'Reassuring' Findings for Second-Generation Antipsychotics During Pregnancy 

Batya Swift Yasgur, MA, LSW

August 17, 2021

Second-generation antipsychotics (SGAs) taken by pregnant women are linked to a low rate of adverse effects in their children, new research suggests.

Data from a large registry study of almost 2000 women showed that 2.5% of the live births in a group that had been exposed to antipsychotics had confirmed major malformations compared with 2% of the live births in a non-exposed group. This translated into an estimated odds ratio (OR) of 1.5 for major malformations.

"The 2.5% absolute risk for major malformations is consistent with the estimates of the Centers for Disease Control and Prevention's national baseline rate of major malformations in the general population," lead author Adele Viguera, MD, MPH, director of research for women's mental health, Cleveland Clinic Neurological Institute, Cleveland, Ohio, told Medscape Medical News.

"Our results are reassuring and suggest that second-generation antipsychotics, as a class, do not substantially increase the risk of major malformations," Viguera said.

The findings were published online August 3 in the Journal of Clinical Psychiatry.

Safety Data Scarce

Despite the increasing use of SGAs to treat a "spectrum of psychiatric disorders," relatively little data are available on the reproductive safety of these agents, Viguera said.

The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established in 2008 to determine risk for major malformation among infants exposed to these medications during the first trimester, relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.

The NPRAA follows pregnant women (aged 18 to 45 years) with psychiatric illness who are exposed or unexposed to SGAs during pregnancy. Participants are recruited through nationwide provider referral, self-referral, and advertisement through the Massachusetts General Hospital Center for Women's Mental Health website.

The women are interviewed by phone at three timepoints: enrollment, 7 months, and 3 months postpartum. Specific data collected are shown in the following table.

Table. Data Collected at Each Timepoint

Interview Information Collected
Initial ·      Demographics

·      Medication use

·      Dosage change (if relevant)

·      Social habits (smoking, alcohol, illicit drug use)

·      Medical/psychiatric history

·      Family history of birth defects

7 months ·      Changes in dosage/medication (if any)

·      Intervening medical problems

Postpartum ·      Pharmacotherapy

·      Labor/delivery

·      Neonatal health outcomes


The researchers also obtained outcome data through systematic review of obstetric, labor, delivery, and pediatric medical records.

Since publication of the first results in 2015, the sample size for the trial has increased — and the absolute and relative risk for major malformations observed in the study population are "more precise," the investigators note. The current study presented updated previous findings.

Demographic Differences

Of the 1906 women who enrolled as of April 2020, 1311 (mean age, 32.6 years; 81.3% White) completed the study and were eligible for inclusion in the analysis.

Although the groups had a virtually identical mean age, fewer women in the exposure group were married compared with those in the non-exposure group (77% vs 90%, respectively); and fewer had a college education (71.2% vs 87.8%). There was also a higher percentage of first-trimester cigarette smokers in the exposure group (18.4% vs 5.1%).

On the other hand, more women in the non-exposure group used alcohol than in the exposure group (28.6% vs 21.4%, respectively).

The most frequent psychiatric disorder in the exposure group was bipolar disorder (63.9%), followed by major depression (12.9%), anxiety (5.8%), and schizophrenia (4.5%). Only 11.4% of women in the non-exposure group were diagnosed with bipolar disorder, whereas 34.1% were diagnosed with major depression, 31.3% with anxiety, and none with schizophrenia.

Notably, a large percentage of women in both groups had a history of postpartum depression and/or psychosis (41.4% and 35.5%, respectively).

The most frequently used SGAs in the exposure group were quetiapine (Seroquel), aripiprazole (Abilify), and lurasidone (Latuda).

Participants in the exposure group had a higher age at initial onset of primary psychiatric diagnosis and a lower proportion of lifetime illness compared with those in the non-exposure group.

Major Clinical Implication?

Among 640 live births in the exposure group, which included 17 twin pregnancies and 1 triplet pregnancy, 2.5% reported major malformations. Among 704 live births in the control group, which included 14 twin pregnancies, 1.99% reported major malformations.

The estimated OR for major malformations comparing exposed and unexposed infants was 1.48 (95% CI, 0.625 - 3.517).

The authors note that their findings were consistent with one of the largest studies to date, which included a nationwide sample of more than 1 million women. Its results showed that, among infants exposed to SGAs vs those who were not exposed, the estimated risk ratio after adjusting for psychiatric conditions was 1.05 (95% CI, 0.96 - 1.16).

Additionally, "a hallmark of a teratogen is that it tends to cause a specific type or pattern of malformations, and we found no preponderance of one single type of major malformation or specific pattern of malformations among the exposed and unexposed groups," Viguera said

"A major clinical implication of these findings is that for women with major mood and/or psychotic disorders, treatment with an atypical antipsychotic during pregnancy may be the most prudent clinical decision, much as continued treatment is recommended for pregnant women with other serious and chronic medical conditions, such as epilepsy," she added.

The Concept of "Satisficing"

Commenting on the study for Medscape Medical News, Vivien Burt, MD, PhD, founder and director/consultant of the Women's Life Center at the Resnick UCLA Neuropsychiatric Hospital, Los Angeles, California, called the findings "reassuring."

The results "support the conclusion that in pregnant women with serious psychiatric illnesses, the use of SGAs is often a better option than avoiding these medications and exposing both the women and their offspring to the adverse consequences of maternal mental illness," she said.

An accompanying editorial co-authored by Burt and colleague Sonya Rasminsky, MD, introduced the concept of "satisficing" — a term coined by Herbert Simon, a behavioral economist and Nobel Laureate. "Satisficing" is a "decision-making strategy that aims for a satisfactory ('good enough') outcome rather than a perfect one."

The concept applies to decision-making beyond the field of economics "and is critical to how physicians help patients make decisions when they are faced with multiple treatment options," said Burt, a professor emeritus of psychiatry at UCLA's David Geffen School of Medicine.

"The goal of 'satisficing' is to plan for the most satisfactory outcome, knowing that there are always unknowns, so in an uncertain world, clinicians should carefully help their patients make decisions that will allow them to achieve an outcome they can best live with," she noted.

The investigators note that their findings may not be generalizable to the larger population of women taking SGAs, given that their participants were "overwhelmingly White, married, and well-educated women."

They add that enrollment into the NPRAA registry is ongoing and larger sample sizes will "further narrow the confidence interval around the risk estimates and allow for adjustment of likely sources of confounding."

The NPRAA is supported by Alkermes, Johnson & Johnson/Janssen Pharmaceuticals, Inc, Otsuka America Pharmaceutical, Inc, Sunovion Pharmaceuticals, Inc, SAGE Therapeutics, Teva Pharmaceuticals, and Aurobindo Pharma. Past sponsors of the NPRAA are listed in the original paper.

Viguera receives research support from the NPRAA, Alkermes Biopharmaceuticals, Aurobindo Pharma, Janssen Pharmaceuticals, Otsuka Pharmaceuticals, Sunovion Pharmaceuticals, Inc, Teva Pharmaceuticals, and SAGE Therapeutics, Inc and receives advisor/consulting fees from Up-to-Date. The other authors' disclosures are listed in the original paper. Burt has been a consultant/speaker for Sage Therapeutics. Rasminsky has disclosed no relevant financial relationships.

J Clin Psychiatry. Published online August 3, 2021. Full text, Editorial

For more Medscape Psychiatry news, join us on Twitter and Facebook


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.