Drugs, Pregnancy & Lactation

The last 15 years have brought increased effort to screen for postpartum psychiatric illness. That’s exceedingly welcome given the morbidity and potential mortality associated with postpartum psychiatric disorders across the country.

From small community hospitals to major academic centers, screening for postpartum depression is part of the clinical fabric of routine obstetrical care. There is a growing appreciation for the complexity of perinatal psychiatric illness, particularly with respect to the commingling of both mood and anxiety disorders during the postpartum period. However, willingness to treat and appreciation of the urgency to treat with both pharmacologic and nonpharmacologic interventions can vary. For women who suffer from postpartum depression and their families, there are real-world implications of both treating and failing to treat this illness, and there is an urgent need to really help these women “climb out of the darkness” that is and defines postpartum depression.

Less common but of great clinical importance is postpartum psychosis, which occurs in approximately 1 in 1,000-2,000 women based on estimates from several studies. As noted in previous columns, the presentation is a dramatic one, with the typical onset of psychotic symptoms in the first days to weeks post partum. The disorder typically has a mood component and is not an exacerbation of underlying chronic psychotic illness. While there have been few systematic treatment studies, the clinical consensus is treatment usually includes hospitalization to ensure the safety of both the patient and infant. Use of medications, including mood stabilizers, antipsychotics, and benzodiazepines may be appropriate when expeditious treatment is needed.

Appropriate treatment by informed clinical staff is essential, as untreated or incompletely treated postpartum psychosis with its attendant morbidity and potential mortality is a very real concern. As I speak with women across the country with histories of postpartum psychosis, I’m often told of the difficult exchanges that women and their partners have at EDs in various clinical settings where diagnosis was delayed, or treatment was incomplete because of staff without expertise in postpartum psychosis management.

Another dilemma that patients and clinicians face after acute treatment is treatment duration, which is derived from how we conceptualize the illness. Even for experts in the area, there is not a consensus on whether postpartum psychosis should be considered as bipolar disorder or whether it is a circumscribed diagnostic entity. This issue has been hotly debated for many years and is one of the reasons why the illness is not included in the DSM classification system.

At Massachusetts General Hospital, we are systematically studying a large cohort of women with histories of postpartum psychosis as part of the MGH Postpartum Psychosis Project to better understand the phenomenology of postpartum psychosis, and also to understand the possible genomic underpinning of the illness. Most recently, we are conducting a neuroimaging study of women with histories of postpartum psychosis, compared with women in a healthy control group. We hope the results of this novel investigation will help to answer whether there is a neural signature identifiable with neuroimaging techniques such as functional MRI, if those findings are similar to other findings of neural circuitry we see in other forms of psychotic illness, or if the illness has a more distinct neural signature.

A question patients and colleagues often ask is what is the long-term nature of postpartum psychosis. If one considers it clearly to be bipolar disorder, the most intuitive approach would be long-term treatment with mood stabilizers. We now have a growing amount of data on the longitudinal course of postpartum psychosis. In one meta-analysis, 64% of women who had an episode of postpartum psychosis developed episodes of recurrent psychiatric disorder mostly consistent with bipolar illness. However, 36% of women appear to have more circumscribed illness without recurrence. In those women with recurrent disease, the presumption was those patients who had bipolar disorder and their presentation postpartum was simply their index episode of bipolar illness. However, there were other women who looked as if they had developed subsequent illness over the 11-26 years of follow-up, and those women did not receive long-term treatment.

A more recent prospective study of 106 women with postpartum psychosis who had their medication tapered and discontinued showed that 32% of women went on to have recurrent disease with a median time to illness of 20.3 months, and those patients presented primarily with illness that looked like bipolar disorder.

These accumulating data support the impression we’ve had for years that there’s a very strong relationship between bipolar disorder and postpartum psychiatric illness. Regardless of what side of the debate you fall on, the acute treatment is really the same. The real question for the clinician is what to do over the long term. Frequently, patients feel very strongly about a taper and discontinuation of medicine, and even the data show between 30% and 45% of women seem to have relatively circumscribed disease. There may be an issue in terms of prophylaxis if a patient gets pregnant and delivers another child, but that’s a separate issue. The issue is really whether there is a way to “thread the clinical needle” and meet patients where they are who do not want to continue long-term treatment.

I think we are at a point where we could argue the clinical treatment algorithm for patients who present with a new-onset manic-like psychosis postpartum is clear: initial treatment to stabilize, and then treatment with mood stabilizers for at least 12 months to follow is indicated. However, it may also be reasonable to taper treatment at 12-18 months, particularly for patients who have discussed this option with their clinician and who have been totally well for a year. (Women with previously documented bipolar disorder who have episodes of postpartum psychosis should obviously be treated with longer-term treatment aimed at maintenance of euthymia, as discontinuation of mood stabilizer is well known to be associated with risk for relapse.)

It should be noted that the longitudinal course and the treatment implications for women with postpartum psychosis are not etched in stone absent a clear evidence base driving care guidelines. Treatment must still be individualized. Women with underlying mood diatheses will typically declare themselves over time, and others may do well if they discontinue treatment, particularly if they are followed closely and instructed to present to a clinician at the earliest symptoms of mood dysregulation. The good news is we’ve seen an evolution of both interest and expertise in acute management of postpartum psychosis and a richer appreciation of the potential heterogeneity of this sample of women. There may be some variability in terms of long-term course requiring personalized treatment and obviously close follow-up of these women.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

The last 15 years have brought increased effort to screen for postpartum psychiatric illness. That’s exceedingly welcome given the morbidity and potential mortality associated with postpartum psychiatric disorders across the country.

From small community hospitals to major academic centers, screening for postpartum depression is part of the clinical fabric of routine obstetrical care. There is a growing appreciation for the complexity of perinatal psychiatric illness, particularly with respect to the commingling of both mood and anxiety disorders during the postpartum period. However, willingness to treat and appreciation of the urgency to treat with both pharmacologic and nonpharmacologic interventions can vary. For women who suffer from postpartum depression and their families, there are real-world implications of both treating and failing to treat this illness, and there is an urgent need to really help these women “climb out of the darkness” that is and defines postpartum depression.

Less common but of great clinical importance is postpartum psychosis, which occurs in approximately 1 in 1,000-2,000 women based on estimates from several studies. As noted in previous columns, the presentation is a dramatic one, with the typical onset of psychotic symptoms in the first days to weeks post partum. The disorder typically has a mood component and is not an exacerbation of underlying chronic psychotic illness. While there have been few systematic treatment studies, the clinical consensus is treatment usually includes hospitalization to ensure the safety of both the patient and infant. Use of medications, including mood stabilizers, antipsychotics, and benzodiazepines may be appropriate when expeditious treatment is needed.

Appropriate treatment by informed clinical staff is essential, as untreated or incompletely treated postpartum psychosis with its attendant morbidity and potential mortality is a very real concern. As I speak with women across the country with histories of postpartum psychosis, I’m often told of the difficult exchanges that women and their partners have at EDs in various clinical settings where diagnosis was delayed, or treatment was incomplete because of staff without expertise in postpartum psychosis management.

Another dilemma that patients and clinicians face after acute treatment is treatment duration, which is derived from how we conceptualize the illness. Even for experts in the area, there is not a consensus on whether postpartum psychosis should be considered as bipolar disorder or whether it is a circumscribed diagnostic entity. This issue has been hotly debated for many years and is one of the reasons why the illness is not included in the DSM classification system.

At Massachusetts General Hospital, we are systematically studying a large cohort of women with histories of postpartum psychosis as part of the MGH Postpartum Psychosis Project to better understand the phenomenology of postpartum psychosis, and also to understand the possible genomic underpinning of the illness. Most recently, we are conducting a neuroimaging study of women with histories of postpartum psychosis, compared with women in a healthy control group. We hope the results of this novel investigation will help to answer whether there is a neural signature identifiable with neuroimaging techniques such as functional MRI, if those findings are similar to other findings of neural circuitry we see in other forms of psychotic illness, or if the illness has a more distinct neural signature.

A question patients and colleagues often ask is what is the long-term nature of postpartum psychosis. If one considers it clearly to be bipolar disorder, the most intuitive approach would be long-term treatment with mood stabilizers. We now have a growing amount of data on the longitudinal course of postpartum psychosis. In one meta-analysis, 64% of women who had an episode of postpartum psychosis developed episodes of recurrent psychiatric disorder mostly consistent with bipolar illness. However, 36% of women appear to have more circumscribed illness without recurrence. In those women with recurrent disease, the presumption was those patients who had bipolar disorder and their presentation postpartum was simply their index episode of bipolar illness. However, there were other women who looked as if they had developed subsequent illness over the 11-26 years of follow-up, and those women did not receive long-term treatment.

A more recent prospective study of 106 women with postpartum psychosis who had their medication tapered and discontinued showed that 32% of women went on to have recurrent disease with a median time to illness of 20.3 months, and those patients presented primarily with illness that looked like bipolar disorder.

These accumulating data support the impression we’ve had for years that there’s a very strong relationship between bipolar disorder and postpartum psychiatric illness. Regardless of what side of the debate you fall on, the acute treatment is really the same. The real question for the clinician is what to do over the long term. Frequently, patients feel very strongly about a taper and discontinuation of medicine, and even the data show between 30% and 45% of women seem to have relatively circumscribed disease. There may be an issue in terms of prophylaxis if a patient gets pregnant and delivers another child, but that’s a separate issue. The issue is really whether there is a way to “thread the clinical needle” and meet patients where they are who do not want to continue long-term treatment.

I think we are at a point where we could argue the clinical treatment algorithm for patients who present with a new-onset manic-like psychosis postpartum is clear: initial treatment to stabilize, and then treatment with mood stabilizers for at least 12 months to follow is indicated. However, it may also be reasonable to taper treatment at 12-18 months, particularly for patients who have discussed this option with their clinician and who have been totally well for a year. (Women with previously documented bipolar disorder who have episodes of postpartum psychosis should obviously be treated with longer-term treatment aimed at maintenance of euthymia, as discontinuation of mood stabilizer is well known to be associated with risk for relapse.)

It should be noted that the longitudinal course and the treatment implications for women with postpartum psychosis are not etched in stone absent a clear evidence base driving care guidelines. Treatment must still be individualized. Women with underlying mood diatheses will typically declare themselves over time, and others may do well if they discontinue treatment, particularly if they are followed closely and instructed to present to a clinician at the earliest symptoms of mood dysregulation. The good news is we’ve seen an evolution of both interest and expertise in acute management of postpartum psychosis and a richer appreciation of the potential heterogeneity of this sample of women. There may be some variability in terms of long-term course requiring personalized treatment and obviously close follow-up of these women.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

The last 15 years have brought increased effort to screen for postpartum psychiatric illness. That’s exceedingly welcome given the morbidity and potential mortality associated with postpartum psychiatric disorders across the country.

From small community hospitals to major academic centers, screening for postpartum depression is part of the clinical fabric of routine obstetrical care. There is a growing appreciation for the complexity of perinatal psychiatric illness, particularly with respect to the commingling of both mood and anxiety disorders during the postpartum period. However, willingness to treat and appreciation of the urgency to treat with both pharmacologic and nonpharmacologic interventions can vary. For women who suffer from postpartum depression and their families, there are real-world implications of both treating and failing to treat this illness, and there is an urgent need to really help these women “climb out of the darkness” that is and defines postpartum depression.

Less common but of great clinical importance is postpartum psychosis, which occurs in approximately 1 in 1,000-2,000 women based on estimates from several studies. As noted in previous columns, the presentation is a dramatic one, with the typical onset of psychotic symptoms in the first days to weeks post partum. The disorder typically has a mood component and is not an exacerbation of underlying chronic psychotic illness. While there have been few systematic treatment studies, the clinical consensus is treatment usually includes hospitalization to ensure the safety of both the patient and infant. Use of medications, including mood stabilizers, antipsychotics, and benzodiazepines may be appropriate when expeditious treatment is needed.

Appropriate treatment by informed clinical staff is essential, as untreated or incompletely treated postpartum psychosis with its attendant morbidity and potential mortality is a very real concern. As I speak with women across the country with histories of postpartum psychosis, I’m often told of the difficult exchanges that women and their partners have at EDs in various clinical settings where diagnosis was delayed, or treatment was incomplete because of staff without expertise in postpartum psychosis management.

Another dilemma that patients and clinicians face after acute treatment is treatment duration, which is derived from how we conceptualize the illness. Even for experts in the area, there is not a consensus on whether postpartum psychosis should be considered as bipolar disorder or whether it is a circumscribed diagnostic entity. This issue has been hotly debated for many years and is one of the reasons why the illness is not included in the DSM classification system.

At Massachusetts General Hospital, we are systematically studying a large cohort of women with histories of postpartum psychosis as part of the MGH Postpartum Psychosis Project to better understand the phenomenology of postpartum psychosis, and also to understand the possible genomic underpinning of the illness. Most recently, we are conducting a neuroimaging study of women with histories of postpartum psychosis, compared with women in a healthy control group. We hope the results of this novel investigation will help to answer whether there is a neural signature identifiable with neuroimaging techniques such as functional MRI, if those findings are similar to other findings of neural circuitry we see in other forms of psychotic illness, or if the illness has a more distinct neural signature.

A question patients and colleagues often ask is what is the long-term nature of postpartum psychosis. If one considers it clearly to be bipolar disorder, the most intuitive approach would be long-term treatment with mood stabilizers. We now have a growing amount of data on the longitudinal course of postpartum psychosis. In one meta-analysis, 64% of women who had an episode of postpartum psychosis developed episodes of recurrent psychiatric disorder mostly consistent with bipolar illness. However, 36% of women appear to have more circumscribed illness without recurrence. In those women with recurrent disease, the presumption was those patients who had bipolar disorder and their presentation postpartum was simply their index episode of bipolar illness. However, there were other women who looked as if they had developed subsequent illness over the 11-26 years of follow-up, and those women did not receive long-term treatment.

A more recent prospective study of 106 women with postpartum psychosis who had their medication tapered and discontinued showed that 32% of women went on to have recurrent disease with a median time to illness of 20.3 months, and those patients presented primarily with illness that looked like bipolar disorder.

These accumulating data support the impression we’ve had for years that there’s a very strong relationship between bipolar disorder and postpartum psychiatric illness. Regardless of what side of the debate you fall on, the acute treatment is really the same. The real question for the clinician is what to do over the long term. Frequently, patients feel very strongly about a taper and discontinuation of medicine, and even the data show between 30% and 45% of women seem to have relatively circumscribed disease. There may be an issue in terms of prophylaxis if a patient gets pregnant and delivers another child, but that’s a separate issue. The issue is really whether there is a way to “thread the clinical needle” and meet patients where they are who do not want to continue long-term treatment.

I think we are at a point where we could argue the clinical treatment algorithm for patients who present with a new-onset manic-like psychosis postpartum is clear: initial treatment to stabilize, and then treatment with mood stabilizers for at least 12 months to follow is indicated. However, it may also be reasonable to taper treatment at 12-18 months, particularly for patients who have discussed this option with their clinician and who have been totally well for a year. (Women with previously documented bipolar disorder who have episodes of postpartum psychosis should obviously be treated with longer-term treatment aimed at maintenance of euthymia, as discontinuation of mood stabilizer is well known to be associated with risk for relapse.)

It should be noted that the longitudinal course and the treatment implications for women with postpartum psychosis are not etched in stone absent a clear evidence base driving care guidelines. Treatment must still be individualized. Women with underlying mood diatheses will typically declare themselves over time, and others may do well if they discontinue treatment, particularly if they are followed closely and instructed to present to a clinician at the earliest symptoms of mood dysregulation. The good news is we’ve seen an evolution of both interest and expertise in acute management of postpartum psychosis and a richer appreciation of the potential heterogeneity of this sample of women. There may be some variability in terms of long-term course requiring personalized treatment and obviously close follow-up of these women.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

In 2021, the Food and Drug Administration approved 50 new drugs, but 24 will not be described here because they would probably not be used in pregnancy. The 24 are Aduhelm (aducanumab) to treat Alzheimer’s disease; Azstarys (serdexmethylphenidate and dexmethylphenidate), a combination CNS stimulant indicated for the treatment of ADHD; Cabenuva (cabotegravir and rilpivirine) to treat HIV; Voxzogo (vosoritide) for children with achondroplasia and open epiphyses; Qelbree (viloxazine) used in children aged 6-17 years to treat ADHD; and Pylarify (piflufolastat) for prostate cancer. Other anticancer drugs that will not be covered are Cosela (trilaciclib), Cytalux (pafolacianine), Exkivity (mobocertinib); Fotivda (tivozanib), Jemperli (dostarlimab-gxly), Lumakras (sotorasib), Pepaxto (melphalan flufenamide), Rybrevant (amivantamab-vmjw), Rylaze (asparaginase erwinia chrysanthemi), Scemblix (asciminib), Tepmetko (tepotinib), Tivdak (tisotumab vedotin-tftv), Truseltiq (infigratinib), Ukoniq (umbralisib), and Zynlonta (loncastuximab tesirine-lpyl).

Skytrofa (lonapegsomatropin-tcgd) will not be described below because it is indicated to treat short stature and is unlikely to be used in pregnancy. Nextstellis (drospirenone and estetrol) is used to prevent pregnancy.

Typically, for new drugs there will be no published reports describing their use in pregnant women. That information will come much later. In the sections below, the indications, effects on pregnant animals, and the potential for harm of a fetus/embryo are described. However, the relevance of animal data to human pregnancies is not great.

Adbry (tralokinumab) (molecular weight [MW], 147 kilodaltons), is indicated for the treatment of moderate to severe atopic dermatitis in adult patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The drug did not harm fetal monkeys at doses that were 10 times the maximum recommended human dose.

Besremi (ropeginterferon alfa-2b-njft) (MW, 60 kDa) is an interferon alfa-2b indicated for the treatment of adults with polycythemia vera. It is given by subcutaneous injection every 2 weeks. Animal studies assessing reproductive toxicity have not been conducted. The manufacturer states that the drug may cause fetal harm and should be assumed to have abortifacient potential.

Brexafemme (ibrexafungerp) (MW, 922) is indicated for the treatment of vulvovaginal candidiasis. The drug was teratogenic in pregnant rabbits but not in pregnant rats. The manufacturer recommends females with reproductive potential should use effective contraception during treatment and for 4 days after the final dose.

Bylvay (odevixibat) (MW unknown) is indicated for the treatment of pruritus in patients aged 3 months and older. There are no human data regarding its use in pregnant women. The drug was teratogenic in pregnant rabbits. Although there are no data, the drug has low absorption following oral administration and breastfeeding is not expected to result in exposure of the infant.

Empaveli (pegcetacoplan) (MW, 44 kDa) is used to treat paroxysmal nocturnal hemoglobinuria. When the drug was given to pregnant cynomolgus monkeys there was an increase in abortions and stillbirths.

Evkeeza (evinacumab-dgnb) (MW, 146k) is used to treat homozygous familial hypercholesterolemia. The drug was teratogenic in rabbits but not rats.

Fexinidazole (MW not specified) is indicated to treat human African trypanosomiasis caused by the parasite Trypanosoma brucei gambiense. Additional information not available.

Kerendia (finerenone) (MW, 378), is indicated to reduce the risk of kidney and heart complications in chronic kidney disease associated with type 2 diabetes. The drug was teratogenic in rats.

Korsuva (difelikefalin) (MW, 679) is a kappa opioid–receptor agonist indicated for the treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. No adverse effects were observed in pregnant rats and rabbits. The limited human data on use of Korsuva in pregnant women are not sufficient to evaluate a drug associated risk for major birth defects or miscarriage.

Leqvio (inclisiran) (MW, 17,285) is indicated to treat heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease as an add-on therapy. The drug was not teratogenic in rats and rabbits.

Livmarli (maralixibat) (MW, 710) is indicated for the treatment of cholestatic pruritus associated with Alagille syndrome. Because systemic absorption is low, the recommended clinical dose is not expected to result in measurable fetal exposure. No effects on fetal rats were observed.

Livtencity (maribavir) (MW, 376) is used to treat posttransplant cytomegalovirus infection that has not responded to other treatment. Embryo/fetal survival was reduced in rats but not in rabbits at doses less then the human dose.

Lupkynis (voclosporin) (MW, 1,215) is used to treat nephritis. Avoid use of Lupkynis in pregnant women because of the alcohol content of the drug formulation. The drug was embryocidal and feticidal in rats and rabbits but with no treatment-related fetal malformations or variations.

Lybalvi (olanzapine and samidorphan) (MW, 312 and 505) is a combination drug used to treat schizophrenia and bipolar disorder. It was fetal toxic in pregnant rats and rabbits but with no evidence of malformations. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including this drug, during pregnancy. Health care providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit the Reproductive Psychiatry Resource and Information Center of the MGH Center for Women’s Mental Health.

Nexviazyme (avalglucosidase alfa-ngpt) (MW, 124k) is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients aged 1 year and older with late-onset Pompe disease. The drug was not teratogenic in mice and rabbits.

Nulibry (fosdenopterin) (MW, 480) is used to reduce the risk of mortality in molybdenum cofactor deficiency type A. Studies have not been conducted in pregnant animals.

Ponvory (ponesimod) (MW, 461) is used to treat relapsing forms of multiple sclerosis. The drug caused severe adverse effects in pregnant rats and rabbits.

Qulipta (atogepant) (MW, 604) is indicated to prevent episodic migraines. It is embryo/fetal toxic in rats and rabbits.

Saphnelo (anifrolumab-fnia) (MW, 148k) is used to treat moderate to severe systemic lupus erythematosus along with standard therapy. In pregnant cynomolgus monkeys, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 28 times the exposure at the maximum recommended human dose.

