Prenatal exposure to antidepressants and persistent pulmonary hypertension of the newborn: systematic review and meta-analysis

Strengths and limitations of this study

The strength of our work rests on the attention to potential confounding factors. We were only able to assess for the effects of potential modifying variables on the pooled effects in our group exposed to SSRIs in late pregnancy. Heterogeneity in the late exposure group was not significant (although the I² was indicative of medium level heterogeneity) and, not surprisingly, none of the potential moderator variables accounted for significant heterogeneity. As the late exposure group was based on only five studies, the lack of significance for the moderator variable analysis may be a reflection of the limited number of studies that were pooled. Our modified pooled effect, following our assessment of publication bias using statistical estimates, resulted in a marginally higher odds ratio, suggesting that positive studies were missing.

Although meta-analytical techniques pool all available data, limitations include those of the original articles. Despite our attempt to determine if an association exists between all antidepressants with persistent pulmonary hypertension of the newborn, we were only able to examine SSRIs because of the lack of data on the other antidepressant classes; future research should determine if other classes of antidepressants show similar associations. The difference in definition of early versus late exposure among the studies was a further limitation. The early exposure analysis was not significant whereas the later one was significant. The early grouping included women exposed from three months before the start of pregnancy until 55 days’ gestation (<8 weeks),3 before week 20 of pregnancy,2 and before the first antenatal visit.1 The late exposure included women exposed after week 20 of pregnancy,2 12 in week 20 or later (from 140 days’ gestation until birth),3 in the third trimester,10 or after the first antenatal visit.1 Owing to the small number of studies eligible for inclusion in these analyses, it was not possible to assess further for this potential confounder beyond a sensitivity analysis for the late exposure subgroup. Removing the study1 that included an earlier definition of late exposure (after the first antenatal visit which is generally after the first trimester although unknown when exactly) resulted in a marginally non-significant result. Interestingly, both the early and the late exposure groups in the original study were significantly associated with persistent pulmonary hypertension of the newborn. A more uniform definition of early and late exposure in future research would be beneficial towards eliminating this potential confounding.

Our main analysis was based on five studies.1 2 3 10 12 Two of the studies1 3 potentially had some overlap in the study samples, as both included women from the Swedish medical birth register, with some overlap of the period sampled. These two studies did account for the most weight; however, the results were only altered when one of the studies1 was removed in sensitivity analyses (P=0.06). Another study10 had few cases of persistent pulmonary hypertension of the newborn and yet another study12 was underpowered. Although most of the studies did use adjusted data in an attempt to control for confounding influences, not all controlled for the same potential confounding variables (see supplementary table). Two studies,2 12 for example, did exclude congenital malformations known to be associated with persistent pulmonary hypertension of the newborn, but they did not exclude all malformations. Another study3 statistically controlled for several variables and excluded meconium aspiration in subanalyses, but did not exclude other known causes, leaving potential confounding. Moreover, we included this study3 in our analysis that controlled for meconium, as the authors reported “after excluding infants with meconium aspiration, the risk estimates increased slightly,” and in the discussion they concluded that exclusion of meconium aspiration resulted in no major difference in risk but that the odds ratio with the exclusion in the group exposed to SSRIs in late pregnancy was not provided; thus in our “controlled for” analysis we used the odds ratio for infants with meconium aspiration. Three of the 33 infants with persistent pulmonary hypertension of the newborn in this study who were exposed to SSRIs in late pregnancy had meconium aspiration, one of the known risk factors for persistent pulmonary hypertension of the newborn.6 The lack of significance within our moderator analyses may be secondary to not only the small number of studies for inclusion but also the way in which the variables were handled in the studies pooled.

