The PPHN story has been a bit of a rollercoaster. Just to review…
- The first report came in 2006 when Chambers and colleagues published an article linking selective serotonin reuptake inhibitor (SSRI) antidepressant use during late pregnancy to an increased risk of persistent pulmonary hypertension in the newborn (PPHN).
- Based on these findings, the FDA recommended a change in the labeling for SRRI antidepressants to include a warning regarding the risk of PPHN.
- As of January 2012, a total of six studies evaluating the association between PPHN and SSRI exposure (reviewed here) had been published. Three of these studies showed no association between SSRI exposure and PPHN. Three other studies showed an increased risk of PPHN in SSRI-exposed infants, with estimated odds ratios ranging from 2.4 to 6.1.
- Based on this new information, the FDA issued a revision of the warning for SSRIs, stating that “it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN. The FDA will update the SSRI drug labels to reflect the new data and the conflicting results.”
And now we have another study evaluating the risk of PPHN in SSRI-exposed infants. Mind you, this is not really new data. What we have here is a meta-analysis, a study which pools the data from the previous reports in attempt to use the greater statistical power to better evaluate the association between PPHN and SSRI exposure and to assess the importance of other factors which may modulate risk for PPHN. This type of study can help us get a more accurate calculation of risk, but because it relies on data from the previous studies, it carries with it all the methodologic limitations of those earlier studies.
In this meta-analysis, the authors reviewed 3077 abstracts, and seven cohort and case-control English language studies were included in the final analysis. Quantitative analysis was only possible for SSRI antidepressants. They observed that:
- Exposure to SSRIs in early pregnancy was not associated with PPHN (odds ratio 1.23, 95% confidence interval 0.58 to 2.60; P=0.58).
- Exposure in late pregnancy (after 20 weeks) was associated with an increased risk of PPHN (OR=2.50, 1.32 to 4.73; P=0.005).
Persistent pulmonary hypertension of the newborn occurs infrequently, affecting about 1 out of every 1000 births in the general population. It appears that many factors may lead to or increase the risk of PPHN; several risk factors have been identified. These risk factors include, but are not limited to, certain congenital malformations, premature birth, meconium aspiration, maternal obesity, and caesarean section. One of the limitations of previous studies on this topic is that they examined exposure to SSRIs in isolation and did not control for these or other known risk factors.
The meta-analysis found that study design, congenital malformations, or meconium aspiration did not affect the estimates of risk. They were not able, however, to determine the impact of other potential confounding factors, including caesarean section, preterm birth, maternal obesity, or smoking. The inability to adequately control for these factors is relevant given that:
- Obesity and smoking, established risk factors for PPHN, are more common in depressed women.
- Risk of PPHN is increased fourfold in babies born at 34–36 weeks’ gestation. Untreated depression and treatment with SSRIs during pregnancy have been linked to reduced length of gestation.
- Cesarean section, a known risk factor for PPHN, is more common among women with depression.
Given these unknowns, the authors also emphasize that the word “association” does not necessarily mean “causation.” Because depression, and therefore antidepressant use, may be associated with other factors which may modulate risk for PPHN, we cannot simply conclude that SSRI exposure causes PPHN.
The authors point out other important limitations. The pooled results were dominated by the registry studies, and in those studies there may be questions as to whether exposure has actually occurred. Data collected from prescription registries do not always accurately reflect that the drug was taken as prescribed, and there is also uncertainty regarding dose and duration of medication use. In general, it is felt that while case control studies may be helpful in detecting an association between exposure and a particular outcome, they may overestimate the magnitude of the risk. They are vulnerable to recall bias if drug use is self-reported (as in the Chambers study). Risks may be overestimated if mothers of children with poor outcomes are more likely to recall or report drug exposures than women who gave birth to healthy infants.
Setting aside these limitations, let us assume for the sake of discussion that the estimate generated by this meta-analysis is accurate. While the pooled odds ratio of 2.5 for exposure to SSRIs in late pregnancy is statistically significant, it is important to understand that the incidence of PPHN is low (about 1 per 1000 births) absent any exposure. If SSRIs are associated with PPHN, the absolute risk would be quite small – the authors estimate that it is around 0.3% — and this degree of risk may not justify avoiding or discontinuing antidepressants proximate to delivery. In women with histories of recurrent or severe depression, avoiding antidepressants increases the risk of recurrent depression and thus may not be the safest option.
Ruta Nonacs, MD PhD
Grigoriadis S, Vonderporten EH, Mamisashvili L, et al. Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis. BMJ. 2014 Jan 14.