Tavneos (avacopan) (MW, 582) is indicated to treat severe active antineutrophil cytoplasmic autoantibody–associated vasculitis in combination with standard therapy including glucocorticoids. There appears to be an increased risk for hepatotoxicity. The drug caused no defects in hamsters and rabbits, but in rabbits there was an increase in abortions.

Tezspire (tezepelumab-ekko) (MW, 147k) is indicated to treat severe asthma as an add-on maintenance therapy. No adverse fetal effects were observed in pregnant cynomolgus monkeys.

Verquvo (vericiguat) (MW, 426) is used to mitigate the risk of cardiovascular death and hospitalization for chronic heart failure. The drug was teratogenic in pregnant rabbits but not rats.

Vyvgart (efgartigimod alfa-fcab) (MW, 54k) is indicated to treat generalized myasthenia gravis. The drug did not cause birth defects in rats and rabbits.

Welireg (belzutifan) (MW, 383) is used to treat von Hippel–Lindau disease. In pregnant rats, the drug caused embryo-fetal lethality, reduced fetal body weight, and caused fetal skeletal malformations at maternal exposures of at least 0.2 times the human exposures.

Zegalogue (dasiglucagon) (MW, 3,382) is used to treat severe hypoglycemia. The drug did not cause birth defects in pregnant rats and rabbits.
 

Breastfeeding

It is not known if the above drugs will be in breast milk, but the safest course for an infant is to not breast feed if the mother is taking any of the above drugs.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

In 2021, the Food and Drug Administration approved 50 new drugs, but 24 will not be described here because they would probably not be used in pregnancy. The 24 are Aduhelm (aducanumab) to treat Alzheimer’s disease; Azstarys (serdexmethylphenidate and dexmethylphenidate), a combination CNS stimulant indicated for the treatment of ADHD; Cabenuva (cabotegravir and rilpivirine) to treat HIV; Voxzogo (vosoritide) for children with achondroplasia and open epiphyses; Qelbree (viloxazine) used in children aged 6-17 years to treat ADHD; and Pylarify (piflufolastat) for prostate cancer. Other anticancer drugs that will not be covered are Cosela (trilaciclib), Cytalux (pafolacianine), Exkivity (mobocertinib); Fotivda (tivozanib), Jemperli (dostarlimab-gxly), Lumakras (sotorasib), Pepaxto (melphalan flufenamide), Rybrevant (amivantamab-vmjw), Rylaze (asparaginase erwinia chrysanthemi), Scemblix (asciminib), Tepmetko (tepotinib), Tivdak (tisotumab vedotin-tftv), Truseltiq (infigratinib), Ukoniq (umbralisib), and Zynlonta (loncastuximab tesirine-lpyl).

Skytrofa (lonapegsomatropin-tcgd) will not be described below because it is indicated to treat short stature and is unlikely to be used in pregnancy. Nextstellis (drospirenone and estetrol) is used to prevent pregnancy.

Typically, for new drugs there will be no published reports describing their use in pregnant women. That information will come much later. In the sections below, the indications, effects on pregnant animals, and the potential for harm of a fetus/embryo are described. However, the relevance of animal data to human pregnancies is not great.

Adbry (tralokinumab) (molecular weight [MW], 147 kilodaltons), is indicated for the treatment of moderate to severe atopic dermatitis in adult patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The drug did not harm fetal monkeys at doses that were 10 times the maximum recommended human dose.

Besremi (ropeginterferon alfa-2b-njft) (MW, 60 kDa) is an interferon alfa-2b indicated for the treatment of adults with polycythemia vera. It is given by subcutaneous injection every 2 weeks. Animal studies assessing reproductive toxicity have not been conducted. The manufacturer states that the drug may cause fetal harm and should be assumed to have abortifacient potential.

Brexafemme (ibrexafungerp) (MW, 922) is indicated for the treatment of vulvovaginal candidiasis. The drug was teratogenic in pregnant rabbits but not in pregnant rats. The manufacturer recommends females with reproductive potential should use effective contraception during treatment and for 4 days after the final dose.

Bylvay (odevixibat) (MW unknown) is indicated for the treatment of pruritus in patients aged 3 months and older. There are no human data regarding its use in pregnant women. The drug was teratogenic in pregnant rabbits. Although there are no data, the drug has low absorption following oral administration and breastfeeding is not expected to result in exposure of the infant.

Empaveli (pegcetacoplan) (MW, 44 kDa) is used to treat paroxysmal nocturnal hemoglobinuria. When the drug was given to pregnant cynomolgus monkeys there was an increase in abortions and stillbirths.

Evkeeza (evinacumab-dgnb) (MW, 146k) is used to treat homozygous familial hypercholesterolemia. The drug was teratogenic in rabbits but not rats.

Fexinidazole (MW not specified) is indicated to treat human African trypanosomiasis caused by the parasite Trypanosoma brucei gambiense. Additional information not available.

Kerendia (finerenone) (MW, 378), is indicated to reduce the risk of kidney and heart complications in chronic kidney disease associated with type 2 diabetes. The drug was teratogenic in rats.

Korsuva (difelikefalin) (MW, 679) is a kappa opioid–receptor agonist indicated for the treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. No adverse effects were observed in pregnant rats and rabbits. The limited human data on use of Korsuva in pregnant women are not sufficient to evaluate a drug associated risk for major birth defects or miscarriage.

Leqvio (inclisiran) (MW, 17,285) is indicated to treat heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease as an add-on therapy. The drug was not teratogenic in rats and rabbits.

Livmarli (maralixibat) (MW, 710) is indicated for the treatment of cholestatic pruritus associated with Alagille syndrome. Because systemic absorption is low, the recommended clinical dose is not expected to result in measurable fetal exposure. No effects on fetal rats were observed.

Livtencity (maribavir) (MW, 376) is used to treat posttransplant cytomegalovirus infection that has not responded to other treatment. Embryo/fetal survival was reduced in rats but not in rabbits at doses less then the human dose.

Lupkynis (voclosporin) (MW, 1,215) is used to treat nephritis. Avoid use of Lupkynis in pregnant women because of the alcohol content of the drug formulation. The drug was embryocidal and feticidal in rats and rabbits but with no treatment-related fetal malformations or variations.

Lybalvi (olanzapine and samidorphan) (MW, 312 and 505) is a combination drug used to treat schizophrenia and bipolar disorder. It was fetal toxic in pregnant rats and rabbits but with no evidence of malformations. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including this drug, during pregnancy. Health care providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit the Reproductive Psychiatry Resource and Information Center of the MGH Center for Women’s Mental Health.

Nexviazyme (avalglucosidase alfa-ngpt) (MW, 124k) is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients aged 1 year and older with late-onset Pompe disease. The drug was not teratogenic in mice and rabbits.

Nulibry (fosdenopterin) (MW, 480) is used to reduce the risk of mortality in molybdenum cofactor deficiency type A. Studies have not been conducted in pregnant animals.

Ponvory (ponesimod) (MW, 461) is used to treat relapsing forms of multiple sclerosis. The drug caused severe adverse effects in pregnant rats and rabbits.

Qulipta (atogepant) (MW, 604) is indicated to prevent episodic migraines. It is embryo/fetal toxic in rats and rabbits.

Saphnelo (anifrolumab-fnia) (MW, 148k) is used to treat moderate to severe systemic lupus erythematosus along with standard therapy. In pregnant cynomolgus monkeys, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 28 times the exposure at the maximum recommended human dose.

Tavneos (avacopan) (MW, 582) is indicated to treat severe active antineutrophil cytoplasmic autoantibody–associated vasculitis in combination with standard therapy including glucocorticoids. There appears to be an increased risk for hepatotoxicity. The drug caused no defects in hamsters and rabbits, but in rabbits there was an increase in abortions.

Tezspire (tezepelumab-ekko) (MW, 147k) is indicated to treat severe asthma as an add-on maintenance therapy. No adverse fetal effects were observed in pregnant cynomolgus monkeys.

Verquvo (vericiguat) (MW, 426) is used to mitigate the risk of cardiovascular death and hospitalization for chronic heart failure. The drug was teratogenic in pregnant rabbits but not rats.

Vyvgart (efgartigimod alfa-fcab) (MW, 54k) is indicated to treat generalized myasthenia gravis. The drug did not cause birth defects in rats and rabbits.

Welireg (belzutifan) (MW, 383) is used to treat von Hippel–Lindau disease. In pregnant rats, the drug caused embryo-fetal lethality, reduced fetal body weight, and caused fetal skeletal malformations at maternal exposures of at least 0.2 times the human exposures.

Zegalogue (dasiglucagon) (MW, 3,382) is used to treat severe hypoglycemia. The drug did not cause birth defects in pregnant rats and rabbits.
 

Breastfeeding

It is not known if the above drugs will be in breast milk, but the safest course for an infant is to not breast feed if the mother is taking any of the above drugs.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

In 2021, the Food and Drug Administration approved 50 new drugs, but 24 will not be described here because they would probably not be used in pregnancy. The 24 are Aduhelm (aducanumab) to treat Alzheimer’s disease; Azstarys (serdexmethylphenidate and dexmethylphenidate), a combination CNS stimulant indicated for the treatment of ADHD; Cabenuva (cabotegravir and rilpivirine) to treat HIV; Voxzogo (vosoritide) for children with achondroplasia and open epiphyses; Qelbree (viloxazine) used in children aged 6-17 years to treat ADHD; and Pylarify (piflufolastat) for prostate cancer. Other anticancer drugs that will not be covered are Cosela (trilaciclib), Cytalux (pafolacianine), Exkivity (mobocertinib); Fotivda (tivozanib), Jemperli (dostarlimab-gxly), Lumakras (sotorasib), Pepaxto (melphalan flufenamide), Rybrevant (amivantamab-vmjw), Rylaze (asparaginase erwinia chrysanthemi), Scemblix (asciminib), Tepmetko (tepotinib), Tivdak (tisotumab vedotin-tftv), Truseltiq (infigratinib), Ukoniq (umbralisib), and Zynlonta (loncastuximab tesirine-lpyl).

Skytrofa (lonapegsomatropin-tcgd) will not be described below because it is indicated to treat short stature and is unlikely to be used in pregnancy. Nextstellis (drospirenone and estetrol) is used to prevent pregnancy.

Typically, for new drugs there will be no published reports describing their use in pregnant women. That information will come much later. In the sections below, the indications, effects on pregnant animals, and the potential for harm of a fetus/embryo are described. However, the relevance of animal data to human pregnancies is not great.

Adbry (tralokinumab) (molecular weight [MW], 147 kilodaltons), is indicated for the treatment of moderate to severe atopic dermatitis in adult patients whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. The drug did not harm fetal monkeys at doses that were 10 times the maximum recommended human dose.

Besremi (ropeginterferon alfa-2b-njft) (MW, 60 kDa) is an interferon alfa-2b indicated for the treatment of adults with polycythemia vera. It is given by subcutaneous injection every 2 weeks. Animal studies assessing reproductive toxicity have not been conducted. The manufacturer states that the drug may cause fetal harm and should be assumed to have abortifacient potential.

Brexafemme (ibrexafungerp) (MW, 922) is indicated for the treatment of vulvovaginal candidiasis. The drug was teratogenic in pregnant rabbits but not in pregnant rats. The manufacturer recommends females with reproductive potential should use effective contraception during treatment and for 4 days after the final dose.

Bylvay (odevixibat) (MW unknown) is indicated for the treatment of pruritus in patients aged 3 months and older. There are no human data regarding its use in pregnant women. The drug was teratogenic in pregnant rabbits. Although there are no data, the drug has low absorption following oral administration and breastfeeding is not expected to result in exposure of the infant.

Empaveli (pegcetacoplan) (MW, 44 kDa) is used to treat paroxysmal nocturnal hemoglobinuria. When the drug was given to pregnant cynomolgus monkeys there was an increase in abortions and stillbirths.

Evkeeza (evinacumab-dgnb) (MW, 146k) is used to treat homozygous familial hypercholesterolemia. The drug was teratogenic in rabbits but not rats.

Fexinidazole (MW not specified) is indicated to treat human African trypanosomiasis caused by the parasite Trypanosoma brucei gambiense. Additional information not available.

Kerendia (finerenone) (MW, 378), is indicated to reduce the risk of kidney and heart complications in chronic kidney disease associated with type 2 diabetes. The drug was teratogenic in rats.

Korsuva (difelikefalin) (MW, 679) is a kappa opioid–receptor agonist indicated for the treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. No adverse effects were observed in pregnant rats and rabbits. The limited human data on use of Korsuva in pregnant women are not sufficient to evaluate a drug associated risk for major birth defects or miscarriage.

Leqvio (inclisiran) (MW, 17,285) is indicated to treat heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease as an add-on therapy. The drug was not teratogenic in rats and rabbits.

Livmarli (maralixibat) (MW, 710) is indicated for the treatment of cholestatic pruritus associated with Alagille syndrome. Because systemic absorption is low, the recommended clinical dose is not expected to result in measurable fetal exposure. No effects on fetal rats were observed.

Livtencity (maribavir) (MW, 376) is used to treat posttransplant cytomegalovirus infection that has not responded to other treatment. Embryo/fetal survival was reduced in rats but not in rabbits at doses less then the human dose.

Lupkynis (voclosporin) (MW, 1,215) is used to treat nephritis. Avoid use of Lupkynis in pregnant women because of the alcohol content of the drug formulation. The drug was embryocidal and feticidal in rats and rabbits but with no treatment-related fetal malformations or variations.

Lybalvi (olanzapine and samidorphan) (MW, 312 and 505) is a combination drug used to treat schizophrenia and bipolar disorder. It was fetal toxic in pregnant rats and rabbits but with no evidence of malformations. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including this drug, during pregnancy. Health care providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit the Reproductive Psychiatry Resource and Information Center of the MGH Center for Women’s Mental Health.

Nexviazyme (avalglucosidase alfa-ngpt) (MW, 124k) is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients aged 1 year and older with late-onset Pompe disease. The drug was not teratogenic in mice and rabbits.

Nulibry (fosdenopterin) (MW, 480) is used to reduce the risk of mortality in molybdenum cofactor deficiency type A. Studies have not been conducted in pregnant animals.

Ponvory (ponesimod) (MW, 461) is used to treat relapsing forms of multiple sclerosis. The drug caused severe adverse effects in pregnant rats and rabbits.

Qulipta (atogepant) (MW, 604) is indicated to prevent episodic migraines. It is embryo/fetal toxic in rats and rabbits.

Saphnelo (anifrolumab-fnia) (MW, 148k) is used to treat moderate to severe systemic lupus erythematosus along with standard therapy. In pregnant cynomolgus monkeys, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 28 times the exposure at the maximum recommended human dose.

Tavneos (avacopan) (MW, 582) is indicated to treat severe active antineutrophil cytoplasmic autoantibody–associated vasculitis in combination with standard therapy including glucocorticoids. There appears to be an increased risk for hepatotoxicity. The drug caused no defects in hamsters and rabbits, but in rabbits there was an increase in abortions.

Tezspire (tezepelumab-ekko) (MW, 147k) is indicated to treat severe asthma as an add-on maintenance therapy. No adverse fetal effects were observed in pregnant cynomolgus monkeys.

Verquvo (vericiguat) (MW, 426) is used to mitigate the risk of cardiovascular death and hospitalization for chronic heart failure. The drug was teratogenic in pregnant rabbits but not rats.

Vyvgart (efgartigimod alfa-fcab) (MW, 54k) is indicated to treat generalized myasthenia gravis. The drug did not cause birth defects in rats and rabbits.

Welireg (belzutifan) (MW, 383) is used to treat von Hippel–Lindau disease. In pregnant rats, the drug caused embryo-fetal lethality, reduced fetal body weight, and caused fetal skeletal malformations at maternal exposures of at least 0.2 times the human exposures.

Zegalogue (dasiglucagon) (MW, 3,382) is used to treat severe hypoglycemia. The drug did not cause birth defects in pregnant rats and rabbits.
 

Breastfeeding

It is not known if the above drugs will be in breast milk, but the safest course for an infant is to not breast feed if the mother is taking any of the above drugs.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

The last 15-20 years have brought enormous attention to the relevant clinical issues regarding prescribing antidepressants during pregnancy. Concern about the effects of fetal exposure to selective serotonin reuptake inhibitors (SSRIs) is appropriate given the consistent data that approximately 7% of women use antidepressants during pregnancy, and that risk for relapse of depression during pregnancy in women who have stopped antidepressants during pregnancy is very high.

We have learned so much from studies of relevant questions regarding SSRI exposure. Concerns about increased risk for organ malformation have been set aside. An extraordinary number of studies across a broad range of patients around the globe looked at the issue of risk for organ malformation following in utero SSRI exposure – even looking specifically at risk for cardiac malformations, which had been an earlier concern in the literature – with the evidence supporting absence of increased risk. Also clarified has been, first, the absence of risk of complications such as persistent pulmonary hypertension of the newborn (PPHN) and, second, a delineation of the prevalence and clinical implications of transient neonatal symptoms such as jitteriness and tachypnea in offspring of women who used antidepressants during pregnancy – so-called “poor neonatal adaptation syndrome.”

However, for so many clinicians and for patients, the missing piece in the risk-benefit equation has been the issue of long-term neurodevelopmental sequelae in children whose mothers used antidepressants during pregnancy. While the accumulated data have shown sparse evidence linking SSRI exposure with autism or attention-deficit/hyperactivity disorder (ADHD), the evidence has been mixed regarding neurobehavioral sequelae associated with fetal exposure using developmental outcomes such as language ability, cognition, academic performance, language, math, and other cognitive outcomes. As far back as the 1990s, colleagues in Canada failed to show a difference in neurobehavioral outcomes in 5- to 7-year-old children whose mothers used SSRIs or older tricyclic antidepressants during pregnancy compared to nonexposed women (N Engl J Med. 1997 Jan 23;336[4]:258-62). Even early on, it was noted that one of the strongest predictors of neurodevelopmental outcome was untreated maternal psychiatric illness.

Since those early studies and over the last decade, there have been numerous small studies with conflicting data regarding a whole host of neurodevelopmental outcomes with inconsistent methodologies, different assessments, and failure to control for the presence or absence of maternal psychiatric illness during pregnancy – one of the most critical predictors of neurodevelopmental outcome and one we are beginning to appreciate plays a very significant role.

Most recently, the authors of a very large population-based retrospective cohort study in Denmark linked population-based registries with obstetrical data and examined language and math performance among 575,369 public schoolchildren whose mothers used or didn’t use antidepressants during pregnancy (JAMA. 2021 Nov 2;326[17]:1725-35). These investigators found a decrease in mean test scores for language (53.4 vs. 56.6) and math (52.1 vs. 57.4) in children whose mothers received antidepressant prescriptions during pregnancy compared with children who did not have that exposure. However, when they adjusted for maternal psychiatric illness and other relevant confounders, the finding went to null for language (adjusted difference, –0.1; 95% confidence interval, –0.6 to 0.3), but did not for math (adjusted difference, −2.2; 95% CI, −2.7 to −1.6). The results ultimately showed a modest finding for exposure and a small decrement in mathematical performance. The takeaway is that antidepressant use may be a proxy for neurodevelopmental deficit but is unlikely to be the etiology or direct cause of that deficit.

With that said, patients and their doctors can be reassured with respect to how much we have learned about SSRIs during pregnancy across the last decade. Yet there are appropriate concerns about long-term neurodevelopmental sequelae in this patient population. I think that what we can say in 2022 is that there is a growing appreciation for the effect of maternal psychiatric illness on long-term outcomes in children and the effect of maternal psychiatric illness on risk for postpartum depression, which we know influences long-term neurodevelopmental outcomes in children. Perhaps more than in years past, there is now also an appreciation of the effect of a dysregulated stress axis on the intrauterine fetal neuronal programming, which is perhaps the newest frontier, and which may hold the answers with respect to how to weigh the effect of maternal psychiatric illness on decisions about psychotropic use during pregnancy. But for today, there is an appreciation that exposure to maternal psychopathology is not a benign exposure.

Although some of the data remain incomplete, in 2022, patients will continue to make individual decisions based on the available data, factoring in the effect of maternal adversity in a more deliberate way and with a refined lens through with which to see their options with respect to using or not using SSRIs during pregnancy.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

The last 15-20 years have brought enormous attention to the relevant clinical issues regarding prescribing antidepressants during pregnancy. Concern about the effects of fetal exposure to selective serotonin reuptake inhibitors (SSRIs) is appropriate given the consistent data that approximately 7% of women use antidepressants during pregnancy, and that risk for relapse of depression during pregnancy in women who have stopped antidepressants during pregnancy is very high.

We have learned so much from studies of relevant questions regarding SSRI exposure. Concerns about increased risk for organ malformation have been set aside. An extraordinary number of studies across a broad range of patients around the globe looked at the issue of risk for organ malformation following in utero SSRI exposure – even looking specifically at risk for cardiac malformations, which had been an earlier concern in the literature – with the evidence supporting absence of increased risk. Also clarified has been, first, the absence of risk of complications such as persistent pulmonary hypertension of the newborn (PPHN) and, second, a delineation of the prevalence and clinical implications of transient neonatal symptoms such as jitteriness and tachypnea in offspring of women who used antidepressants during pregnancy – so-called “poor neonatal adaptation syndrome.”

However, for so many clinicians and for patients, the missing piece in the risk-benefit equation has been the issue of long-term neurodevelopmental sequelae in children whose mothers used antidepressants during pregnancy. While the accumulated data have shown sparse evidence linking SSRI exposure with autism or attention-deficit/hyperactivity disorder (ADHD), the evidence has been mixed regarding neurobehavioral sequelae associated with fetal exposure using developmental outcomes such as language ability, cognition, academic performance, language, math, and other cognitive outcomes. As far back as the 1990s, colleagues in Canada failed to show a difference in neurobehavioral outcomes in 5- to 7-year-old children whose mothers used SSRIs or older tricyclic antidepressants during pregnancy compared to nonexposed women (N Engl J Med. 1997 Jan 23;336[4]:258-62). Even early on, it was noted that one of the strongest predictors of neurodevelopmental outcome was untreated maternal psychiatric illness.

