The focus of this article is to help help clinicians interpret research related to a clinical question. Perhaps more importantly, discussion of the issues and the tips aim to bolster understanding of research methodology and of critical appraisal of the literature in general.
A landmark paper published in 2006 reported that the use of SSRIs after the 20th week of pregnancy is associated with an elevated risk of a rare but serious abnormality—persistent pulmonary hypertension of the newborn (PPHN).1 PPHN involves persistence after birth of the normal fetal high pulmonary vascular resistance. This leads to right-to-left shunting of blood, low pulmonary blood flow, hypoxemia, and severe respiratory failure.2 At least 6 subsequent studies have addressed this association between use of SSRIs and PPHN, with apparently contradictory results, which has led to uncertainty about the association.3-8
The FDA reviewed the literature on the subject and issued a notification in December 2011, stating, “given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN.”9 The agency advised health care professionals “not to alter their current clinical practice of treating depression during pregnancy.” Health care professionals were also advised to “weigh the small potential risk of PPHN that may be associated with SSRI use in pregnancy against the substantial risks associated with under-treatment or no treatment of depression during pregnancy.”
These studies offer an excellent opportunity to understand which study designs are best-suited to evaluate rare outcomes. If an outcome occurs rarely (eg, PPHN), an extremely large number of patients with and without the risk factor (eg, treatment of the pregnant woman with an antidepressant) would have to be followed to be able to evaluate whether patients who did or did not have the risk factor were equally at risk for the outcome.
Early in an investigation of a potential association, it is not viable to study very large numbers of subjects. Instead, a case-control study is often used. Case-control studies are well suited to initial investigation of rare outcomes and outcomes that take a long time to develop (eg, lung cancer with smoking). The researchers start with a sufficient number of subjects who have the outcome of interest, identify an appropriate control group without the outcome, and then assess the proportion of subjects with or without the outcome who were exposed to the risk factor being studied.
Because case-control studies can have certain problems, such as recall bias (subjects may be more likely to remember exposure to the risk factor than the controls), their findings usually need to be confirmed by large cohort studies. In cohort studies, subjects with or without the risk factor are identified and followed up over time to determine whether they develop the outcome of interest.
When studying potential risk factors, confounders need to be taken into account. The confounder is a third factor that is associated with both the putative risk factor and the outcome and, therefore, results in an apparent association between the putative risk factor and the outcome.
Factors other than the putative risk factor being evaluated that are associated with an outcome (ie, potential confounders) can be controlled for in several ways. First, inclusion criteria can limit the subjects to a more homogeneous subgroup (eg, the studies cited in this article usually only included infants born after 33 or 34 weeks of gestation). Second, in case-control studies, the controls can be matched to cases on specific factors. To illustrate, Chambers and colleagues1 matched the controls to the cases on the hospital of birth and the approximate date of birth. Third, the potential confounders can be controlled for in the statistical analysis.
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.
Studies of potential association of persistent pulmonary hypertension of the newborn with maternal use of an antidepressant
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.
1. Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med. 2006;354:579-587.
2. Occhiogrosso M, Omran SS, Altemus M. Persistent pulmonary hypertension of the newborn and selective serotonin reuptake inhibitors: lessons from clinical and translational studies. Am J Psychiatry. 2012;169:134-140.
3. Källén B, Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Safe. 2008;17:801-806.
4. Andrade SE, McPhillips H, Loren D, et al. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Saf. 2009;18:246-252.
5. Wichman CL, Morre KM, Lang TR, et al. Congenital heart disease associated with selective serotonin reuptake inhibitor use during pregnancy. Mayo Clin Proc. 2009;84:23-27.
6. Reis M, Källén B. Delivery outcome after maternal use of antidepressant drugs in pregnancy: an update using Swedish data. Psychol Med. 2010;40:1723-1733.
7. Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ. 2012;344:d8012.
8. Wilson KL, Zelig CM, Harvey JP, et al. Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol. 2011;28:19-24.
9. US Food and Drug Administration. FDA Drug safety communication: selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and reports of a rare heart and lung condition in newborn babies. http://www.fda.gov/Drugs/DrugSafety/ucm283375.htm#data. Accessed June 14, 2012.
10. Hernández-Díaz S, Van Marter LJ, Werler MM, et al. Risk factors for persistent pulmonary hypertension of the newborn. Pediatrics. 2007;120:e272-e282.
11. Delaney C, Cornfield DN. Risk factors for persistent pulmonary hypertension of the newborn. Pulm Circ. 2012;2:15-20.