Commentary

The field of “reproductive rheumatology” has received growing attention in recent years as we learn more about how autoimmune rheumatic diseases and their treatment affect women of reproductive age. In 2020, the American College of Rheumatology published a comprehensive guideline that includes recommendations and supporting evidence for managing issues related to reproductive health in patients with rheumatic diseases and has since launched an ongoing Reproductive Health Initiative, with the goal of translating established guidelines into practice through various education and awareness campaigns. One area addressed by the guideline that comes up commonly in practice but receives less attention and research is the use of assisted reproductive technology (ART) in patients with rheumatic diseases.

Literature is conflicting regarding whether patients with autoimmune rheumatic diseases are inherently at increased risk for infertility, defined as failure to achieve a clinical pregnancy after 12 months or more of regular unprotected intercourse, or subfertility, defined as a delay in conception. Regardless, several factors indirectly contribute to a disproportionate risk for infertility or subfertility in this patient population, including active inflammatory disease, reduced ovarian reserve, and medications.

Patients with subfertility or infertility who desire pregnancy may pursue ovulation induction with timed intercourse or intrauterine insemination, in vitro fertilization (IVF)/intracytoplasmic sperm injection with either embryo transfer, or gestational surrogacy. Those who require treatment with cyclophosphamide or who plan to defer pregnancy for whatever reason can opt for oocyte cryopreservation (colloquially known as “egg freezing”). For IVF and oocyte cryopreservation, controlled ovarian stimulation is typically the first step (except in unstimulated, or “natural cycle,” IVF).

Various protocols are used for ovarian stimulation and ovulation induction, the nuances of which are beyond the scope of this article. In general, ovarian stimulation involves gonadotropin therapy (follicle-stimulating hormone and/or human menopausal gonadotropin) administered via scheduled subcutaneous injections to stimulate follicular growth, as well as gonadotropin-releasing hormone (GnRH) agonists or antagonists to suppress luteinizing hormone, preventing ovulation. Adjunctive oral therapy (clomiphene citrate or letrozole, an aromatase inhibitor) may be used as well. The patient has frequent lab monitoring of hormone levels and transvaginal ultrasounds to measure follicle number and size and, when the timing is right, receives an “ovulation trigger” – either human chorionic gonadotropin or GnRH agonist, depending on the protocol. At this point, transvaginal ultrasound–guided egg retrieval is done under sedation. Recovered oocytes are then either frozen for later use or fertilized in the lab for embryo transfer. Lastly, exogenous hormones are often used: estrogen to support frozen embryo transfers and progesterone for so-called luteal phase support.

ART is not contraindicated in patients with autoimmune rheumatic diseases, but there may be additional factors to consider, particularly for those with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and antiphospholipid antibodies (aPL) without clinical APS.

Ovarian stimulation elevates estrogen levels to varying degrees depending on the patient and the medications used. In all cases, though, peak levels are significantly lower than levels reached during pregnancy. It is well established that elevated estrogen – whether from hormone therapies or pregnancy – significantly increases thrombotic risk, even in healthy people. High-risk patients should receive low-molecular-weight heparin – a prophylactic dose for patients with either positive aPL without clinical APS (including those with SLE) or with obstetric APS, and a therapeutic dose for those with thrombotic APS – during ART procedures.

In patients with SLE, another concern is that increased estrogen will cause disease flare. One case series published in 2017 reported 37 patients with SLE and/or APS who underwent 97 IVF cycles, of which 8% were complicated by flare or thrombotic events. Notably, half of these complications occurred in patients who stopped prescribed therapies (immunomodulatory therapy in two patients with SLE, anticoagulation in two patients with APS) after failure to conceive. In a separate study from 2000 including 19 patients with SLE, APS, or high-titer aPL who underwent 68 IVF cycles, 19% of cycles in patients with SLE were complicated by flare, and no thrombotic events occurred in the cohort. The authors concluded that ovulation induction does not exacerbate SLE or APS. In these studies, the overall pregnancy rates were felt to be consistent with those achieved by the general population through IVF. Although obstetric complications, such as preeclampsia and preterm delivery, were reported in about half of the pregnancies described, these are known to occur more frequently in those with SLE and APS, especially when active disease or other risk factors are present. There are no large-scale, controlled studies evaluating ART outcomes in patients with autoimmune rheumatic diseases to date.

Finally, ovarian hyperstimulation syndrome (OHSS) is an increasingly rare but severe complication of ovarian stimulation. OHSS is characterized by capillary leak, fluid overload, and cytokine release syndrome and can lead to thromboembolic events. Comorbidities like hypertension and renal failure, which can go along with autoimmune rheumatic diseases, are risk factors for OHSS. The use of human chorionic gonadotropin to trigger ovulation is also associated with an increased risk for OHSS, so a GnRH agonist trigger may be preferable.

The ACR guideline recommends that individuals with any of these underlying conditions undergo ART only in expert centers. The ovarian stimulation protocol needs to be tailored to the individual patient to minimize risk and optimize outcomes. The overall goal when managing patients with autoimmune rheumatic diseases during ART is to establish and maintain disease control with pregnancy-compatible medications (when pregnancy is the goal). With adequate planning, appropriate treatment, and collaboration between obstetricians and rheumatologists, individuals with autoimmune rheumatic diseases can safely pursue ART and go on to have successful pregnancies.

Dr. Siegel is a 2022-2023 UCB Women’s Health rheumatology fellow in the rheumatology reproductive health program of the Barbara Volcker Center for Women and Rheumatic Diseases at Hospital for Special Surgery/Weill Cornell Medicine, New York. Her clinical and research focus is on reproductive health issues in individuals with rheumatic disease. Dr. Chan is an assistant professor at Weill Cornell Medical College and an attending physician at Hospital for Special Surgery and Memorial Sloan Kettering Cancer Center in New York. Before moving to New York City, she spent 7 years in private practice in Rhode Island and was a columnist for a monthly rheumatology publication, writing about the challenges of starting life as a full-fledged rheumatologist in a private practice. Follow Dr Chan on Twitter. Dr. Siegel and Dr. Chan disclosed no relevant financial relationships.

A version of this article – an editorial collaboration between Medscape and the Hospital for Special Surgery – first appeared on Medscape.com.

The field of “reproductive rheumatology” has received growing attention in recent years as we learn more about how autoimmune rheumatic diseases and their treatment affect women of reproductive age. In 2020, the American College of Rheumatology published a comprehensive guideline that includes recommendations and supporting evidence for managing issues related to reproductive health in patients with rheumatic diseases and has since launched an ongoing Reproductive Health Initiative, with the goal of translating established guidelines into practice through various education and awareness campaigns. One area addressed by the guideline that comes up commonly in practice but receives less attention and research is the use of assisted reproductive technology (ART) in patients with rheumatic diseases.

Literature is conflicting regarding whether patients with autoimmune rheumatic diseases are inherently at increased risk for infertility, defined as failure to achieve a clinical pregnancy after 12 months or more of regular unprotected intercourse, or subfertility, defined as a delay in conception. Regardless, several factors indirectly contribute to a disproportionate risk for infertility or subfertility in this patient population, including active inflammatory disease, reduced ovarian reserve, and medications.

Patients with subfertility or infertility who desire pregnancy may pursue ovulation induction with timed intercourse or intrauterine insemination, in vitro fertilization (IVF)/intracytoplasmic sperm injection with either embryo transfer, or gestational surrogacy. Those who require treatment with cyclophosphamide or who plan to defer pregnancy for whatever reason can opt for oocyte cryopreservation (colloquially known as “egg freezing”). For IVF and oocyte cryopreservation, controlled ovarian stimulation is typically the first step (except in unstimulated, or “natural cycle,” IVF).

Various protocols are used for ovarian stimulation and ovulation induction, the nuances of which are beyond the scope of this article. In general, ovarian stimulation involves gonadotropin therapy (follicle-stimulating hormone and/or human menopausal gonadotropin) administered via scheduled subcutaneous injections to stimulate follicular growth, as well as gonadotropin-releasing hormone (GnRH) agonists or antagonists to suppress luteinizing hormone, preventing ovulation. Adjunctive oral therapy (clomiphene citrate or letrozole, an aromatase inhibitor) may be used as well. The patient has frequent lab monitoring of hormone levels and transvaginal ultrasounds to measure follicle number and size and, when the timing is right, receives an “ovulation trigger” – either human chorionic gonadotropin or GnRH agonist, depending on the protocol. At this point, transvaginal ultrasound–guided egg retrieval is done under sedation. Recovered oocytes are then either frozen for later use or fertilized in the lab for embryo transfer. Lastly, exogenous hormones are often used: estrogen to support frozen embryo transfers and progesterone for so-called luteal phase support.

ART is not contraindicated in patients with autoimmune rheumatic diseases, but there may be additional factors to consider, particularly for those with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and antiphospholipid antibodies (aPL) without clinical APS.

Ovarian stimulation elevates estrogen levels to varying degrees depending on the patient and the medications used. In all cases, though, peak levels are significantly lower than levels reached during pregnancy. It is well established that elevated estrogen – whether from hormone therapies or pregnancy – significantly increases thrombotic risk, even in healthy people. High-risk patients should receive low-molecular-weight heparin – a prophylactic dose for patients with either positive aPL without clinical APS (including those with SLE) or with obstetric APS, and a therapeutic dose for those with thrombotic APS – during ART procedures.

In patients with SLE, another concern is that increased estrogen will cause disease flare. One case series published in 2017 reported 37 patients with SLE and/or APS who underwent 97 IVF cycles, of which 8% were complicated by flare or thrombotic events. Notably, half of these complications occurred in patients who stopped prescribed therapies (immunomodulatory therapy in two patients with SLE, anticoagulation in two patients with APS) after failure to conceive. In a separate study from 2000 including 19 patients with SLE, APS, or high-titer aPL who underwent 68 IVF cycles, 19% of cycles in patients with SLE were complicated by flare, and no thrombotic events occurred in the cohort. The authors concluded that ovulation induction does not exacerbate SLE or APS. In these studies, the overall pregnancy rates were felt to be consistent with those achieved by the general population through IVF. Although obstetric complications, such as preeclampsia and preterm delivery, were reported in about half of the pregnancies described, these are known to occur more frequently in those with SLE and APS, especially when active disease or other risk factors are present. There are no large-scale, controlled studies evaluating ART outcomes in patients with autoimmune rheumatic diseases to date.

Finally, ovarian hyperstimulation syndrome (OHSS) is an increasingly rare but severe complication of ovarian stimulation. OHSS is characterized by capillary leak, fluid overload, and cytokine release syndrome and can lead to thromboembolic events. Comorbidities like hypertension and renal failure, which can go along with autoimmune rheumatic diseases, are risk factors for OHSS. The use of human chorionic gonadotropin to trigger ovulation is also associated with an increased risk for OHSS, so a GnRH agonist trigger may be preferable.

The ACR guideline recommends that individuals with any of these underlying conditions undergo ART only in expert centers. The ovarian stimulation protocol needs to be tailored to the individual patient to minimize risk and optimize outcomes. The overall goal when managing patients with autoimmune rheumatic diseases during ART is to establish and maintain disease control with pregnancy-compatible medications (when pregnancy is the goal). With adequate planning, appropriate treatment, and collaboration between obstetricians and rheumatologists, individuals with autoimmune rheumatic diseases can safely pursue ART and go on to have successful pregnancies.

Dr. Siegel is a 2022-2023 UCB Women’s Health rheumatology fellow in the rheumatology reproductive health program of the Barbara Volcker Center for Women and Rheumatic Diseases at Hospital for Special Surgery/Weill Cornell Medicine, New York. Her clinical and research focus is on reproductive health issues in individuals with rheumatic disease. Dr. Chan is an assistant professor at Weill Cornell Medical College and an attending physician at Hospital for Special Surgery and Memorial Sloan Kettering Cancer Center in New York. Before moving to New York City, she spent 7 years in private practice in Rhode Island and was a columnist for a monthly rheumatology publication, writing about the challenges of starting life as a full-fledged rheumatologist in a private practice. Follow Dr Chan on Twitter. Dr. Siegel and Dr. Chan disclosed no relevant financial relationships.

A version of this article – an editorial collaboration between Medscape and the Hospital for Special Surgery – first appeared on Medscape.com.

The field of “reproductive rheumatology” has received growing attention in recent years as we learn more about how autoimmune rheumatic diseases and their treatment affect women of reproductive age. In 2020, the American College of Rheumatology published a comprehensive guideline that includes recommendations and supporting evidence for managing issues related to reproductive health in patients with rheumatic diseases and has since launched an ongoing Reproductive Health Initiative, with the goal of translating established guidelines into practice through various education and awareness campaigns. One area addressed by the guideline that comes up commonly in practice but receives less attention and research is the use of assisted reproductive technology (ART) in patients with rheumatic diseases.

Literature is conflicting regarding whether patients with autoimmune rheumatic diseases are inherently at increased risk for infertility, defined as failure to achieve a clinical pregnancy after 12 months or more of regular unprotected intercourse, or subfertility, defined as a delay in conception. Regardless, several factors indirectly contribute to a disproportionate risk for infertility or subfertility in this patient population, including active inflammatory disease, reduced ovarian reserve, and medications.

Patients with subfertility or infertility who desire pregnancy may pursue ovulation induction with timed intercourse or intrauterine insemination, in vitro fertilization (IVF)/intracytoplasmic sperm injection with either embryo transfer, or gestational surrogacy. Those who require treatment with cyclophosphamide or who plan to defer pregnancy for whatever reason can opt for oocyte cryopreservation (colloquially known as “egg freezing”). For IVF and oocyte cryopreservation, controlled ovarian stimulation is typically the first step (except in unstimulated, or “natural cycle,” IVF).

Various protocols are used for ovarian stimulation and ovulation induction, the nuances of which are beyond the scope of this article. In general, ovarian stimulation involves gonadotropin therapy (follicle-stimulating hormone and/or human menopausal gonadotropin) administered via scheduled subcutaneous injections to stimulate follicular growth, as well as gonadotropin-releasing hormone (GnRH) agonists or antagonists to suppress luteinizing hormone, preventing ovulation. Adjunctive oral therapy (clomiphene citrate or letrozole, an aromatase inhibitor) may be used as well. The patient has frequent lab monitoring of hormone levels and transvaginal ultrasounds to measure follicle number and size and, when the timing is right, receives an “ovulation trigger” – either human chorionic gonadotropin or GnRH agonist, depending on the protocol. At this point, transvaginal ultrasound–guided egg retrieval is done under sedation. Recovered oocytes are then either frozen for later use or fertilized in the lab for embryo transfer. Lastly, exogenous hormones are often used: estrogen to support frozen embryo transfers and progesterone for so-called luteal phase support.

ART is not contraindicated in patients with autoimmune rheumatic diseases, but there may be additional factors to consider, particularly for those with systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and antiphospholipid antibodies (aPL) without clinical APS.

Ovarian stimulation elevates estrogen levels to varying degrees depending on the patient and the medications used. In all cases, though, peak levels are significantly lower than levels reached during pregnancy. It is well established that elevated estrogen – whether from hormone therapies or pregnancy – significantly increases thrombotic risk, even in healthy people. High-risk patients should receive low-molecular-weight heparin – a prophylactic dose for patients with either positive aPL without clinical APS (including those with SLE) or with obstetric APS, and a therapeutic dose for those with thrombotic APS – during ART procedures.