Since those early studies and over the last decade, there have been numerous small studies with conflicting data regarding a whole host of neurodevelopmental outcomes with inconsistent methodologies, different assessments, and failure to control for the presence or absence of maternal psychiatric illness during pregnancy – one of the most critical predictors of neurodevelopmental outcome and one we are beginning to appreciate plays a very significant role.

Most recently, the authors of a very large population-based retrospective cohort study in Denmark linked population-based registries with obstetrical data and examined language and math performance among 575,369 public schoolchildren whose mothers used or didn’t use antidepressants during pregnancy (JAMA. 2021 Nov 2;326[17]:1725-35). These investigators found a decrease in mean test scores for language (53.4 vs. 56.6) and math (52.1 vs. 57.4) in children whose mothers received antidepressant prescriptions during pregnancy compared with children who did not have that exposure. However, when they adjusted for maternal psychiatric illness and other relevant confounders, the finding went to null for language (adjusted difference, –0.1; 95% confidence interval, –0.6 to 0.3), but did not for math (adjusted difference, −2.2; 95% CI, −2.7 to −1.6). The results ultimately showed a modest finding for exposure and a small decrement in mathematical performance. The takeaway is that antidepressant use may be a proxy for neurodevelopmental deficit but is unlikely to be the etiology or direct cause of that deficit.

With that said, patients and their doctors can be reassured with respect to how much we have learned about SSRIs during pregnancy across the last decade. Yet there are appropriate concerns about long-term neurodevelopmental sequelae in this patient population. I think that what we can say in 2022 is that there is a growing appreciation for the effect of maternal psychiatric illness on long-term outcomes in children and the effect of maternal psychiatric illness on risk for postpartum depression, which we know influences long-term neurodevelopmental outcomes in children. Perhaps more than in years past, there is now also an appreciation of the effect of a dysregulated stress axis on the intrauterine fetal neuronal programming, which is perhaps the newest frontier, and which may hold the answers with respect to how to weigh the effect of maternal psychiatric illness on decisions about psychotropic use during pregnancy. But for today, there is an appreciation that exposure to maternal psychopathology is not a benign exposure.

Although some of the data remain incomplete, in 2022, patients will continue to make individual decisions based on the available data, factoring in the effect of maternal adversity in a more deliberate way and with a refined lens through with which to see their options with respect to using or not using SSRIs during pregnancy.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

The last 15-20 years have brought enormous attention to the relevant clinical issues regarding prescribing antidepressants during pregnancy. Concern about the effects of fetal exposure to selective serotonin reuptake inhibitors (SSRIs) is appropriate given the consistent data that approximately 7% of women use antidepressants during pregnancy, and that risk for relapse of depression during pregnancy in women who have stopped antidepressants during pregnancy is very high.

We have learned so much from studies of relevant questions regarding SSRI exposure. Concerns about increased risk for organ malformation have been set aside. An extraordinary number of studies across a broad range of patients around the globe looked at the issue of risk for organ malformation following in utero SSRI exposure – even looking specifically at risk for cardiac malformations, which had been an earlier concern in the literature – with the evidence supporting absence of increased risk. Also clarified has been, first, the absence of risk of complications such as persistent pulmonary hypertension of the newborn (PPHN) and, second, a delineation of the prevalence and clinical implications of transient neonatal symptoms such as jitteriness and tachypnea in offspring of women who used antidepressants during pregnancy – so-called “poor neonatal adaptation syndrome.”

However, for so many clinicians and for patients, the missing piece in the risk-benefit equation has been the issue of long-term neurodevelopmental sequelae in children whose mothers used antidepressants during pregnancy. While the accumulated data have shown sparse evidence linking SSRI exposure with autism or attention-deficit/hyperactivity disorder (ADHD), the evidence has been mixed regarding neurobehavioral sequelae associated with fetal exposure using developmental outcomes such as language ability, cognition, academic performance, language, math, and other cognitive outcomes. As far back as the 1990s, colleagues in Canada failed to show a difference in neurobehavioral outcomes in 5- to 7-year-old children whose mothers used SSRIs or older tricyclic antidepressants during pregnancy compared to nonexposed women (N Engl J Med. 1997 Jan 23;336[4]:258-62). Even early on, it was noted that one of the strongest predictors of neurodevelopmental outcome was untreated maternal psychiatric illness.

Since those early studies and over the last decade, there have been numerous small studies with conflicting data regarding a whole host of neurodevelopmental outcomes with inconsistent methodologies, different assessments, and failure to control for the presence or absence of maternal psychiatric illness during pregnancy – one of the most critical predictors of neurodevelopmental outcome and one we are beginning to appreciate plays a very significant role.

Most recently, the authors of a very large population-based retrospective cohort study in Denmark linked population-based registries with obstetrical data and examined language and math performance among 575,369 public schoolchildren whose mothers used or didn’t use antidepressants during pregnancy (JAMA. 2021 Nov 2;326[17]:1725-35). These investigators found a decrease in mean test scores for language (53.4 vs. 56.6) and math (52.1 vs. 57.4) in children whose mothers received antidepressant prescriptions during pregnancy compared with children who did not have that exposure. However, when they adjusted for maternal psychiatric illness and other relevant confounders, the finding went to null for language (adjusted difference, –0.1; 95% confidence interval, –0.6 to 0.3), but did not for math (adjusted difference, −2.2; 95% CI, −2.7 to −1.6). The results ultimately showed a modest finding for exposure and a small decrement in mathematical performance. The takeaway is that antidepressant use may be a proxy for neurodevelopmental deficit but is unlikely to be the etiology or direct cause of that deficit.

With that said, patients and their doctors can be reassured with respect to how much we have learned about SSRIs during pregnancy across the last decade. Yet there are appropriate concerns about long-term neurodevelopmental sequelae in this patient population. I think that what we can say in 2022 is that there is a growing appreciation for the effect of maternal psychiatric illness on long-term outcomes in children and the effect of maternal psychiatric illness on risk for postpartum depression, which we know influences long-term neurodevelopmental outcomes in children. Perhaps more than in years past, there is now also an appreciation of the effect of a dysregulated stress axis on the intrauterine fetal neuronal programming, which is perhaps the newest frontier, and which may hold the answers with respect to how to weigh the effect of maternal psychiatric illness on decisions about psychotropic use during pregnancy. But for today, there is an appreciation that exposure to maternal psychopathology is not a benign exposure.

Although some of the data remain incomplete, in 2022, patients will continue to make individual decisions based on the available data, factoring in the effect of maternal adversity in a more deliberate way and with a refined lens through with which to see their options with respect to using or not using SSRIs during pregnancy.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

The experience of practicing reproductive psychiatry in the context of the pandemic has highlighted unique situations I’ve written about in previous columns that have affected pregnant and postpartum women during the pandemic, such as the management of anxiety and insomnia.

The pandemic has also seen a shift to telemedicine and an opportunity to use virtual platforms to engage with colleagues in our subspecialty across the country. These forums of engagement, which we realize virtually with so many of our colleagues, has prompted me to refine and galvanize what I consider to be some principles that guide frequently encountered clinical scenarios in reproductive psychiatry.

To open 2022, I wanted to revisit the practices I nearly “always” (or conversely, “never”) follow as a reproductive psychiatrist across the numerous clinical situations and variations on the associated clinical themes encountered as we see patients during pregnancy and the postpartum period.
 

Things we ‘always’ do

1. I continue to make maternal euthymia the North Star of treatment before, during, and after pregnancy.

Before pregnancy, maternal euthymia may be realized through optimization of pharmacologic and nonpharmacologic treatments and waiting to conceive until patients are emotionally well. Sustaining euthymia during pregnancy is a critical issue because of the extent to which euthymia during pregnancy predicts postpartum course. According to many studies, postpartum euthymia is the strongest predictor of long-term neurobehavioral outcome and risk for later child psychopathology. At the end of the day, there are few things I would not do with respect to treatment of maternal psychiatric disorder if the upside afforded maternal euthymia.

2. I almost always treat with consistency of medication across the peripartum period.

Although there have been discussions about the wisdom of changing medications, such as antidepressants, benzodiazepines, and mood stabilizers, that have afforded euthymia during pregnancy as patients approach their delivery date, the evidence base supporting switching medications at that time is exceedingly sparse. The time to adjust or to modify is typically not just prior to delivery unless it is to prevent postpartum psychiatric disorder (see below).

3. I simplify regimens before pregnancy if it’s unclear which medications have afforded patients euthymia.

We have a growing appreciation that polypharmacy is the rule in treatment of affective disorder for both unipolar and bipolar illness. Consultation before pregnancy is the ideal time to take a particularly careful history and think about simplifying regimens where adding medicines hasn’t clearly provided enhanced clinical benefit to the patient.

4. When making a treatment plan for psychiatric disorder during pregnancy, I consider the impact of untreated psychiatric disorder (even if not absolutely quantifiable) on fetal, neonatal, and maternal well-being.

Perhaps now more than even 5-10 years ago, we have better data describing the adverse effects of untreated psychiatric illness on fetal, neonatal, and maternal well-being.

We always try to deliberately consider the effect of a specific treatment on fetal well-being. Less attention (and science) has focused on the effect on pregnancy of deferring treatment; historically, this has not been adequately quantified in the risk-benefit decision. Yet, there is growing evidence of the increased adverse effects of activating the stress axis on everything from intrauterine fetal programming in the brain to effects on obstetrical outcomes such as preterm labor and delivery.

5. I appreciate the value of postpartum prophylaxis for pregnant women with bipolar disorder to mitigate risk of relapse.

We have spoken over the last 20 months of the pandemic, particularly in reproductive psychiatry circles, about the importance of keeping reproductive-age women with bipolar disorder emotionally well as they plan to conceive, during pregnancy, and in the postpartum period. The management of bipolar disorder during this time can be a humbling experience. Clinical roughening can be quick and severe, and so we do everything that we can for these women.

The area in which we have the strongest evidence base for mitigating risk with bipolar women is the value of postpartum prophylaxis during the peripartum period, regardless of what patients have done with their mood-stabilizing medications during pregnancy. Given the risk for postpartum disease, even though there are varying amounts of evidence on prophylactic benefit of specific mood stabilizers (i.e., lithium vs. atypical antipsychotics), the value of prophylaxis against worsening of bipolar disorder postpartum is widely accepted.

The importance of this has been particularly underscored during the pandemic where postpartum support, although available, has been more tenuous given the fluctuations in COVID-19 status around the country. The availability of friends and loved ones as support during the postpartum period has become less reliable in certain circumstances during the pandemic. In some cases, COVID-19 surges have wreaked havoc on travel plans and support persons have contracted the virus, rendering on-site support nonviable given safety concerns. Last-minute shifts of support plans have been responsible for disruption of care plans for new moms and by extension, have affected the ability to protect the sleep of bipolar women, which is critical. Keeping bipolar women well during the postpartum period with plans and backup plans for management remains critical.
 

Things we ‘never’ do

1. I never taper antidepressants (just prior to delivery), I never check plasma levels of selective serotonin reuptake inhibitors (across pregnancy, or just prior to labor and delivery), and I never use sodium valproate (during pregnancy).

Although there has been some discussion about the potential to mitigate risk for maternal or neonatal toxicity with lowering of agents such as lithium or lamotrigine during pregnancy, I do not routinely check plasma levels or arbitrarily change the dose of antidepressants, lithium, or lamotrigine during pregnancy in the absence of clinical symptoms.

We know full well that plasma levels of medications decline during pregnancy because of hemodilution with lithium and antidepressants and, in the case of lamotrigine, the effects of rising estrogen concentration during pregnancy on the metabolism of lamotrigine. While several studies have shown the decrease of SSRI concentration during pregnancy absent a change in dose of medication, these data have not correlated changes in plasma concentration of SSRI with a frank change in clinical status across pregnancy. Unlike what we see in conditions like epilepsy, where doses are increased to maintain therapeutic plasma levels to mitigate risk for seizure, those therapeutic plasma levels do not clearly exist for the psychiatric medications most widely used to treat psychiatric disorders.

We also almost never use sodium valproate in reproductive-age women despite its efficacy in both the acute and maintenance treatment of bipolar disorder given the risk of both major malformations associated with first-trimester fetal exposure to valproate and the data suggesting longer-term adverse neurobehavioral effects associated with its use during pregnancy.

2. We never suggest patients defer pregnancy based on their underlying psychiatric disorder.

Our role is to provide the best information regarding reproductive safety of psychiatric medications and risks of untreated psychiatric disorder to patients as they and relevant parties weigh the risks of pursuing one treatment or another. Those are private choices, and women and their partners make private decisions applying their own calculus with respect to moving forward with plans to conceive.

3. We never switch antidepressants once a woman has become pregnant.

Although we continue to see patients switched to older SSRIs such as sertraline with documentation of pregnancy, a patient’s road to getting well is sometimes very lengthy. In the absence of indicting reproductive safety data for any particular antidepressant, for patients who have gotten well on an antidepressant, even one for which we have less information, we stay the course and do not switch arbitrarily to an older SSRI for which we may have more reproductive safety data.

If we have the luxury prior to pregnancy to switch a patient to an untried and better studied antidepressant with more data supporting safety, we do so. But this is rarely the case. More often, we see women presenting with a newly documented pregnancy (frequently unplanned, with half of pregnancies across the country still being unplanned across sociodemographic lines) on an antidepressant with varying amounts of reproductive safety information available for the medicine being taken, and frequently after failed previous trials of other antidepressants. In this scenario, we rarely see the time of a newly documented pregnancy as an opportunity to pursue a new trial of an antidepressant without known efficacy for that patient; we stay the course and hope for sustained euthymia on the drug which has afforded euthymia to date.
 

Final thoughts

Dos and don’ts are relative in reproductive psychiatry. We tend to apply available data and clinical experience as we guide patients on a case-by-case basis, considering the most currently available rigorous reproductive safety data, as well as the individual patient’s clinical status and her personal wishes.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

The experience of practicing reproductive psychiatry in the context of the pandemic has highlighted unique situations I’ve written about in previous columns that have affected pregnant and postpartum women during the pandemic, such as the management of anxiety and insomnia.

The pandemic has also seen a shift to telemedicine and an opportunity to use virtual platforms to engage with colleagues in our subspecialty across the country. These forums of engagement, which we realize virtually with so many of our colleagues, has prompted me to refine and galvanize what I consider to be some principles that guide frequently encountered clinical scenarios in reproductive psychiatry.

To open 2022, I wanted to revisit the practices I nearly “always” (or conversely, “never”) follow as a reproductive psychiatrist across the numerous clinical situations and variations on the associated clinical themes encountered as we see patients during pregnancy and the postpartum period.
 

Things we ‘always’ do

1. I continue to make maternal euthymia the North Star of treatment before, during, and after pregnancy.

Before pregnancy, maternal euthymia may be realized through optimization of pharmacologic and nonpharmacologic treatments and waiting to conceive until patients are emotionally well. Sustaining euthymia during pregnancy is a critical issue because of the extent to which euthymia during pregnancy predicts postpartum course. According to many studies, postpartum euthymia is the strongest predictor of long-term neurobehavioral outcome and risk for later child psychopathology. At the end of the day, there are few things I would not do with respect to treatment of maternal psychiatric disorder if the upside afforded maternal euthymia.

2. I almost always treat with consistency of medication across the peripartum period.

Although there have been discussions about the wisdom of changing medications, such as antidepressants, benzodiazepines, and mood stabilizers, that have afforded euthymia during pregnancy as patients approach their delivery date, the evidence base supporting switching medications at that time is exceedingly sparse. The time to adjust or to modify is typically not just prior to delivery unless it is to prevent postpartum psychiatric disorder (see below).

3. I simplify regimens before pregnancy if it’s unclear which medications have afforded patients euthymia.

We have a growing appreciation that polypharmacy is the rule in treatment of affective disorder for both unipolar and bipolar illness. Consultation before pregnancy is the ideal time to take a particularly careful history and think about simplifying regimens where adding medicines hasn’t clearly provided enhanced clinical benefit to the patient.

4. When making a treatment plan for psychiatric disorder during pregnancy, I consider the impact of untreated psychiatric disorder (even if not absolutely quantifiable) on fetal, neonatal, and maternal well-being.

Perhaps now more than even 5-10 years ago, we have better data describing the adverse effects of untreated psychiatric illness on fetal, neonatal, and maternal well-being.

We always try to deliberately consider the effect of a specific treatment on fetal well-being. Less attention (and science) has focused on the effect on pregnancy of deferring treatment; historically, this has not been adequately quantified in the risk-benefit decision. Yet, there is growing evidence of the increased adverse effects of activating the stress axis on everything from intrauterine fetal programming in the brain to effects on obstetrical outcomes such as preterm labor and delivery.

5. I appreciate the value of postpartum prophylaxis for pregnant women with bipolar disorder to mitigate risk of relapse.

We have spoken over the last 20 months of the pandemic, particularly in reproductive psychiatry circles, about the importance of keeping reproductive-age women with bipolar disorder emotionally well as they plan to conceive, during pregnancy, and in the postpartum period. The management of bipolar disorder during this time can be a humbling experience. Clinical roughening can be quick and severe, and so we do everything that we can for these women.

The area in which we have the strongest evidence base for mitigating risk with bipolar women is the value of postpartum prophylaxis during the peripartum period, regardless of what patients have done with their mood-stabilizing medications during pregnancy. Given the risk for postpartum disease, even though there are varying amounts of evidence on prophylactic benefit of specific mood stabilizers (i.e., lithium vs. atypical antipsychotics), the value of prophylaxis against worsening of bipolar disorder postpartum is widely accepted.

The importance of this has been particularly underscored during the pandemic where postpartum support, although available, has been more tenuous given the fluctuations in COVID-19 status around the country. The availability of friends and loved ones as support during the postpartum period has become less reliable in certain circumstances during the pandemic. In some cases, COVID-19 surges have wreaked havoc on travel plans and support persons have contracted the virus, rendering on-site support nonviable given safety concerns. Last-minute shifts of support plans have been responsible for disruption of care plans for new moms and by extension, have affected the ability to protect the sleep of bipolar women, which is critical. Keeping bipolar women well during the postpartum period with plans and backup plans for management remains critical.
 

Things we ‘never’ do

1. I never taper antidepressants (just prior to delivery), I never check plasma levels of selective serotonin reuptake inhibitors (across pregnancy, or just prior to labor and delivery), and I never use sodium valproate (during pregnancy).

Although there has been some discussion about the potential to mitigate risk for maternal or neonatal toxicity with lowering of agents such as lithium or lamotrigine during pregnancy, I do not routinely check plasma levels or arbitrarily change the dose of antidepressants, lithium, or lamotrigine during pregnancy in the absence of clinical symptoms.

We know full well that plasma levels of medications decline during pregnancy because of hemodilution with lithium and antidepressants and, in the case of lamotrigine, the effects of rising estrogen concentration during pregnancy on the metabolism of lamotrigine. While several studies have shown the decrease of SSRI concentration during pregnancy absent a change in dose of medication, these data have not correlated changes in plasma concentration of SSRI with a frank change in clinical status across pregnancy. Unlike what we see in conditions like epilepsy, where doses are increased to maintain therapeutic plasma levels to mitigate risk for seizure, those therapeutic plasma levels do not clearly exist for the psychiatric medications most widely used to treat psychiatric disorders.

We also almost never use sodium valproate in reproductive-age women despite its efficacy in both the acute and maintenance treatment of bipolar disorder given the risk of both major malformations associated with first-trimester fetal exposure to valproate and the data suggesting longer-term adverse neurobehavioral effects associated with its use during pregnancy.

2. We never suggest patients defer pregnancy based on their underlying psychiatric disorder.

Our role is to provide the best information regarding reproductive safety of psychiatric medications and risks of untreated psychiatric disorder to patients as they and relevant parties weigh the risks of pursuing one treatment or another. Those are private choices, and women and their partners make private decisions applying their own calculus with respect to moving forward with plans to conceive.

3. We never switch antidepressants once a woman has become pregnant.

Although we continue to see patients switched to older SSRIs such as sertraline with documentation of pregnancy, a patient’s road to getting well is sometimes very lengthy. In the absence of indicting reproductive safety data for any particular antidepressant, for patients who have gotten well on an antidepressant, even one for which we have less information, we stay the course and do not switch arbitrarily to an older SSRI for which we may have more reproductive safety data.

If we have the luxury prior to pregnancy to switch a patient to an untried and better studied antidepressant with more data supporting safety, we do so. But this is rarely the case. More often, we see women presenting with a newly documented pregnancy (frequently unplanned, with half of pregnancies across the country still being unplanned across sociodemographic lines) on an antidepressant with varying amounts of reproductive safety information available for the medicine being taken, and frequently after failed previous trials of other antidepressants. In this scenario, we rarely see the time of a newly documented pregnancy as an opportunity to pursue a new trial of an antidepressant without known efficacy for that patient; we stay the course and hope for sustained euthymia on the drug which has afforded euthymia to date.
 

Final thoughts

Dos and don’ts are relative in reproductive psychiatry. We tend to apply available data and clinical experience as we guide patients on a case-by-case basis, considering the most currently available rigorous reproductive safety data, as well as the individual patient’s clinical status and her personal wishes.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

The experience of practicing reproductive psychiatry in the context of the pandemic has highlighted unique situations I’ve written about in previous columns that have affected pregnant and postpartum women during the pandemic, such as the management of anxiety and insomnia.

