Antidepressant use in pregnancy and severe cardiac malformations: Danish register-based study


Kolding L, Ehrenstein V, Pedersen L, Sandager P, Petersen OB, Uldbjerg N, Pedersen LH.BJOG. 2021 Nov;128(12):1949-1957. doi: 10.1111/1471-0528.16772. Epub 2021 Jun 22. PMID: 34036715


Take Home Message

  • This is a nation-wide registry study in Denmark of the association of antidepressant use in the first trimester of pregnancy with the development of congenital heart disease.
  • The use of antidepressants in the first trimester results in a prevalence of cardiac malformations in 12/1000 pregnancies.
  • The use of SSRIs in the first trimester of pregnancy may increase the risk for non-severe cardiac malformations but NOT of severe cardiac malformations, while the use of venlafaxine (a SNRI) in the first trimester increases the risk for severe cardiac malformations and specifically HLHS 17-fold, although the risk is still low (4.4/1000).
  • The risk of severe malformations may be underestimated in studies that only involve live births, as termination is not accounted for.

Commentary from Dr. Anna Tsirka (Hartford, CT, USA), section editor of Pediatric and Fetal Cardiology Journal Watch


Depression is a very common comorbidity in pregnancy, affecting 6-15% of pregnant women. Antidepressants are commonly prescribed in pregnancy. The most commonly prescribed agents are selective serotonin reuptake inhibitors (SSRIs) followed by serotonin-norepinephrine reuptake inhibitors (SNRIs).

Serotonin is a signaling molecule involved in embryogenesis. Several studies have shown increased incidence of septal defects, RVOT abnormalities and Ebstein’s anomalies in liveborn infants, while little is known about the effects of SNRIs in the development of CHD.

All studies investigating these effects to date are limited to live births.

The current study evaluates the association between first trimester use of SSRIs and SNRis and risk of cardiac malformations among clinically recognized pregnancies over 11 weeks, regardless of survival.



This was a prevalence study based on routinely collected data from nationwide registries in Denmark that register pregnancies, terminations, deliveries, malformations diagnosed both prenatally and postnatally and prescriptions. The study population included all pregnancies alive at 11 weeks between November of 2007 and February of 2014. The individuals were categorized in 3 groups in terms of exposure to antidepressants: unexposed, exposed and former users. Medications were classified as any antidepressant, SSRI, SNRI, tricyclic antidepressants (TCA) and other.



Of 364012 singleton pregnancies, 1.1% of pregnant women had exposure to antidepressants in the first trimester using the criterion of at least 2 filled prescriptions, while 3.2% based on at least one filled prescription. The prevalence of former use of antidepressants without use during the pregnancy was 1.8%.

The prevalence of cardiac malformations (CM), both severe (SCM) and non-severe (non-SCM) among 1st trimester users of antidepressants was 12/1000. Among the SCM, 24 % were terminated, and would not have been captured in studies of live births.

The prevalence rate (PR) of SCM in pregnancies exposed to any antidepressant (AD) adjusted for all other variables evaluated was 1.31 (95% CI 0.78–2.22). The PR was 2.13 (95% CI 0.89–5.13) for exposure to venlafaxine, and 1.09 (95% CI 0.52–2.30) for SSRIs . Venlafaxine (SNRI) the majority of exposed cases represented HLHS, with a crude PR of 17.4 (95% CI 6.41–47.2) and an absolute risk of 4.4/1000 (95% CI 0.2 to 9.1/1000).

The fully adjusted PRs for non-SCM were 1.65 (95% CI 1.31–2.08) for any antidepressant, 1.38 (95% CI 1.00–1.92) for SSRIs, and 1.73 (95% CI 1.08–2.77) for venlafaxine.

As venlafaxine resulted in a significant increase in the development of HLHS, and those fetuses were more likely to be aborted in Denmark, the association would not have been evident if only live births were evaluated. A typical analysis restricted to live births yielded the PRs for venlafaxine 0.62 (95% CI 0.09–4.40) and for SSRIs 1.87 (95% CI 1.00–3.48).

The number needed to harm (NNH) for venlafaxine was 307 for SCM and 225 for HLHS. For non-SCM, the NNH was 162 for SSRI and 90 for venlafaxine.





First trimester exposure to antidepressants is associated with a 30% increase in severe cardiac malformations, and a 65% increase in the prevalence of non-severe cardiac malformations. Specifically, SSRIs were associated with increase in non-SCM, while venlafaxine increases the prevalence of SCM and especially HLHS with a PR of over 17. It is important to note however that still the absolute risk is low at 4.4/1000 and risk and benefit should be taken into consideration when treatment decisions are being made. Given the high termination rate in the Danish population of fetuses with HLHS, this association would not have been discovered in a study evaluating only live births.