First Trimester Antipsychotic Exposure and Pregnancy Outcomes

Will it hurt my baby? Researchers investigated associations between first trimester exposure to second-generation antipsychotics and major congenital malformations.

CASE VIGNETTE

“Ms James” is a 23-year-old African-American female with a 5-year history of schizophrenia. She is currently stable on a second-generation antipsychotic medication, with no hospitalizations in the past 4 years. Her BMI is normal. She does not smoke, drink alcohol, or use illicit drugs. She sees her outpatient psychiatrist every 3 months. Two months after her last appointment, she calls the clinic because she is 9 weeks pregnant. She asks whether it is safe for the baby to continue her current second-generation antipsychotic medication. She also informs the nurse that when she briefly stopped this medication in the past, she experienced an increase in paranoia as well as suicidal ideation. As her psychiatrist, how would you advise and manage this patient?

Untreated perinatal psychotic disorders can have a range of serious adverse effects on the physical and mental health of women and their children.1 Untreated or inadequately treated maternal psychosis is also a risk factor for maternal suicide.2 There is evidence for increased use of second-generation antipsychotics (SGAs) during pregnancy.3 The association between maternal SCA exposure and risk of congenital malformations is unclear, with both negative4-6 and positive7,8 studies. No previous studies have investigated this association in Asian patients.

The Current Study

Yakuwa and colleagues9 investigated the association between first-trimester antipsychotic exposure and major congenital malformations in Japan. The authors studied pregnant women who had accessed the Japan Drug Information Institute in Pregnancy between October 2005 and December 2016 and consented to a pregnancy outcome survey (prepaid mailer) 1 month after the expected date of delivery. They included only women with singleton pregnancies; women with multifetal pregnancies were excluded.

Background demographic and clinical characteristics were obtained. Women self-reported medical diagnoses. Timing of SGA exposure was based on the last menstrual period (estimated from gestational age at delivery and the survey date). The SGA group consisted of women with exposure to at least 1 SGA during the first trimester. The comparison group consisted of women with no exposure to any known teratogens. Women with SGA use before pregnancy or during the second or third trimesters were excluded.

The primary study outcomes were live birth rate and the rate of major congenital malformations. Elective abortions were a secondary outcome. Malformations were diagnosed by pediatricians during the 1-month medical examination and recorded in maternal and child health handbooks, which are given to all pregnant women in Japan. Data were analyzed using logistic regression, and adjustment for potential confounders by inverse probability weighting.

During the study period, 7249 women were enrolled, of whom 593 had first-trimester SGA exposure; 520 (885) of these women and 5139 (90%) of control women consented to the pregnancy outcome survey, which was completed by 404 (78%) in the SGA group and 4328 (84%) in the control group. The most common SGAs were aripiprazole (n=147), quetiapine (n=91), olanzapine (n=83), and risperidone (n=71). The SGA group had a higher percentage of primiparas, preconception BMI, maternal diabetes (3% vs 1%), and smoking (24% vs 14%). After becoming aware of pregnancy, more women in the SGA group continued to smoke (10% vs 4%). The prevalence of illicit drug use was <0.25% in both groups. The prevalence of occupational exposures to radiation or organic solvents was <1.3% in both groups.

The live birth rate was 87% in the SGA group and 90% in the control group. Major congenital malformation occurred in 0.9% of live births (3/351) in the SGA group and 1.8% (70/3899) in the control group, which was not statistically significant. The malformations in the SGA group were right hydronephrosis, complex malformation, spina bifida, and hydrocephalus. Six children in the SGA group had minor congenital malformations (hemangioma, patent foramen ovale, inguinal hernia [2], hydrocele, and hypertrophic pyloric stenosis). The elective abortion rate was non-significantly higher in the SGA group (4% vs 2%).

Study Conclusions

The authors concluded that SGA exposure during the first trimester was not associated with increased risk of major congenital malformations in Japan. Study strengths include that this was the first Japanese observational cohort study of this association, and findings were consistent with studies from several other countries. Limitations included the absence of data on maternal diagnosis or illness severity and the lower rate of survey completion in the SGA group (which could lead to an underestimation of risk), and the higher prevalence of elective abortions in the SGA group (potentially due to malformations).

The Bottom Line

This study did not find evidence for an association between first-trimester SGA exposure and risk of major congenital malformations. Findings provide some reassurance for pregnant women who require these medications.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Jones I, Chandra PS, Dazzan P, Howard LM. Bipolar disorder, affective psychosis, and schizophrenia in pregnancy and the post-partum periodLancet. 2014;384(9956):1789-1799.

2. Orsolini L, Valchera A, Vecchiotti R, et al. Suicide during perinatal period: epidemiology, risk factors, and clinical correlatesFront Psychiatry. 2016;7:138.

3. Reutfors J, Cesta CE, Cohen JM, et al. Antipsychotic drug use in pregnancy: a multinational study from ten countriesSchizophr Res. 2020;220:106-115.

4. Viguera AC, Freeman MP, Góez-Mogollón L, et al. Reproductive safety of second-generation antipsychotics: updated data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics [published correction appears in J Clin Psychiatry. 2021 Oct 5;5(82):]. J Clin Psychiatry. 2021;82(4):20m13745.

5. Huybrechts KF, Hernández-Díaz S, Patorno E, et al. Antipsychotic use in pregnancy and the risk for congenital malformationsJAMA Psychiatry. 2016;73(9):938-946.

6. McKenna K, Koren G, Tetelbaum M, et al. Pregnancy outcome of women using atypical antipsychotic drugs: a prospective comparative studyJ Clin Psychiatry. 2005;66(4):444-546.

7. Habermann F, Fritzsche J, Fuhlbrück F, et al. Atypical antipsychotic drugs and pregnancy outcome: a prospective, cohort studyJ Clin Psychopharmacol. 2013;33(4):453-462.

8. Kulkarni J, Worsley R, Gilbert H, et al. A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babiesPLoS One. 2014;9(5):e94788.

9. Yakuwa N, Takahashi K, Anzai T, et al. Pregnancy outcomes with exposure to second-generation antipsychotics during the first trimesterJ Clin Psychiatry. 2022;83(4):21m14081.