The pandemic has also seen a shift to telemedicine and an opportunity to use virtual platforms to engage with colleagues in our subspecialty across the country. These forums of engagement, which we realize virtually with so many of our colleagues, has prompted me to refine and galvanize what I consider to be some principles that guide frequently encountered clinical scenarios in reproductive psychiatry.

To open 2022, I wanted to revisit the practices I nearly “always” (or conversely, “never”) follow as a reproductive psychiatrist across the numerous clinical situations and variations on the associated clinical themes encountered as we see patients during pregnancy and the postpartum period.
 

Things we ‘always’ do

1. I continue to make maternal euthymia the North Star of treatment before, during, and after pregnancy.

Before pregnancy, maternal euthymia may be realized through optimization of pharmacologic and nonpharmacologic treatments and waiting to conceive until patients are emotionally well. Sustaining euthymia during pregnancy is a critical issue because of the extent to which euthymia during pregnancy predicts postpartum course. According to many studies, postpartum euthymia is the strongest predictor of long-term neurobehavioral outcome and risk for later child psychopathology. At the end of the day, there are few things I would not do with respect to treatment of maternal psychiatric disorder if the upside afforded maternal euthymia.

2. I almost always treat with consistency of medication across the peripartum period.

Although there have been discussions about the wisdom of changing medications, such as antidepressants, benzodiazepines, and mood stabilizers, that have afforded euthymia during pregnancy as patients approach their delivery date, the evidence base supporting switching medications at that time is exceedingly sparse. The time to adjust or to modify is typically not just prior to delivery unless it is to prevent postpartum psychiatric disorder (see below).

3. I simplify regimens before pregnancy if it’s unclear which medications have afforded patients euthymia.

We have a growing appreciation that polypharmacy is the rule in treatment of affective disorder for both unipolar and bipolar illness. Consultation before pregnancy is the ideal time to take a particularly careful history and think about simplifying regimens where adding medicines hasn’t clearly provided enhanced clinical benefit to the patient.

4. When making a treatment plan for psychiatric disorder during pregnancy, I consider the impact of untreated psychiatric disorder (even if not absolutely quantifiable) on fetal, neonatal, and maternal well-being.

Perhaps now more than even 5-10 years ago, we have better data describing the adverse effects of untreated psychiatric illness on fetal, neonatal, and maternal well-being.

We always try to deliberately consider the effect of a specific treatment on fetal well-being. Less attention (and science) has focused on the effect on pregnancy of deferring treatment; historically, this has not been adequately quantified in the risk-benefit decision. Yet, there is growing evidence of the increased adverse effects of activating the stress axis on everything from intrauterine fetal programming in the brain to effects on obstetrical outcomes such as preterm labor and delivery.

5. I appreciate the value of postpartum prophylaxis for pregnant women with bipolar disorder to mitigate risk of relapse.

We have spoken over the last 20 months of the pandemic, particularly in reproductive psychiatry circles, about the importance of keeping reproductive-age women with bipolar disorder emotionally well as they plan to conceive, during pregnancy, and in the postpartum period. The management of bipolar disorder during this time can be a humbling experience. Clinical roughening can be quick and severe, and so we do everything that we can for these women.

The area in which we have the strongest evidence base for mitigating risk with bipolar women is the value of postpartum prophylaxis during the peripartum period, regardless of what patients have done with their mood-stabilizing medications during pregnancy. Given the risk for postpartum disease, even though there are varying amounts of evidence on prophylactic benefit of specific mood stabilizers (i.e., lithium vs. atypical antipsychotics), the value of prophylaxis against worsening of bipolar disorder postpartum is widely accepted.

The importance of this has been particularly underscored during the pandemic where postpartum support, although available, has been more tenuous given the fluctuations in COVID-19 status around the country. The availability of friends and loved ones as support during the postpartum period has become less reliable in certain circumstances during the pandemic. In some cases, COVID-19 surges have wreaked havoc on travel plans and support persons have contracted the virus, rendering on-site support nonviable given safety concerns. Last-minute shifts of support plans have been responsible for disruption of care plans for new moms and by extension, have affected the ability to protect the sleep of bipolar women, which is critical. Keeping bipolar women well during the postpartum period with plans and backup plans for management remains critical.
 

Things we ‘never’ do

1. I never taper antidepressants (just prior to delivery), I never check plasma levels of selective serotonin reuptake inhibitors (across pregnancy, or just prior to labor and delivery), and I never use sodium valproate (during pregnancy).

Although there has been some discussion about the potential to mitigate risk for maternal or neonatal toxicity with lowering of agents such as lithium or lamotrigine during pregnancy, I do not routinely check plasma levels or arbitrarily change the dose of antidepressants, lithium, or lamotrigine during pregnancy in the absence of clinical symptoms.

We know full well that plasma levels of medications decline during pregnancy because of hemodilution with lithium and antidepressants and, in the case of lamotrigine, the effects of rising estrogen concentration during pregnancy on the metabolism of lamotrigine. While several studies have shown the decrease of SSRI concentration during pregnancy absent a change in dose of medication, these data have not correlated changes in plasma concentration of SSRI with a frank change in clinical status across pregnancy. Unlike what we see in conditions like epilepsy, where doses are increased to maintain therapeutic plasma levels to mitigate risk for seizure, those therapeutic plasma levels do not clearly exist for the psychiatric medications most widely used to treat psychiatric disorders.

We also almost never use sodium valproate in reproductive-age women despite its efficacy in both the acute and maintenance treatment of bipolar disorder given the risk of both major malformations associated with first-trimester fetal exposure to valproate and the data suggesting longer-term adverse neurobehavioral effects associated with its use during pregnancy.

2. We never suggest patients defer pregnancy based on their underlying psychiatric disorder.

Our role is to provide the best information regarding reproductive safety of psychiatric medications and risks of untreated psychiatric disorder to patients as they and relevant parties weigh the risks of pursuing one treatment or another. Those are private choices, and women and their partners make private decisions applying their own calculus with respect to moving forward with plans to conceive.

3. We never switch antidepressants once a woman has become pregnant.

Although we continue to see patients switched to older SSRIs such as sertraline with documentation of pregnancy, a patient’s road to getting well is sometimes very lengthy. In the absence of indicting reproductive safety data for any particular antidepressant, for patients who have gotten well on an antidepressant, even one for which we have less information, we stay the course and do not switch arbitrarily to an older SSRI for which we may have more reproductive safety data.

If we have the luxury prior to pregnancy to switch a patient to an untried and better studied antidepressant with more data supporting safety, we do so. But this is rarely the case. More often, we see women presenting with a newly documented pregnancy (frequently unplanned, with half of pregnancies across the country still being unplanned across sociodemographic lines) on an antidepressant with varying amounts of reproductive safety information available for the medicine being taken, and frequently after failed previous trials of other antidepressants. In this scenario, we rarely see the time of a newly documented pregnancy as an opportunity to pursue a new trial of an antidepressant without known efficacy for that patient; we stay the course and hope for sustained euthymia on the drug which has afforded euthymia to date.
 

Final thoughts

Dos and don’ts are relative in reproductive psychiatry. We tend to apply available data and clinical experience as we guide patients on a case-by-case basis, considering the most currently available rigorous reproductive safety data, as well as the individual patient’s clinical status and her personal wishes.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

For the last 25 years, my colleagues have spent midday on Wednesdays at clinical rounds as a group – a time spent reviewing cases in perinatal psychiatry and important new scientific findings in the literature that inform patient care. At the start of the pandemic, my colleague Marlene Freeman, MD, and I started Virtual Rounds at the Center for Women’s Mental Health to open our rounds to colleagues involved in multiple aspects of perinatal psychiatric care.

In my last column of 2021, I wanted to take the opportunity to reflect on some of what we have learned from 19 months of virtual rounding as a community of clinicians during the pandemic.

Telemedicine

Telemedicine allows us to see into the homes, relationships, and environments of our pregnant and postpartum women in a way we could never have imagined. It’s an opportunity to follow patients closely and intervene sooner rather than later, which might have been constrained by pre–COVID-19 typical scheduled office appointments. Telemedicine also gives us a clearer sense of some of the issues faced by underserved and marginalized populations of patients as we look to increase outreach to those groups.

COVID-19 vaccines in pregnancy

We now know much more about the potential for COVID-19 to cause complications during pregnancy than we did earlier in the pandemic. Although there may be a variety of factors fueling whether those in the general population decide to get vaccinated or not, there is no ambiguity in the message from our colleagues in obstetrics about the importance of vaccination for pregnant and postpartum women.

Bipolar disorder

Appropriate treatment for the spectrum of subtypes of bipolar disorder during pregnancy in the postpartum period is a frequent topic of discussion that colleagues raise. The pandemic has kindled clinical worsening for women with mood and anxiety disorders presumably driven by a host of factors ranging from shifts in medication adherence to sleep dysregulation to name just a few. Bipolar II disorder is underdiagnosed, yet there’s a growing appreciation of the morbidity associated with this subtype of bipolar disorder, which probably equals that of other groups on the bipolar spectrum such as those with bipolar I disorder.

Sustaining emotional well-being for bipolar women during pregnancy has never been more important than during the pandemic since psychiatric illness during pregnancy is the strongest predictor of risk for postpartum psychiatric disorder and the literature demonstrates that bipolar women are at particular risk for postpartum mood disorder. Historically, treatment of bipolar disorder during pregnancy was particularly problematic for clinicians and patients deciding about potential use of pharmacotherapy because options were finite; some treatments were known teratogens (valproate and to a far less extent lithium) and other newer treatments for bipolar disorder had sparse reproductive safety data (second-generation antipsychotics).

The message today is we have tools to safely treat bipolar disorder during pregnancy and the postpartum period not available 10 years ago. Lithium is likely underused and can be safely used during pregnancy; we have vast data on the effectiveness of lithium in bipolar disorder. Clinicians should also know that lamotrigine is safe to use for pregnant women with bipolar disorder and the data show no increased risk for major malformations associated with first trimester exposure. In the case of atypical antipsychotics, which increasingly are used in the treatment of bipolar disorder, the take-home message is our comfort level using these medicines during pregnancy is growing given more data supporting that atypical antipsychotics are not major teratogens.

We’ve also learned polytherapy is the rule, not the exception. As my colleague Adele Viguera, MD, recently referenced in Virtual Rounds: Polytherapy is a small price to pay when the other side is sustaining euthymia in bipolar disorder.

What we’ve learned about treating perinatal mood disorder is it takes a village of clinicians and resources to treat and mitigate risk for recurrence. Nothing is more important than either ensuring or recapturing maternal euthymia. The flip side is a recent report that maternal self-harm/suicide is the leading cause of death in the first year postpartum. It is a charge to the medical community at large to screen for maternal psychiatric illness and, more importantly, to refer patients and ensure they receive adequate care during the postpartum period.
 

Anxiety

Anxiety and insomnia have been prevalent during the pandemic. Pregnancy-associated and postpartum anxiety have been underappreciated in lieu of focusing on perinatal depression, and we lack consensus regarding the most appropriate treatment of perinatal anxiety. Nonpharmacologic interventions have been extremely helpful for women whose anxiety is mild to moderate or as an adjunct to pharmacologic intervention for patients with more severe anxiety disorders.

Robust data on untreated anxiety during pregnancy suggest it leads to adverse outcomes. The reproductive safety rules above for depression also apply for anxiety. Here, we find a multimodal approach, both nonpharmacologic and pharmacologic, optimizes treatment for that population.

Clinicians have asked about other medicines many women take to treat anxiety including gabapentin, hydroxyzine, and benzodiazepines. Because of concerns about dependence and about using benzodiazepines during pregnancy, hydroxyzine is frequently used despite sparse reproductive safety data. Data on the effectiveness of hydroxyzine is even smaller and tends to be incomplete for patients with more moderate to severe anxiety.

Our comfort level in our center is greater for using benzodiazepines in patients who are clearly not at risk for substance use disorder because particularly when used with selective serotonin reuptake inhibitors, we find it optimizes treatment, mitigates symptoms, and attenuates suffering.
 

Insomnia

For insomnia, cognitive behavioral therapy for insomnia (CBTI) has the most data for effectiveness. Pharmacologic interventions such as gabapentin and benzodiazepines are also frequently used as therapies for insomnia.

Concern about treating insomnia by perinatal psychiatrists comes from the knowledge that insomnia is so often comorbid with anxiety and depression. Psychiatrists must consider the possibility that complaints of insomnia are part of an underlying mood or anxiety disorder; it would be unfortunate to miss the underlying illness and only treat just symptoms of insomnia. That being said, circumscribed insomnia is not uncommon during pregnancy and needs to be managed accordingly.
 

Postpartum psychosis

It’s been noteworthy the extent to which rare cases of postpartum psychosis have been presented in our Virtual Round meetings during the pandemic. As discussed previously, postpartum psychosis is one of the most serious illnesses we treat in reproductive psychiatry.

The debate as to whether postpartum psychosis is a discrete circumscribed illness or an illness that recurs over time won’t be answered without better longitudinal data. What we can say is there is no role, particularly during the pandemic, for outpatient management of postpartum psychosis. The waxing and waning of psychotic symptoms, while reassuring when patients are compensated, are of great concern when patients are psychotic and not in a safe environment.

While there are no consensus guidelines for postpartum psychosis treatment, the data support use of agents such as lithium. Growing data exist on the use of atypical antipsychotics to ameliorate psychotic symptoms and get patients functioning as quickly as possible. Resolution of postpartum psychosis may take a considerable amount of time. During the pandemic, it is critical that appropriate resources be managed before patients leave the hospital, including support by family, open communication with community-based providers, and support groups.

Nineteen months into the pandemic, it seems we’ve learned much: how to leverage technology like telemedicine, and the upsides of folding in our multidisciplinary colleagues to reduce barriers around collaboration and learn from one another to provide the best care for our shared patients.

*This column was updated on Jan. 11. 2022.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

For the last 25 years, my colleagues have spent midday on Wednesdays at clinical rounds as a group – a time spent reviewing cases in perinatal psychiatry and important new scientific findings in the literature that inform patient care. At the start of the pandemic, my colleague Marlene Freeman, MD, and I started Virtual Rounds at the Center for Women’s Mental Health to open our rounds to colleagues involved in multiple aspects of perinatal psychiatric care.

In my last column of 2021, I wanted to take the opportunity to reflect on some of what we have learned from 19 months of virtual rounding as a community of clinicians during the pandemic.

Telemedicine

Telemedicine allows us to see into the homes, relationships, and environments of our pregnant and postpartum women in a way we could never have imagined. It’s an opportunity to follow patients closely and intervene sooner rather than later, which might have been constrained by pre–COVID-19 typical scheduled office appointments. Telemedicine also gives us a clearer sense of some of the issues faced by underserved and marginalized populations of patients as we look to increase outreach to those groups.

COVID-19 vaccines in pregnancy

We now know much more about the potential for COVID-19 to cause complications during pregnancy than we did earlier in the pandemic. Although there may be a variety of factors fueling whether those in the general population decide to get vaccinated or not, there is no ambiguity in the message from our colleagues in obstetrics about the importance of vaccination for pregnant and postpartum women.

Bipolar disorder

Appropriate treatment for the spectrum of subtypes of bipolar disorder during pregnancy in the postpartum period is a frequent topic of discussion that colleagues raise. The pandemic has kindled clinical worsening for women with mood and anxiety disorders presumably driven by a host of factors ranging from shifts in medication adherence to sleep dysregulation to name just a few. Bipolar II disorder is underdiagnosed, yet there’s a growing appreciation of the morbidity associated with this subtype of bipolar disorder, which probably equals that of other groups on the bipolar spectrum such as those with bipolar I disorder.

Sustaining emotional well-being for bipolar women during pregnancy has never been more important than during the pandemic since psychiatric illness during pregnancy is the strongest predictor of risk for postpartum psychiatric disorder and the literature demonstrates that bipolar women are at particular risk for postpartum mood disorder. Historically, treatment of bipolar disorder during pregnancy was particularly problematic for clinicians and patients deciding about potential use of pharmacotherapy because options were finite; some treatments were known teratogens (valproate and to a far less extent lithium) and other newer treatments for bipolar disorder had sparse reproductive safety data (second-generation antipsychotics).

The message today is we have tools to safely treat bipolar disorder during pregnancy and the postpartum period not available 10 years ago. Lithium is likely underused and can be safely used during pregnancy; we have vast data on the effectiveness of lithium in bipolar disorder. Clinicians should also know that lamotrigine is safe to use for pregnant women with bipolar disorder and the data show no increased risk for major malformations associated with first trimester exposure. In the case of atypical antipsychotics, which increasingly are used in the treatment of bipolar disorder, the take-home message is our comfort level using these medicines during pregnancy is growing given more data supporting that atypical antipsychotics are not major teratogens.

We’ve also learned polytherapy is the rule, not the exception. As my colleague Adele Viguera, MD, recently referenced in Virtual Rounds: Polytherapy is a small price to pay when the other side is sustaining euthymia in bipolar disorder.

What we’ve learned about treating perinatal mood disorder is it takes a village of clinicians and resources to treat and mitigate risk for recurrence. Nothing is more important than either ensuring or recapturing maternal euthymia. The flip side is a recent report that maternal self-harm/suicide is the leading cause of death in the first year postpartum. It is a charge to the medical community at large to screen for maternal psychiatric illness and, more importantly, to refer patients and ensure they receive adequate care during the postpartum period.
 

Anxiety

Anxiety and insomnia have been prevalent during the pandemic. Pregnancy-associated and postpartum anxiety have been underappreciated in lieu of focusing on perinatal depression, and we lack consensus regarding the most appropriate treatment of perinatal anxiety. Nonpharmacologic interventions have been extremely helpful for women whose anxiety is mild to moderate or as an adjunct to pharmacologic intervention for patients with more severe anxiety disorders.

Robust data on untreated anxiety during pregnancy suggest it leads to adverse outcomes. The reproductive safety rules above for depression also apply for anxiety. Here, we find a multimodal approach, both nonpharmacologic and pharmacologic, optimizes treatment for that population.

Clinicians have asked about other medicines many women take to treat anxiety including gabapentin, hydroxyzine, and benzodiazepines. Because of concerns about dependence and about using benzodiazepines during pregnancy, hydroxyzine is frequently used despite sparse reproductive safety data. Data on the effectiveness of hydroxyzine is even smaller and tends to be incomplete for patients with more moderate to severe anxiety.

Our comfort level in our center is greater for using benzodiazepines in patients who are clearly not at risk for substance use disorder because particularly when used with selective serotonin reuptake inhibitors, we find it optimizes treatment, mitigates symptoms, and attenuates suffering.
 

Insomnia

For insomnia, cognitive behavioral therapy for insomnia (CBTI) has the most data for effectiveness. Pharmacologic interventions such as gabapentin and benzodiazepines are also frequently used as therapies for insomnia.

Concern about treating insomnia by perinatal psychiatrists comes from the knowledge that insomnia is so often comorbid with anxiety and depression. Psychiatrists must consider the possibility that complaints of insomnia are part of an underlying mood or anxiety disorder; it would be unfortunate to miss the underlying illness and only treat just symptoms of insomnia. That being said, circumscribed insomnia is not uncommon during pregnancy and needs to be managed accordingly.
 

Postpartum psychosis

It’s been noteworthy the extent to which rare cases of postpartum psychosis have been presented in our Virtual Round meetings during the pandemic. As discussed previously, postpartum psychosis is one of the most serious illnesses we treat in reproductive psychiatry.

The debate as to whether postpartum psychosis is a discrete circumscribed illness or an illness that recurs over time won’t be answered without better longitudinal data. What we can say is there is no role, particularly during the pandemic, for outpatient management of postpartum psychosis. The waxing and waning of psychotic symptoms, while reassuring when patients are compensated, are of great concern when patients are psychotic and not in a safe environment.

While there are no consensus guidelines for postpartum psychosis treatment, the data support use of agents such as lithium. Growing data exist on the use of atypical antipsychotics to ameliorate psychotic symptoms and get patients functioning as quickly as possible. Resolution of postpartum psychosis may take a considerable amount of time. During the pandemic, it is critical that appropriate resources be managed before patients leave the hospital, including support by family, open communication with community-based providers, and support groups.

Nineteen months into the pandemic, it seems we’ve learned much: how to leverage technology like telemedicine, and the upsides of folding in our multidisciplinary colleagues to reduce barriers around collaboration and learn from one another to provide the best care for our shared patients.

*This column was updated on Jan. 11. 2022.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

For the last 25 years, my colleagues have spent midday on Wednesdays at clinical rounds as a group – a time spent reviewing cases in perinatal psychiatry and important new scientific findings in the literature that inform patient care. At the start of the pandemic, my colleague Marlene Freeman, MD, and I started Virtual Rounds at the Center for Women’s Mental Health to open our rounds to colleagues involved in multiple aspects of perinatal psychiatric care.

In my last column of 2021, I wanted to take the opportunity to reflect on some of what we have learned from 19 months of virtual rounding as a community of clinicians during the pandemic.

Telemedicine

Telemedicine allows us to see into the homes, relationships, and environments of our pregnant and postpartum women in a way we could never have imagined. It’s an opportunity to follow patients closely and intervene sooner rather than later, which might have been constrained by pre–COVID-19 typical scheduled office appointments. Telemedicine also gives us a clearer sense of some of the issues faced by underserved and marginalized populations of patients as we look to increase outreach to those groups.

COVID-19 vaccines in pregnancy

We now know much more about the potential for COVID-19 to cause complications during pregnancy than we did earlier in the pandemic. Although there may be a variety of factors fueling whether those in the general population decide to get vaccinated or not, there is no ambiguity in the message from our colleagues in obstetrics about the importance of vaccination for pregnant and postpartum women.

