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Abstract

Background: In 2005, the FDA cautioned that exposure to paroxetine, a selective serotonin reuptake inhibitor (SSRI), during the first trimester of pregnancy may increase the risk of cardiac malformations. Since then, the association between maternal use of SSRIs during pregnancy and congenital malformations in infants has been the subject of much discussion and controversy. The aim of this study is to systematically review the associations between SSRIs use during early pregnancy and the risk of congenital malformations, with particular attention to the potential confounding by indication.

Methods: The study protocol was registered with PROSPERO (CRD42018088358). Cohort studies on congenital malformations in infants born to mothers with first-trimester exposure to SSRIs were identified via PubMed, Embase, Web of Science, and the Cochrane Library databases through 17 January 2018. Random-effects models were used to calculate summary relative risks (RRs).

Results: Twenty-nine cohort studies including 9,085,954 births were identified. Overall, use of SSRIs was associated with an increased risk of overall major congenital anomalies (MCAs, RR 1.11, 95% CI 1.03 to 1.19) and congenital heart defects (CHD, RR 1.24, 95% CI 1.11 to 1.37). No significantly increased risk was observed when restricted to women with a psychiatric diagnosis (MCAs, RR 1.04, 95% CI 0.95 to 1.13; CHD, RR 1.06, 95% CI 0.90 to 1.26). Similar significant associations were observed using maternal citalopram exposure (MCAs, RR 1.20, 95% CI 1.09 to 1.31; CHD, RR 1.24, 95% CI 1.02 to 1.51), fluoxetine (MCAs, RR 1.17, 95% CI 1.07 to 1.28; CHD, 1.30, 95% CI 1.12 to 1.53), and paroxetine (MCAs, RR 1.18, 95% CI 1.05 to 1.32; CHD, RR 1.17, 95% CI 0.97 to 1.41) and analyses restricted to using women with a psychiatric diagnosis were not statistically significant. Sertraline was associated with septal defects (RR 2.69, 95% CI 1.76 to 4.10), atrial septal defects (RR 2.07, 95% CI 1.26 to 3.39), and respiratory system defects (RR 2.65, 95% CI 1.32 to 5.32).

Conclusions: The evidence suggests a generally small risk of congenital malformations and argues against a substantial teratogenic effect of SSRIs. Caution is advisable in making decisions about whether to continue or stop treatment with SSRIs during pregnancy.

Keywords: Antidepressant; Cohort studies; Congenital malformations; Meta-analysis; Pregnancy; Serotonin uptake inhibitors.

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Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
PRISMA of evidence search and selection for SSRIs use in early pregnancy and congenital malformations
Fig. 2
Fig. 2
Risk of congenital malformations in infants, according to maternal exposure to SSRIs. Relative risks and 95% confidence intervals are presented to show the risk of congenital malformations among infants born to women with exposure to SSRIs during the first trimester, as compared with the risk among infants born to women in the general population without such exposure. SSRIs, selective serotonin reuptake inhibitors
Fig. 3
Fig. 3
Risk of major congenital anomalies in infants, according to maternal exposure to SSRIs. Relative risks and 95% confidence intervals are presented to show the risk of major congenital anomalies among infants born to women with exposure to SSRIs during the first trimester, as compared with the risk among infants born to women without such exposure. SSRIs, selective serotonin reuptake inhibitors
Fig. 4
Fig. 4
Risk of congenital heart defects in infants, according to maternal exposure to SSRIs. Relative risks and 95% confidence intervals are presented to show the risk of congenital heart defects among infants born to women with exposure to SSRIs during the first trimester, as compared with the risk among infants born to women without such exposure. SSRIs, selective serotonin reuptake inhibitors
Fig. 5
Fig. 5
Risk of septal defects in infants, according to maternal exposure to SSRIs. Relative risks and 95% confidence intervals are presented to show the risk of septal defects among infants born to women with exposure to SSRIs during the first trimester, as compared with the risk among infants born to women in the general population without such exposure. SSRIs, selective serotonin reuptake inhibitors
See this image and copyright information in PMC

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