In patients with SLE, another concern is that increased estrogen will cause disease flare. One case series published in 2017 reported 37 patients with SLE and/or APS who underwent 97 IVF cycles, of which 8% were complicated by flare or thrombotic events. Notably, half of these complications occurred in patients who stopped prescribed therapies (immunomodulatory therapy in two patients with SLE, anticoagulation in two patients with APS) after failure to conceive. In a separate study from 2000 including 19 patients with SLE, APS, or high-titer aPL who underwent 68 IVF cycles, 19% of cycles in patients with SLE were complicated by flare, and no thrombotic events occurred in the cohort. The authors concluded that ovulation induction does not exacerbate SLE or APS. In these studies, the overall pregnancy rates were felt to be consistent with those achieved by the general population through IVF. Although obstetric complications, such as preeclampsia and preterm delivery, were reported in about half of the pregnancies described, these are known to occur more frequently in those with SLE and APS, especially when active disease or other risk factors are present. There are no large-scale, controlled studies evaluating ART outcomes in patients with autoimmune rheumatic diseases to date.

Finally, ovarian hyperstimulation syndrome (OHSS) is an increasingly rare but severe complication of ovarian stimulation. OHSS is characterized by capillary leak, fluid overload, and cytokine release syndrome and can lead to thromboembolic events. Comorbidities like hypertension and renal failure, which can go along with autoimmune rheumatic diseases, are risk factors for OHSS. The use of human chorionic gonadotropin to trigger ovulation is also associated with an increased risk for OHSS, so a GnRH agonist trigger may be preferable.

The ACR guideline recommends that individuals with any of these underlying conditions undergo ART only in expert centers. The ovarian stimulation protocol needs to be tailored to the individual patient to minimize risk and optimize outcomes. The overall goal when managing patients with autoimmune rheumatic diseases during ART is to establish and maintain disease control with pregnancy-compatible medications (when pregnancy is the goal). With adequate planning, appropriate treatment, and collaboration between obstetricians and rheumatologists, individuals with autoimmune rheumatic diseases can safely pursue ART and go on to have successful pregnancies.

Dr. Siegel is a 2022-2023 UCB Women’s Health rheumatology fellow in the rheumatology reproductive health program of the Barbara Volcker Center for Women and Rheumatic Diseases at Hospital for Special Surgery/Weill Cornell Medicine, New York. Her clinical and research focus is on reproductive health issues in individuals with rheumatic disease. Dr. Chan is an assistant professor at Weill Cornell Medical College and an attending physician at Hospital for Special Surgery and Memorial Sloan Kettering Cancer Center in New York. Before moving to New York City, she spent 7 years in private practice in Rhode Island and was a columnist for a monthly rheumatology publication, writing about the challenges of starting life as a full-fledged rheumatologist in a private practice. Follow Dr Chan on Twitter. Dr. Siegel and Dr. Chan disclosed no relevant financial relationships.

A version of this article – an editorial collaboration between Medscape and the Hospital for Special Surgery – first appeared on Medscape.com.

Of all the dazzling achievements of evolution, the most glorious by far is the emergence of the advanced human brain, especially the prefrontal cortex. Homo sapiens (the wise humans) are without doubt the most transformative development in the consequential annals of evolution. It was evolution’s spectacular “moonshot.” Ironically, it may also have been the seed of its destruction.

The unprecedented growth of the human brain over the past 7 million years (tripling in size) was a monumental tipping point in evolution that ultimately disrupted the entire orderly cascade of evolution on Planet Earth. Because of their superior intelligence, Homo sapiens have substantially “tinkered” with the foundations of evolution, such as “natural selection” and “survival of the fittest,” and may eventually change the course of evolution, or even reverse it. It should also be recognized that 20% of the human genome is Neanderthal, and the 2022 Nobel Prize in Physiology or Medicine was awarded to Svante Pääbo, the founder of the field of paleogenetics, who demonstrated genetically that Homo sapiens interbred with Homo neanderthalensis (who disappeared 30,000 years ago).

The majestic evolution of the human brain, in both size and complexity, led to monumental changes in the history of humankind compared to their primitive predecessors. Thanks to a superior cerebral cortex, humans developed traits and abilities that were nonexistent, even unimaginable, in the rest of animal kingdom, including primates and other mammals. These include thoughts; speech (hundreds of languages), spoken and written, to communicate among themselves; composed music and created numerous instruments to play it; invented mathematics, physics, and chemistry; developed agriculture to sustain and feed the masses; built homes, palaces, and pyramids, with water and sewage systems; hatched hundreds of religions and built thousands of houses of worship; built machines to transport themselves (cars, trains, ships, planes, and space shuttles); paved airports and countless miles of roads and railways; established companies, universities, hospitals, and research laboratories; built sports facilities such as stadiums for Olympic games and all its athletics; created hotels, restaurants, coffee shops, newspapers, and magazines; discovered the amazing DNA double helix and its genome with 23,000 coding genes containing instructions to build the brain and 200 other body tissues; developed surgeries and invented medications for diseases that would have killed millions every year; and established paper money to replace gold and silver coins. Humans established governments that included monarchies, dictatorships, democracies, and pseudodemocracies; stipulated constitutions, laws, and regulations to maintain various societies; and created several civilizations around the world that thrived and then faded. Over the past century, the advanced human brain elevated human existence to a higher sophistication with technologies such as electricity, phones, computers, internet, artificial intelligence, and machine learning. Using powerful rockets and space stations, humans have begun to expand their influence to the moon and planets of the solar system. Humans are very likely to continue achieving what evolution could never have done without evolving the human brain to become the most powerful force in nature.

The key ingredient of the brain that has enabled humans to achieve so much is the development of an advanced cognition, with superior functions that far exceed those of other living organisms. These include neurocognitive functions such as memory and attention, and executive functions that include planning, problem-solving, decision-making, abstract thinking, and insight. Those cognitive functions generate lofty prose, splendiferous poetry, and heavenly symphonies that inspire those who create it and others. The human brain also developed social cognition, with empathy, theory of mind, recognition of facial expressions, and courtship rituals that can trigger infatuation and love. Homo sapiens can experience a wide range of emotions in addition to love and attachment (necessary for procreation), including shame, guilt, surprise, embarrassment, disgust, and indifference, and a unique sense of right and wrong.

Perhaps the most distinctive human attribute, generated by an advanced prefrontal cortex, is a belief system that includes philosophy, politics, religion, and faith. Hundreds of different religions sprouted throughout human history (each claiming a monopoly on “the truth”), mandating rituals and behaviors, but also promoting a profound and unshakable belief in a divine “higher being” and an afterlife that mitigates the fear of death. Humans, unlike other animals, are painfully aware of mortality and the inevitability of death. Faith is an antidote for thanatophobia. Unfortunately, religious beliefs often generated severe and protracted schisms and warfare, with fatal consequences for their followers.

The anti-evolution aspect of the advanced brain

Despite remarkable talents and achievements, the unprecedented evolutionary expansion of the human brain also has a detrimental downside. The same intellectual power that led to astonishing positive accomplishments has a wicked side as well. While most animals have a predator, humans have become the “omni-predator” that preys on all living things. The balanced ecosystems of animals and plants has been dominated and disrupted by humans. Thousands of species that evolution had so ingeniously spawned became extinct because of human actions. The rainforests, jewels of nature’s plantation system, were victimized by human indifference to the deleterious effects on nature and climate. The excavation of coal and oil, exploited as necessary sources of energy for societal infrastructure, came back to haunt humans with climate consequences. In many ways, human “progress” corrupted evolution and dismantled its components. Survival of the fittest among various species was whittled down to “survival of humans” (and their domesticated animals) at the expense of all other organisms, animals, or plants.

Among Homo sapiens, momentous scientific, medical, and technological advances completely undermined the principle of survival of the fittest. Very premature infants, who would have certainly died, were kept alive. Children with disabling genetic disorders who would have perished in childhood were kept alive into the age of procreation, perpetuating the genetic mutations. The discovery of antibiotic and antiviral medications, and especially vaccines, ensured the survival of millions of humans who would have succumbed to infections. With evolution’s natural selection, humans who survived severe infections without medications would have passed on their “infection-resistant genes” to their progeny. The triumph of human medical progress can be conceptualized as a setback for the principles of evolution.

Continue to: The most malignant...

The most malignant consequence of the exceptional human brain is the evil of which it is capable. Human ingenuity led to the development of weapons of individual killing (guns), large-scale murder (machine guns), and massive destruction (nuclear weapons). And because aggression and warfare are an inherent part of human nature, the most potent predator for a human is another human. The history of humans is riddled with conflict and death on a large scale. Ironically, many wars were instigated by various religious groups around the world, who developed intense hostility towards one another.

There are other downsides to the advanced human brain. It can channel its talents and skills into unimaginably wicked and depraved behaviors, such as premeditated and well-planned murder, slavery, cults, child abuse, domestic abuse, pornography, fascism, dictatorships, and political corruption. Astonishingly, the same brain that can be loving, kind, friendly, and empathetic can suddenly become hateful, vengeful, cruel, vile, sinister, vicious, diabolical, and capable of unimaginable violence and atrocities. The advanced human brain definitely has a very dark side.

Finally, unlike other members of the animal kingdom, the human brain generates its virtual counterpart: the highly complex human mind, which is prone to various maladies, labeled as “psychiatric disorders.” No other animal species develops delusions, hallucinations, thought disorders, melancholia, mania, obsessive-compulsive disorder, generalized anxiety, panic attacks, posttraumatic stress disorder, psychopathy, narcissistic and borderline personality disorders, alcohol addiction, and drug abuse. Homo sapiens are the only species whose members decide to end their own life in large numbers. About 25% of human minds are afflicted with one or more of those psychiatric ailments.^1,2 The redeeming grace of the large human brain is that it led to the development of pharmacologic and somatic treatments for most of them, including psychotherapy, which is a uniquely human treatment strategy that can mend many psychiatric disorders.

Evolution may not realize what it hath wrought when it evolved the dramatically expanded human brain, with its extraordinary cognition. This awe-inspiring “biological computer” can be creative and adaptive, with superlative survival abilities, but it can also degenerate and become nefarious, villainous, murderous, and even demonic. The human brain has essentially brought evolution to a screeching halt and may at some point end up destroying Earth and all of its Homo sapien inhabitants, who may foolishly use their weapons of mass destruction. The historic achievement of evolution has become the ultimate example of “the law of unintended consequences.”

Of all the dazzling achievements of evolution, the most glorious by far is the emergence of the advanced human brain, especially the prefrontal cortex. Homo sapiens (the wise humans) are without doubt the most transformative development in the consequential annals of evolution. It was evolution’s spectacular “moonshot.” Ironically, it may also have been the seed of its destruction.

The unprecedented growth of the human brain over the past 7 million years (tripling in size) was a monumental tipping point in evolution that ultimately disrupted the entire orderly cascade of evolution on Planet Earth. Because of their superior intelligence, Homo sapiens have substantially “tinkered” with the foundations of evolution, such as “natural selection” and “survival of the fittest,” and may eventually change the course of evolution, or even reverse it. It should also be recognized that 20% of the human genome is Neanderthal, and the 2022 Nobel Prize in Physiology or Medicine was awarded to Svante Pääbo, the founder of the field of paleogenetics, who demonstrated genetically that Homo sapiens interbred with Homo neanderthalensis (who disappeared 30,000 years ago).

The majestic evolution of the human brain, in both size and complexity, led to monumental changes in the history of humankind compared to their primitive predecessors. Thanks to a superior cerebral cortex, humans developed traits and abilities that were nonexistent, even unimaginable, in the rest of animal kingdom, including primates and other mammals. These include thoughts; speech (hundreds of languages), spoken and written, to communicate among themselves; composed music and created numerous instruments to play it; invented mathematics, physics, and chemistry; developed agriculture to sustain and feed the masses; built homes, palaces, and pyramids, with water and sewage systems; hatched hundreds of religions and built thousands of houses of worship; built machines to transport themselves (cars, trains, ships, planes, and space shuttles); paved airports and countless miles of roads and railways; established companies, universities, hospitals, and research laboratories; built sports facilities such as stadiums for Olympic games and all its athletics; created hotels, restaurants, coffee shops, newspapers, and magazines; discovered the amazing DNA double helix and its genome with 23,000 coding genes containing instructions to build the brain and 200 other body tissues; developed surgeries and invented medications for diseases that would have killed millions every year; and established paper money to replace gold and silver coins. Humans established governments that included monarchies, dictatorships, democracies, and pseudodemocracies; stipulated constitutions, laws, and regulations to maintain various societies; and created several civilizations around the world that thrived and then faded. Over the past century, the advanced human brain elevated human existence to a higher sophistication with technologies such as electricity, phones, computers, internet, artificial intelligence, and machine learning. Using powerful rockets and space stations, humans have begun to expand their influence to the moon and planets of the solar system. Humans are very likely to continue achieving what evolution could never have done without evolving the human brain to become the most powerful force in nature.

The key ingredient of the brain that has enabled humans to achieve so much is the development of an advanced cognition, with superior functions that far exceed those of other living organisms. These include neurocognitive functions such as memory and attention, and executive functions that include planning, problem-solving, decision-making, abstract thinking, and insight. Those cognitive functions generate lofty prose, splendiferous poetry, and heavenly symphonies that inspire those who create it and others. The human brain also developed social cognition, with empathy, theory of mind, recognition of facial expressions, and courtship rituals that can trigger infatuation and love. Homo sapiens can experience a wide range of emotions in addition to love and attachment (necessary for procreation), including shame, guilt, surprise, embarrassment, disgust, and indifference, and a unique sense of right and wrong.

Perhaps the most distinctive human attribute, generated by an advanced prefrontal cortex, is a belief system that includes philosophy, politics, religion, and faith. Hundreds of different religions sprouted throughout human history (each claiming a monopoly on “the truth”), mandating rituals and behaviors, but also promoting a profound and unshakable belief in a divine “higher being” and an afterlife that mitigates the fear of death. Humans, unlike other animals, are painfully aware of mortality and the inevitability of death. Faith is an antidote for thanatophobia. Unfortunately, religious beliefs often generated severe and protracted schisms and warfare, with fatal consequences for their followers.

The anti-evolution aspect of the advanced brain

Despite remarkable talents and achievements, the unprecedented evolutionary expansion of the human brain also has a detrimental downside. The same intellectual power that led to astonishing positive accomplishments has a wicked side as well. While most animals have a predator, humans have become the “omni-predator” that preys on all living things. The balanced ecosystems of animals and plants has been dominated and disrupted by humans. Thousands of species that evolution had so ingeniously spawned became extinct because of human actions. The rainforests, jewels of nature’s plantation system, were victimized by human indifference to the deleterious effects on nature and climate. The excavation of coal and oil, exploited as necessary sources of energy for societal infrastructure, came back to haunt humans with climate consequences. In many ways, human “progress” corrupted evolution and dismantled its components. Survival of the fittest among various species was whittled down to “survival of humans” (and their domesticated animals) at the expense of all other organisms, animals, or plants.

Among Homo sapiens, momentous scientific, medical, and technological advances completely undermined the principle of survival of the fittest. Very premature infants, who would have certainly died, were kept alive. Children with disabling genetic disorders who would have perished in childhood were kept alive into the age of procreation, perpetuating the genetic mutations. The discovery of antibiotic and antiviral medications, and especially vaccines, ensured the survival of millions of humans who would have succumbed to infections. With evolution’s natural selection, humans who survived severe infections without medications would have passed on their “infection-resistant genes” to their progeny. The triumph of human medical progress can be conceptualized as a setback for the principles of evolution.