Bipolar disorder

Appropriate treatment for the spectrum of subtypes of bipolar disorder during pregnancy in the postpartum period is a frequent topic of discussion that colleagues raise. The pandemic has kindled clinical worsening for women with mood and anxiety disorders presumably driven by a host of factors ranging from shifts in medication adherence to sleep dysregulation to name just a few. Bipolar II disorder is underdiagnosed, yet there’s a growing appreciation of the morbidity associated with this subtype of bipolar disorder, which probably equals that of other groups on the bipolar spectrum such as those with bipolar I disorder.

Sustaining emotional well-being for bipolar women during pregnancy has never been more important than during the pandemic since psychiatric illness during pregnancy is the strongest predictor of risk for postpartum psychiatric disorder and the literature demonstrates that bipolar women are at particular risk for postpartum mood disorder. Historically, treatment of bipolar disorder during pregnancy was particularly problematic for clinicians and patients deciding about potential use of pharmacotherapy because options were finite; some treatments were known teratogens (valproate and to a far less extent lithium) and other newer treatments for bipolar disorder had sparse reproductive safety data (second-generation antipsychotics).

The message today is we have tools to safely treat bipolar disorder during pregnancy and the postpartum period not available 10 years ago. Lithium is likely underused and can be safely used during pregnancy; we have vast data on the effectiveness of lithium in bipolar disorder. Clinicians should also know that lamotrigine is safe to use for pregnant women with bipolar disorder and the data show no increased risk for major malformations associated with first trimester exposure. In the case of atypical antipsychotics, which increasingly are used in the treatment of bipolar disorder, the take-home message is our comfort level using these medicines during pregnancy is growing given more data supporting that atypical antipsychotics are not major teratogens.

We’ve also learned polytherapy is the rule, not the exception. As my colleague Adele Viguera, MD, recently referenced in Virtual Rounds: Polytherapy is a small price to pay when the other side is sustaining euthymia in bipolar disorder.

What we’ve learned about treating perinatal mood disorder is it takes a village of clinicians and resources to treat and mitigate risk for recurrence. Nothing is more important than either ensuring or recapturing maternal euthymia. The flip side is a recent report that maternal self-harm/suicide is the leading cause of death in the first year postpartum. It is a charge to the medical community at large to screen for maternal psychiatric illness and, more importantly, to refer patients and ensure they receive adequate care during the postpartum period.
 

Anxiety

Anxiety and insomnia have been prevalent during the pandemic. Pregnancy-associated and postpartum anxiety have been underappreciated in lieu of focusing on perinatal depression, and we lack consensus regarding the most appropriate treatment of perinatal anxiety. Nonpharmacologic interventions have been extremely helpful for women whose anxiety is mild to moderate or as an adjunct to pharmacologic intervention for patients with more severe anxiety disorders.

Robust data on untreated anxiety during pregnancy suggest it leads to adverse outcomes. The reproductive safety rules above for depression also apply for anxiety. Here, we find a multimodal approach, both nonpharmacologic and pharmacologic, optimizes treatment for that population.

Clinicians have asked about other medicines many women take to treat anxiety including gabapentin, hydroxyzine, and benzodiazepines. Because of concerns about dependence and about using benzodiazepines during pregnancy, hydroxyzine is frequently used despite sparse reproductive safety data. Data on the effectiveness of hydroxyzine is even smaller and tends to be incomplete for patients with more moderate to severe anxiety.

Our comfort level in our center is greater for using benzodiazepines in patients who are clearly not at risk for substance use disorder because particularly when used with selective serotonin reuptake inhibitors, we find it optimizes treatment, mitigates symptoms, and attenuates suffering.
 

Insomnia

For insomnia, cognitive behavioral therapy for insomnia (CBTI) has the most data for effectiveness. Pharmacologic interventions such as gabapentin and benzodiazepines are also frequently used as therapies for insomnia.

Concern about treating insomnia by perinatal psychiatrists comes from the knowledge that insomnia is so often comorbid with anxiety and depression. Psychiatrists must consider the possibility that complaints of insomnia are part of an underlying mood or anxiety disorder; it would be unfortunate to miss the underlying illness and only treat just symptoms of insomnia. That being said, circumscribed insomnia is not uncommon during pregnancy and needs to be managed accordingly.
 

Postpartum psychosis

It’s been noteworthy the extent to which rare cases of postpartum psychosis have been presented in our Virtual Round meetings during the pandemic. As discussed previously, postpartum psychosis is one of the most serious illnesses we treat in reproductive psychiatry.

The debate as to whether postpartum psychosis is a discrete circumscribed illness or an illness that recurs over time won’t be answered without better longitudinal data. What we can say is there is no role, particularly during the pandemic, for outpatient management of postpartum psychosis. The waxing and waning of psychotic symptoms, while reassuring when patients are compensated, are of great concern when patients are psychotic and not in a safe environment.

While there are no consensus guidelines for postpartum psychosis treatment, the data support use of agents such as lithium. Growing data exist on the use of atypical antipsychotics to ameliorate psychotic symptoms and get patients functioning as quickly as possible. Resolution of postpartum psychosis may take a considerable amount of time. During the pandemic, it is critical that appropriate resources be managed before patients leave the hospital, including support by family, open communication with community-based providers, and support groups.

Nineteen months into the pandemic, it seems we’ve learned much: how to leverage technology like telemedicine, and the upsides of folding in our multidisciplinary colleagues to reduce barriers around collaboration and learn from one another to provide the best care for our shared patients.

*This column was updated on Jan. 11. 2022.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Nearly 9 in 10 U.S. women take a medication at some point in their pregnancy, with approximately 50% of women taking at least one prescription medication.¹ These medications may be prescribed without the benefit of knowledge gained through clinical trials. Knowledge is gained after market, often after multiple years, and potentially following widespread use. The situation is similar for vaccines, as was recently seen with the SARS-CoV2 pandemic. Early in the pandemic, evidence emerged that pregnancy increased the risk for severe illness from COVID-19, yet pregnant people and their providers were forced to make a difficult decision of risk/benefit with little data to guide them.

The FDA product label provides a summary and narrative of animal and human safety studies relating to pregnancy. But what if that label contains little to no information, or reports studies with conflicting results? Perhaps the product is new on the market or is infrequently used during pregnancy. Regardless, health care providers and pregnant patients still need to make decisions about medication use. The following list outlines information that can be found, and strategies to support providers and patients in making informed choices for a treatment plan.


Taking stock of the available information:

• If possible, connect with the specialist who prescribed the patient’s medication in question. They may have already assembled information regarding use of that medication in pregnancy.
• The sponsor may have published useful information from the phase 3 trials, including the outcomes of enrolled patients who inadvertently became pregnant.
• Review the animal data in the product label. Regulators require the careful selection of animal models, and this data can present a source of adjunct information regarding the medication’s effects on pregnancy, reproduction, and development. Negative results can be as revealing as positive results.
• Pharmacologic data in the label can also be informative. Although most labels have pharmacologic data based on trials in healthy nonpregnant individuals, understanding pregnancy physiology and the patient’s preexisting or pregnancy-specific condition(s) can provide insights.² Close patient monitoring and follow-up are of key importance.
• Consider viable alternatives that may address the patient’s needs. There may be effective alternatives that have been better studied and shown to have low reproductive toxicity.
• Consider the risks to the patient as well as the developing fetus if the preexisting or pregnancy-specific condition is uncontrolled.
• Consult a teratogen specialist who can provide information to both patients and health care providers on the reproductive hazards or safety of many exposures, even those with limited data regarding use in pregnancy. For example, MotherToBaby provides a network of teratogen specialists.

Understanding perceptions of risk, decision-making, and strategies to support informed choices:

• Perceptions of risk: Each person perceives risk and benefit differently. The few studies that have attempted to investigate perception of teratogenic risk have found that many pregnant people overestimate the magnitude of teratogenic risk associated with a particular exposure.³ Alternatively, a medication’s benefit in controlling the maternal condition is often not considered sufficiently. Health care providers may have their own distorted perceptions of risk, even in the presence of evidence.
• Decision-making: Most teratogen data inherently involve uncertainty; it is rare to have completely nonconflicting data with which to make a decision. This makes decisions about whether or not to utilize a particular medication or other agent in pregnancy very difficult. For example, a patient would prefer to be told a black and white answer such as vaccines are either 100% safe or 100% harmful. However, no medical treatment is held to that standard of certainty. Even though it may be more comfortable to avoid an action and “just let things happen,” the lack of a decision is still a decision. The decision to not take medication may have risks inherent in not treating a condition and may result in adverse outcomes in the developing fetus. Lastly, presenting teratogen information often involves challenges in portraying and interpreting numerical risk. For example, when considering data presented in fraction format, patients and some health care providers may focus on the numerator or count of adverse events, while ignoring the magnitude of the denominator.
• Strategies: Health literacy “best practice” strategies are useful whether there is a lot of data or very little. These include the of use plain language and messages delivered in a clear and respectful voice, the use of visual aids, and the use effective teaching methods such as asking open-ended questions to assess understanding. Other strategies include using caution in framing information: for example, discussing a 1% increase in risk for a baby to have a medication-associated birth defect should also be presented as a 99% chance the medication will not cause a birth defect. Numeracy challenges can also be addressed by using natural numbers rather than fractions or percentages: for example, if there were 100 women in this room, one would have a baby with a birth defect after taking this medication in pregnancy, but 99 of these women would not.

In today’s medical world, shared decision-making is the preferred approach to choices. Communicating and appropriately utilizing information to make choices about medication safety in pregnancy are vital undertakings. An important provider responsibility is helping patients understand that science is built on evidence that amasses and changes over time and that it represents rich shades of gray rather than “black and white” options.

Dr. Hardy is executive director, head of pharmacoepidemiology, Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention (BDRP), 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. Conover is the director of Nebraska MotherToBaby. She is assistant professor at the Munroe Meyer Institute, University of Nebraska Medical Center.

References

1. Mitchell AA et al. Am J Obstet Gynecol. 2011;205(1):51:e1-e8.

2. Feghali M et al. Semin Perinatol 2015;39:512-9.

3. Conover EA, Polifka JE. Am J Med Genet Part C Semin Med Genet 2011;157:227-33.

Nearly 9 in 10 U.S. women take a medication at some point in their pregnancy, with approximately 50% of women taking at least one prescription medication.¹ These medications may be prescribed without the benefit of knowledge gained through clinical trials. Knowledge is gained after market, often after multiple years, and potentially following widespread use. The situation is similar for vaccines, as was recently seen with the SARS-CoV2 pandemic. Early in the pandemic, evidence emerged that pregnancy increased the risk for severe illness from COVID-19, yet pregnant people and their providers were forced to make a difficult decision of risk/benefit with little data to guide them.

The FDA product label provides a summary and narrative of animal and human safety studies relating to pregnancy. But what if that label contains little to no information, or reports studies with conflicting results? Perhaps the product is new on the market or is infrequently used during pregnancy. Regardless, health care providers and pregnant patients still need to make decisions about medication use. The following list outlines information that can be found, and strategies to support providers and patients in making informed choices for a treatment plan.


Taking stock of the available information:

• If possible, connect with the specialist who prescribed the patient’s medication in question. They may have already assembled information regarding use of that medication in pregnancy.
• The sponsor may have published useful information from the phase 3 trials, including the outcomes of enrolled patients who inadvertently became pregnant.
• Review the animal data in the product label. Regulators require the careful selection of animal models, and this data can present a source of adjunct information regarding the medication’s effects on pregnancy, reproduction, and development. Negative results can be as revealing as positive results.
• Pharmacologic data in the label can also be informative. Although most labels have pharmacologic data based on trials in healthy nonpregnant individuals, understanding pregnancy physiology and the patient’s preexisting or pregnancy-specific condition(s) can provide insights.² Close patient monitoring and follow-up are of key importance.
• Consider viable alternatives that may address the patient’s needs. There may be effective alternatives that have been better studied and shown to have low reproductive toxicity.
• Consider the risks to the patient as well as the developing fetus if the preexisting or pregnancy-specific condition is uncontrolled.
• Consult a teratogen specialist who can provide information to both patients and health care providers on the reproductive hazards or safety of many exposures, even those with limited data regarding use in pregnancy. For example, MotherToBaby provides a network of teratogen specialists.

Understanding perceptions of risk, decision-making, and strategies to support informed choices:

• Perceptions of risk: Each person perceives risk and benefit differently. The few studies that have attempted to investigate perception of teratogenic risk have found that many pregnant people overestimate the magnitude of teratogenic risk associated with a particular exposure.³ Alternatively, a medication’s benefit in controlling the maternal condition is often not considered sufficiently. Health care providers may have their own distorted perceptions of risk, even in the presence of evidence.
• Decision-making: Most teratogen data inherently involve uncertainty; it is rare to have completely nonconflicting data with which to make a decision. This makes decisions about whether or not to utilize a particular medication or other agent in pregnancy very difficult. For example, a patient would prefer to be told a black and white answer such as vaccines are either 100% safe or 100% harmful. However, no medical treatment is held to that standard of certainty. Even though it may be more comfortable to avoid an action and “just let things happen,” the lack of a decision is still a decision. The decision to not take medication may have risks inherent in not treating a condition and may result in adverse outcomes in the developing fetus. Lastly, presenting teratogen information often involves challenges in portraying and interpreting numerical risk. For example, when considering data presented in fraction format, patients and some health care providers may focus on the numerator or count of adverse events, while ignoring the magnitude of the denominator.
• Strategies: Health literacy “best practice” strategies are useful whether there is a lot of data or very little. These include the of use plain language and messages delivered in a clear and respectful voice, the use of visual aids, and the use effective teaching methods such as asking open-ended questions to assess understanding. Other strategies include using caution in framing information: for example, discussing a 1% increase in risk for a baby to have a medication-associated birth defect should also be presented as a 99% chance the medication will not cause a birth defect. Numeracy challenges can also be addressed by using natural numbers rather than fractions or percentages: for example, if there were 100 women in this room, one would have a baby with a birth defect after taking this medication in pregnancy, but 99 of these women would not.

In today’s medical world, shared decision-making is the preferred approach to choices. Communicating and appropriately utilizing information to make choices about medication safety in pregnancy are vital undertakings. An important provider responsibility is helping patients understand that science is built on evidence that amasses and changes over time and that it represents rich shades of gray rather than “black and white” options.

Dr. Hardy is executive director, head of pharmacoepidemiology, Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention (BDRP), 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. Conover is the director of Nebraska MotherToBaby. She is assistant professor at the Munroe Meyer Institute, University of Nebraska Medical Center.

References

1. Mitchell AA et al. Am J Obstet Gynecol. 2011;205(1):51:e1-e8.

2. Feghali M et al. Semin Perinatol 2015;39:512-9.

3. Conover EA, Polifka JE. Am J Med Genet Part C Semin Med Genet 2011;157:227-33.

Nearly 9 in 10 U.S. women take a medication at some point in their pregnancy, with approximately 50% of women taking at least one prescription medication.¹ These medications may be prescribed without the benefit of knowledge gained through clinical trials. Knowledge is gained after market, often after multiple years, and potentially following widespread use. The situation is similar for vaccines, as was recently seen with the SARS-CoV2 pandemic. Early in the pandemic, evidence emerged that pregnancy increased the risk for severe illness from COVID-19, yet pregnant people and their providers were forced to make a difficult decision of risk/benefit with little data to guide them.

The FDA product label provides a summary and narrative of animal and human safety studies relating to pregnancy. But what if that label contains little to no information, or reports studies with conflicting results? Perhaps the product is new on the market or is infrequently used during pregnancy. Regardless, health care providers and pregnant patients still need to make decisions about medication use. The following list outlines information that can be found, and strategies to support providers and patients in making informed choices for a treatment plan.


Taking stock of the available information:

• If possible, connect with the specialist who prescribed the patient’s medication in question. They may have already assembled information regarding use of that medication in pregnancy.
• The sponsor may have published useful information from the phase 3 trials, including the outcomes of enrolled patients who inadvertently became pregnant.
• Review the animal data in the product label. Regulators require the careful selection of animal models, and this data can present a source of adjunct information regarding the medication’s effects on pregnancy, reproduction, and development. Negative results can be as revealing as positive results.
• Pharmacologic data in the label can also be informative. Although most labels have pharmacologic data based on trials in healthy nonpregnant individuals, understanding pregnancy physiology and the patient’s preexisting or pregnancy-specific condition(s) can provide insights.² Close patient monitoring and follow-up are of key importance.
• Consider viable alternatives that may address the patient’s needs. There may be effective alternatives that have been better studied and shown to have low reproductive toxicity.
• Consider the risks to the patient as well as the developing fetus if the preexisting or pregnancy-specific condition is uncontrolled.
• Consult a teratogen specialist who can provide information to both patients and health care providers on the reproductive hazards or safety of many exposures, even those with limited data regarding use in pregnancy. For example, MotherToBaby provides a network of teratogen specialists.

Understanding perceptions of risk, decision-making, and strategies to support informed choices:

• Perceptions of risk: Each person perceives risk and benefit differently. The few studies that have attempted to investigate perception of teratogenic risk have found that many pregnant people overestimate the magnitude of teratogenic risk associated with a particular exposure.³ Alternatively, a medication’s benefit in controlling the maternal condition is often not considered sufficiently. Health care providers may have their own distorted perceptions of risk, even in the presence of evidence.
• Decision-making: Most teratogen data inherently involve uncertainty; it is rare to have completely nonconflicting data with which to make a decision. This makes decisions about whether or not to utilize a particular medication or other agent in pregnancy very difficult. For example, a patient would prefer to be told a black and white answer such as vaccines are either 100% safe or 100% harmful. However, no medical treatment is held to that standard of certainty. Even though it may be more comfortable to avoid an action and “just let things happen,” the lack of a decision is still a decision. The decision to not take medication may have risks inherent in not treating a condition and may result in adverse outcomes in the developing fetus. Lastly, presenting teratogen information often involves challenges in portraying and interpreting numerical risk. For example, when considering data presented in fraction format, patients and some health care providers may focus on the numerator or count of adverse events, while ignoring the magnitude of the denominator.
• Strategies: Health literacy “best practice” strategies are useful whether there is a lot of data or very little. These include the of use plain language and messages delivered in a clear and respectful voice, the use of visual aids, and the use effective teaching methods such as asking open-ended questions to assess understanding. Other strategies include using caution in framing information: for example, discussing a 1% increase in risk for a baby to have a medication-associated birth defect should also be presented as a 99% chance the medication will not cause a birth defect. Numeracy challenges can also be addressed by using natural numbers rather than fractions or percentages: for example, if there were 100 women in this room, one would have a baby with a birth defect after taking this medication in pregnancy, but 99 of these women would not.

In today’s medical world, shared decision-making is the preferred approach to choices. Communicating and appropriately utilizing information to make choices about medication safety in pregnancy are vital undertakings. An important provider responsibility is helping patients understand that science is built on evidence that amasses and changes over time and that it represents rich shades of gray rather than “black and white” options.

Dr. Hardy is executive director, head of pharmacoepidemiology, Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention (BDRP), 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. Conover is the director of Nebraska MotherToBaby. She is assistant professor at the Munroe Meyer Institute, University of Nebraska Medical Center.

References

1. Mitchell AA et al. Am J Obstet Gynecol. 2011;205(1):51:e1-e8.

2. Feghali M et al. Semin Perinatol 2015;39:512-9.

3. Conover EA, Polifka JE. Am J Med Genet Part C Semin Med Genet 2011;157:227-33.

Postpartum depression, in many respects, has become a household term. Over the last decade, there has been increasing awareness of the importance of screening for postpartum depression, with increased systematic screening across clinical settings where care is delivered to women during pregnancy and the postpartum period. There have also been greater efforts to identify women who are suffering postpartum depression and to support them with appropriate clinical interventions, whether through psychotherapy and/or pharmacologic therapy. Clinical interventions are supplemented by the increasing awareness of the value of community-based support groups for women who are suffering from postpartum mood and anxiety disorders.

Despite the growing, appropriate focus on recognition and acute treatment of postpartum depression as well as assessing clinical outcomes for those who suffer from postpartum mood and anxiety disorders, less attention has been given to postpartum psychosis, the most severe form of postpartum depression. It is indeed, the least common postpartum psychiatric syndrome (1 in 1,000 births) and comes to public attention when there has been a tragedy during the acute postpartum period such as maternal suicide or infanticide. In this sense, postpartum psychosis is ironically an underappreciated clinical entity across America given its severity, the effect it has on longer-term psychiatric morbidity, and its effect on children and families.

Our group at the Center for Women’s Mental Health has been interested in postpartum psychosis for years and started the Postpartum Psychosis Project in an effort to better understand the phenomenology, course, treatment, outcome, and genomic underpinnings of postpartum psychosis. Risk factors that are well established for postpartum psychosis have been described and overwhelmingly include patients with bipolar disorder. The risk for recurrent postpartum psychosis in women who have had a previous episode is as great as 75%-90% in the absence of prophylactic intervention. With that said, we are extremely interested in understanding the etiology of postpartum psychosis. Various studies over the last 5 years have looked at a whole host of psychosocial as well as neurobiologic variables that may contribute to risk for postpartum psychosis, including dysregulation of the stress axis, heightened inflammation as well as a history of child adversity and heightened experience of stress during the perinatal period.

There have also been anecdotal reports during Virtual Rounds at the Center for Women’s Mental Health of higher recent rates of postpartum psychosis manifesting during the postpartum period. This is a clinical observation and has not been systematically studied. However, one can wonder whether the experience of the pandemic has constituted a stressor for at-risk women, tipping the scales toward women becoming ill, or whether clinicians are seeing this finding more because of our ability to observe it more within the context of the pandemic.

Precise quantification of risk for postpartum psychosis is complicated; as noted, women with bipolar disorder have a predictably high risk for getting ill during the postpartum period and many go on to have clinical courses consistent with recurrent bipolar disorder. However, there are other women who have circumscribed episodes of psychotic illness in the postpartum period who recover and are totally well without any evidence of psychiatric disorder until they have another child, at which time the risk for recurrence of postpartum psychosis is very high. Interest in developing a model of risk that could reliably predict an illness as serious as postpartum psychosis is on the minds of researchers around the world.

