Risk of Major Malformations Following First-Trimester Quetiapine Exposure

November 22, 2018

Study findings suggest that quetiapine is not a major teratogen, but the risk of malformations must be considered in the context of therapeutic risk-benefit balance.

In 2008, the National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established at Massachusetts General Hospital to systematically gather post-marketing reproductive safety data for second-generation antipsychotics (SGAs). Presently available data do not suggest that SGAs as a class are major teratogens, nor has a specific pattern of malformations associated with exposure to these agents been identified. Quetiapine is the most commonly prescribed SGA, and therefore an understanding of its reproductive safety profile from rigorously designed cohort studies is critical.1

Cohen and colleagues2 determined the risk of major malformations among infants exposed to quetiapine during pregnancy compared with a group of infants whose mothers had a history of psychiatric morbidity but who did not use a second-generation antipsychotic during pregnancy. Pregnant women aged 18 to 45 years with a history of psychiatric illness were enrolled. Participants were systematically interviewed at enrollment, at 7 months’ gestation, and at 12 weeks’ postpartum, and provided consent to the release of obstetric and pediatric records. Data from interviews and medical records were abstracted using a standardized outcome template. Redacted records of suspected major malformations were sent to a dysmorphologist for final blind adjudication, to rule out chromosomal, single-gene, and minor anomalies.

Baseline demographic and clinical characteristics were compared between quetiapine-exposed and control groups. The exposure of interest was defined as use of quetiapine during the first trimester of pregnancy (<13 weeks gestational age). The comparison group comprised women with psychiatric disorders who did not use SGAs during pregnancy (but may have used other psychotropic medications). The primary outcome measure was the presence of a major malformation-defined as a structural abnormality with surgical, medical, or cosmetic importance-identified within 6 months of birth. The researchers used unconditional logistic regression to estimate the odds for major malformations between groups, controlling for potential confounding factors.

Between 2008 and 2017, 888 women were enrolled in the registry, of whom 357 had evaluable data and first-trimester SGA exposure; 152 of these women used quetiapine during the first trimester, resulting in 155 live births (3 sets of twins). A total of 205 control women with evaluable data had 210 live births (5 sets of twins). Medical records were reviewed for 88% of participants. Mean age was 33, and mean baseline BMI was 26. Women exposed to quetiapine were more likely to have a diagnosis of bipolar disorder, and unexposed women were more likely to have a diagnosis of either depression or anxiety. Some women in the exposed group (83%) used quetiapine throughout pregnancy.

The prevalence of major malformations was 1.3% among infants with first trimester quetiapine exposure and 1.4% among infants unexposed to SGAs. Two major malformations were reported among infants with quetiapine exposure: transposition of the great arteries, and pulmonary stenosis due to dysplastic pulmonary valve. Three malformations were reported in the control group: midshaft hypospadias, isolated cleft lip and palate, and thickened pulmonary valve associated with mild pulmonary stenosis. The unadjusted odds ratio of major malformations in infants with first trimester quetiapine exposure was 0.90 (95% confidence interval 0.15-5.46, P=.91). Maternal BMI moved the odds ratio downward (OR=.77), and use of anticonvulsants moved the odds ratio upward (OR=1.36).

The bottom line

Findings from the study suggest that quetiapine is not a major teratogen. However, the results can rule out only an approximately 5-fold increased risk of major malformations (comparable to that seen with medications such as valproate). They note that risk of malformations must be considered in the context of therapeutic risk-benefit balance.

The strengths of the study include the prospective design, inclusion of a psychiatric control group, and careful collection of potential confounding factors. Limitations include the relatively modest number of participants exposed to quetiapine, which contributed to wide confidence intervals.

The findings are consistent with existing evidence, which does not suggest a strong association between fetal exposure to SGAs and risk of major malformations.


1. Park Y, Huybrechts KF, Cohen JM, et al. Antipsychotic medication use among publicly insured pregnant women in the United States. Psychiatr Serv. 2017;68:1112-1119.

2. Cohen LS, Goez-Mogollon L, Sosinsky AZ. Risk of major malformations in infants following first-trimester exposure to quetiapine. Am J Psychiatry. August 2018; Epub ahead of print. 

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