Continue to: The most malignant...

The most malignant consequence of the exceptional human brain is the evil of which it is capable. Human ingenuity led to the development of weapons of individual killing (guns), large-scale murder (machine guns), and massive destruction (nuclear weapons). And because aggression and warfare are an inherent part of human nature, the most potent predator for a human is another human. The history of humans is riddled with conflict and death on a large scale. Ironically, many wars were instigated by various religious groups around the world, who developed intense hostility towards one another.

There are other downsides to the advanced human brain. It can channel its talents and skills into unimaginably wicked and depraved behaviors, such as premeditated and well-planned murder, slavery, cults, child abuse, domestic abuse, pornography, fascism, dictatorships, and political corruption. Astonishingly, the same brain that can be loving, kind, friendly, and empathetic can suddenly become hateful, vengeful, cruel, vile, sinister, vicious, diabolical, and capable of unimaginable violence and atrocities. The advanced human brain definitely has a very dark side.

Finally, unlike other members of the animal kingdom, the human brain generates its virtual counterpart: the highly complex human mind, which is prone to various maladies, labeled as “psychiatric disorders.” No other animal species develops delusions, hallucinations, thought disorders, melancholia, mania, obsessive-compulsive disorder, generalized anxiety, panic attacks, posttraumatic stress disorder, psychopathy, narcissistic and borderline personality disorders, alcohol addiction, and drug abuse. Homo sapiens are the only species whose members decide to end their own life in large numbers. About 25% of human minds are afflicted with one or more of those psychiatric ailments.^1,2 The redeeming grace of the large human brain is that it led to the development of pharmacologic and somatic treatments for most of them, including psychotherapy, which is a uniquely human treatment strategy that can mend many psychiatric disorders.

Evolution may not realize what it hath wrought when it evolved the dramatically expanded human brain, with its extraordinary cognition. This awe-inspiring “biological computer” can be creative and adaptive, with superlative survival abilities, but it can also degenerate and become nefarious, villainous, murderous, and even demonic. The human brain has essentially brought evolution to a screeching halt and may at some point end up destroying Earth and all of its Homo sapien inhabitants, who may foolishly use their weapons of mass destruction. The historic achievement of evolution has become the ultimate example of “the law of unintended consequences.”

Of all the dazzling achievements of evolution, the most glorious by far is the emergence of the advanced human brain, especially the prefrontal cortex. Homo sapiens (the wise humans) are without doubt the most transformative development in the consequential annals of evolution. It was evolution’s spectacular “moonshot.” Ironically, it may also have been the seed of its destruction.

The unprecedented growth of the human brain over the past 7 million years (tripling in size) was a monumental tipping point in evolution that ultimately disrupted the entire orderly cascade of evolution on Planet Earth. Because of their superior intelligence, Homo sapiens have substantially “tinkered” with the foundations of evolution, such as “natural selection” and “survival of the fittest,” and may eventually change the course of evolution, or even reverse it. It should also be recognized that 20% of the human genome is Neanderthal, and the 2022 Nobel Prize in Physiology or Medicine was awarded to Svante Pääbo, the founder of the field of paleogenetics, who demonstrated genetically that Homo sapiens interbred with Homo neanderthalensis (who disappeared 30,000 years ago).

The majestic evolution of the human brain, in both size and complexity, led to monumental changes in the history of humankind compared to their primitive predecessors. Thanks to a superior cerebral cortex, humans developed traits and abilities that were nonexistent, even unimaginable, in the rest of animal kingdom, including primates and other mammals. These include thoughts; speech (hundreds of languages), spoken and written, to communicate among themselves; composed music and created numerous instruments to play it; invented mathematics, physics, and chemistry; developed agriculture to sustain and feed the masses; built homes, palaces, and pyramids, with water and sewage systems; hatched hundreds of religions and built thousands of houses of worship; built machines to transport themselves (cars, trains, ships, planes, and space shuttles); paved airports and countless miles of roads and railways; established companies, universities, hospitals, and research laboratories; built sports facilities such as stadiums for Olympic games and all its athletics; created hotels, restaurants, coffee shops, newspapers, and magazines; discovered the amazing DNA double helix and its genome with 23,000 coding genes containing instructions to build the brain and 200 other body tissues; developed surgeries and invented medications for diseases that would have killed millions every year; and established paper money to replace gold and silver coins. Humans established governments that included monarchies, dictatorships, democracies, and pseudodemocracies; stipulated constitutions, laws, and regulations to maintain various societies; and created several civilizations around the world that thrived and then faded. Over the past century, the advanced human brain elevated human existence to a higher sophistication with technologies such as electricity, phones, computers, internet, artificial intelligence, and machine learning. Using powerful rockets and space stations, humans have begun to expand their influence to the moon and planets of the solar system. Humans are very likely to continue achieving what evolution could never have done without evolving the human brain to become the most powerful force in nature.

The key ingredient of the brain that has enabled humans to achieve so much is the development of an advanced cognition, with superior functions that far exceed those of other living organisms. These include neurocognitive functions such as memory and attention, and executive functions that include planning, problem-solving, decision-making, abstract thinking, and insight. Those cognitive functions generate lofty prose, splendiferous poetry, and heavenly symphonies that inspire those who create it and others. The human brain also developed social cognition, with empathy, theory of mind, recognition of facial expressions, and courtship rituals that can trigger infatuation and love. Homo sapiens can experience a wide range of emotions in addition to love and attachment (necessary for procreation), including shame, guilt, surprise, embarrassment, disgust, and indifference, and a unique sense of right and wrong.

Perhaps the most distinctive human attribute, generated by an advanced prefrontal cortex, is a belief system that includes philosophy, politics, religion, and faith. Hundreds of different religions sprouted throughout human history (each claiming a monopoly on “the truth”), mandating rituals and behaviors, but also promoting a profound and unshakable belief in a divine “higher being” and an afterlife that mitigates the fear of death. Humans, unlike other animals, are painfully aware of mortality and the inevitability of death. Faith is an antidote for thanatophobia. Unfortunately, religious beliefs often generated severe and protracted schisms and warfare, with fatal consequences for their followers.

The anti-evolution aspect of the advanced brain

Despite remarkable talents and achievements, the unprecedented evolutionary expansion of the human brain also has a detrimental downside. The same intellectual power that led to astonishing positive accomplishments has a wicked side as well. While most animals have a predator, humans have become the “omni-predator” that preys on all living things. The balanced ecosystems of animals and plants has been dominated and disrupted by humans. Thousands of species that evolution had so ingeniously spawned became extinct because of human actions. The rainforests, jewels of nature’s plantation system, were victimized by human indifference to the deleterious effects on nature and climate. The excavation of coal and oil, exploited as necessary sources of energy for societal infrastructure, came back to haunt humans with climate consequences. In many ways, human “progress” corrupted evolution and dismantled its components. Survival of the fittest among various species was whittled down to “survival of humans” (and their domesticated animals) at the expense of all other organisms, animals, or plants.

Among Homo sapiens, momentous scientific, medical, and technological advances completely undermined the principle of survival of the fittest. Very premature infants, who would have certainly died, were kept alive. Children with disabling genetic disorders who would have perished in childhood were kept alive into the age of procreation, perpetuating the genetic mutations. The discovery of antibiotic and antiviral medications, and especially vaccines, ensured the survival of millions of humans who would have succumbed to infections. With evolution’s natural selection, humans who survived severe infections without medications would have passed on their “infection-resistant genes” to their progeny. The triumph of human medical progress can be conceptualized as a setback for the principles of evolution.

Continue to: The most malignant...

The most malignant consequence of the exceptional human brain is the evil of which it is capable. Human ingenuity led to the development of weapons of individual killing (guns), large-scale murder (machine guns), and massive destruction (nuclear weapons). And because aggression and warfare are an inherent part of human nature, the most potent predator for a human is another human. The history of humans is riddled with conflict and death on a large scale. Ironically, many wars were instigated by various religious groups around the world, who developed intense hostility towards one another.

There are other downsides to the advanced human brain. It can channel its talents and skills into unimaginably wicked and depraved behaviors, such as premeditated and well-planned murder, slavery, cults, child abuse, domestic abuse, pornography, fascism, dictatorships, and political corruption. Astonishingly, the same brain that can be loving, kind, friendly, and empathetic can suddenly become hateful, vengeful, cruel, vile, sinister, vicious, diabolical, and capable of unimaginable violence and atrocities. The advanced human brain definitely has a very dark side.

Finally, unlike other members of the animal kingdom, the human brain generates its virtual counterpart: the highly complex human mind, which is prone to various maladies, labeled as “psychiatric disorders.” No other animal species develops delusions, hallucinations, thought disorders, melancholia, mania, obsessive-compulsive disorder, generalized anxiety, panic attacks, posttraumatic stress disorder, psychopathy, narcissistic and borderline personality disorders, alcohol addiction, and drug abuse. Homo sapiens are the only species whose members decide to end their own life in large numbers. About 25% of human minds are afflicted with one or more of those psychiatric ailments.^1,2 The redeeming grace of the large human brain is that it led to the development of pharmacologic and somatic treatments for most of them, including psychotherapy, which is a uniquely human treatment strategy that can mend many psychiatric disorders.

Evolution may not realize what it hath wrought when it evolved the dramatically expanded human brain, with its extraordinary cognition. This awe-inspiring “biological computer” can be creative and adaptive, with superlative survival abilities, but it can also degenerate and become nefarious, villainous, murderous, and even demonic. The human brain has essentially brought evolution to a screeching halt and may at some point end up destroying Earth and all of its Homo sapien inhabitants, who may foolishly use their weapons of mass destruction. The historic achievement of evolution has become the ultimate example of “the law of unintended consequences.”

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

I (MZP) recently started medical school, and one of the first things we learned in our Human Dimension class was to listen to our patients. While this may seem prosaic to seasoned practitioners, I quickly realized the important, real-world consequences of doing so.

Clinicians rightfully presume that when they send a prescription to a pharmacy, the patient will receive what they have ordered or the generic equivalent unless it is ordered “Dispense as written.” Unfortunately, a confluence of increased demand and supply chain disruptions has produced nationwide shortages of generic Adderall extended-release (XR) and Adderall, which are commonly prescribed to patients with attention-deficit/hyperactivity disorder (ADHD).¹ While pharmacies should notify patients when they do not have these medications in stock, we have encountered numerous cases where due to shortages, prescriptions for generic dextroamphetamine/amphetamine salts XR or immediate-release (IR) have been filled with the same milligrams of only dextroamphetamine XR or IR, respectively, without notifying the patient or the prescribing clinician. Pharmacies have included several national chains and local independent stores in the New York/New Jersey region.

Over the past several months, we have encountered patients who had been well stabilized on their ADHD medication regimen who began to report anxiety, jitteriness, agitation, fatigue, poor concentration, and/or hyperactivity, and who also reported that their pills “look different.” First, we considered their symptoms could be attributed to a switch between generic manufacturers. However, upon further inspection, we discovered that the medication name printed on the label was different from what had been prescribed. We confirmed this by checking the Prescription Monitoring Program database.

Pharmacists have recently won prescribing privileges for nirmatrelvir/ritonavir (Paxlovid) to treat COVID-19, but they certainly are not permitted to fill prescriptions for psychoactive controlled substances that have different pharmacologic profiles than the medication the clinician ordered. Adderall contains D-amphetamine and L-amphetamine in a ratio of 3:1, which makes it different in potency from dextroamphetamine alone and requires adjustment to the dosage and potentially to the frequency to achieve near equivalency.

Once we realized the issue and helped our patients locate a pharmacy that had generic Adderall XR and Adderall in stock so they could resume their previous regimen, their symptoms resolved.

It is important for all clinicians to add “medication substitution reaction” to their differential diagnosis of new-onset ADHD-related symptoms in previously stable patients.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

I (MZP) recently started medical school, and one of the first things we learned in our Human Dimension class was to listen to our patients. While this may seem prosaic to seasoned practitioners, I quickly realized the important, real-world consequences of doing so.

Clinicians rightfully presume that when they send a prescription to a pharmacy, the patient will receive what they have ordered or the generic equivalent unless it is ordered “Dispense as written.” Unfortunately, a confluence of increased demand and supply chain disruptions has produced nationwide shortages of generic Adderall extended-release (XR) and Adderall, which are commonly prescribed to patients with attention-deficit/hyperactivity disorder (ADHD).¹ While pharmacies should notify patients when they do not have these medications in stock, we have encountered numerous cases where due to shortages, prescriptions for generic dextroamphetamine/amphetamine salts XR or immediate-release (IR) have been filled with the same milligrams of only dextroamphetamine XR or IR, respectively, without notifying the patient or the prescribing clinician. Pharmacies have included several national chains and local independent stores in the New York/New Jersey region.

Over the past several months, we have encountered patients who had been well stabilized on their ADHD medication regimen who began to report anxiety, jitteriness, agitation, fatigue, poor concentration, and/or hyperactivity, and who also reported that their pills “look different.” First, we considered their symptoms could be attributed to a switch between generic manufacturers. However, upon further inspection, we discovered that the medication name printed on the label was different from what had been prescribed. We confirmed this by checking the Prescription Monitoring Program database.

Pharmacists have recently won prescribing privileges for nirmatrelvir/ritonavir (Paxlovid) to treat COVID-19, but they certainly are not permitted to fill prescriptions for psychoactive controlled substances that have different pharmacologic profiles than the medication the clinician ordered. Adderall contains D-amphetamine and L-amphetamine in a ratio of 3:1, which makes it different in potency from dextroamphetamine alone and requires adjustment to the dosage and potentially to the frequency to achieve near equivalency.

Once we realized the issue and helped our patients locate a pharmacy that had generic Adderall XR and Adderall in stock so they could resume their previous regimen, their symptoms resolved.

It is important for all clinicians to add “medication substitution reaction” to their differential diagnosis of new-onset ADHD-related symptoms in previously stable patients.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry . All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact [email protected].

I (MZP) recently started medical school, and one of the first things we learned in our Human Dimension class was to listen to our patients. While this may seem prosaic to seasoned practitioners, I quickly realized the important, real-world consequences of doing so.

Clinicians rightfully presume that when they send a prescription to a pharmacy, the patient will receive what they have ordered or the generic equivalent unless it is ordered “Dispense as written.” Unfortunately, a confluence of increased demand and supply chain disruptions has produced nationwide shortages of generic Adderall extended-release (XR) and Adderall, which are commonly prescribed to patients with attention-deficit/hyperactivity disorder (ADHD).¹ While pharmacies should notify patients when they do not have these medications in stock, we have encountered numerous cases where due to shortages, prescriptions for generic dextroamphetamine/amphetamine salts XR or immediate-release (IR) have been filled with the same milligrams of only dextroamphetamine XR or IR, respectively, without notifying the patient or the prescribing clinician. Pharmacies have included several national chains and local independent stores in the New York/New Jersey region.

Over the past several months, we have encountered patients who had been well stabilized on their ADHD medication regimen who began to report anxiety, jitteriness, agitation, fatigue, poor concentration, and/or hyperactivity, and who also reported that their pills “look different.” First, we considered their symptoms could be attributed to a switch between generic manufacturers. However, upon further inspection, we discovered that the medication name printed on the label was different from what had been prescribed. We confirmed this by checking the Prescription Monitoring Program database.

