The Table shows the various published studies of the potential association of PPHN with maternal use of an antidepressant during the pregnancy. The studies variably controlled statistically for some potential confounders. For example, while one study controlled for maternal diabetes, race, BMI, and date of birth, another controlled for high maternal age, first parity, maternal BMI, maternal smoking, and year of birth.1,3 Unfortunately, none of the studies took all possible confounding factors into account. Apparent risk factors for PPHN include male sex, black or Asian race, high pre-pregnancy BMI, high infant weight, cesarean section, maternal diabetes or asthma, and maternal use of aspirin(Drug information on aspirin) and NSAIDs.10,11 It is therefore possible that some or all of the apparent association between antidepressant use during pregnancy and PPHN is a result of these confounding factors (or other, unknown confounding factors) that were not adequately controlled for.
In its notification of December 2011, the FDA referred to various studies, all of which had very few patients with PPHN.1,3-5,8,9 The FDA data summary did not include 2 more recently published large cohort studies that did find an association between the use of SSRIs and PPHN.6,7 All 4 of the studies with a substantial number of infants with PPHN found a statistically significant association between maternal use of antidepressants and PPHN in the infant.1,3,6,7 The results of the 3 studies with only a few infants with PPHN showed no statistically significant association.4,5,8 This illustrates the main point of this article: for rare outcomes, either a very large number of subjects must be studied in a cohort study or a case-control study that starts with an adequate number of cases must be used.
Translation for clinical practice
Finally, a few brief comments about issues that are not the focus of this column but are important. It is essential to keep in mind that the risk of PPHN in infants of mothers treated with serotonergic antidepressants during pregnancy, even if real, is quite small: the risk is about 0.05% to 0.1%.3,6,7 It appears that the risk is greater with antidepressant use during late pregnancy but may be elevated with use during early pregnancy as well.
No significant differences were found between the various SSRIs regarding risk of PPHN.6 While one study suggests that non-SSRI antidepressants may not be associated with increased risk of PPHN, the power of the study to detect such effects was limited and this finding has not been verified.1 Tricyclic antidepressants have been associated with higher rates of congenital malformations and a variety of neonatal complications.6 Thus, these agents are not recommended as alternatives to SSRIs in pregnant women.
Untreated mental disorders (eg, MDD) may also have negative consequences for the pregnancy, although this has not been well studied. From data on groups of patients, it is hard to predict for a particular patient what the risk of not treating with an antidepressant will be. Some patients may not exhibit behaviors that can mediate the effect of depression or other mental disorders on pregnancy outcomes; it is not clear whether the depression will lead to poor outcomes for the fetuses or neonates in these cases.
Do not assume that antidepressants are effective for all patients with MDD or that an effective treatment is being withheld; only a minority of patients are likely to have a true antidepressant response. Lastly, withholding treatment is not the only alternative to using a serotonergic antidepressant in a pregnant woman. Bupropion may be safer, and psychotherapy may be a viable alternative treatment for many patients.