Although we wanted to assess for the effects of preterm birth, four of the five studies did not assess for gestational age but rather excluded infants born before at least 33 weeks. One study2 of the five did conduct an analysis restricted to full term births (≥37 weeks) and found results similar to those when they had restricted births to greater than 34 weeks’ gestation. However, persistent pulmonary hypertension of the newborn has been reported to be more common in infants born at 34 weeks compared with those born at term (37 to 41 weeks).29 31 It is also important to note that preterm birth has been associated with both antidepressant use and maternal depression.28 32 The independent effects of preterm birth and exposure to SSRIs remain to be determined.

Only one study in the late exposure analysis3 examined for the effect of caesarean section on the potential relation between prenatal exposure to SSRIs and persistent pulmonary hypertension of the newborn; however, it did not present an odds ratio with this mode of delivery controlled for or excluded. Rather, caesarean section was examined as an effect modifier and was determined to be non-significant (P>0.18). One study12 had no events of persistent pulmonary hypertension of the newborn in their group exposed to SSRIs and also examined caesarean section. That study12 found caesarean delivery before onset of labour to be associated with persistent pulmonary hypertension of the newborn (odds ratios 4.9, 95% confidence interval 1.7 to 14.0). Whereas one study10 reported no increased risk of persistent pulmonary hypertension of the newborn after exposure to SSRIs in late pregnancy, the rates of caesarean section were “similar” between exposed and unexposed groups. The caesarean section mode of delivery, however, has been found to be more common in infants with persistent pulmonary hypertension of the newborn,33 34 been considered a risk factor for persistent pulmonary hypertension of the newborn,6 and been noted in women with depression.35 It is possible that the increased prevalence for this mode of delivery may be due to maternal preference.36 37 The effect of maternal obesity was also not examined, as in the original papers the authors either did not examine it as a moderator or they analysed it in a way that was not comparable. As obesity is a known risk factor for persistent pulmonary hypertension of the newborn,33 and depression itself seems to be a reciprocal risk factor for obesity,38 the relation with persistent pulmonary hypertension of the newborn may be confounded. Future studies should control for caesarean section and consider obesity when exploring potential associations with persistent pulmonary hypertension of the newborn.

None of the five studies evaluated for the effects of a clinical depression on persistent pulmonary hypertension of the newborn. One study3 did show that women who were not using antidepressants while pregnant but who had a history of admission to hospital for a psychiatric condition also had an increased risk of delivering an infant with persistent pulmonary hypertension of the newborn (odds ratios 1.3, 95% confidence interval 1.1 to 1.6). The adjusted odds ratio in those women who used SSRIs in late pregnancy and had a history of admission to hospital for a psychiatric condition was even higher at 3.1 (95% confidence interval 1.9 to 4.9), suggesting that the combination of a psychiatric disorder and antidepressant use might confer a higher risk. One study2 did note that maternal depression may not be independently associated with persistent pulmonary hypertension of the newborn, as the study did not find an association with the condition for non-SSRI antidepressants or when exposure to SSRIs was restricted to the first half of pregnancy. Although the effect of depression may not be direct, it is possible that in combination with other factors the risk for persistent pulmonary hypertension of the newborn after exposure to maternal depression may be attenuated—that is, depression in combination with caesarean section. Women with depression have been found to have an increase in some of the known risk factors for persistent pulmonary hypertension of the newborn, such as caesarean section, obesity, and preterm delivery, which may also confound the results and association. As has been often noted in research evaluating possible adverse outcomes after prenatal exposure to antidepressants, it is important to emphasise that antidepressants are also prescribed for other psychiatric conditions that may exert an unknown independent effect. SSRIs are prescribed for anxiety disorders, which are increasingly recognised as being common in pregnancy39 and are themselves associated with adverse birth outcomes.40 41 42

Another important limitation of the literature, and thus our meta-analysis, is that the included studies1 2 3 10 11 12 13 either did or did not consistently control for or examine the severity of the persistent pulmonary hypertension of the newborn cases included, as well as the underlying factors that may result in higher mortality rates of these infants. Only three studies2 3 10 reported on infant outcome: one reported frequency of infant death within six months after delivery2; one reported on infant death, without specifying a time frame3; and one reported the mechanism of treatment for persistent pulmonary hypertension of the newborn and outcome (all resolved)10 (see supplementary table). Furthermore, some studies excluded cases with more or less severe complications (for example, congenital malformations, meconium aspiration, preterm delivery (≤34 weeks), neonatal pneumonia, or sepsis, see supplementary table), whereas others did not. This inconsistency thus inhibits further analysis of the severity of persistent pulmonary hypertension of the newborn within the context of SSRI exposure as a risk factor.