Pharmacists have recently won prescribing privileges for nirmatrelvir/ritonavir (Paxlovid) to treat COVID-19, but they certainly are not permitted to fill prescriptions for psychoactive controlled substances that have different pharmacologic profiles than the medication the clinician ordered. Adderall contains D-amphetamine and L-amphetamine in a ratio of 3:1, which makes it different in potency from dextroamphetamine alone and requires adjustment to the dosage and potentially to the frequency to achieve near equivalency.

Once we realized the issue and helped our patients locate a pharmacy that had generic Adderall XR and Adderall in stock so they could resume their previous regimen, their symptoms resolved.

It is important for all clinicians to add “medication substitution reaction” to their differential diagnosis of new-onset ADHD-related symptoms in previously stable patients.

Throughout my training, a common refrain from more senior colleagues was that training “goes by quickly.” At the risk of sounding cliché, and even after a 7-year journey spanning psychiatry and preventive medicine residencies as well as a consultation-liaison psychiatry fellowship, I agree without reservations that it does indeed go quickly. In the waning days of my training, reflection and nostalgia have become commonplace, as one might expect after such a meaningful pursuit. In sharing my reflections, I hope others progressing through training will also reflect on elements that added meaning to their experience and how they might improve the journey for future trainees.

Residency is a team sport

One realization that quickly struck me was that residency is a team sport, and finding supportive communities is essential to survival. Other residents, colleagues, and mentors played integral roles in making my experience rewarding. Training might be considered a shared traumatic experience, but having peers to commiserate with at each step has been among its greatest rewards. Residency automatically provided a cohort of colleagues who shared and validated my experiences. Additionally, having mentors who have been through it themselves and find ways to improve the training experience made mine superlative. Mentors assisted me in tailoring my training and developing interests that I could integrate into my future practice. The interpersonal connections I made were critical in helping me survive and thrive during training.

See one, do one, teach one

Residency and fellowship programs might be considered “see one, do one, teach one”¹ at large scale. Since their inception, these programs—designed to develop junior physicians—have been inherently educational in nature. The structure is elegant, allowing trainees to continue learning while incrementally gaining more autonomy and teaching responsibility.² Naively, I did not understand that implicit within my education was an expectation to become an educator and hone my teaching skills. Initially, being a newly minted resident receiving brand-new 3rd-year medical students charged me with apprehension. Thoughts I internalized, such as “these students probably know more than me” or “how can I be responsible for patients and students simultaneously,” may have resulted from a paucity of instruction about teaching available during medical school.^3,4 I quickly found, though, that teaching was among the most rewarding facets of training. Helping other learners grow became one of my passions and added to my experience.

Iron sharpens iron

Although my experience was enjoyable, I would be remiss without also considering accompanying trials and tribulations. Seemingly interminable night shifts, sleep deprivation, lack of autonomy, and system inefficiencies frustrated me. Eventually, these frustrations seemed less bothersome. These challenges likely had not vanished with time, but perhaps my capacity to tolerate distress improved—likely corresponding with increasing skill and confidence. These challenges allowed me to hone my clinical decision-making abilities while under duress. My struggles and frustrations were not unique but perhaps lessons themselves.

Residency is not meant to be easy. The crucible of residency taught me that I had resilience to draw upon during challenging times. “Iron sharpens iron,” as the adage goes, and I believe adversity ultimately helped me become a better psychiatrist.

Self-reflection is part of completing training

Reminders that my journey is at an end are everywhere. Seeing notes written by past residents or fellows reminds me that soon I too will merely be a name in the chart to future trainees. Perhaps this line of thought is unfair, reducing my training experience to notes I signed—whereas my training experience was defined by connections made with colleagues and mentors, opportunities to teach junior learners, and confidence gained by overcoming adversity.

While becoming an attending psychiatrist fills me with trepidation, fear need not be an inherent aspect of new beginnings. Reflection has been a powerful practice, allowing me to realize what made my experience so meaningful, and that training is meant to be process-oriented rather than outcome-oriented. My reflection has underscored the realization that challenges are inherent in training, although not without purpose. I believe these struggles were meant to allow me to build meaningful relationships with colleagues, discover joy in teaching, and build resiliency.

The purpose of residencies and fellowships should be to produce clinically excellent psychiatrists, but I feel the journey was as important as the destination. Psychiatrists likely understand this better than most, as we were trained to thoughtfully approach the process of termination with patients.⁵ While the conclusion of our training journeys may seem unceremonious or anticlimactic, the termination process should include self-reflection on meaningful facets of training. For me, this reflection has itself been invaluable, while also making me hopeful to contribute value to the training journeys of future psychiatrists.

Throughout my training, a common refrain from more senior colleagues was that training “goes by quickly.” At the risk of sounding cliché, and even after a 7-year journey spanning psychiatry and preventive medicine residencies as well as a consultation-liaison psychiatry fellowship, I agree without reservations that it does indeed go quickly. In the waning days of my training, reflection and nostalgia have become commonplace, as one might expect after such a meaningful pursuit. In sharing my reflections, I hope others progressing through training will also reflect on elements that added meaning to their experience and how they might improve the journey for future trainees.

Residency is a team sport

One realization that quickly struck me was that residency is a team sport, and finding supportive communities is essential to survival. Other residents, colleagues, and mentors played integral roles in making my experience rewarding. Training might be considered a shared traumatic experience, but having peers to commiserate with at each step has been among its greatest rewards. Residency automatically provided a cohort of colleagues who shared and validated my experiences. Additionally, having mentors who have been through it themselves and find ways to improve the training experience made mine superlative. Mentors assisted me in tailoring my training and developing interests that I could integrate into my future practice. The interpersonal connections I made were critical in helping me survive and thrive during training.

See one, do one, teach one

Residency and fellowship programs might be considered “see one, do one, teach one”¹ at large scale. Since their inception, these programs—designed to develop junior physicians—have been inherently educational in nature. The structure is elegant, allowing trainees to continue learning while incrementally gaining more autonomy and teaching responsibility.² Naively, I did not understand that implicit within my education was an expectation to become an educator and hone my teaching skills. Initially, being a newly minted resident receiving brand-new 3rd-year medical students charged me with apprehension. Thoughts I internalized, such as “these students probably know more than me” or “how can I be responsible for patients and students simultaneously,” may have resulted from a paucity of instruction about teaching available during medical school.^3,4 I quickly found, though, that teaching was among the most rewarding facets of training. Helping other learners grow became one of my passions and added to my experience.

Iron sharpens iron

Although my experience was enjoyable, I would be remiss without also considering accompanying trials and tribulations. Seemingly interminable night shifts, sleep deprivation, lack of autonomy, and system inefficiencies frustrated me. Eventually, these frustrations seemed less bothersome. These challenges likely had not vanished with time, but perhaps my capacity to tolerate distress improved—likely corresponding with increasing skill and confidence. These challenges allowed me to hone my clinical decision-making abilities while under duress. My struggles and frustrations were not unique but perhaps lessons themselves.

Residency is not meant to be easy. The crucible of residency taught me that I had resilience to draw upon during challenging times. “Iron sharpens iron,” as the adage goes, and I believe adversity ultimately helped me become a better psychiatrist.

Self-reflection is part of completing training

Reminders that my journey is at an end are everywhere. Seeing notes written by past residents or fellows reminds me that soon I too will merely be a name in the chart to future trainees. Perhaps this line of thought is unfair, reducing my training experience to notes I signed—whereas my training experience was defined by connections made with colleagues and mentors, opportunities to teach junior learners, and confidence gained by overcoming adversity.

While becoming an attending psychiatrist fills me with trepidation, fear need not be an inherent aspect of new beginnings. Reflection has been a powerful practice, allowing me to realize what made my experience so meaningful, and that training is meant to be process-oriented rather than outcome-oriented. My reflection has underscored the realization that challenges are inherent in training, although not without purpose. I believe these struggles were meant to allow me to build meaningful relationships with colleagues, discover joy in teaching, and build resiliency.

The purpose of residencies and fellowships should be to produce clinically excellent psychiatrists, but I feel the journey was as important as the destination. Psychiatrists likely understand this better than most, as we were trained to thoughtfully approach the process of termination with patients.⁵ While the conclusion of our training journeys may seem unceremonious or anticlimactic, the termination process should include self-reflection on meaningful facets of training. For me, this reflection has itself been invaluable, while also making me hopeful to contribute value to the training journeys of future psychiatrists.

Throughout my training, a common refrain from more senior colleagues was that training “goes by quickly.” At the risk of sounding cliché, and even after a 7-year journey spanning psychiatry and preventive medicine residencies as well as a consultation-liaison psychiatry fellowship, I agree without reservations that it does indeed go quickly. In the waning days of my training, reflection and nostalgia have become commonplace, as one might expect after such a meaningful pursuit. In sharing my reflections, I hope others progressing through training will also reflect on elements that added meaning to their experience and how they might improve the journey for future trainees.

Residency is a team sport

One realization that quickly struck me was that residency is a team sport, and finding supportive communities is essential to survival. Other residents, colleagues, and mentors played integral roles in making my experience rewarding. Training might be considered a shared traumatic experience, but having peers to commiserate with at each step has been among its greatest rewards. Residency automatically provided a cohort of colleagues who shared and validated my experiences. Additionally, having mentors who have been through it themselves and find ways to improve the training experience made mine superlative. Mentors assisted me in tailoring my training and developing interests that I could integrate into my future practice. The interpersonal connections I made were critical in helping me survive and thrive during training.

See one, do one, teach one

Residency and fellowship programs might be considered “see one, do one, teach one”¹ at large scale. Since their inception, these programs—designed to develop junior physicians—have been inherently educational in nature. The structure is elegant, allowing trainees to continue learning while incrementally gaining more autonomy and teaching responsibility.² Naively, I did not understand that implicit within my education was an expectation to become an educator and hone my teaching skills. Initially, being a newly minted resident receiving brand-new 3rd-year medical students charged me with apprehension. Thoughts I internalized, such as “these students probably know more than me” or “how can I be responsible for patients and students simultaneously,” may have resulted from a paucity of instruction about teaching available during medical school.^3,4 I quickly found, though, that teaching was among the most rewarding facets of training. Helping other learners grow became one of my passions and added to my experience.

Iron sharpens iron

Although my experience was enjoyable, I would be remiss without also considering accompanying trials and tribulations. Seemingly interminable night shifts, sleep deprivation, lack of autonomy, and system inefficiencies frustrated me. Eventually, these frustrations seemed less bothersome. These challenges likely had not vanished with time, but perhaps my capacity to tolerate distress improved—likely corresponding with increasing skill and confidence. These challenges allowed me to hone my clinical decision-making abilities while under duress. My struggles and frustrations were not unique but perhaps lessons themselves.

Residency is not meant to be easy. The crucible of residency taught me that I had resilience to draw upon during challenging times. “Iron sharpens iron,” as the adage goes, and I believe adversity ultimately helped me become a better psychiatrist.

Self-reflection is part of completing training

Reminders that my journey is at an end are everywhere. Seeing notes written by past residents or fellows reminds me that soon I too will merely be a name in the chart to future trainees. Perhaps this line of thought is unfair, reducing my training experience to notes I signed—whereas my training experience was defined by connections made with colleagues and mentors, opportunities to teach junior learners, and confidence gained by overcoming adversity.

While becoming an attending psychiatrist fills me with trepidation, fear need not be an inherent aspect of new beginnings. Reflection has been a powerful practice, allowing me to realize what made my experience so meaningful, and that training is meant to be process-oriented rather than outcome-oriented. My reflection has underscored the realization that challenges are inherent in training, although not without purpose. I believe these struggles were meant to allow me to build meaningful relationships with colleagues, discover joy in teaching, and build resiliency.

The purpose of residencies and fellowships should be to produce clinically excellent psychiatrists, but I feel the journey was as important as the destination. Psychiatrists likely understand this better than most, as we were trained to thoughtfully approach the process of termination with patients.⁵ While the conclusion of our training journeys may seem unceremonious or anticlimactic, the termination process should include self-reflection on meaningful facets of training. For me, this reflection has itself been invaluable, while also making me hopeful to contribute value to the training journeys of future psychiatrists.

In reading Dr. Nasrallah's August 2022 editorial (“Reversing depression: A plethora of therapeutic strategies and mechanisms,” Current Psychiatry, August 2022, p. 4-6), I was curious why he did not mention lamotrigine as an adjunctive therapy for bipolar depression. Was that an editing error, or an important statement about the questionable value of that drug for current, ongoing bipolar depression?

Dr. Nasrallah responds

Thanks for your message. Lamotrigine is not FDA-approved for bipolar or unipolar depression, either as monotherapy or as an adjunctive therapy. It has never been approved for mania, either (no efficacy at all). Its only FDA-approved psychiatric indication is maintenance therapy after a patient with bipolar I disorder emerges from mania with the help of one of the antimanic drugs. Yet many clinicians may perceive lamotrigine as useful for bipolar depression because more than 20 years ago the manufacturer sponsored several small studies (not FDA trials). Two studies that showed efficacy were published, but 4 other studies that failed to show efficacy were not published. As a result, many clinicians got the false impression that lamotrigine is an effective antidepressant. I hope this explains why lamotrigine was not included in the list of antidepressants in my editorial.

In reading Dr. Nasrallah's August 2022 editorial (“Reversing depression: A plethora of therapeutic strategies and mechanisms,” Current Psychiatry, August 2022, p. 4-6), I was curious why he did not mention lamotrigine as an adjunctive therapy for bipolar depression. Was that an editing error, or an important statement about the questionable value of that drug for current, ongoing bipolar depression?

Dr. Nasrallah responds

Thanks for your message. Lamotrigine is not FDA-approved for bipolar or unipolar depression, either as monotherapy or as an adjunctive therapy. It has never been approved for mania, either (no efficacy at all). Its only FDA-approved psychiatric indication is maintenance therapy after a patient with bipolar I disorder emerges from mania with the help of one of the antimanic drugs. Yet many clinicians may perceive lamotrigine as useful for bipolar depression because more than 20 years ago the manufacturer sponsored several small studies (not FDA trials). Two studies that showed efficacy were published, but 4 other studies that failed to show efficacy were not published. As a result, many clinicians got the false impression that lamotrigine is an effective antidepressant. I hope this explains why lamotrigine was not included in the list of antidepressants in my editorial.

In reading Dr. Nasrallah's August 2022 editorial (“Reversing depression: A plethora of therapeutic strategies and mechanisms,” Current Psychiatry, August 2022, p. 4-6), I was curious why he did not mention lamotrigine as an adjunctive therapy for bipolar depression. Was that an editing error, or an important statement about the questionable value of that drug for current, ongoing bipolar depression?

Dr. Nasrallah responds

Thanks for your message. Lamotrigine is not FDA-approved for bipolar or unipolar depression, either as monotherapy or as an adjunctive therapy. It has never been approved for mania, either (no efficacy at all). Its only FDA-approved psychiatric indication is maintenance therapy after a patient with bipolar I disorder emerges from mania with the help of one of the antimanic drugs. Yet many clinicians may perceive lamotrigine as useful for bipolar depression because more than 20 years ago the manufacturer sponsored several small studies (not FDA trials). Two studies that showed efficacy were published, but 4 other studies that failed to show efficacy were not published. As a result, many clinicians got the false impression that lamotrigine is an effective antidepressant. I hope this explains why lamotrigine was not included in the list of antidepressants in my editorial.

