arteries that were able to maximally dilate when stressed. In this scenario, nicotine’s dilatory effects are offset by nicotine’s α-receptor–mediated vasoconstriction effects.⁹ Of note, patients in the study group experienced a somewhat diminished increase in coronary blood flow at rest with nicotine use, suggesting that even a short smoking history may damage the myocardial endothelium, rendering it less responsive to nicotine’s vasodilatory effects.⁹

Nicotine Replacement Therapy and Stress Testing

Given the association between cigarette smoking and CAD, medical practitioners strongly encourage patients to quit smoking to reduce their risk of adverse cardiovascular outcomes. Various smoking cessation treatments are available for patients. Common, readily accessible forms of therapy include nicotine replacement products (Table 2).

Early studies of NRT in patients with underlying CVD found an increased risk of cardiovascular events, such as myocardial infarction, presumably due to the nicotine content of these products.^13,14 However, the concentration of nicotine in NRT is substantially lower than that found in cigarettes and in some formulations, such as transdermal patches, nicotine is delivered over a prolonged period of time.¹⁵ For this reason, NRT is thought to be safe in patients with underlying CVD and stable ischemic heart disease. A recent systematic review and meta-analysis found that while NRT may be associated with tachycardia, it did not increase the risk of more serious cardiovascular adverse effects (AEs).^16,17

Given the lower nicotine concentration in NRT products, the associated hemodynamic effect of nicotine also is thought to be less pronounced. In a study conducted by Tzivoni and colleagues in patients with CAD using transdermal nicotine patches, no differences in blood pressure, heart rate, ischemia, or arrhythmias were found from baseline to 2 weeks.¹⁸ These findings were further confirmed in a small study by Lucini and colleagues, which found that nicotine patches produced slight hemodynamic effects, but to a lesser extent than cigarette smoking.¹⁹ For the NRT gum formulation, while a small study found that 4 mg produced coronary vasoconstriction in patients with underlying CAD, a study by Nitenberg and Antony demonstrated that healthy and diseased coronary arteries did not significantly constrict while patients were using nicotine gum both before and after a cold pressor test, suggesting a lesser degree of coronary vasoconstriction than nicotine from cigarette smoking.^20,21 Similar findings have been described with the nicotine intranasal spray in a study by Keeley and colleagues, which showed no additional AEs on myocardial demand or vasoconstriction when an intranasal nicotine spray was added to cigarette smoking.²² Importantly, a review of the transdermal and gum formulations found that these less pronounced hemodynamic effects were observed across different doses of NRT; however, further studies are needed to clarify the relationship between NRT dose and cardiovascular effects.²³

Overall, NRT does not seem to activate the SNS to the same degree as nicotine obtained via cigarette smoking and likely does not increase the myocardial oxygen demand as much. Additionally, by containing a lower concentration of nicotine, NRT may not impair the myocardium’s ability to supply oxygen to coronary arteries to the same extent as nicotine from cigarette smoking. Therefore, the effects of NRT on MPI using a stress-inducing medication may not be as pronounced. However, due to study limitations, results should be interpreted cautiously.^18-23

Conclusions

Because of the close relationship between cigarette smoking and CAD, many patients with underlying CVD are either current smokers or may be using NRT for smoking cessation. Therefore, the question of whether to refrain from nicotine use prior to MPI is clinically relevant. Currently, there is a lack of high-quality studies demonstrating the effects of nicotine and NRT on coronary perfusion. Because of this, the impact of nicotine and NRT use on the accuracy of MPI using stress-inducing medications remains uncertain. Nevertheless, given that nicotine and NRT may largely affect the accuracy of imaging results, several institutions have adopted protocols that prohibit patients from using these drugs on the day of nuclear stress testing.

There are currently no data specifying the number of hours to hold nicotine products prior to cardiac stress testing. It is generally recommended that other medications that affect coronary blood flow be held for 5 half-lives before conducting MPI.⁴ Following the same guidance for nicotine and NRT may present a reasonable approach to ensure accurate imaging results. Based on the discussed literature, patients should be instructed to refrain from cigarette smoking for at least 5 to 10 hours prior to MPI, given nicotine’s half-life of about 1 to 2 hours.²⁴

The data for NRT are less clear. While use of NRT may not be an absolute contraindication to conducting MPI, it is important to consider that this may affect the accuracy of results. Given this uncertainty, it is likely ideal to hold NRT prior to MPI, based on the specific formulation of NRT and that product's half-life. Further robust studies are needed to analyze the impact of nicotine and NRT on the accuracy of nuclear stress testing using a medication.