One recent study that highlights the multiple factors involved in risk of postpartum psychosis involved a prospective longitudinal study of a group of women who were followed across the peripartum period from the third trimester until 4 weeks postpartum. In this group, 51 women were at increased risk for postpartum psychosis based on their diagnosis of bipolar disorder, schizoaffective disorder, or a previous episode of postpartum psychosis. These women were matched with a control group with no past or current diagnosis of psychiatric disorder or family history of postpartum psychosis. The findings suggested that women at risk for postpartum psychosis who experienced a psychiatric relapse during the first 4 weeks postpartum relative to women at risk who remained well had histories of severe childhood adversity as well as biomarkers consistent with a dysregulated stress axis (a statistically higher daily cortisol level). This is consistent with other data that have implicated the complex role between psychosocial variables as well as neurobiologic variables, such as a dysregulation in the hypothalamic pituitary adrenal axis and other studies that suggest that dysregulated inflammatory status may also drive risk for postpartum psychosis (Hazelgrove K et al. Psychoneuroendocrinology. 2021 Jun. doi: 10.1016/j.psyneuen.2021.105218).

At the end of the day, postpartum psychosis is a psychiatric and obstetrical emergency. In our center, it is rare for women not to be hospitalized with this condition to ensure the safety of the mother as well as her newborn, and to also get her recompensated and functioning as quickly and as significantly as possible. However, an interesting extrapolation of the findings noted by Hazelgrove and colleagues is that it raises the question of what effective treatments might be used to mitigate risk for those at greatest risk for postpartum psychosis. For example, are there other treatments over and above the few effective ones that have been studied as prophylactic pharmacologic interventions that might mitigate risk for recurrence of an illness as serious as postpartum psychosis?

The data suggesting dysregulation of the stress axis as a predictor variable for risk in women vulnerable to postpartum psychosis opens an array of opportunities that are nonpharmacologic, such as mindfulness-based cognitive therapy or other interventions that help to modulate the stress axis. This is a terrific opportunity to have pharmacologic intervention meet nonpharmacologic intervention to potentially mitigate risk for postpartum psychosis with its attendant serious sequelae.

In our own work, where we are evaluating genomic data in an extremely well-characterized group of women with known histories of postpartum psychosis, we are interested to see if we can enhance understanding of the model of risk for postpartum psychosis by factoring in genomic underpinning, history of diagnosis, and psychosocial variables to optimally craft interventions for this population of at-risk women. This brings us one step closer to the future in women’s mental health, to the practice of “precision reproductive psychiatry,” matching interventions to specific presentations across perinatal populations.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Postpartum depression, in many respects, has become a household term. Over the last decade, there has been increasing awareness of the importance of screening for postpartum depression, with increased systematic screening across clinical settings where care is delivered to women during pregnancy and the postpartum period. There have also been greater efforts to identify women who are suffering postpartum depression and to support them with appropriate clinical interventions, whether through psychotherapy and/or pharmacologic therapy. Clinical interventions are supplemented by the increasing awareness of the value of community-based support groups for women who are suffering from postpartum mood and anxiety disorders.

Despite the growing, appropriate focus on recognition and acute treatment of postpartum depression as well as assessing clinical outcomes for those who suffer from postpartum mood and anxiety disorders, less attention has been given to postpartum psychosis, the most severe form of postpartum depression. It is indeed, the least common postpartum psychiatric syndrome (1 in 1,000 births) and comes to public attention when there has been a tragedy during the acute postpartum period such as maternal suicide or infanticide. In this sense, postpartum psychosis is ironically an underappreciated clinical entity across America given its severity, the effect it has on longer-term psychiatric morbidity, and its effect on children and families.

Our group at the Center for Women’s Mental Health has been interested in postpartum psychosis for years and started the Postpartum Psychosis Project in an effort to better understand the phenomenology, course, treatment, outcome, and genomic underpinnings of postpartum psychosis. Risk factors that are well established for postpartum psychosis have been described and overwhelmingly include patients with bipolar disorder. The risk for recurrent postpartum psychosis in women who have had a previous episode is as great as 75%-90% in the absence of prophylactic intervention. With that said, we are extremely interested in understanding the etiology of postpartum psychosis. Various studies over the last 5 years have looked at a whole host of psychosocial as well as neurobiologic variables that may contribute to risk for postpartum psychosis, including dysregulation of the stress axis, heightened inflammation as well as a history of child adversity and heightened experience of stress during the perinatal period.

There have also been anecdotal reports during Virtual Rounds at the Center for Women’s Mental Health of higher recent rates of postpartum psychosis manifesting during the postpartum period. This is a clinical observation and has not been systematically studied. However, one can wonder whether the experience of the pandemic has constituted a stressor for at-risk women, tipping the scales toward women becoming ill, or whether clinicians are seeing this finding more because of our ability to observe it more within the context of the pandemic.

Precise quantification of risk for postpartum psychosis is complicated; as noted, women with bipolar disorder have a predictably high risk for getting ill during the postpartum period and many go on to have clinical courses consistent with recurrent bipolar disorder. However, there are other women who have circumscribed episodes of psychotic illness in the postpartum period who recover and are totally well without any evidence of psychiatric disorder until they have another child, at which time the risk for recurrence of postpartum psychosis is very high. Interest in developing a model of risk that could reliably predict an illness as serious as postpartum psychosis is on the minds of researchers around the world.

One recent study that highlights the multiple factors involved in risk of postpartum psychosis involved a prospective longitudinal study of a group of women who were followed across the peripartum period from the third trimester until 4 weeks postpartum. In this group, 51 women were at increased risk for postpartum psychosis based on their diagnosis of bipolar disorder, schizoaffective disorder, or a previous episode of postpartum psychosis. These women were matched with a control group with no past or current diagnosis of psychiatric disorder or family history of postpartum psychosis. The findings suggested that women at risk for postpartum psychosis who experienced a psychiatric relapse during the first 4 weeks postpartum relative to women at risk who remained well had histories of severe childhood adversity as well as biomarkers consistent with a dysregulated stress axis (a statistically higher daily cortisol level). This is consistent with other data that have implicated the complex role between psychosocial variables as well as neurobiologic variables, such as a dysregulation in the hypothalamic pituitary adrenal axis and other studies that suggest that dysregulated inflammatory status may also drive risk for postpartum psychosis (Hazelgrove K et al. Psychoneuroendocrinology. 2021 Jun. doi: 10.1016/j.psyneuen.2021.105218).

At the end of the day, postpartum psychosis is a psychiatric and obstetrical emergency. In our center, it is rare for women not to be hospitalized with this condition to ensure the safety of the mother as well as her newborn, and to also get her recompensated and functioning as quickly and as significantly as possible. However, an interesting extrapolation of the findings noted by Hazelgrove and colleagues is that it raises the question of what effective treatments might be used to mitigate risk for those at greatest risk for postpartum psychosis. For example, are there other treatments over and above the few effective ones that have been studied as prophylactic pharmacologic interventions that might mitigate risk for recurrence of an illness as serious as postpartum psychosis?

The data suggesting dysregulation of the stress axis as a predictor variable for risk in women vulnerable to postpartum psychosis opens an array of opportunities that are nonpharmacologic, such as mindfulness-based cognitive therapy or other interventions that help to modulate the stress axis. This is a terrific opportunity to have pharmacologic intervention meet nonpharmacologic intervention to potentially mitigate risk for postpartum psychosis with its attendant serious sequelae.

In our own work, where we are evaluating genomic data in an extremely well-characterized group of women with known histories of postpartum psychosis, we are interested to see if we can enhance understanding of the model of risk for postpartum psychosis by factoring in genomic underpinning, history of diagnosis, and psychosocial variables to optimally craft interventions for this population of at-risk women. This brings us one step closer to the future in women’s mental health, to the practice of “precision reproductive psychiatry,” matching interventions to specific presentations across perinatal populations.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Postpartum depression, in many respects, has become a household term. Over the last decade, there has been increasing awareness of the importance of screening for postpartum depression, with increased systematic screening across clinical settings where care is delivered to women during pregnancy and the postpartum period. There have also been greater efforts to identify women who are suffering postpartum depression and to support them with appropriate clinical interventions, whether through psychotherapy and/or pharmacologic therapy. Clinical interventions are supplemented by the increasing awareness of the value of community-based support groups for women who are suffering from postpartum mood and anxiety disorders.

Despite the growing, appropriate focus on recognition and acute treatment of postpartum depression as well as assessing clinical outcomes for those who suffer from postpartum mood and anxiety disorders, less attention has been given to postpartum psychosis, the most severe form of postpartum depression. It is indeed, the least common postpartum psychiatric syndrome (1 in 1,000 births) and comes to public attention when there has been a tragedy during the acute postpartum period such as maternal suicide or infanticide. In this sense, postpartum psychosis is ironically an underappreciated clinical entity across America given its severity, the effect it has on longer-term psychiatric morbidity, and its effect on children and families.

Our group at the Center for Women’s Mental Health has been interested in postpartum psychosis for years and started the Postpartum Psychosis Project in an effort to better understand the phenomenology, course, treatment, outcome, and genomic underpinnings of postpartum psychosis. Risk factors that are well established for postpartum psychosis have been described and overwhelmingly include patients with bipolar disorder. The risk for recurrent postpartum psychosis in women who have had a previous episode is as great as 75%-90% in the absence of prophylactic intervention. With that said, we are extremely interested in understanding the etiology of postpartum psychosis. Various studies over the last 5 years have looked at a whole host of psychosocial as well as neurobiologic variables that may contribute to risk for postpartum psychosis, including dysregulation of the stress axis, heightened inflammation as well as a history of child adversity and heightened experience of stress during the perinatal period.

There have also been anecdotal reports during Virtual Rounds at the Center for Women’s Mental Health of higher recent rates of postpartum psychosis manifesting during the postpartum period. This is a clinical observation and has not been systematically studied. However, one can wonder whether the experience of the pandemic has constituted a stressor for at-risk women, tipping the scales toward women becoming ill, or whether clinicians are seeing this finding more because of our ability to observe it more within the context of the pandemic.

Precise quantification of risk for postpartum psychosis is complicated; as noted, women with bipolar disorder have a predictably high risk for getting ill during the postpartum period and many go on to have clinical courses consistent with recurrent bipolar disorder. However, there are other women who have circumscribed episodes of psychotic illness in the postpartum period who recover and are totally well without any evidence of psychiatric disorder until they have another child, at which time the risk for recurrence of postpartum psychosis is very high. Interest in developing a model of risk that could reliably predict an illness as serious as postpartum psychosis is on the minds of researchers around the world.

One recent study that highlights the multiple factors involved in risk of postpartum psychosis involved a prospective longitudinal study of a group of women who were followed across the peripartum period from the third trimester until 4 weeks postpartum. In this group, 51 women were at increased risk for postpartum psychosis based on their diagnosis of bipolar disorder, schizoaffective disorder, or a previous episode of postpartum psychosis. These women were matched with a control group with no past or current diagnosis of psychiatric disorder or family history of postpartum psychosis. The findings suggested that women at risk for postpartum psychosis who experienced a psychiatric relapse during the first 4 weeks postpartum relative to women at risk who remained well had histories of severe childhood adversity as well as biomarkers consistent with a dysregulated stress axis (a statistically higher daily cortisol level). This is consistent with other data that have implicated the complex role between psychosocial variables as well as neurobiologic variables, such as a dysregulation in the hypothalamic pituitary adrenal axis and other studies that suggest that dysregulated inflammatory status may also drive risk for postpartum psychosis (Hazelgrove K et al. Psychoneuroendocrinology. 2021 Jun. doi: 10.1016/j.psyneuen.2021.105218).

At the end of the day, postpartum psychosis is a psychiatric and obstetrical emergency. In our center, it is rare for women not to be hospitalized with this condition to ensure the safety of the mother as well as her newborn, and to also get her recompensated and functioning as quickly and as significantly as possible. However, an interesting extrapolation of the findings noted by Hazelgrove and colleagues is that it raises the question of what effective treatments might be used to mitigate risk for those at greatest risk for postpartum psychosis. For example, are there other treatments over and above the few effective ones that have been studied as prophylactic pharmacologic interventions that might mitigate risk for recurrence of an illness as serious as postpartum psychosis?

The data suggesting dysregulation of the stress axis as a predictor variable for risk in women vulnerable to postpartum psychosis opens an array of opportunities that are nonpharmacologic, such as mindfulness-based cognitive therapy or other interventions that help to modulate the stress axis. This is a terrific opportunity to have pharmacologic intervention meet nonpharmacologic intervention to potentially mitigate risk for postpartum psychosis with its attendant serious sequelae.

In our own work, where we are evaluating genomic data in an extremely well-characterized group of women with known histories of postpartum psychosis, we are interested to see if we can enhance understanding of the model of risk for postpartum psychosis by factoring in genomic underpinning, history of diagnosis, and psychosocial variables to optimally craft interventions for this population of at-risk women. This brings us one step closer to the future in women’s mental health, to the practice of “precision reproductive psychiatry,” matching interventions to specific presentations across perinatal populations.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

In 2020, the Food and Drug Administration approved 53 new drugs for humans. One of these agents, Annovera (segesterone and ethinyl estradiol), is a vaginal ring to prevent pregnancy and is not relevant in this article. A second drug, Asparlas (calaspargase pegol), indicated to treat acute lymphoblastic leukemia, has not yet been released by its manufacturer. Orgovyx (relugolix) is used for prostate cancer and Lampit (nifurtimox) is drug used in children – neither of these two agents will be covered. The remaining 49 are covered below. The agents with molecular weights less than 1,000 probably cross the placenta in the first half of pregnancy, but nearly all, regardless of MW, will cross in the second half of pregnancy.

No human pregnancy data for these agents has been found, but there are five drugs included in pregnancy registries. It will take some time before the outcomes of these drugs are published. The routine absence of pregnancy data for most drugs was pointed out in an article that I coauthored, “Should pregnant women be included in phase 4 clinical drug trials?”. The article makes a strong argument for including some pregnant women in these trials.
 

Anti-infectives

Artesunate (384)

The drug appears low risk when used in the second and third trimesters. There is inadequate information regarding its use in the first trimester, so the safest course for the embryo appears to be avoiding its use during this period. A single intravenous dose given to rats early in gestation resulted in embryolethality.

Ebanga (ansuvimab) (147,000)

Studies on its use in pregnant animals have not been conducted.

Inmazeb (atoltivimab, maftivimab, odesivimab) (144,000-146,000)

Inmazeb is a combination of the three agents. Studies on its use in pregnant animals have not been conducted.

Veklury (remdesivir) (603)

Veklury is indicated for the treatment of pregnant women hospitalized with COVID-19 who are at risk for serious morbidity and mortality. The drug should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.

Antineoplastics

Ayvakit (avapritinib) (499)

The drug may cause fetal harm. The drug was teratogenic in animals.

Blenrep (belantamab mafodotin-blmf) (152,000)

A B-cell maturation antigen, it is indicated for the treatment of multiple myeloma. No human or animal pregnancy data have been located.

Danyelza (naxitamab-gqgk) (144,000)

This agent is used for the treatment of neuroblastoma. Based on its mechanism of action it may cause fetal harm if used in pregnancy.

Gavreto (pralsetinib) (534)

Gavreto is indicated for the treatment of small cell lung cancer. It may cause embryo-fetal harm if used in pregnancy.

Inqovi (cedazuridine + decitabine) (268,228)

The drug combination can cause fetal harm in human pregnancy. It is toxic in pregnant animals.

Margenza (margetuximab-cmkb) (149,000)

Although there are no data on the use of this drug in human pregnancy, the findings in animals and mechanism of action suggest that it will cause fetal harm.

Monjuvi (tafasitamab-cxix) (150,000)

This drug is a cytolytic antibody that is indicated in combination with lenalidomide. The combination may cause fetal harm.

Pemazyre (pemigatinib) (488)

It is indicated for the treatment of cholangiocarcinoma. In an animal study, the drug caused fetal defects, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure.

Qinlock (ripretinib) (510)

This drug is used for the treatment of patients with advanced gastrointestinal stromal tumor. The drug was teratogenic in pregnant animals.

Retevmo (selpercatinib) (526)

This is a kinase inhibitor used for the treatment of small cell lung cancer. The drug is teratogenic in animals.

Sarclisa (isatuximab-irfc) (148,000)This drug is used in combination with pomalidomide and dexamethasone. The combination would probably cause major toxicity in an embryo or fetus.

Tabrecta (capmatinib) (412 – free base)Capmatinib is a kinase inhibitor used for the treatment of metastatic non–small cell lung cancer. It is teratogenic in animals.

Tazverik (tazemetostat) (654)Tazemetostat is indicated for the treatment of epithelioid sarcoma and follicular lymphoma, The drug is teratogenic in animals.

Trodelvy (sacituzumab govitecan-hziy) (1,602)This agent is used for the treatment of breast cancer. The drug has not been tested in pregnant animals. However, according to the manufacturer, there is a high possibility of human teratogenicity if it is given to a pregnant woman.

Tukysa (tucatinib) (481)

Tukysa is a tyrosine kinase inhibitor that is used in combination with trastuzumab and capecitabine for the treatment of breast cancer. The drug is teratogenic in animals.

Zeposia (ozanimod) (441)

Zeposia is indicated for the treatment of multiple sclerosis. The drug takes about 3 months to eliminate from the body. The drug is teratogenic in animals.

Zepzelca (lurbinectedin) (785)

This agent is used for the treatment of metastatic small cell lung cancer. The drug is teratogenic in animals.
 

Antiemetics

Barhemsys (amisulpride) (369)

This agent is Indicated to prevent nausea and vomiting. Animal data suggest low risk of embryo/fetal birth defects.

Antimigraine

Nurtec (rimegepant) (611)

Nurtec is indicated for acute treatment of migraine. Development toxicity was not observed in animals given doses similar to those used in humans.

Vyepti (eptinezumab-jjmr) (143,000)

A humanized monoclonal antibody that is given every 3 months to prevent migraine. There was no embryo-fetal harm in animals given the drug.
 

CNS

Byfavo (remimazolam) (493 – free base)

This drug is indicated for procedural sedation in adults undergoing procedures lasting 30 minutes or less. No defects were observed in animals.
 

Diagnostics

Cerianna (fluoroestradiol F 18) (289)

It is indicated for use with PET for characterization of estrogen receptor status in patients with ER-positive breast cancer. It has the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. There are no data on its use in pregnant women or animals.

Detectnet (copper CU-64 dotatate) (1,497)

All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. There are no pregnancy data in humans or animals

Miscellaneous

Dojolvi (triheptanoin) (429)

This agent is indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders. Advise patients that there is a pregnancy safety study that collects pregnancy outcome data in women taking Dojolvi during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657.

Enspryng (satralizumab-mwge) (143,000)

It is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. No information is available on the risks, if any, in pregnancy. No adverse effects on maternal or fetal development were observed in pregnant monkeys and their offspring.

Evrysdi (risdiplam) (401)

This is a prescription medicine used to treat spinal muscular atrophy in adults and children aged 2 months and older. In pregnant animals the drug caused adverse effects on fetal development.

Gemtesa (vibegron) (445)

Gemtesa is used in adults to treat the symptoms of overactive bladder. The drug had no adverse effects on pregnant animals.

Imcivree (setmelanotide) (1,117)

This drug is indicated for chronic weight management in adult and pediatric patients aged 6 years and older with obesity because of proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. The drug was not embryo toxic in animals.

Isturisa (osilodrostat) (325)

Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease. No adverse fetal effects were observed in pregnant animals.

Klisyri (tirbanibulin) (431)

Tirbanibulin ointment is a microtubule inhibitor that is used to treat actinic keratosis. Information on its effects in pregnancy is not available.

Koselugo (selumetinib) (556)

This is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older. The drug is toxic in pregnant animals but its effects in human pregnancy are not known.

Nexletol (bempedoic acid) (344)

Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. The drug was not teratogenic in animals. Discontinue Nexletol when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

Olinvyk (oliceridine) (503)

Olinvyk injection is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic. Prolonged use of Olinvyk during pregnancy can result in neonatal opioid withdrawal syndrome. The drug was not teratogenic in animals.

Ongentys (opicapone) (413)

Ongentys is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. The drug was teratogenic in rabbits but not in rats.

Orladeyo (berotralstat) (635)

This drug is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. It was not teratogenic in animals.

Oxlumo (lumasiran) (17,286)

Oxlumo is a HAO1-directed small interfering ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels. No adverse effects on pregnancy or embryo-fetal development related to the drug were observed in animals.

Pizensy (lactitol) (344)

Lactitol is minimally absorbed systemically following oral administration. It is unknown whether maternal use will result in fetal exposure to the drug. No effects on embryo-fetal development were observed in animals at doses much higher than the maximum recommended human dosage.

Rukobia (fostemsavir) (705; 584 for free acid)

This drug is an HIV-1–directed attachment inhibitor, in combination with other antiretrovirals. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the drug during pregnancy. Health care providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Sogroya (somapacitan-beco) (23,305)

This is a human growth hormone analog indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency. The drug was not teratogenic in animals.

Tepezza (teprotumumab-trbw) (148,000)

Drug is indicated for the treatment of thyroid eye disease. The drug was teratogenic in cynomolgus monkeys. The manufacturer states that because of the risk, the drug should not be used in pregnancy.

Tauvid (flortaucipir F-18) (262)

This drug is indicated for use with PET imaging of the brain to evaluate for Alzheimer’s disease. It is a radioactive drug and should not be used in pregnant women.