In 2007 (coinciding with the inaugural year of GI & Hepatology News), the National Institutes of Health launched the initial phase of the Human Microbiome Project (HMP), marking an important milestone in our study and understanding of the gut microbiome. The HMP, which was supported by “only” approximately $20 million of funding in its first year, served as a catalyst for the development of computational tools, clinical protocols, and reference datasets for an emerging field that now approaches nearly $2 billion per year in market value of diagnostics and therapeutics.

Over the past 15 years, many important discoveries about the microbiome have been made, particularly in the fields of gastroenterology, hepatology, and nutrition. The transplantation of gut microbiome from one person to another has been shown to be more than 90% effective in the treatment of recurrent C. difficile infection, disrupting our current therapeutic algorithms of repetitive antibiotics. Other exciting discoveries have included the relationship between the gut microbiome and enteric nervous system, and its roles in the regulation of metabolism and obesity and in the progression of liver fibrosis and cancer.

ChrisChrisW/Getty Images

Looking ahead, several exciting areas related to digestive health and the microbiome are being prioritized, including the role of probiotics in nutrition, the complex relationship of the bidirectional “gut-brain” axis, and further development of analytics to define and deliver precision medicine across a wide range of digestive disorders. Without a doubt, emerging microbiome discoveries will be prominently featured in the pages of GI & Hepatology News over the coming years to keep our readers informed of these cutting-edge findings.

Dr. Rosenberg is medical director of the North Shore Endoscopy Center and director of clinical research at GI Alliance of Illinois in Gurnee, Ill. Dr. Rosenberg is a consultant for Aimmune Therapeutics and performs clinical research with Ferring Pharmaceuticals.

In 2007 (coinciding with the inaugural year of GI & Hepatology News), the National Institutes of Health launched the initial phase of the Human Microbiome Project (HMP), marking an important milestone in our study and understanding of the gut microbiome. The HMP, which was supported by “only” approximately $20 million of funding in its first year, served as a catalyst for the development of computational tools, clinical protocols, and reference datasets for an emerging field that now approaches nearly $2 billion per year in market value of diagnostics and therapeutics.

Over the past 15 years, many important discoveries about the microbiome have been made, particularly in the fields of gastroenterology, hepatology, and nutrition. The transplantation of gut microbiome from one person to another has been shown to be more than 90% effective in the treatment of recurrent C. difficile infection, disrupting our current therapeutic algorithms of repetitive antibiotics. Other exciting discoveries have included the relationship between the gut microbiome and enteric nervous system, and its roles in the regulation of metabolism and obesity and in the progression of liver fibrosis and cancer.

ChrisChrisW/Getty Images

Looking ahead, several exciting areas related to digestive health and the microbiome are being prioritized, including the role of probiotics in nutrition, the complex relationship of the bidirectional “gut-brain” axis, and further development of analytics to define and deliver precision medicine across a wide range of digestive disorders. Without a doubt, emerging microbiome discoveries will be prominently featured in the pages of GI & Hepatology News over the coming years to keep our readers informed of these cutting-edge findings.

Dr. Rosenberg is medical director of the North Shore Endoscopy Center and director of clinical research at GI Alliance of Illinois in Gurnee, Ill. Dr. Rosenberg is a consultant for Aimmune Therapeutics and performs clinical research with Ferring Pharmaceuticals.

In 2007 (coinciding with the inaugural year of GI & Hepatology News), the National Institutes of Health launched the initial phase of the Human Microbiome Project (HMP), marking an important milestone in our study and understanding of the gut microbiome. The HMP, which was supported by “only” approximately $20 million of funding in its first year, served as a catalyst for the development of computational tools, clinical protocols, and reference datasets for an emerging field that now approaches nearly $2 billion per year in market value of diagnostics and therapeutics.

Over the past 15 years, many important discoveries about the microbiome have been made, particularly in the fields of gastroenterology, hepatology, and nutrition. The transplantation of gut microbiome from one person to another has been shown to be more than 90% effective in the treatment of recurrent C. difficile infection, disrupting our current therapeutic algorithms of repetitive antibiotics. Other exciting discoveries have included the relationship between the gut microbiome and enteric nervous system, and its roles in the regulation of metabolism and obesity and in the progression of liver fibrosis and cancer.

ChrisChrisW/Getty Images

Looking ahead, several exciting areas related to digestive health and the microbiome are being prioritized, including the role of probiotics in nutrition, the complex relationship of the bidirectional “gut-brain” axis, and further development of analytics to define and deliver precision medicine across a wide range of digestive disorders. Without a doubt, emerging microbiome discoveries will be prominently featured in the pages of GI & Hepatology News over the coming years to keep our readers informed of these cutting-edge findings.

Dr. Rosenberg is medical director of the North Shore Endoscopy Center and director of clinical research at GI Alliance of Illinois in Gurnee, Ill. Dr. Rosenberg is a consultant for Aimmune Therapeutics and performs clinical research with Ferring Pharmaceuticals.

One in 5. It almost seems unimaginable that this is the real number of people who are struggling with long COVID, especially considering how many people in the United States have had COVID-19 at this point (more than 96 million). Yet I continue to hear of people who are struggling, and we continue to see a flood of people in the long COVID clinic. It isn’t over, and long COVID is the new pandemic.

Even more unimaginable at this time is that it’s happening to me. I’ve experienced not only the disabling effects of long COVID, but I’ve also seen, firsthand, the frustration of navigating diagnosis and treatment. It’s given me a taste of what millions of other patients are going through.
 

Vaxxed, masked, and (too) relaxed

I caught COVID-19 (probably Omicron BA.5) that presented as sniffles, making me think it was probably just allergies. However, my resting heart rate was up on my Garmin watch, so of course I got tested and was positive.

With my symptoms virtually nonexistent, it seemed, at the time, merely an inconvenience, because I was forced to isolate away from family and friends, who all stayed negative.

But 2 weeks later, I began to have urticaria – hives – after physical exertion. Did that mean my mast cells were angry? There’s some evidence these immune cells become overactivated in some patients with COVID. Next, I began to experience lightheadedness and the rapid heartbeat of tachycardia. The tachycardia was especially bad any time I physically exerted myself, including on a walk. Imagine me – a lover of all bargain shopping – cutting short a trip to the outlet mall on a particularly bad day when my heart rate was 140 after taking just a few steps. This was orthostatic intolerance.

Then came the severe worsening of my migraines – which are often vestibular, making me nauseated and dizzy on top of the throbbing.

I was of course familiar with these symptoms, as professor and chair of the department of rehabilitation medicine at the Joe R. and Teresa Lozano Long School of Medicine at University of Texas Health Science Center, San Antonio. I developed a post-COVID recovery clinic to help patients.

So I knew about postexertional malaise (PEM) and postexertional symptom exacerbation (PESE), but I was now experiencing these distressing symptoms firsthand.

Clinicians really need to look for this cardinal sign of long COVID as well as evidence of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). ME/CFS is marked by exacerbation of fatigue or symptoms after an activity that could previously be done without these aftereffects. In my case, as an All-American Masters miler with several marathons under my belt, running 5 miles is a walk in the park. But now, I pay for those 5 miles for the rest of the day on the couch or with palpitations, dizziness, and fatigue the following day. Busy clinic day full of procedures? I would have to be sitting by the end of it. Bed by 9 PM was not always early enough.
 

Becoming a statistic

Here I am, one of the leading experts in the country on caring for people with long COVID, featured in the national news and having testified in front of Congress, and now I am part of that lived experience. Me – a healthy athlete, with no comorbidities, a normal BMI, vaccinated and boosted, and after an almost asymptomatic bout of COVID-19, a victim to long COVID.

You just never know how your body is going to react. Neuroinflammation occurred in studies with mice with mild respiratory COVID and could be happening to me. I did not want a chronic immune-mediated vasculopathy.

So, I did what any other hyperaware physician-researcher would do. I enrolled in the RECOVER trial – a study my own institution is taking part in and one that I recommend to my own patients.

I also decided that I need to access care and not just ignore my symptoms or try to treat them myself.

That’s when things got difficult. There was a wait of at least a month to see my primary care provider – but I was able to use my privileged position as a physician to get in sooner.

My provider said that she had limited knowledge of long COVID, and she hesitated to order some of the tests and treatments that I recommended because they were not yet considered standard of care. I can understand the hesitation. It is engrained in medical education to follow evidence based on the highest-quality research studies. We are slowly learning more about long COVID, but acknowledging the learning curve offers little to patients who need help now.

This has made me realize that we cannot wait on an evidence-based approach – which can take decades to develop – while people are suffering. And it’s important that everyone on the front line learn about some of the manifestations and disease management of long COVID.

I left this first physician visit feeling more defeated than anything and decided to try to push through. That, I quickly realized, was not the right thing to do.

So again, after a couple of significant crashes and days of severe migraines, I phoned a friend: Ratna Bhavaraju-Sanka, MD, the amazing neurologist who treats patients with long COVID alongside me. She squeezed me in on a non-clinic day. Again, I had the privilege to see a specialist most people wait half a year to see. I was diagnosed with both autonomic dysfunction and intractable migraine.

She ordered some intravenous fluids and IV magnesium that would probably help both. But then another obstacle arose. My institution’s infusion center is focused on patients with cancer, and I was unable to schedule treatments there.

Luckily, I knew about the concierge mobile IV hydration therapy companies that come to your house – mostly offering a hangover treatment service. And I am thankful that I had the health literacy and financial ability to pay for some fluids at home.

On another particularly bad day, I phoned other friends – higher-ups at the hospital – who expedited a slot at the hospital infusion center and approval for the IV magnesium.

Thanks to my access, knowledge, and other privileges, I got fairly quick if imperfect care, enrolled in a research trial, and received medications. I knew to pace myself. The vast majority of others with long COVID lack these advantages.
 

The patient with long COVID

Things I have learned that others can learn, too:

• Acknowledge and recognize that long COVID is a disease that is affecting 1 in 5 Americans who catch COVID. Many look completely “normal on the outside.” Please listen to your patients.
• Autonomic dysfunction is a common manifestation of long COVID. A 10-minute stand test goes a long way in diagnosing this condition, from the American Academy of Physical Medicine and Rehabilitation. It is not just anxiety.
• “That’s only in research” is dismissive and harmful. Think outside the box. Follow guidelines. Consider encouraging patients to sign up for trials.
• Screen for PEM/PESE and teach your patients to pace themselves, because pushing through it or doing graded exercises will be harmful.
• We need to train more physicians to treat postacute sequelae of SARS-CoV-2 infection () and other postinfectious conditions, such as ME/CFS.

If long COVID is hard for physicians to understand and deal with, imagine how difficult it is for patients with no expertise in this area.

It is exponentially harder for those with fewer resources, time, and health literacy. My lived experience with long COVID has shown me that being a patient is never easy. You put your body and fate into the hands of trusted professionals and expect validation and assistance, not gaslighting or gatekeeping.

Along with millions of others, I am tired of waiting.

Dr. Gutierrez is Professor and Distinguished Chair, department of rehabilitation medicine, University of Texas Health Science Center at San Antonio. She reported receiving honoraria for lecturing on long COVID and receiving a research grant from Co-PI for the NIH RECOVER trial.

A version of this article first appeared on Medscape.com.

One in 5. It almost seems unimaginable that this is the real number of people who are struggling with long COVID, especially considering how many people in the United States have had COVID-19 at this point (more than 96 million). Yet I continue to hear of people who are struggling, and we continue to see a flood of people in the long COVID clinic. It isn’t over, and long COVID is the new pandemic.

Even more unimaginable at this time is that it’s happening to me. I’ve experienced not only the disabling effects of long COVID, but I’ve also seen, firsthand, the frustration of navigating diagnosis and treatment. It’s given me a taste of what millions of other patients are going through.
 

Vaxxed, masked, and (too) relaxed

I caught COVID-19 (probably Omicron BA.5) that presented as sniffles, making me think it was probably just allergies. However, my resting heart rate was up on my Garmin watch, so of course I got tested and was positive.

With my symptoms virtually nonexistent, it seemed, at the time, merely an inconvenience, because I was forced to isolate away from family and friends, who all stayed negative.

But 2 weeks later, I began to have urticaria – hives – after physical exertion. Did that mean my mast cells were angry? There’s some evidence these immune cells become overactivated in some patients with COVID. Next, I began to experience lightheadedness and the rapid heartbeat of tachycardia. The tachycardia was especially bad any time I physically exerted myself, including on a walk. Imagine me – a lover of all bargain shopping – cutting short a trip to the outlet mall on a particularly bad day when my heart rate was 140 after taking just a few steps. This was orthostatic intolerance.

Then came the severe worsening of my migraines – which are often vestibular, making me nauseated and dizzy on top of the throbbing.

I was of course familiar with these symptoms, as professor and chair of the department of rehabilitation medicine at the Joe R. and Teresa Lozano Long School of Medicine at University of Texas Health Science Center, San Antonio. I developed a post-COVID recovery clinic to help patients.

So I knew about postexertional malaise (PEM) and postexertional symptom exacerbation (PESE), but I was now experiencing these distressing symptoms firsthand.

Clinicians really need to look for this cardinal sign of long COVID as well as evidence of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). ME/CFS is marked by exacerbation of fatigue or symptoms after an activity that could previously be done without these aftereffects. In my case, as an All-American Masters miler with several marathons under my belt, running 5 miles is a walk in the park. But now, I pay for those 5 miles for the rest of the day on the couch or with palpitations, dizziness, and fatigue the following day. Busy clinic day full of procedures? I would have to be sitting by the end of it. Bed by 9 PM was not always early enough.
 

Becoming a statistic

Here I am, one of the leading experts in the country on caring for people with long COVID, featured in the national news and having testified in front of Congress, and now I am part of that lived experience. Me – a healthy athlete, with no comorbidities, a normal BMI, vaccinated and boosted, and after an almost asymptomatic bout of COVID-19, a victim to long COVID.

You just never know how your body is going to react. Neuroinflammation occurred in studies with mice with mild respiratory COVID and could be happening to me. I did not want a chronic immune-mediated vasculopathy.

So, I did what any other hyperaware physician-researcher would do. I enrolled in the RECOVER trial – a study my own institution is taking part in and one that I recommend to my own patients.

I also decided that I need to access care and not just ignore my symptoms or try to treat them myself.

That’s when things got difficult. There was a wait of at least a month to see my primary care provider – but I was able to use my privileged position as a physician to get in sooner.

My provider said that she had limited knowledge of long COVID, and she hesitated to order some of the tests and treatments that I recommended because they were not yet considered standard of care. I can understand the hesitation. It is engrained in medical education to follow evidence based on the highest-quality research studies. We are slowly learning more about long COVID, but acknowledging the learning curve offers little to patients who need help now.

This has made me realize that we cannot wait on an evidence-based approach – which can take decades to develop – while people are suffering. And it’s important that everyone on the front line learn about some of the manifestations and disease management of long COVID.

I left this first physician visit feeling more defeated than anything and decided to try to push through. That, I quickly realized, was not the right thing to do.

So again, after a couple of significant crashes and days of severe migraines, I phoned a friend: Ratna Bhavaraju-Sanka, MD, the amazing neurologist who treats patients with long COVID alongside me. She squeezed me in on a non-clinic day. Again, I had the privilege to see a specialist most people wait half a year to see. I was diagnosed with both autonomic dysfunction and intractable migraine.

She ordered some intravenous fluids and IV magnesium that would probably help both. But then another obstacle arose. My institution’s infusion center is focused on patients with cancer, and I was unable to schedule treatments there.

