The final study population comprised 496
881 liveborn singletons. For these children, 1370 mothers had two or more redemptions for individual SSRIs in the exposure window. These pregnancies were regarded as exposed. In keeping with a previous study,8
women taking an SSRI were more likely to be older, living alone, unmarried, and smokers (data not shown).
The combined prevalence of major malformations (odds ratio 1.21, 95% confidence interval 0.91 to 1.62) or non-cardiac malformations (1.12, 0.79 to 1.59) was not significantly higher among exposed children, but SSRI use was associated with an increased prevalence of septal heart defects (1.99, 1.13 to 3.53) (table 1).
Table 1 Odds ratios for malformations according to two or more redemptions for selective serotonin reuptake inhibitors (SSRIs)
No specific SSRI was significantly associated with major malformations overall or non-cardiac malformations (table 2). There was an increased prevalence of septal heart defects for children of women who used sertraline (3.25, 1.21 to 8.75) and citalopram (2.52, 1.04 to 6.10), but not fluoxetine (1.34, 0.33 to 5.41). Among the 299 exposed to paroxetine we found one septal heart malformation (crude odds ratio 0.76). Redemption of more than one type of SSRI in the exposure window was associated with heart malformations (3.42, 1.40 to 8.34), particularly septal heart defects (4.70, 1.74 to 12.7) (table 2).
Table 2 Odds ratios for malformations according to two or more prescriptions for individual selective serotonin reuptake inhibitors (SSRIs)*
In women with no recorded use of antidepressants, 1.2% redeemed a prescription for psychotropic medication, compared with 16% of women who had been prescribed an SSRI. The estimates remained virtually unchanged, however, when these women were included in the analyses—for example, SSRI use was still associated with septal heart defects (2.00, 1.41 to 2.85).
We found 84 women with two or more redemptions for tricyclic antidepressants and 91 for venlafaxine in the exposure window. The numbers were too small to allow for informative adjusted analyses—for instance, we found three major malformations among the children exposed to tricyclic antidepressants (crude odds ratio 1.14, 0.23 to 3.45) and one among those exposed to venlafaxine (0.35).
In subanalyses, we included women with one or more redemptions for antidepressants. We found that 3010 women redeemed one or more SSRI, 265 for tricyclic antidepressants, and 150 for venlafaxine. None of the antidepressants were associated with the combined prevalence of major malformations with the less strict exposure definition (see table A on bmj.com). Septal heart defects were associated with any SSRI use (1.83, 1.22 to 2.75), in particular citalopram (2.16, 1.12 to 4.17) and sertraline (2.01, 0.83 to 4.86), albeit the estimates of sertraline did not reach significance (see table B on bmj.com). In eight women prescribed fluvoxamine there were no reported malformations. Again, the numbers were too small to allow investigation of associations between tricyclic antidepressants or venlafaxine and specific malformations (table A on bmj.com).
Analyses excluding information on smoking had comparable results—for example, septal heart malformations were associated with sertraline (3.18, 1.18 to 8.56) and more than one SSRI (4.45, 1.65 to 12.0), but the confidence interval for citalopram included zero (2.36, 0.98 to 5.71).
Follow-up of the children for two years after birth with regards to congenital malformation resulted in similar results to the one year follow-up—for example, an odds ratio of 1.70 (1.13 to 2.55) for SSRI and septal heart malformations.
As expected, the absolute differences in prevalence of birth defects were limited. We found septal heart defects in 12 (0.9%) children of women with one or more redemption of SSRI, four (2.1%) children of women who redeemed more than one type of SSRI (2.1%), and 2315 (0.5%) children of unexposed women. The prevalence of septal heart defects among the children exposed to a specific SSRI was 0.6% for fluoxetine, 1.1% for citalopram, and 1.5% for sertraline (table 2). Thus, the prevalence of septal heart defects was 0.4 percentage points higher for children of women with one or more redemption of SSRI compared with children of unexposed women, corresponding to a number needed to treat to harm (NNH) of 246. The corresponding number for children of women who redeemed more than one type of SSRI was 62.