Uplizna (inebilizumab-cdon) (149,000)

Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti-AQP4 antibody positive. It is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Based on animal data, the drug can cause fetal harm because of B-cell lymphopenia and reduce antibody response in offspring exposed to the drug. Women of childbearing potential should use contraception while receiving Uplizna and for 6 months after the last dose.

Winlevi (clascoterone) (403)

This cream is an androgen receptor inhibitor that is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Subcutaneous use in animals was associated with fetal defects.

Xeglyze (abametapir) (1,840)

Xeglyze is indicated for the topical treatment of head lice infestation in patients aged 6 months and older. The drug was not teratogenic in animals.

Zokinvy (lonafarnib) (639)

Zokinvy is indicated in patients 12 months or older to reduce the risk of mortality in several conditions. Animal studies have found embryo-fetal harm.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

In 2020, the Food and Drug Administration approved 53 new drugs for humans. One of these agents, Annovera (segesterone and ethinyl estradiol), is a vaginal ring to prevent pregnancy and is not relevant in this article. A second drug, Asparlas (calaspargase pegol), indicated to treat acute lymphoblastic leukemia, has not yet been released by its manufacturer. Orgovyx (relugolix) is used for prostate cancer and Lampit (nifurtimox) is drug used in children – neither of these two agents will be covered. The remaining 49 are covered below. The agents with molecular weights less than 1,000 probably cross the placenta in the first half of pregnancy, but nearly all, regardless of MW, will cross in the second half of pregnancy.

No human pregnancy data for these agents has been found, but there are five drugs included in pregnancy registries. It will take some time before the outcomes of these drugs are published. The routine absence of pregnancy data for most drugs was pointed out in an article that I coauthored, “Should pregnant women be included in phase 4 clinical drug trials?”. The article makes a strong argument for including some pregnant women in these trials.
 

Anti-infectives

Artesunate (384)

The drug appears low risk when used in the second and third trimesters. There is inadequate information regarding its use in the first trimester, so the safest course for the embryo appears to be avoiding its use during this period. A single intravenous dose given to rats early in gestation resulted in embryolethality.

Ebanga (ansuvimab) (147,000)

Studies on its use in pregnant animals have not been conducted.

Inmazeb (atoltivimab, maftivimab, odesivimab) (144,000-146,000)

Inmazeb is a combination of the three agents. Studies on its use in pregnant animals have not been conducted.

Veklury (remdesivir) (603)

Veklury is indicated for the treatment of pregnant women hospitalized with COVID-19 who are at risk for serious morbidity and mortality. The drug should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.

Antineoplastics

Ayvakit (avapritinib) (499)

The drug may cause fetal harm. The drug was teratogenic in animals.

Blenrep (belantamab mafodotin-blmf) (152,000)

A B-cell maturation antigen, it is indicated for the treatment of multiple myeloma. No human or animal pregnancy data have been located.

Danyelza (naxitamab-gqgk) (144,000)

This agent is used for the treatment of neuroblastoma. Based on its mechanism of action it may cause fetal harm if used in pregnancy.

Gavreto (pralsetinib) (534)

Gavreto is indicated for the treatment of small cell lung cancer. It may cause embryo-fetal harm if used in pregnancy.

Inqovi (cedazuridine + decitabine) (268,228)

The drug combination can cause fetal harm in human pregnancy. It is toxic in pregnant animals.

Margenza (margetuximab-cmkb) (149,000)

Although there are no data on the use of this drug in human pregnancy, the findings in animals and mechanism of action suggest that it will cause fetal harm.

Monjuvi (tafasitamab-cxix) (150,000)

This drug is a cytolytic antibody that is indicated in combination with lenalidomide. The combination may cause fetal harm.

Pemazyre (pemigatinib) (488)

It is indicated for the treatment of cholangiocarcinoma. In an animal study, the drug caused fetal defects, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure.

Qinlock (ripretinib) (510)

This drug is used for the treatment of patients with advanced gastrointestinal stromal tumor. The drug was teratogenic in pregnant animals.

Retevmo (selpercatinib) (526)

This is a kinase inhibitor used for the treatment of small cell lung cancer. The drug is teratogenic in animals.

Sarclisa (isatuximab-irfc) (148,000)This drug is used in combination with pomalidomide and dexamethasone. The combination would probably cause major toxicity in an embryo or fetus.

Tabrecta (capmatinib) (412 – free base)Capmatinib is a kinase inhibitor used for the treatment of metastatic non–small cell lung cancer. It is teratogenic in animals.

Tazverik (tazemetostat) (654)Tazemetostat is indicated for the treatment of epithelioid sarcoma and follicular lymphoma, The drug is teratogenic in animals.

Trodelvy (sacituzumab govitecan-hziy) (1,602)This agent is used for the treatment of breast cancer. The drug has not been tested in pregnant animals. However, according to the manufacturer, there is a high possibility of human teratogenicity if it is given to a pregnant woman.

Tukysa (tucatinib) (481)

Tukysa is a tyrosine kinase inhibitor that is used in combination with trastuzumab and capecitabine for the treatment of breast cancer. The drug is teratogenic in animals.

Zeposia (ozanimod) (441)

Zeposia is indicated for the treatment of multiple sclerosis. The drug takes about 3 months to eliminate from the body. The drug is teratogenic in animals.

Zepzelca (lurbinectedin) (785)

This agent is used for the treatment of metastatic small cell lung cancer. The drug is teratogenic in animals.
 

Antiemetics

Barhemsys (amisulpride) (369)

This agent is Indicated to prevent nausea and vomiting. Animal data suggest low risk of embryo/fetal birth defects.

Antimigraine

Nurtec (rimegepant) (611)

Nurtec is indicated for acute treatment of migraine. Development toxicity was not observed in animals given doses similar to those used in humans.

Vyepti (eptinezumab-jjmr) (143,000)

A humanized monoclonal antibody that is given every 3 months to prevent migraine. There was no embryo-fetal harm in animals given the drug.
 

CNS

Byfavo (remimazolam) (493 – free base)

This drug is indicated for procedural sedation in adults undergoing procedures lasting 30 minutes or less. No defects were observed in animals.
 

Diagnostics

Cerianna (fluoroestradiol F 18) (289)

It is indicated for use with PET for characterization of estrogen receptor status in patients with ER-positive breast cancer. It has the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. There are no data on its use in pregnant women or animals.

Detectnet (copper CU-64 dotatate) (1,497)

All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. There are no pregnancy data in humans or animals

Miscellaneous

Dojolvi (triheptanoin) (429)

This agent is indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders. Advise patients that there is a pregnancy safety study that collects pregnancy outcome data in women taking Dojolvi during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657.

Enspryng (satralizumab-mwge) (143,000)

It is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. No information is available on the risks, if any, in pregnancy. No adverse effects on maternal or fetal development were observed in pregnant monkeys and their offspring.

Evrysdi (risdiplam) (401)

This is a prescription medicine used to treat spinal muscular atrophy in adults and children aged 2 months and older. In pregnant animals the drug caused adverse effects on fetal development.

Gemtesa (vibegron) (445)

Gemtesa is used in adults to treat the symptoms of overactive bladder. The drug had no adverse effects on pregnant animals.

Imcivree (setmelanotide) (1,117)

This drug is indicated for chronic weight management in adult and pediatric patients aged 6 years and older with obesity because of proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. The drug was not embryo toxic in animals.

Isturisa (osilodrostat) (325)

Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease. No adverse fetal effects were observed in pregnant animals.

Klisyri (tirbanibulin) (431)

Tirbanibulin ointment is a microtubule inhibitor that is used to treat actinic keratosis. Information on its effects in pregnancy is not available.

Koselugo (selumetinib) (556)

This is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older. The drug is toxic in pregnant animals but its effects in human pregnancy are not known.

Nexletol (bempedoic acid) (344)

Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. The drug was not teratogenic in animals. Discontinue Nexletol when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

Olinvyk (oliceridine) (503)

Olinvyk injection is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic. Prolonged use of Olinvyk during pregnancy can result in neonatal opioid withdrawal syndrome. The drug was not teratogenic in animals.

Ongentys (opicapone) (413)

Ongentys is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. The drug was teratogenic in rabbits but not in rats.

Orladeyo (berotralstat) (635)

This drug is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. It was not teratogenic in animals.

Oxlumo (lumasiran) (17,286)

Oxlumo is a HAO1-directed small interfering ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels. No adverse effects on pregnancy or embryo-fetal development related to the drug were observed in animals.

Pizensy (lactitol) (344)

Lactitol is minimally absorbed systemically following oral administration. It is unknown whether maternal use will result in fetal exposure to the drug. No effects on embryo-fetal development were observed in animals at doses much higher than the maximum recommended human dosage.

Rukobia (fostemsavir) (705; 584 for free acid)

This drug is an HIV-1–directed attachment inhibitor, in combination with other antiretrovirals. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the drug during pregnancy. Health care providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Sogroya (somapacitan-beco) (23,305)

This is a human growth hormone analog indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency. The drug was not teratogenic in animals.

Tepezza (teprotumumab-trbw) (148,000)

Drug is indicated for the treatment of thyroid eye disease. The drug was teratogenic in cynomolgus monkeys. The manufacturer states that because of the risk, the drug should not be used in pregnancy.

Tauvid (flortaucipir F-18) (262)

This drug is indicated for use with PET imaging of the brain to evaluate for Alzheimer’s disease. It is a radioactive drug and should not be used in pregnant women.

Uplizna (inebilizumab-cdon) (149,000)

Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti-AQP4 antibody positive. It is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Based on animal data, the drug can cause fetal harm because of B-cell lymphopenia and reduce antibody response in offspring exposed to the drug. Women of childbearing potential should use contraception while receiving Uplizna and for 6 months after the last dose.

Winlevi (clascoterone) (403)

This cream is an androgen receptor inhibitor that is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Subcutaneous use in animals was associated with fetal defects.

Xeglyze (abametapir) (1,840)

Xeglyze is indicated for the topical treatment of head lice infestation in patients aged 6 months and older. The drug was not teratogenic in animals.

Zokinvy (lonafarnib) (639)

Zokinvy is indicated in patients 12 months or older to reduce the risk of mortality in several conditions. Animal studies have found embryo-fetal harm.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

In 2020, the Food and Drug Administration approved 53 new drugs for humans. One of these agents, Annovera (segesterone and ethinyl estradiol), is a vaginal ring to prevent pregnancy and is not relevant in this article. A second drug, Asparlas (calaspargase pegol), indicated to treat acute lymphoblastic leukemia, has not yet been released by its manufacturer. Orgovyx (relugolix) is used for prostate cancer and Lampit (nifurtimox) is drug used in children – neither of these two agents will be covered. The remaining 49 are covered below. The agents with molecular weights less than 1,000 probably cross the placenta in the first half of pregnancy, but nearly all, regardless of MW, will cross in the second half of pregnancy.

No human pregnancy data for these agents has been found, but there are five drugs included in pregnancy registries. It will take some time before the outcomes of these drugs are published. The routine absence of pregnancy data for most drugs was pointed out in an article that I coauthored, “Should pregnant women be included in phase 4 clinical drug trials?”. The article makes a strong argument for including some pregnant women in these trials.
 

Anti-infectives

Artesunate (384)

The drug appears low risk when used in the second and third trimesters. There is inadequate information regarding its use in the first trimester, so the safest course for the embryo appears to be avoiding its use during this period. A single intravenous dose given to rats early in gestation resulted in embryolethality.

Ebanga (ansuvimab) (147,000)

Studies on its use in pregnant animals have not been conducted.

Inmazeb (atoltivimab, maftivimab, odesivimab) (144,000-146,000)

Inmazeb is a combination of the three agents. Studies on its use in pregnant animals have not been conducted.

Veklury (remdesivir) (603)

Veklury is indicated for the treatment of pregnant women hospitalized with COVID-19 who are at risk for serious morbidity and mortality. The drug should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.

Antineoplastics

Ayvakit (avapritinib) (499)

The drug may cause fetal harm. The drug was teratogenic in animals.

Blenrep (belantamab mafodotin-blmf) (152,000)

A B-cell maturation antigen, it is indicated for the treatment of multiple myeloma. No human or animal pregnancy data have been located.

Danyelza (naxitamab-gqgk) (144,000)

This agent is used for the treatment of neuroblastoma. Based on its mechanism of action it may cause fetal harm if used in pregnancy.

Gavreto (pralsetinib) (534)

Gavreto is indicated for the treatment of small cell lung cancer. It may cause embryo-fetal harm if used in pregnancy.

Inqovi (cedazuridine + decitabine) (268,228)

The drug combination can cause fetal harm in human pregnancy. It is toxic in pregnant animals.

Margenza (margetuximab-cmkb) (149,000)

Although there are no data on the use of this drug in human pregnancy, the findings in animals and mechanism of action suggest that it will cause fetal harm.

Monjuvi (tafasitamab-cxix) (150,000)

This drug is a cytolytic antibody that is indicated in combination with lenalidomide. The combination may cause fetal harm.

Pemazyre (pemigatinib) (488)

It is indicated for the treatment of cholangiocarcinoma. In an animal study, the drug caused fetal defects, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure.

Qinlock (ripretinib) (510)

This drug is used for the treatment of patients with advanced gastrointestinal stromal tumor. The drug was teratogenic in pregnant animals.

Retevmo (selpercatinib) (526)

This is a kinase inhibitor used for the treatment of small cell lung cancer. The drug is teratogenic in animals.

Sarclisa (isatuximab-irfc) (148,000)This drug is used in combination with pomalidomide and dexamethasone. The combination would probably cause major toxicity in an embryo or fetus.

Tabrecta (capmatinib) (412 – free base)Capmatinib is a kinase inhibitor used for the treatment of metastatic non–small cell lung cancer. It is teratogenic in animals.

Tazverik (tazemetostat) (654)Tazemetostat is indicated for the treatment of epithelioid sarcoma and follicular lymphoma, The drug is teratogenic in animals.

Trodelvy (sacituzumab govitecan-hziy) (1,602)This agent is used for the treatment of breast cancer. The drug has not been tested in pregnant animals. However, according to the manufacturer, there is a high possibility of human teratogenicity if it is given to a pregnant woman.

Tukysa (tucatinib) (481)

Tukysa is a tyrosine kinase inhibitor that is used in combination with trastuzumab and capecitabine for the treatment of breast cancer. The drug is teratogenic in animals.

Zeposia (ozanimod) (441)

Zeposia is indicated for the treatment of multiple sclerosis. The drug takes about 3 months to eliminate from the body. The drug is teratogenic in animals.

Zepzelca (lurbinectedin) (785)

This agent is used for the treatment of metastatic small cell lung cancer. The drug is teratogenic in animals.
 

Antiemetics

Barhemsys (amisulpride) (369)

This agent is Indicated to prevent nausea and vomiting. Animal data suggest low risk of embryo/fetal birth defects.

Antimigraine

Nurtec (rimegepant) (611)

Nurtec is indicated for acute treatment of migraine. Development toxicity was not observed in animals given doses similar to those used in humans.

Vyepti (eptinezumab-jjmr) (143,000)

A humanized monoclonal antibody that is given every 3 months to prevent migraine. There was no embryo-fetal harm in animals given the drug.
 

CNS

Byfavo (remimazolam) (493 – free base)

This drug is indicated for procedural sedation in adults undergoing procedures lasting 30 minutes or less. No defects were observed in animals.
 

Diagnostics

Cerianna (fluoroestradiol F 18) (289)

It is indicated for use with PET for characterization of estrogen receptor status in patients with ER-positive breast cancer. It has the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. There are no data on its use in pregnant women or animals.

Detectnet (copper CU-64 dotatate) (1,497)

All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. There are no pregnancy data in humans or animals

Miscellaneous

Dojolvi (triheptanoin) (429)

This agent is indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders. Advise patients that there is a pregnancy safety study that collects pregnancy outcome data in women taking Dojolvi during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657.

Enspryng (satralizumab-mwge) (143,000)

It is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. No information is available on the risks, if any, in pregnancy. No adverse effects on maternal or fetal development were observed in pregnant monkeys and their offspring.

Evrysdi (risdiplam) (401)

This is a prescription medicine used to treat spinal muscular atrophy in adults and children aged 2 months and older. In pregnant animals the drug caused adverse effects on fetal development.

Gemtesa (vibegron) (445)

Gemtesa is used in adults to treat the symptoms of overactive bladder. The drug had no adverse effects on pregnant animals.

Imcivree (setmelanotide) (1,117)

This drug is indicated for chronic weight management in adult and pediatric patients aged 6 years and older with obesity because of proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. The drug was not embryo toxic in animals.

Isturisa (osilodrostat) (325)

Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease. No adverse fetal effects were observed in pregnant animals.

Klisyri (tirbanibulin) (431)

Tirbanibulin ointment is a microtubule inhibitor that is used to treat actinic keratosis. Information on its effects in pregnancy is not available.

Koselugo (selumetinib) (556)

This is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older. The drug is toxic in pregnant animals but its effects in human pregnancy are not known.

Nexletol (bempedoic acid) (344)

Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. The drug was not teratogenic in animals. Discontinue Nexletol when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.

Olinvyk (oliceridine) (503)

Olinvyk injection is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic. Prolonged use of Olinvyk during pregnancy can result in neonatal opioid withdrawal syndrome. The drug was not teratogenic in animals.

Ongentys (opicapone) (413)

Ongentys is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. The drug was teratogenic in rabbits but not in rats.

Orladeyo (berotralstat) (635)

This drug is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. It was not teratogenic in animals.

Oxlumo (lumasiran) (17,286)

Oxlumo is a HAO1-directed small interfering ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels. No adverse effects on pregnancy or embryo-fetal development related to the drug were observed in animals.

Pizensy (lactitol) (344)

Lactitol is minimally absorbed systemically following oral administration. It is unknown whether maternal use will result in fetal exposure to the drug. No effects on embryo-fetal development were observed in animals at doses much higher than the maximum recommended human dosage.

Rukobia (fostemsavir) (705; 584 for free acid)

This drug is an HIV-1–directed attachment inhibitor, in combination with other antiretrovirals. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the drug during pregnancy. Health care providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Sogroya (somapacitan-beco) (23,305)

This is a human growth hormone analog indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency. The drug was not teratogenic in animals.

Tepezza (teprotumumab-trbw) (148,000)

Drug is indicated for the treatment of thyroid eye disease. The drug was teratogenic in cynomolgus monkeys. The manufacturer states that because of the risk, the drug should not be used in pregnancy.

Tauvid (flortaucipir F-18) (262)

This drug is indicated for use with PET imaging of the brain to evaluate for Alzheimer’s disease. It is a radioactive drug and should not be used in pregnant women.

Uplizna (inebilizumab-cdon) (149,000)

Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti-AQP4 antibody positive. It is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Based on animal data, the drug can cause fetal harm because of B-cell lymphopenia and reduce antibody response in offspring exposed to the drug. Women of childbearing potential should use contraception while receiving Uplizna and for 6 months after the last dose.

Winlevi (clascoterone) (403)

This cream is an androgen receptor inhibitor that is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Subcutaneous use in animals was associated with fetal defects.

Xeglyze (abametapir) (1,840)

Xeglyze is indicated for the topical treatment of head lice infestation in patients aged 6 months and older. The drug was not teratogenic in animals.

Zokinvy (lonafarnib) (639)

Zokinvy is indicated in patients 12 months or older to reduce the risk of mortality in several conditions. Animal studies have found embryo-fetal harm.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

There are three general classes of antifungal agents (number of agents): azole antifungals (9), echinocandins (3), and polyenes (5). The azole antifungals contain an azole ring and inhibit a wide range of fungi. Echinocandins target the fungal cell wall and the polyenes increase the fungal membrane permeability and lead to cell death.

Pregnancy

Azole antifungals inhibit the growth of fungi. Their trade names and molecular weights:

• Clotrimazole (Mycelex), an over-the-counter product, is available as a topical cream. Several studies have found no association between the drug and birth defects.
• Fluconazole (Diflucan) is a teratogen when doses of ≥400 mg/day are used during the first trimester. Smaller doses do not appear to cause embryo/fetal harm.
• Isavuconazonium (Cresemba) if used in pregnancy, exposure of the embryo/fetus would probably be low based on the >99% plasma protein binding, but the plasma half-life is 130 hours. Moreover, the drug is a potent animal teratogen and is best avoided in pregnancy.
• Itraconazole (Onmel, Sporanox, Tolsura), has a low risk, if any, of structural defects, according to what reported human experience suggests.
• Ketoconazole (Xolegel, Extina, Nizoral; 531) does not appear to adversely effect embryos and fetuses, but the human data are very limited. As with any drug, avoiding organogenesis is the best recommendation.
• Miconazole (Oravig) is usually used topically. Small amounts are absorbed from the vagina. The available evidence suggests that the drug does not increase the risk of congenital malformations.
• Posaconazole (Noxafil) does not have reported use in human pregnancy. The animal reproduction data suggest risk. Based on its molecular weight (about 701), the drug will most likely cross the placenta to the embryo/fetus. Thus, the best course is to avoid the drug during pregnancy, especially in the first trimester.
• Voriconazole (Vfend) has one human report of the drug use in pregnancy. The drug was started at about 19 weeks and continued until the woman gave birth at 35 weeks to a healthy male baby. At 6 months of age, the baby remained normal.

Echinocandin antifungals target the fungal cell wall by inhibiting its synthesis. Their trade names and molecular weights:

• Anidulafungin (Eraxis; 1,140) has no published human data. It is indicated for the treatment of candidemia and other forms of Candida infections. The animal data suggest low risk.
• Caspofungin (Cancidas; 1,213) has no published human data. It is indicated for presumed fungal infections in febrile, neutropenic patients. The animal data are suggestive of human risk, especially if exposure occurs in the first trimester. If possible, maternal treatment should be avoided in the first trimester.
• Micafungin (Mycamine; 1,292) has no published human data. It is indicated for the treatment of patients with esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. The animal data in one species suggest high risk. If possible, maternal treatment should be avoided in the first trimester.