Luckily, I knew about the concierge mobile IV hydration therapy companies that come to your house – mostly offering a hangover treatment service. And I am thankful that I had the health literacy and financial ability to pay for some fluids at home.

On another particularly bad day, I phoned other friends – higher-ups at the hospital – who expedited a slot at the hospital infusion center and approval for the IV magnesium.

Thanks to my access, knowledge, and other privileges, I got fairly quick if imperfect care, enrolled in a research trial, and received medications. I knew to pace myself. The vast majority of others with long COVID lack these advantages.
 

The patient with long COVID

Things I have learned that others can learn, too:

• Acknowledge and recognize that long COVID is a disease that is affecting 1 in 5 Americans who catch COVID. Many look completely “normal on the outside.” Please listen to your patients.
• Autonomic dysfunction is a common manifestation of long COVID. A 10-minute stand test goes a long way in diagnosing this condition, from the American Academy of Physical Medicine and Rehabilitation. It is not just anxiety.
• “That’s only in research” is dismissive and harmful. Think outside the box. Follow guidelines. Consider encouraging patients to sign up for trials.
• Screen for PEM/PESE and teach your patients to pace themselves, because pushing through it or doing graded exercises will be harmful.
• We need to train more physicians to treat postacute sequelae of SARS-CoV-2 infection () and other postinfectious conditions, such as ME/CFS.

If long COVID is hard for physicians to understand and deal with, imagine how difficult it is for patients with no expertise in this area.

It is exponentially harder for those with fewer resources, time, and health literacy. My lived experience with long COVID has shown me that being a patient is never easy. You put your body and fate into the hands of trusted professionals and expect validation and assistance, not gaslighting or gatekeeping.

Along with millions of others, I am tired of waiting.

Dr. Gutierrez is Professor and Distinguished Chair, department of rehabilitation medicine, University of Texas Health Science Center at San Antonio. She reported receiving honoraria for lecturing on long COVID and receiving a research grant from Co-PI for the NIH RECOVER trial.

A version of this article first appeared on Medscape.com.

One in 5. It almost seems unimaginable that this is the real number of people who are struggling with long COVID, especially considering how many people in the United States have had COVID-19 at this point (more than 96 million). Yet I continue to hear of people who are struggling, and we continue to see a flood of people in the long COVID clinic. It isn’t over, and long COVID is the new pandemic.

Even more unimaginable at this time is that it’s happening to me. I’ve experienced not only the disabling effects of long COVID, but I’ve also seen, firsthand, the frustration of navigating diagnosis and treatment. It’s given me a taste of what millions of other patients are going through.
 

Vaxxed, masked, and (too) relaxed

I caught COVID-19 (probably Omicron BA.5) that presented as sniffles, making me think it was probably just allergies. However, my resting heart rate was up on my Garmin watch, so of course I got tested and was positive.

With my symptoms virtually nonexistent, it seemed, at the time, merely an inconvenience, because I was forced to isolate away from family and friends, who all stayed negative.

But 2 weeks later, I began to have urticaria – hives – after physical exertion. Did that mean my mast cells were angry? There’s some evidence these immune cells become overactivated in some patients with COVID. Next, I began to experience lightheadedness and the rapid heartbeat of tachycardia. The tachycardia was especially bad any time I physically exerted myself, including on a walk. Imagine me – a lover of all bargain shopping – cutting short a trip to the outlet mall on a particularly bad day when my heart rate was 140 after taking just a few steps. This was orthostatic intolerance.

Then came the severe worsening of my migraines – which are often vestibular, making me nauseated and dizzy on top of the throbbing.

I was of course familiar with these symptoms, as professor and chair of the department of rehabilitation medicine at the Joe R. and Teresa Lozano Long School of Medicine at University of Texas Health Science Center, San Antonio. I developed a post-COVID recovery clinic to help patients.

So I knew about postexertional malaise (PEM) and postexertional symptom exacerbation (PESE), but I was now experiencing these distressing symptoms firsthand.

Clinicians really need to look for this cardinal sign of long COVID as well as evidence of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). ME/CFS is marked by exacerbation of fatigue or symptoms after an activity that could previously be done without these aftereffects. In my case, as an All-American Masters miler with several marathons under my belt, running 5 miles is a walk in the park. But now, I pay for those 5 miles for the rest of the day on the couch or with palpitations, dizziness, and fatigue the following day. Busy clinic day full of procedures? I would have to be sitting by the end of it. Bed by 9 PM was not always early enough.
 

Becoming a statistic

Here I am, one of the leading experts in the country on caring for people with long COVID, featured in the national news and having testified in front of Congress, and now I am part of that lived experience. Me – a healthy athlete, with no comorbidities, a normal BMI, vaccinated and boosted, and after an almost asymptomatic bout of COVID-19, a victim to long COVID.

You just never know how your body is going to react. Neuroinflammation occurred in studies with mice with mild respiratory COVID and could be happening to me. I did not want a chronic immune-mediated vasculopathy.

So, I did what any other hyperaware physician-researcher would do. I enrolled in the RECOVER trial – a study my own institution is taking part in and one that I recommend to my own patients.

I also decided that I need to access care and not just ignore my symptoms or try to treat them myself.

That’s when things got difficult. There was a wait of at least a month to see my primary care provider – but I was able to use my privileged position as a physician to get in sooner.

My provider said that she had limited knowledge of long COVID, and she hesitated to order some of the tests and treatments that I recommended because they were not yet considered standard of care. I can understand the hesitation. It is engrained in medical education to follow evidence based on the highest-quality research studies. We are slowly learning more about long COVID, but acknowledging the learning curve offers little to patients who need help now.

This has made me realize that we cannot wait on an evidence-based approach – which can take decades to develop – while people are suffering. And it’s important that everyone on the front line learn about some of the manifestations and disease management of long COVID.

I left this first physician visit feeling more defeated than anything and decided to try to push through. That, I quickly realized, was not the right thing to do.

So again, after a couple of significant crashes and days of severe migraines, I phoned a friend: Ratna Bhavaraju-Sanka, MD, the amazing neurologist who treats patients with long COVID alongside me. She squeezed me in on a non-clinic day. Again, I had the privilege to see a specialist most people wait half a year to see. I was diagnosed with both autonomic dysfunction and intractable migraine.

She ordered some intravenous fluids and IV magnesium that would probably help both. But then another obstacle arose. My institution’s infusion center is focused on patients with cancer, and I was unable to schedule treatments there.

Luckily, I knew about the concierge mobile IV hydration therapy companies that come to your house – mostly offering a hangover treatment service. And I am thankful that I had the health literacy and financial ability to pay for some fluids at home.

On another particularly bad day, I phoned other friends – higher-ups at the hospital – who expedited a slot at the hospital infusion center and approval for the IV magnesium.

Thanks to my access, knowledge, and other privileges, I got fairly quick if imperfect care, enrolled in a research trial, and received medications. I knew to pace myself. The vast majority of others with long COVID lack these advantages.
 

The patient with long COVID

Things I have learned that others can learn, too:

• Acknowledge and recognize that long COVID is a disease that is affecting 1 in 5 Americans who catch COVID. Many look completely “normal on the outside.” Please listen to your patients.
• Autonomic dysfunction is a common manifestation of long COVID. A 10-minute stand test goes a long way in diagnosing this condition, from the American Academy of Physical Medicine and Rehabilitation. It is not just anxiety.
• “That’s only in research” is dismissive and harmful. Think outside the box. Follow guidelines. Consider encouraging patients to sign up for trials.
• Screen for PEM/PESE and teach your patients to pace themselves, because pushing through it or doing graded exercises will be harmful.
• We need to train more physicians to treat postacute sequelae of SARS-CoV-2 infection () and other postinfectious conditions, such as ME/CFS.

If long COVID is hard for physicians to understand and deal with, imagine how difficult it is for patients with no expertise in this area.

It is exponentially harder for those with fewer resources, time, and health literacy. My lived experience with long COVID has shown me that being a patient is never easy. You put your body and fate into the hands of trusted professionals and expect validation and assistance, not gaslighting or gatekeeping.

Along with millions of others, I am tired of waiting.

Dr. Gutierrez is Professor and Distinguished Chair, department of rehabilitation medicine, University of Texas Health Science Center at San Antonio. She reported receiving honoraria for lecturing on long COVID and receiving a research grant from Co-PI for the NIH RECOVER trial.

A version of this article first appeared on Medscape.com.

Arguably, no topic during an infertility consultation generates more of an emotional reaction than discussing body mass index (BMI), particularly when it is high. Patients have become increasingly sensitive to weight discussions with their physicians because of concerns about body shaming. Among patients with an elevated BMI, criticism on social media of health care professionals’ counseling and a preemptive presentation of “Don’t Weigh Me” cards have become popular responses. Despite the medical evidence on impaired reproduction with an abnormal BMI, patients are choosing to forgo the topic. Research has demonstrated “extensive evidence [of] strong weight bias” in a wide range of health staff.¹ A “viral” TikTok study revealed that medical “gaslighting” founded in weight stigma and bias is harmful, as reported on KevinMD.com.² This month, we review the effect of abnormal BMI, both high and low, on reproduction and pregnancy.

A method to assess relative weight was first described in 1832 as its ratio in kilograms divided by the square of the height in meters, or the Quetelet Index. The search for a functional assessment of relative body weight began after World War II when reports by actuaries noted the increased mortality of overweight policyholders. The relationship between weight and cardiovascular disease was further revealed in epidemiologic studies. The Quetelet Index became the BMI in 1972.³

Weight measurement is a mainstay in the assessment of a patient’s vital signs along with blood pressure, pulse rate, respiration rate, and temperature. Weight is vital to the calculation of medication dosage – for instance, administration of conscious sedative drugs, methotrexate, and gonadotropins. Some state boards of medicine, such as Florida, have a limitation on patient BMI at office-based surgery centers (40 kg/m²).
 

Obesity is a disease

As reported by the World Health Organization in 2022, the disease of obesity is an epidemic afflicting more than 1 billion people worldwide, or 1 in 8 individuals globally.⁴ The health implications of an elevated BMI include increased mortality, diabetes, heart disease, and stroke, physical limitations to activities of daily living, and complications affecting reproduction.

Female obesity is related to poorer outcomes in natural and assisted conception, including an increased risk of miscarriage. Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction,⁵ infertility,⁶ a lower chance for conception,⁷ higher rate of miscarriage, and low birth weight.^8,9During pregnancy, women with obesity have three to four times higher rates of gestational diabetes and preeclampsia,¹⁰ as well as likelihood of delivering preterm,¹¹ having a fetus with macrosomia and birth defects, and a 1.3- to 2.1-times higher risk of stillbirth.¹²

Obesity is present in 40%-80% of women with polycystic ovary syndrome,¹³ the most common cause of ovulatory dysfunction from dysregulation of the hypothalamic-pituitary-ovarian axis. While PCOS is associated with reproductive and metabolic consequences, even in regularly ovulating women, increasing obesity appears to be associated with decreasing spontaneous pregnancy rates and increased time to pregnancy.¹⁴

Obesity and IVF

Women with obesity have reduced success with assisted reproductive technology, an increased number of canceled cycles, and poorer quality oocytes retrieved. A prospective cohort study of nearly 2,000 women reported that every 5 kg of body weight increase (from the patient’s baseline weight at age 18) was associated with a 5% increase in the mean duration of time required for conception (95% confidence interval, 3%-7%).¹⁵ Given that approximately 90% of these women had regular menstrual cycles, ovulatory dysfunction was not the suspected pathophysiology.

A meta-analysis of 21 cohort studies reported a lower likelihood of live birth following in vitro fertilization for women with obesity, compared with normal-weight women (risk ratio, 0.85; 95% CI, 0.82-0.87).¹⁶ A further subgroup analysis that evaluated only women with PCOS showed a reduction in the live birth rate following IVF for individuals with obesity, compared with normal-weight individuals (RR, 0.78; 95% CI, 0.74-0.82).

In a retrospective study of almost 500,000 fresh autologous IVF cycles, women with obesity had a 6% reduction in pregnancy rates and a 13% reduction in live birth rates, compared with normal-weight women. Both high and low BMI were associated with an increased risk of low birth weight and preterm delivery.¹⁷ The live birth rates per transfer for normal-weight and higher-weight women were 38% and 33%, respectively.

Contrarily, a randomized controlled trial showed that an intensive weight-reduction program resulted in a large weight loss but did not substantially affect live birth rates in women with obesity scheduled for IVF.¹⁸

Low BMI

A noteworthy cause of low BMI is functional hypothalamic amenorrhea (FHA), a disorder with low energy availability either from decreased caloric intake and/or excessive energy expenditure associated with eating disorders, excessive exercise, and stress. Consequently, a reduced GnRH drive results in a decreased pulse frequency and amplitude leading to low levels of follicle-stimulating hormone and luteinizing hormone, resulting in anovulation. Correction of lifestyle behaviors related to FHA can restore menstrual cycles. After normal weight is achieved, it appears unlikely that fertility is affected.¹⁹ In 47% of adolescent patients with anorexia, menses spontaneously returned within the first 12 months after admission, with an improved prognosis in secondary over primary amenorrhea.^20,21 Interestingly, mildly and significantly underweight infertile women have pregnancy and live birth rates similar to normal-weight patients after IVF treatment.²²

Pregnancy is complicated in underweight women, resulting in an increased risk of anemia, fetal growth retardation, and low birth weight, as well as preterm birth.²¹

Take-home message

The extremes of BMI both impair natural reproduction. Elevated BMI reduces success with IVF but rapid weight loss prior to IVF does not improve outcomes. A normal BMI is the goal for optimal reproductive and pregnancy health.

Dr. Trolice is director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Talumaa B et al. Obesity Rev. 2022;23:e13494.

2. https://bit.ly/3rHCivE.

3. Eknoyan G. Nephrol Dial Transplant. 2008;23:47-51.

4. Wells JCK. Dis Models Mech. 2012;5:595-607.

5. Brewer CJ and Balen AH. Reproduction. 2010;140:347-64.

6. Silvestris E et al. Reprod Biol Endocrinol. 2018;16:22.

7. Wise LA et al. Hum Reprod. 2010;25:253-64.

8. Bellver J. Curr Opin Obstet Gynecol. 2022;34:114-21.

9. Dickey RP et al. Am J Obstet Gynecol. 2013;209:349.e1.

10. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

11. Cnattingius S et al. JAMA. 2013;309:2362-70.

12. Aune D et al. JAMA. 2014;311:1536-46.

13. Sam S. Obes Manag. 2007;3:69-73.

14. van der Steeg JW et al. Hum Reprod. 2008;23:324-8.

15. Gaskins AJ et al. Obstet Gynecol. 2015;126:850-8.

16. Sermondade N et al. Hum Reprod Update. 2019;25:439-519.

17. Kawwass JF et al. Fertil Steril. 2016;106[7]:1742-50.

18. Einarsson S et al. Hum Reprod. 2017;32:1621-30.

19. Chaer R et al. Diseases. 2020;8:46.

20. Dempfle A et al. Psychiatry. 2013;13:308.

21. Verma A and Shrimali L. J Clin Diagn Res. 2012;6:1531-3.

22. Romanski PA et al. Reprod Biomed Online. 2020;42:366-74.

Arguably, no topic during an infertility consultation generates more of an emotional reaction than discussing body mass index (BMI), particularly when it is high. Patients have become increasingly sensitive to weight discussions with their physicians because of concerns about body shaming. Among patients with an elevated BMI, criticism on social media of health care professionals’ counseling and a preemptive presentation of “Don’t Weigh Me” cards have become popular responses. Despite the medical evidence on impaired reproduction with an abnormal BMI, patients are choosing to forgo the topic. Research has demonstrated “extensive evidence [of] strong weight bias” in a wide range of health staff.¹ A “viral” TikTok study revealed that medical “gaslighting” founded in weight stigma and bias is harmful, as reported on KevinMD.com.² This month, we review the effect of abnormal BMI, both high and low, on reproduction and pregnancy.