Lastly, an association between exposure to SSRIs and persistent pulmonary hypertension of the newborn does not imply causation, as discussed by one study,15 particularly when there are questions around whether exposure has occurred (for example, in prescription based registry studies). The pooled effects were dominated by the registry studies, and yet we cannot be confident that the mothers used the drugs as prescribed. Data collected from prescription registries do not always precisely reflect that the drug was taken as prescribed.43 Moreover, there is also uncertainty regarding dose, length of use, and the method used for handling women who cease to use the medication at any point in pregnancy.44 In addition, when data are retrospective, potential bias can exist. In the case of one study,2 for example, the authors determined exposure retrospectively by telephone interview, and thus recall bias and consequently inflated or inaccurate odds ratios cannot be ruled out. Proof of exposure is fundamental for the meaningfulness of these study’s findings, and yet it is not without question in the data associating exposure to SSRIs and persistent pulmonary hypertension of the newborn.15 43 44

Conclusions and policy implications

Depression during pregnancy must not be left untreated, as the potential for untoward effects is not negligible and can extend into the postpartum period. Selection of treatment is based on several factors, and antidepressant drugs may be necessary, especially in severe depressive episodes.45 Although the odds for persistent pulmonary hypertension of the newborn seem to be greater with the use of SSRIs later in pregnancy, despite the limitations of the original studies, the risk is still low. Results from this meta-analysis still concur with earlier statements,3 15 46 that fewer than about 1 infant in 100 will develop persistent pulmonary hypertension of the newborn after antenatal exposure to SSRIs. Although this condition is serious and death rates between 5% and 10% have been reported, when it is associated with other conditions (such as some congenital malformations, meconium aspiration, sepsis, and idiopathic disease), it can be managed favourably.46 The death rate in infants with persistent pulmonary hypertension of the newborn who have been exposed to SSRIs, however, remains unknown (although one study did report 9.1% of the infants died who were exposed to SSRIs compared with 9.5% of those who were not exposed3). Conversely, although suicide during the perinatal period has not been well researched, there is some existing data, and during the postpartum period suicide may not be less common than suicide at other times of the life cycle in women.47 One study reported suicide to be the leading cause of maternal mortality in the United Kingdom, being responsible for 28% of maternal deaths47; 68% of the women who died by suicide had a major mental illness such as severe depression or psychosis. Others have also found maternal psychiatric illness to be a leading cause of maternal mortality.48 Although also poorly researched, a high proportion of infanticides (murder in the first year of life) have been cited as occurring in the context of postpartum psychiatric illness.49 Maternal psychiatric illness is also known to increase the risk of filicide (child murder by mother),50 and maternal filicide with suicide, although rare, has been found to occur in the setting of psychiatric illness (more than the majority of the mothers in one study were found to have depression51). It is imperative that the mother’s health be weighed heavily in treatment decisions; she and her family must be counselled on both the risks of exposing the fetus to antidepressant drugs and the risks of severe depressive illness. Although more research controlling for risk factors discussed in this study as well as others not reviewed here, is needed, pregnant women considering or using SSRIs and their families should be educated about persistent pulmonary hypertension of the newborn, how the symptoms can range in severity, what treatments are available for it at the institution where the birth will take place, and that it can typically be managed successfully if it does occur in the context of SSRI use. To avoid delays in diagnosis and treatment of persistent pulmonary hypertension of the newborn, neonatologists must be made aware of exposure to SSRIs.