Polyene antifungals cause depolarization of the fungal cell membrane to increase the membrane permeability, which leads to cell death. Their trade names and molecular weights:

• Amphotericin b (Amphocin; Fungizone; 924) There are three other amphotericin agents: amphotericin b cholesteryl sulfate (Amphotec); amphotericin b lipid complex (Abelcet); amphotericin b liposomal (AmBisome). No reports linking amphotericin b with congenital defects have been found. The drug does cross the human placenta. Although there was a higher rate of spontaneous abortions in rabbits given amphotericin b, there was no fetal harm in rats and rabbits when given amphotericin b lipid complex.
• Nystatin (Bio-Statin; Mycostatin; Nilstat; 926). The drug does not appear to cause embryo-fetal harm. Based on published data, the drug can be used at any time in pregnancy.

Breastfeeding

Small amounts of all the above drugs are probably excreted into breast milk if they are used close to breastfeeding. Most can probably be used during breastfeeding, but there are no data for any of these agents. The safest decision is to not use these drugs when breastfeeding.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

There are three general classes of antifungal agents (number of agents): azole antifungals (9), echinocandins (3), and polyenes (5). The azole antifungals contain an azole ring and inhibit a wide range of fungi. Echinocandins target the fungal cell wall and the polyenes increase the fungal membrane permeability and lead to cell death.

Pregnancy

Azole antifungals inhibit the growth of fungi. Their trade names and molecular weights:

• Clotrimazole (Mycelex), an over-the-counter product, is available as a topical cream. Several studies have found no association between the drug and birth defects.
• Fluconazole (Diflucan) is a teratogen when doses of ≥400 mg/day are used during the first trimester. Smaller doses do not appear to cause embryo/fetal harm.
• Isavuconazonium (Cresemba) if used in pregnancy, exposure of the embryo/fetus would probably be low based on the >99% plasma protein binding, but the plasma half-life is 130 hours. Moreover, the drug is a potent animal teratogen and is best avoided in pregnancy.
• Itraconazole (Onmel, Sporanox, Tolsura), has a low risk, if any, of structural defects, according to what reported human experience suggests.
• Ketoconazole (Xolegel, Extina, Nizoral; 531) does not appear to adversely effect embryos and fetuses, but the human data are very limited. As with any drug, avoiding organogenesis is the best recommendation.
• Miconazole (Oravig) is usually used topically. Small amounts are absorbed from the vagina. The available evidence suggests that the drug does not increase the risk of congenital malformations.
• Posaconazole (Noxafil) does not have reported use in human pregnancy. The animal reproduction data suggest risk. Based on its molecular weight (about 701), the drug will most likely cross the placenta to the embryo/fetus. Thus, the best course is to avoid the drug during pregnancy, especially in the first trimester.
• Voriconazole (Vfend) has one human report of the drug use in pregnancy. The drug was started at about 19 weeks and continued until the woman gave birth at 35 weeks to a healthy male baby. At 6 months of age, the baby remained normal.

Echinocandin antifungals target the fungal cell wall by inhibiting its synthesis. Their trade names and molecular weights:

• Anidulafungin (Eraxis; 1,140) has no published human data. It is indicated for the treatment of candidemia and other forms of Candida infections. The animal data suggest low risk.
• Caspofungin (Cancidas; 1,213) has no published human data. It is indicated for presumed fungal infections in febrile, neutropenic patients. The animal data are suggestive of human risk, especially if exposure occurs in the first trimester. If possible, maternal treatment should be avoided in the first trimester.
• Micafungin (Mycamine; 1,292) has no published human data. It is indicated for the treatment of patients with esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. The animal data in one species suggest high risk. If possible, maternal treatment should be avoided in the first trimester.

Polyene antifungals cause depolarization of the fungal cell membrane to increase the membrane permeability, which leads to cell death. Their trade names and molecular weights:

• Amphotericin b (Amphocin; Fungizone; 924) There are three other amphotericin agents: amphotericin b cholesteryl sulfate (Amphotec); amphotericin b lipid complex (Abelcet); amphotericin b liposomal (AmBisome). No reports linking amphotericin b with congenital defects have been found. The drug does cross the human placenta. Although there was a higher rate of spontaneous abortions in rabbits given amphotericin b, there was no fetal harm in rats and rabbits when given amphotericin b lipid complex.
• Nystatin (Bio-Statin; Mycostatin; Nilstat; 926). The drug does not appear to cause embryo-fetal harm. Based on published data, the drug can be used at any time in pregnancy.

Breastfeeding

Small amounts of all the above drugs are probably excreted into breast milk if they are used close to breastfeeding. Most can probably be used during breastfeeding, but there are no data for any of these agents. The safest decision is to not use these drugs when breastfeeding.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

There are three general classes of antifungal agents (number of agents): azole antifungals (9), echinocandins (3), and polyenes (5). The azole antifungals contain an azole ring and inhibit a wide range of fungi. Echinocandins target the fungal cell wall and the polyenes increase the fungal membrane permeability and lead to cell death.

Pregnancy

Azole antifungals inhibit the growth of fungi. Their trade names and molecular weights:

• Clotrimazole (Mycelex), an over-the-counter product, is available as a topical cream. Several studies have found no association between the drug and birth defects.
• Fluconazole (Diflucan) is a teratogen when doses of ≥400 mg/day are used during the first trimester. Smaller doses do not appear to cause embryo/fetal harm.
• Isavuconazonium (Cresemba) if used in pregnancy, exposure of the embryo/fetus would probably be low based on the >99% plasma protein binding, but the plasma half-life is 130 hours. Moreover, the drug is a potent animal teratogen and is best avoided in pregnancy.
• Itraconazole (Onmel, Sporanox, Tolsura), has a low risk, if any, of structural defects, according to what reported human experience suggests.
• Ketoconazole (Xolegel, Extina, Nizoral; 531) does not appear to adversely effect embryos and fetuses, but the human data are very limited. As with any drug, avoiding organogenesis is the best recommendation.
• Miconazole (Oravig) is usually used topically. Small amounts are absorbed from the vagina. The available evidence suggests that the drug does not increase the risk of congenital malformations.
• Posaconazole (Noxafil) does not have reported use in human pregnancy. The animal reproduction data suggest risk. Based on its molecular weight (about 701), the drug will most likely cross the placenta to the embryo/fetus. Thus, the best course is to avoid the drug during pregnancy, especially in the first trimester.
• Voriconazole (Vfend) has one human report of the drug use in pregnancy. The drug was started at about 19 weeks and continued until the woman gave birth at 35 weeks to a healthy male baby. At 6 months of age, the baby remained normal.

Echinocandin antifungals target the fungal cell wall by inhibiting its synthesis. Their trade names and molecular weights:

• Anidulafungin (Eraxis; 1,140) has no published human data. It is indicated for the treatment of candidemia and other forms of Candida infections. The animal data suggest low risk.
• Caspofungin (Cancidas; 1,213) has no published human data. It is indicated for presumed fungal infections in febrile, neutropenic patients. The animal data are suggestive of human risk, especially if exposure occurs in the first trimester. If possible, maternal treatment should be avoided in the first trimester.
• Micafungin (Mycamine; 1,292) has no published human data. It is indicated for the treatment of patients with esophageal candidiasis and for the prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation. The animal data in one species suggest high risk. If possible, maternal treatment should be avoided in the first trimester.

Polyene antifungals cause depolarization of the fungal cell membrane to increase the membrane permeability, which leads to cell death. Their trade names and molecular weights:

• Amphotericin b (Amphocin; Fungizone; 924) There are three other amphotericin agents: amphotericin b cholesteryl sulfate (Amphotec); amphotericin b lipid complex (Abelcet); amphotericin b liposomal (AmBisome). No reports linking amphotericin b with congenital defects have been found. The drug does cross the human placenta. Although there was a higher rate of spontaneous abortions in rabbits given amphotericin b, there was no fetal harm in rats and rabbits when given amphotericin b lipid complex.
• Nystatin (Bio-Statin; Mycostatin; Nilstat; 926). The drug does not appear to cause embryo-fetal harm. Based on published data, the drug can be used at any time in pregnancy.

Breastfeeding

Small amounts of all the above drugs are probably excreted into breast milk if they are used close to breastfeeding. Most can probably be used during breastfeeding, but there are no data for any of these agents. The safest decision is to not use these drugs when breastfeeding.

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

Since March 2020, my colleagues and I have conducted Virtual Rounds at the Center for Women’s Mental Health at Massachusetts General Hospital. It has been an opportunity to review the basic tenets of care for reproductive age women before, during, and after pregnancy, and also to learn of extraordinary cases being managed both in the outpatient setting and in the context of the COVID-19 pandemic.

As I’ve noted in previous columns, we have seen a heightening of symptoms of anxiety and insomnia during the pandemic in women who visit our center, and at the centers of the more than 100 clinicians who join Virtual Rounds each week. These colleagues represent people in rural areas, urban environments, and underserved communities across America that have been severely affected by the pandemic. It is clear that the stress of the pandemic is undeniable for patients both with and without psychiatric or mental health issues. We have also seen clinical roughening in women who have been well for a long period of time. In particular, we have noticed that postpartum women are struggling with the stressors of the postpartum period, such as figuring out the logistics of support with respect to childcare, managing maternity leave, and adapting to shifting of anticipated support systems.

Hundreds of women with bipolar disorder come to see us each year about the reproductive safety of the medicines on which they are maintained. Those patients are typically well, and we collaborate with them and their doctors about the safest treatment recommendations. With that said, women with bipolar disorder are at particular risk for postpartum worsening of their mood. The management of their medications during pregnancy requires extremely careful attention because relapse of psychiatric disorder during pregnancy is the strongest predictor of postpartum worsening of underlying psychiatric illness.

This is an opportunity to briefly review the reproductive safety of treatments for these women. We know through initiatives such as the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications that the most widely used medicines for bipolar women during pregnancy include lamotrigine, atypical antipsychotics, and lithium carbonate.
 

Lamotrigine

The last 15 years have generated the most consistent data on the reproductive safety of lamotrigine. One of the issues, however, with respect to lamotrigine is that its use requires very careful and slow titration and it is also more effective in patients who are well and in the maintenance phase of the illness versus those who are more acutely manic or who are suffering from frank bipolar depression.

Critically, the literature does not support the use of lamotrigine for patients with bipolar I or with more manic symptoms. That being said, it remains a mainstay of treatment for many patients with bipolar disorder, is easy to use across pregnancy, and has an attractive side-effect profile and a very strong reproductive safety profile, suggesting the absence of an increased risk for major malformations.
 

Atypical antipsychotics

We have less information but have a growing body of evidence about atypical antipsychotics. Both data from administrative databases as well a growing literature from pregnancy registries, such as the National Pregnancy Registry for Atypical Antipsychotics, fail to show a signal for teratogenicity with respect to use of the medicines as a class, and also with specific reference to some of the most widely used atypical antipsychotics, particularly quetiapine and aripiprazole. Our comfort level, compared with a decade ago, with using the second-generation antipsychotics is much greater. That’s a good thing considering the extent to which patients presenting on a combination of, for example, lamotrigine and atypical antipsychotics.

Lithium carbonate

Another mainstay of treatment for women with bipolar I disorder and prominent symptoms of mania is lithium carbonate. The data for efficacy of lithium carbonate used both acutely and for maintenance treatment of bipolar disorder has been unequivocal. Concerns about the teratogenicity of lithium go back to the 1970s and indicate a small increased absolute and relative risk for cardiovascular malformations. More recently, a meta-analysis of lithium exposure during pregnancy and the postpartum period supports this older data, which suggests this increased risk, and examines other outcomes concerning to women with bipolar disorder who use lithium, such as preterm labor, low birth weight, miscarriage, and other adverse neonatal outcomes.

In 2021, with the backdrop of the pandemic, what we actually see is that, for our pregnant and postpartum patients with bipolar disorder, the imperative to keep them well, keep them out of the hospital, and keep them safe has often required careful coadministration of drugs like lamotrigine, lithium, and atypical antipsychotics (and even benzodiazepines). Keeping this population well during the perinatal period is so critical. We were all trained to use the least number of medications when possible across psychiatric illnesses. But the years, data, and clinical experience have shown that polypharmacy may be required to sustain euthymia in many patients with bipolar disorder. The reflex historically has been to stop medications during pregnancy. We take pause, particularly during the pandemic, before reverting back to the practice of 25 years ago of abruptly stopping medicines such as lithium or atypical antipsychotics in patients with bipolar disorder because we know that the risk for relapse is very high following a shift from the regimen that got the patient well.

The COVID-19 pandemic in many respects has highlighted a need to clinically thread the needle with respect to developing a regimen that minimizes risk of reproductive safety concerns but maximizes the likelihood that we can sustain the emotional well-being of these women across pregnancy and into the postpartum period.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Since March 2020, my colleagues and I have conducted Virtual Rounds at the Center for Women’s Mental Health at Massachusetts General Hospital. It has been an opportunity to review the basic tenets of care for reproductive age women before, during, and after pregnancy, and also to learn of extraordinary cases being managed both in the outpatient setting and in the context of the COVID-19 pandemic.

As I’ve noted in previous columns, we have seen a heightening of symptoms of anxiety and insomnia during the pandemic in women who visit our center, and at the centers of the more than 100 clinicians who join Virtual Rounds each week. These colleagues represent people in rural areas, urban environments, and underserved communities across America that have been severely affected by the pandemic. It is clear that the stress of the pandemic is undeniable for patients both with and without psychiatric or mental health issues. We have also seen clinical roughening in women who have been well for a long period of time. In particular, we have noticed that postpartum women are struggling with the stressors of the postpartum period, such as figuring out the logistics of support with respect to childcare, managing maternity leave, and adapting to shifting of anticipated support systems.

Hundreds of women with bipolar disorder come to see us each year about the reproductive safety of the medicines on which they are maintained. Those patients are typically well, and we collaborate with them and their doctors about the safest treatment recommendations. With that said, women with bipolar disorder are at particular risk for postpartum worsening of their mood. The management of their medications during pregnancy requires extremely careful attention because relapse of psychiatric disorder during pregnancy is the strongest predictor of postpartum worsening of underlying psychiatric illness.

This is an opportunity to briefly review the reproductive safety of treatments for these women. We know through initiatives such as the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications that the most widely used medicines for bipolar women during pregnancy include lamotrigine, atypical antipsychotics, and lithium carbonate.
 

Lamotrigine

The last 15 years have generated the most consistent data on the reproductive safety of lamotrigine. One of the issues, however, with respect to lamotrigine is that its use requires very careful and slow titration and it is also more effective in patients who are well and in the maintenance phase of the illness versus those who are more acutely manic or who are suffering from frank bipolar depression.

Critically, the literature does not support the use of lamotrigine for patients with bipolar I or with more manic symptoms. That being said, it remains a mainstay of treatment for many patients with bipolar disorder, is easy to use across pregnancy, and has an attractive side-effect profile and a very strong reproductive safety profile, suggesting the absence of an increased risk for major malformations.
 

Atypical antipsychotics

We have less information but have a growing body of evidence about atypical antipsychotics. Both data from administrative databases as well a growing literature from pregnancy registries, such as the National Pregnancy Registry for Atypical Antipsychotics, fail to show a signal for teratogenicity with respect to use of the medicines as a class, and also with specific reference to some of the most widely used atypical antipsychotics, particularly quetiapine and aripiprazole. Our comfort level, compared with a decade ago, with using the second-generation antipsychotics is much greater. That’s a good thing considering the extent to which patients presenting on a combination of, for example, lamotrigine and atypical antipsychotics.

Lithium carbonate

Another mainstay of treatment for women with bipolar I disorder and prominent symptoms of mania is lithium carbonate. The data for efficacy of lithium carbonate used both acutely and for maintenance treatment of bipolar disorder has been unequivocal. Concerns about the teratogenicity of lithium go back to the 1970s and indicate a small increased absolute and relative risk for cardiovascular malformations. More recently, a meta-analysis of lithium exposure during pregnancy and the postpartum period supports this older data, which suggests this increased risk, and examines other outcomes concerning to women with bipolar disorder who use lithium, such as preterm labor, low birth weight, miscarriage, and other adverse neonatal outcomes.

In 2021, with the backdrop of the pandemic, what we actually see is that, for our pregnant and postpartum patients with bipolar disorder, the imperative to keep them well, keep them out of the hospital, and keep them safe has often required careful coadministration of drugs like lamotrigine, lithium, and atypical antipsychotics (and even benzodiazepines). Keeping this population well during the perinatal period is so critical. We were all trained to use the least number of medications when possible across psychiatric illnesses. But the years, data, and clinical experience have shown that polypharmacy may be required to sustain euthymia in many patients with bipolar disorder. The reflex historically has been to stop medications during pregnancy. We take pause, particularly during the pandemic, before reverting back to the practice of 25 years ago of abruptly stopping medicines such as lithium or atypical antipsychotics in patients with bipolar disorder because we know that the risk for relapse is very high following a shift from the regimen that got the patient well.

The COVID-19 pandemic in many respects has highlighted a need to clinically thread the needle with respect to developing a regimen that minimizes risk of reproductive safety concerns but maximizes the likelihood that we can sustain the emotional well-being of these women across pregnancy and into the postpartum period.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Since March 2020, my colleagues and I have conducted Virtual Rounds at the Center for Women’s Mental Health at Massachusetts General Hospital. It has been an opportunity to review the basic tenets of care for reproductive age women before, during, and after pregnancy, and also to learn of extraordinary cases being managed both in the outpatient setting and in the context of the COVID-19 pandemic.

As I’ve noted in previous columns, we have seen a heightening of symptoms of anxiety and insomnia during the pandemic in women who visit our center, and at the centers of the more than 100 clinicians who join Virtual Rounds each week. These colleagues represent people in rural areas, urban environments, and underserved communities across America that have been severely affected by the pandemic. It is clear that the stress of the pandemic is undeniable for patients both with and without psychiatric or mental health issues. We have also seen clinical roughening in women who have been well for a long period of time. In particular, we have noticed that postpartum women are struggling with the stressors of the postpartum period, such as figuring out the logistics of support with respect to childcare, managing maternity leave, and adapting to shifting of anticipated support systems.

Hundreds of women with bipolar disorder come to see us each year about the reproductive safety of the medicines on which they are maintained. Those patients are typically well, and we collaborate with them and their doctors about the safest treatment recommendations. With that said, women with bipolar disorder are at particular risk for postpartum worsening of their mood. The management of their medications during pregnancy requires extremely careful attention because relapse of psychiatric disorder during pregnancy is the strongest predictor of postpartum worsening of underlying psychiatric illness.

This is an opportunity to briefly review the reproductive safety of treatments for these women. We know through initiatives such as the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications that the most widely used medicines for bipolar women during pregnancy include lamotrigine, atypical antipsychotics, and lithium carbonate.
 

Lamotrigine

The last 15 years have generated the most consistent data on the reproductive safety of lamotrigine. One of the issues, however, with respect to lamotrigine is that its use requires very careful and slow titration and it is also more effective in patients who are well and in the maintenance phase of the illness versus those who are more acutely manic or who are suffering from frank bipolar depression.

Critically, the literature does not support the use of lamotrigine for patients with bipolar I or with more manic symptoms. That being said, it remains a mainstay of treatment for many patients with bipolar disorder, is easy to use across pregnancy, and has an attractive side-effect profile and a very strong reproductive safety profile, suggesting the absence of an increased risk for major malformations.
 

Atypical antipsychotics

We have less information but have a growing body of evidence about atypical antipsychotics. Both data from administrative databases as well a growing literature from pregnancy registries, such as the National Pregnancy Registry for Atypical Antipsychotics, fail to show a signal for teratogenicity with respect to use of the medicines as a class, and also with specific reference to some of the most widely used atypical antipsychotics, particularly quetiapine and aripiprazole. Our comfort level, compared with a decade ago, with using the second-generation antipsychotics is much greater. That’s a good thing considering the extent to which patients presenting on a combination of, for example, lamotrigine and atypical antipsychotics.

Lithium carbonate

Another mainstay of treatment for women with bipolar I disorder and prominent symptoms of mania is lithium carbonate. The data for efficacy of lithium carbonate used both acutely and for maintenance treatment of bipolar disorder has been unequivocal. Concerns about the teratogenicity of lithium go back to the 1970s and indicate a small increased absolute and relative risk for cardiovascular malformations. More recently, a meta-analysis of lithium exposure during pregnancy and the postpartum period supports this older data, which suggests this increased risk, and examines other outcomes concerning to women with bipolar disorder who use lithium, such as preterm labor, low birth weight, miscarriage, and other adverse neonatal outcomes.

In 2021, with the backdrop of the pandemic, what we actually see is that, for our pregnant and postpartum patients with bipolar disorder, the imperative to keep them well, keep them out of the hospital, and keep them safe has often required careful coadministration of drugs like lamotrigine, lithium, and atypical antipsychotics (and even benzodiazepines). Keeping this population well during the perinatal period is so critical. We were all trained to use the least number of medications when possible across psychiatric illnesses. But the years, data, and clinical experience have shown that polypharmacy may be required to sustain euthymia in many patients with bipolar disorder. The reflex historically has been to stop medications during pregnancy. We take pause, particularly during the pandemic, before reverting back to the practice of 25 years ago of abruptly stopping medicines such as lithium or atypical antipsychotics in patients with bipolar disorder because we know that the risk for relapse is very high following a shift from the regimen that got the patient well.

The COVID-19 pandemic in many respects has highlighted a need to clinically thread the needle with respect to developing a regimen that minimizes risk of reproductive safety concerns but maximizes the likelihood that we can sustain the emotional well-being of these women across pregnancy and into the postpartum period.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].