A method to assess relative weight was first described in 1832 as its ratio in kilograms divided by the square of the height in meters, or the Quetelet Index. The search for a functional assessment of relative body weight began after World War II when reports by actuaries noted the increased mortality of overweight policyholders. The relationship between weight and cardiovascular disease was further revealed in epidemiologic studies. The Quetelet Index became the BMI in 1972.³

Weight measurement is a mainstay in the assessment of a patient’s vital signs along with blood pressure, pulse rate, respiration rate, and temperature. Weight is vital to the calculation of medication dosage – for instance, administration of conscious sedative drugs, methotrexate, and gonadotropins. Some state boards of medicine, such as Florida, have a limitation on patient BMI at office-based surgery centers (40 kg/m²).
 

Obesity is a disease

As reported by the World Health Organization in 2022, the disease of obesity is an epidemic afflicting more than 1 billion people worldwide, or 1 in 8 individuals globally.⁴ The health implications of an elevated BMI include increased mortality, diabetes, heart disease, and stroke, physical limitations to activities of daily living, and complications affecting reproduction.

Female obesity is related to poorer outcomes in natural and assisted conception, including an increased risk of miscarriage. Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction,⁵ infertility,⁶ a lower chance for conception,⁷ higher rate of miscarriage, and low birth weight.^8,9During pregnancy, women with obesity have three to four times higher rates of gestational diabetes and preeclampsia,¹⁰ as well as likelihood of delivering preterm,¹¹ having a fetus with macrosomia and birth defects, and a 1.3- to 2.1-times higher risk of stillbirth.¹²

Obesity is present in 40%-80% of women with polycystic ovary syndrome,¹³ the most common cause of ovulatory dysfunction from dysregulation of the hypothalamic-pituitary-ovarian axis. While PCOS is associated with reproductive and metabolic consequences, even in regularly ovulating women, increasing obesity appears to be associated with decreasing spontaneous pregnancy rates and increased time to pregnancy.¹⁴

Obesity and IVF

Women with obesity have reduced success with assisted reproductive technology, an increased number of canceled cycles, and poorer quality oocytes retrieved. A prospective cohort study of nearly 2,000 women reported that every 5 kg of body weight increase (from the patient’s baseline weight at age 18) was associated with a 5% increase in the mean duration of time required for conception (95% confidence interval, 3%-7%).¹⁵ Given that approximately 90% of these women had regular menstrual cycles, ovulatory dysfunction was not the suspected pathophysiology.

A meta-analysis of 21 cohort studies reported a lower likelihood of live birth following in vitro fertilization for women with obesity, compared with normal-weight women (risk ratio, 0.85; 95% CI, 0.82-0.87).¹⁶ A further subgroup analysis that evaluated only women with PCOS showed a reduction in the live birth rate following IVF for individuals with obesity, compared with normal-weight individuals (RR, 0.78; 95% CI, 0.74-0.82).

In a retrospective study of almost 500,000 fresh autologous IVF cycles, women with obesity had a 6% reduction in pregnancy rates and a 13% reduction in live birth rates, compared with normal-weight women. Both high and low BMI were associated with an increased risk of low birth weight and preterm delivery.¹⁷ The live birth rates per transfer for normal-weight and higher-weight women were 38% and 33%, respectively.

Contrarily, a randomized controlled trial showed that an intensive weight-reduction program resulted in a large weight loss but did not substantially affect live birth rates in women with obesity scheduled for IVF.¹⁸

Low BMI

A noteworthy cause of low BMI is functional hypothalamic amenorrhea (FHA), a disorder with low energy availability either from decreased caloric intake and/or excessive energy expenditure associated with eating disorders, excessive exercise, and stress. Consequently, a reduced GnRH drive results in a decreased pulse frequency and amplitude leading to low levels of follicle-stimulating hormone and luteinizing hormone, resulting in anovulation. Correction of lifestyle behaviors related to FHA can restore menstrual cycles. After normal weight is achieved, it appears unlikely that fertility is affected.¹⁹ In 47% of adolescent patients with anorexia, menses spontaneously returned within the first 12 months after admission, with an improved prognosis in secondary over primary amenorrhea.^20,21 Interestingly, mildly and significantly underweight infertile women have pregnancy and live birth rates similar to normal-weight patients after IVF treatment.²²

Pregnancy is complicated in underweight women, resulting in an increased risk of anemia, fetal growth retardation, and low birth weight, as well as preterm birth.²¹

Take-home message

The extremes of BMI both impair natural reproduction. Elevated BMI reduces success with IVF but rapid weight loss prior to IVF does not improve outcomes. A normal BMI is the goal for optimal reproductive and pregnancy health.

Dr. Trolice is director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Talumaa B et al. Obesity Rev. 2022;23:e13494.

2. https://bit.ly/3rHCivE.

3. Eknoyan G. Nephrol Dial Transplant. 2008;23:47-51.

4. Wells JCK. Dis Models Mech. 2012;5:595-607.

5. Brewer CJ and Balen AH. Reproduction. 2010;140:347-64.

6. Silvestris E et al. Reprod Biol Endocrinol. 2018;16:22.

7. Wise LA et al. Hum Reprod. 2010;25:253-64.

8. Bellver J. Curr Opin Obstet Gynecol. 2022;34:114-21.

9. Dickey RP et al. Am J Obstet Gynecol. 2013;209:349.e1.

10. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

11. Cnattingius S et al. JAMA. 2013;309:2362-70.

12. Aune D et al. JAMA. 2014;311:1536-46.

13. Sam S. Obes Manag. 2007;3:69-73.

14. van der Steeg JW et al. Hum Reprod. 2008;23:324-8.

15. Gaskins AJ et al. Obstet Gynecol. 2015;126:850-8.

16. Sermondade N et al. Hum Reprod Update. 2019;25:439-519.

17. Kawwass JF et al. Fertil Steril. 2016;106[7]:1742-50.

18. Einarsson S et al. Hum Reprod. 2017;32:1621-30.

19. Chaer R et al. Diseases. 2020;8:46.

20. Dempfle A et al. Psychiatry. 2013;13:308.

21. Verma A and Shrimali L. J Clin Diagn Res. 2012;6:1531-3.

22. Romanski PA et al. Reprod Biomed Online. 2020;42:366-74.

Arguably, no topic during an infertility consultation generates more of an emotional reaction than discussing body mass index (BMI), particularly when it is high. Patients have become increasingly sensitive to weight discussions with their physicians because of concerns about body shaming. Among patients with an elevated BMI, criticism on social media of health care professionals’ counseling and a preemptive presentation of “Don’t Weigh Me” cards have become popular responses. Despite the medical evidence on impaired reproduction with an abnormal BMI, patients are choosing to forgo the topic. Research has demonstrated “extensive evidence [of] strong weight bias” in a wide range of health staff.¹ A “viral” TikTok study revealed that medical “gaslighting” founded in weight stigma and bias is harmful, as reported on KevinMD.com.² This month, we review the effect of abnormal BMI, both high and low, on reproduction and pregnancy.

A method to assess relative weight was first described in 1832 as its ratio in kilograms divided by the square of the height in meters, or the Quetelet Index. The search for a functional assessment of relative body weight began after World War II when reports by actuaries noted the increased mortality of overweight policyholders. The relationship between weight and cardiovascular disease was further revealed in epidemiologic studies. The Quetelet Index became the BMI in 1972.³

Weight measurement is a mainstay in the assessment of a patient’s vital signs along with blood pressure, pulse rate, respiration rate, and temperature. Weight is vital to the calculation of medication dosage – for instance, administration of conscious sedative drugs, methotrexate, and gonadotropins. Some state boards of medicine, such as Florida, have a limitation on patient BMI at office-based surgery centers (40 kg/m²).
 

Obesity is a disease

As reported by the World Health Organization in 2022, the disease of obesity is an epidemic afflicting more than 1 billion people worldwide, or 1 in 8 individuals globally.⁴ The health implications of an elevated BMI include increased mortality, diabetes, heart disease, and stroke, physical limitations to activities of daily living, and complications affecting reproduction.

Female obesity is related to poorer outcomes in natural and assisted conception, including an increased risk of miscarriage. Compared with normal-weight women, those with obesity are three times more likely to have ovulatory dysfunction,⁵ infertility,⁶ a lower chance for conception,⁷ higher rate of miscarriage, and low birth weight.^8,9During pregnancy, women with obesity have three to four times higher rates of gestational diabetes and preeclampsia,¹⁰ as well as likelihood of delivering preterm,¹¹ having a fetus with macrosomia and birth defects, and a 1.3- to 2.1-times higher risk of stillbirth.¹²

Obesity is present in 40%-80% of women with polycystic ovary syndrome,¹³ the most common cause of ovulatory dysfunction from dysregulation of the hypothalamic-pituitary-ovarian axis. While PCOS is associated with reproductive and metabolic consequences, even in regularly ovulating women, increasing obesity appears to be associated with decreasing spontaneous pregnancy rates and increased time to pregnancy.¹⁴

Obesity and IVF

Women with obesity have reduced success with assisted reproductive technology, an increased number of canceled cycles, and poorer quality oocytes retrieved. A prospective cohort study of nearly 2,000 women reported that every 5 kg of body weight increase (from the patient’s baseline weight at age 18) was associated with a 5% increase in the mean duration of time required for conception (95% confidence interval, 3%-7%).¹⁵ Given that approximately 90% of these women had regular menstrual cycles, ovulatory dysfunction was not the suspected pathophysiology.

A meta-analysis of 21 cohort studies reported a lower likelihood of live birth following in vitro fertilization for women with obesity, compared with normal-weight women (risk ratio, 0.85; 95% CI, 0.82-0.87).¹⁶ A further subgroup analysis that evaluated only women with PCOS showed a reduction in the live birth rate following IVF for individuals with obesity, compared with normal-weight individuals (RR, 0.78; 95% CI, 0.74-0.82).

In a retrospective study of almost 500,000 fresh autologous IVF cycles, women with obesity had a 6% reduction in pregnancy rates and a 13% reduction in live birth rates, compared with normal-weight women. Both high and low BMI were associated with an increased risk of low birth weight and preterm delivery.¹⁷ The live birth rates per transfer for normal-weight and higher-weight women were 38% and 33%, respectively.

Contrarily, a randomized controlled trial showed that an intensive weight-reduction program resulted in a large weight loss but did not substantially affect live birth rates in women with obesity scheduled for IVF.¹⁸

Low BMI

A noteworthy cause of low BMI is functional hypothalamic amenorrhea (FHA), a disorder with low energy availability either from decreased caloric intake and/or excessive energy expenditure associated with eating disorders, excessive exercise, and stress. Consequently, a reduced GnRH drive results in a decreased pulse frequency and amplitude leading to low levels of follicle-stimulating hormone and luteinizing hormone, resulting in anovulation. Correction of lifestyle behaviors related to FHA can restore menstrual cycles. After normal weight is achieved, it appears unlikely that fertility is affected.¹⁹ In 47% of adolescent patients with anorexia, menses spontaneously returned within the first 12 months after admission, with an improved prognosis in secondary over primary amenorrhea.^20,21 Interestingly, mildly and significantly underweight infertile women have pregnancy and live birth rates similar to normal-weight patients after IVF treatment.²²

Pregnancy is complicated in underweight women, resulting in an increased risk of anemia, fetal growth retardation, and low birth weight, as well as preterm birth.²¹

Take-home message

The extremes of BMI both impair natural reproduction. Elevated BMI reduces success with IVF but rapid weight loss prior to IVF does not improve outcomes. A normal BMI is the goal for optimal reproductive and pregnancy health.

Dr. Trolice is director of the IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.
 

References

1. Talumaa B et al. Obesity Rev. 2022;23:e13494.

2. https://bit.ly/3rHCivE.

3. Eknoyan G. Nephrol Dial Transplant. 2008;23:47-51.

4. Wells JCK. Dis Models Mech. 2012;5:595-607.

5. Brewer CJ and Balen AH. Reproduction. 2010;140:347-64.

6. Silvestris E et al. Reprod Biol Endocrinol. 2018;16:22.

7. Wise LA et al. Hum Reprod. 2010;25:253-64.

8. Bellver J. Curr Opin Obstet Gynecol. 2022;34:114-21.

9. Dickey RP et al. Am J Obstet Gynecol. 2013;209:349.e1.

10. Alwash SM et al. Obes Res Clin Pract. 2021;15:425-30.

11. Cnattingius S et al. JAMA. 2013;309:2362-70.

12. Aune D et al. JAMA. 2014;311:1536-46.

13. Sam S. Obes Manag. 2007;3:69-73.

14. van der Steeg JW et al. Hum Reprod. 2008;23:324-8.

15. Gaskins AJ et al. Obstet Gynecol. 2015;126:850-8.

16. Sermondade N et al. Hum Reprod Update. 2019;25:439-519.

17. Kawwass JF et al. Fertil Steril. 2016;106[7]:1742-50.

18. Einarsson S et al. Hum Reprod. 2017;32:1621-30.

19. Chaer R et al. Diseases. 2020;8:46.

20. Dempfle A et al. Psychiatry. 2013;13:308.

21. Verma A and Shrimali L. J Clin Diagn Res. 2012;6:1531-3.

22. Romanski PA et al. Reprod Biomed Online. 2020;42:366-74.

How exquisitely designed is the human body? Despite our efforts to occasionally derail our health and well-being, our bodies come with helpful built-in protective functional barriers. The blood-brain barrier and the placenta are two examples. In basic terms, both restrict the free flow of substances from the systemic circulation and help prevent harmful substances from reaching the brain and the fetus, respectively. The placenta is unique in that it develops along with the fetus and, at delivery, is expelled after having done its work. But what happens when a disease or treatment alters the ability of the placenta to operate as a control gate for the fetus?

In keeping with this column’s title, let’s start with bugs. Based on the 2021 World Malaria Report, malaria continues to strike hardest against pregnant women and children in Africa.¹ In 2020 in 33 moderate- and high-transmission African countries, 34% of pregnancies (11.6 million of 33.8 million) were exposed to malaria infection. Malaria infection during pregnancy is associated with adverse birth outcomes, including small for gestational age and preterm birth, which in turn increase the risk for neonatal and childhood mortality.

Malaria is caused by the parasite of the genus Plasmodium and is transmitted by infective female Anopheles mosquitoes. The predominant parasite in sub-Saharan Africa is Plasmodium falciparum. Pregnant women are particularly vulnerable. Once a subject is bitten, the P. falciparum parasite is injected into the human blood stream where it is taken up initially by the liver and subsequently by the erythrocytes of the host which adhere to placental receptors, triggering placental inflammation and subsequent damage. This leads to impaired placental development and function, placental insufficiency, and the adverse birth outcomes identified above.² In targeting the placenta, this parasite can cause structural and functional placental alterations through infection and inflammation. A recent review by McColl et al. has shown that placental inflammation with or without infection affects the normal function of placental amino acid transporters, leading to similar adverse pregnancy outcomes.³

Moving on to drugs and drug safety in pregnancy, concern generally focuses on exposure during pregnancy that might directly affect the fetus at critical time windows during growth and development. There is a need to understand not only the size of the drug molecules and the degree to which they cross the placenta, but also how those medications may affect the development and function of the placenta itself. New research methods such as the “placenta-on-a-chip” that models the transport of nutrients and drugs allow direct evaluation of placental function.⁴ Assessing placental function using such tools during drug development will contribute to a better understanding of the safety and efficacy of new medications for use in pregnancy, providing important information at the preclinical phases.⁵

The placenta is a dynamic organ with metabolic, endocrine, immunologic, and transport functions. Most importantly, it protects a healthy pregnancy. It also provides the advantage of immunologic protection to the fetus when maternal antibodies cross the placenta and provide initial protection until the newborn’s own immune system matures. Using our knowledge of placental alteration models and new research methods such as “placenta-on-a-chip” can help expand our understanding of the role of the placenta in medication safety in pregnancy.

Dr. Hardy is executive director, head of pharmacoepidemiology, at Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention, represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Tassinari is a consultant and was formerly employed by Pfizer and the Food and Drug Administration. Dr. Tassinari is a past president of BDRP (formerly the Teratology Society) and currently serves as a member of the External Science Advisory Committee for The Medicines for Malaria Venture and is a member of the Science Advisory Committee for the COVID-19 Vaccines International Pregnancy Exposure Registry.

References

1. World malaria report 2021. Geneva: World Health Organization; 2021.

2. Chua CLL et al. Front Immunol. 2021;12:621382.

3. McColl ER et al. Drug Metab Dispos. May 2022.

4. Blundeli C et al. Adv Healthc Mater. 2018. January;7(2).

5. David AL et al. Ther Innov Regul Sci. 2022.

How exquisitely designed is the human body? Despite our efforts to occasionally derail our health and well-being, our bodies come with helpful built-in protective functional barriers. The blood-brain barrier and the placenta are two examples. In basic terms, both restrict the free flow of substances from the systemic circulation and help prevent harmful substances from reaching the brain and the fetus, respectively. The placenta is unique in that it develops along with the fetus and, at delivery, is expelled after having done its work. But what happens when a disease or treatment alters the ability of the placenta to operate as a control gate for the fetus?

In keeping with this column’s title, let’s start with bugs. Based on the 2021 World Malaria Report, malaria continues to strike hardest against pregnant women and children in Africa.¹ In 2020 in 33 moderate- and high-transmission African countries, 34% of pregnancies (11.6 million of 33.8 million) were exposed to malaria infection. Malaria infection during pregnancy is associated with adverse birth outcomes, including small for gestational age and preterm birth, which in turn increase the risk for neonatal and childhood mortality.

Malaria is caused by the parasite of the genus Plasmodium and is transmitted by infective female Anopheles mosquitoes. The predominant parasite in sub-Saharan Africa is Plasmodium falciparum. Pregnant women are particularly vulnerable. Once a subject is bitten, the P. falciparum parasite is injected into the human blood stream where it is taken up initially by the liver and subsequently by the erythrocytes of the host which adhere to placental receptors, triggering placental inflammation and subsequent damage. This leads to impaired placental development and function, placental insufficiency, and the adverse birth outcomes identified above.² In targeting the placenta, this parasite can cause structural and functional placental alterations through infection and inflammation. A recent review by McColl et al. has shown that placental inflammation with or without infection affects the normal function of placental amino acid transporters, leading to similar adverse pregnancy outcomes.³

Moving on to drugs and drug safety in pregnancy, concern generally focuses on exposure during pregnancy that might directly affect the fetus at critical time windows during growth and development. There is a need to understand not only the size of the drug molecules and the degree to which they cross the placenta, but also how those medications may affect the development and function of the placenta itself. New research methods such as the “placenta-on-a-chip” that models the transport of nutrients and drugs allow direct evaluation of placental function.⁴ Assessing placental function using such tools during drug development will contribute to a better understanding of the safety and efficacy of new medications for use in pregnancy, providing important information at the preclinical phases.⁵

The placenta is a dynamic organ with metabolic, endocrine, immunologic, and transport functions. Most importantly, it protects a healthy pregnancy. It also provides the advantage of immunologic protection to the fetus when maternal antibodies cross the placenta and provide initial protection until the newborn’s own immune system matures. Using our knowledge of placental alteration models and new research methods such as “placenta-on-a-chip” can help expand our understanding of the role of the placenta in medication safety in pregnancy.

Dr. Hardy is executive director, head of pharmacoepidemiology, at Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention, represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Tassinari is a consultant and was formerly employed by Pfizer and the Food and Drug Administration. Dr. Tassinari is a past president of BDRP (formerly the Teratology Society) and currently serves as a member of the External Science Advisory Committee for The Medicines for Malaria Venture and is a member of the Science Advisory Committee for the COVID-19 Vaccines International Pregnancy Exposure Registry.

References

1. World malaria report 2021. Geneva: World Health Organization; 2021.

2. Chua CLL et al. Front Immunol. 2021;12:621382.

3. McColl ER et al. Drug Metab Dispos. May 2022.

4. Blundeli C et al. Adv Healthc Mater. 2018. January;7(2).

5. David AL et al. Ther Innov Regul Sci. 2022.

How exquisitely designed is the human body? Despite our efforts to occasionally derail our health and well-being, our bodies come with helpful built-in protective functional barriers. The blood-brain barrier and the placenta are two examples. In basic terms, both restrict the free flow of substances from the systemic circulation and help prevent harmful substances from reaching the brain and the fetus, respectively. The placenta is unique in that it develops along with the fetus and, at delivery, is expelled after having done its work. But what happens when a disease or treatment alters the ability of the placenta to operate as a control gate for the fetus?

In keeping with this column’s title, let’s start with bugs. Based on the 2021 World Malaria Report, malaria continues to strike hardest against pregnant women and children in Africa.¹ In 2020 in 33 moderate- and high-transmission African countries, 34% of pregnancies (11.6 million of 33.8 million) were exposed to malaria infection. Malaria infection during pregnancy is associated with adverse birth outcomes, including small for gestational age and preterm birth, which in turn increase the risk for neonatal and childhood mortality.

Malaria is caused by the parasite of the genus Plasmodium and is transmitted by infective female Anopheles mosquitoes. The predominant parasite in sub-Saharan Africa is Plasmodium falciparum. Pregnant women are particularly vulnerable. Once a subject is bitten, the P. falciparum parasite is injected into the human blood stream where it is taken up initially by the liver and subsequently by the erythrocytes of the host which adhere to placental receptors, triggering placental inflammation and subsequent damage. This leads to impaired placental development and function, placental insufficiency, and the adverse birth outcomes identified above.² In targeting the placenta, this parasite can cause structural and functional placental alterations through infection and inflammation. A recent review by McColl et al. has shown that placental inflammation with or without infection affects the normal function of placental amino acid transporters, leading to similar adverse pregnancy outcomes.³

Moving on to drugs and drug safety in pregnancy, concern generally focuses on exposure during pregnancy that might directly affect the fetus at critical time windows during growth and development. There is a need to understand not only the size of the drug molecules and the degree to which they cross the placenta, but also how those medications may affect the development and function of the placenta itself. New research methods such as the “placenta-on-a-chip” that models the transport of nutrients and drugs allow direct evaluation of placental function.⁴ Assessing placental function using such tools during drug development will contribute to a better understanding of the safety and efficacy of new medications for use in pregnancy, providing important information at the preclinical phases.⁵

The placenta is a dynamic organ with metabolic, endocrine, immunologic, and transport functions. Most importantly, it protects a healthy pregnancy. It also provides the advantage of immunologic protection to the fetus when maternal antibodies cross the placenta and provide initial protection until the newborn’s own immune system matures. Using our knowledge of placental alteration models and new research methods such as “placenta-on-a-chip” can help expand our understanding of the role of the placenta in medication safety in pregnancy.

Dr. Hardy is executive director, head of pharmacoepidemiology, at Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention, represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Tassinari is a consultant and was formerly employed by Pfizer and the Food and Drug Administration. Dr. Tassinari is a past president of BDRP (formerly the Teratology Society) and currently serves as a member of the External Science Advisory Committee for The Medicines for Malaria Venture and is a member of the Science Advisory Committee for the COVID-19 Vaccines International Pregnancy Exposure Registry.

References

1. World malaria report 2021. Geneva: World Health Organization; 2021.

2. Chua CLL et al. Front Immunol. 2021;12:621382.

3. McColl ER et al. Drug Metab Dispos. May 2022.

4. Blundeli C et al. Adv Healthc Mater. 2018. January;7(2).

5. David AL et al. Ther Innov Regul Sci. 2022.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

It began in a petri dish.

Ivermectin, a widely available, cheap, and well-tolerated drug on the WHO’s list of essential medicines for its critical role in treating river blindness, was shown to dramatically reduce the proliferation of SARS-CoV-2 virus in cell culture.

You know the rest of the story. Despite the fact that the median inhibitory concentration in cell culture is about 100-fold higher than what one can achieve with oral dosing in humans, anecdotal reports of miraculous cures proliferated.

Cohort studies suggested that people who got ivermectin did very well in terms of COVID outcomes.

A narrative started to develop online – one that is still quite present today – that authorities were suppressing the good news about ivermectin in order to line their own pockets and those of the execs at Big Pharma. The official Twitter account of the Food and Drug Administration clapped back, reminding the populace that we are not horses or cows.

And every time a study came out that seemed like the nail in the coffin for the so-called horse paste, it rose again, vampire-like, feasting on the blood of social media outrage.

The truth is that, while excitement for ivermectin mounted online, it crashed quite quickly in scientific circles. Most randomized trials showed no effect of the drug. A couple of larger trials which seemed to show dramatic effects were subsequently shown to be fraudulent.

Then the TOGETHER trial was published. The 1,400-patient study from Brazil, which treated outpatients with COVID-19, found no significant difference in hospitalization or ER visits – the primary outcome – between those randomized to ivermectin vs. placebo or another therapy. 

But still, Brazil. Different population than the United States. Different health systems. And very different rates of Strongyloides infections (this is a parasite that may be incidentally treated by ivermectin, leading to improvement independent of the drug’s effect on COVID). We all wanted a U.S. trial.

And now we have it. ACTIV-6 was published Oct. 21 in JAMA, a study randomizing outpatients with COVID-19 from 93 sites around the United States to ivermectin or placebo.

A total of 1,591 individuals – median age 47, 60% female – with confirmed symptomatic COVID-19 were randomized from June 2021 to February 2022. About half had been vaccinated.

The primary outcome was straightforward: time to clinical recovery. Did ivermectin make people get better, faster?

It did not. The time to recovery, defined as having three symptom-free days, was 12 days in the ivermectin group and 13 days in the placebo group – that’s within the margin of error.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator; his science communication work can be found in the Huffington Post, on NPR, and on Medscape.

A version of this article first appeared on Medscape.com.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

It began in a petri dish.

Ivermectin, a widely available, cheap, and well-tolerated drug on the WHO’s list of essential medicines for its critical role in treating river blindness, was shown to dramatically reduce the proliferation of SARS-CoV-2 virus in cell culture.

You know the rest of the story. Despite the fact that the median inhibitory concentration in cell culture is about 100-fold higher than what one can achieve with oral dosing in humans, anecdotal reports of miraculous cures proliferated.

Cohort studies suggested that people who got ivermectin did very well in terms of COVID outcomes.

A narrative started to develop online – one that is still quite present today – that authorities were suppressing the good news about ivermectin in order to line their own pockets and those of the execs at Big Pharma. The official Twitter account of the Food and Drug Administration clapped back, reminding the populace that we are not horses or cows.

And every time a study came out that seemed like the nail in the coffin for the so-called horse paste, it rose again, vampire-like, feasting on the blood of social media outrage.

The truth is that, while excitement for ivermectin mounted online, it crashed quite quickly in scientific circles. Most randomized trials showed no effect of the drug. A couple of larger trials which seemed to show dramatic effects were subsequently shown to be fraudulent.

Then the TOGETHER trial was published. The 1,400-patient study from Brazil, which treated outpatients with COVID-19, found no significant difference in hospitalization or ER visits – the primary outcome – between those randomized to ivermectin vs. placebo or another therapy. 

But still, Brazil. Different population than the United States. Different health systems. And very different rates of Strongyloides infections (this is a parasite that may be incidentally treated by ivermectin, leading to improvement independent of the drug’s effect on COVID). We all wanted a U.S. trial.

And now we have it. ACTIV-6 was published Oct. 21 in JAMA, a study randomizing outpatients with COVID-19 from 93 sites around the United States to ivermectin or placebo.

A total of 1,591 individuals – median age 47, 60% female – with confirmed symptomatic COVID-19 were randomized from June 2021 to February 2022. About half had been vaccinated.

The primary outcome was straightforward: time to clinical recovery. Did ivermectin make people get better, faster?

It did not. The time to recovery, defined as having three symptom-free days, was 12 days in the ivermectin group and 13 days in the placebo group – that’s within the margin of error.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator; his science communication work can be found in the Huffington Post, on NPR, and on Medscape.

A version of this article first appeared on Medscape.com.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.

It began in a petri dish.

Ivermectin, a widely available, cheap, and well-tolerated drug on the WHO’s list of essential medicines for its critical role in treating river blindness, was shown to dramatically reduce the proliferation of SARS-CoV-2 virus in cell culture.

You know the rest of the story. Despite the fact that the median inhibitory concentration in cell culture is about 100-fold higher than what one can achieve with oral dosing in humans, anecdotal reports of miraculous cures proliferated.

Cohort studies suggested that people who got ivermectin did very well in terms of COVID outcomes.

A narrative started to develop online – one that is still quite present today – that authorities were suppressing the good news about ivermectin in order to line their own pockets and those of the execs at Big Pharma. The official Twitter account of the Food and Drug Administration clapped back, reminding the populace that we are not horses or cows.

And every time a study came out that seemed like the nail in the coffin for the so-called horse paste, it rose again, vampire-like, feasting on the blood of social media outrage.

The truth is that, while excitement for ivermectin mounted online, it crashed quite quickly in scientific circles. Most randomized trials showed no effect of the drug. A couple of larger trials which seemed to show dramatic effects were subsequently shown to be fraudulent.

Then the TOGETHER trial was published. The 1,400-patient study from Brazil, which treated outpatients with COVID-19, found no significant difference in hospitalization or ER visits – the primary outcome – between those randomized to ivermectin vs. placebo or another therapy. 

But still, Brazil. Different population than the United States. Different health systems. And very different rates of Strongyloides infections (this is a parasite that may be incidentally treated by ivermectin, leading to improvement independent of the drug’s effect on COVID). We all wanted a U.S. trial.

And now we have it. ACTIV-6 was published Oct. 21 in JAMA, a study randomizing outpatients with COVID-19 from 93 sites around the United States to ivermectin or placebo.

A total of 1,591 individuals – median age 47, 60% female – with confirmed symptomatic COVID-19 were randomized from June 2021 to February 2022. About half had been vaccinated.

The primary outcome was straightforward: time to clinical recovery. Did ivermectin make people get better, faster?

It did not. The time to recovery, defined as having three symptom-free days, was 12 days in the ivermectin group and 13 days in the placebo group – that’s within the margin of error.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale’s Clinical and Translational Research Accelerator; his science communication work can be found in the Huffington Post, on NPR, and on Medscape.

A version of this article first appeared on Medscape.com.