Literature accumulated over the last decade supports the use of certain selective serotonin reuptake inhibitors (SSRIs) and the older tricyclic antidepressants during pregnancy, indicating no increased risk of congenital malformation in children exposed to these medications during the first trimester of pregnancy. Still, questions remain regarding the purported risk for “toxicity” in newborns exposed to antidepressants around the time of labor and delivery (see Fall 2004 and Spring 2005 Newsletters). In addition, a recent study published in the New England Journal of Medicine has linked SSRI use during late pregnancy to an increased risk of persistent pulmonary hypertension in the newborn (Chambers 2006).
Persistent pulmonary hypertension of the newborn (PPHN) is a cardiovascular syndrome typically occurring in full-term or near-term infants. After birth, the infant’s pulmonary vascular resistance fails to decrease; and blood is shunted away from the lungs and is therefore not fully oxygenated, causing hypoxemia in the newborn. PPHN is usually seen shortly after birth, typically within 12 hours of delivery. Infants present with respiratory distress and, in the worst cases, require assisted ventilation. PPHN occurs in approximately one in 700 births and is often seen when there is an underlying lung disease, such as hyaline membrane disease or meconium aspiration syndrome; however, PPHN may also occur in the absence of underlying lung disease. Maternal factors associated with PPHN include cesarean section, antenatal use of non-steroidal anti-inflammatory agents (NSAIDs), and tobacco use (van Marter 1996).
Based on a previous report suggesting a higher than expected number of cases of PPHN in infants exposed to fluoxetine during pregnancy (Chambers 1996), the investigators used a case-control design to evaluate risk factors for PPHN, focusing on exposure to NSAIDs and SSRIs. The authors identified 637 infants with possible PPHN from 97 institutions in four metropolitan areas (Boston; Philadelphia; San Diego, California; and Toronto). Diagnosis of PPHN was confirmed in 377 infants by review of the medical records by a neonatologist blinded to the mother’s medication status. A control group of 836 women and their infants was also identified. Rates of participation were 73% in the PPHN group and 71% in the control group. The mothers were interviewed using a structured questionnaire within six months of delivery by a study nurse who was unaware of the study hypothesis.
The use of SSRIs at any time in pregnancy was not significantly associated with PPHN. However, when the comparison was stratified according to the timing of exposure in pregnancy, the use of an SSRI antidepressant after the 20th week of gestation was significantly associated with PPHN (adjusted odds ratio, 6.1; 95 percent confidence interval, 2.2 to 16.8). Although body mass index, diabetes, NSAID use, and smoking have been identified as maternal factors associated with PPHN, controlling for these potential confounders did not significantly attenuate the association between SSRI use and PPHN. Neither the use of SSRIs before the 20th week of gestation nor the use of non-SSRI antidepressants at any time during the pregnancy was associated with an increased risk of PPHN.
It is difficult to reconcile these findings with other studies investigating neonatal outcomes in infants exposed to antidepressants in utero. There have been reports of adverse events in exposed infants, most commonly symptoms of jitteriness, sleep disturbance, feeding problems, and excessive crying. There have also been reports of respiratory distress (usually tachypnea or rapid breathing); however, the observed symptoms were relatively mild, transient, and did not require specific medical intervention, suggesting that these cases were not PPHN, a more serious complication with significant morbidity. The only study to report cases of PPHN was from the authors of the current study (Chambers 1996). Clearly further investigation is warranted to clarify the association between SSRI use and PPHN.
These findings are likely to generate significant anxiety among child-bearing women who suffer from depression. About 10% to 15% of women in the general population suffer from depression during pregnancy. The risk is particularly high in women with histories of depression who discontinue antidepressants during pregnancy. Women considering the use of antidepressants during pregnancy must be made aware of this risk but it must be weighed against the risks of untreated illness in the mother. To avoid or withhold antidepressants during pregnancy places these women – and their children – at risk. Depression in the mother is not a benign event and, when left untreated during pregnancy, has been associated with poor neonatal outcomes, including preterm birth, low birthweight, and lower Apgar scores. If we assume that these findings are correct, the risk is still relatively small; the authors estimate the risk of PPHN to be less than 1% in infants exposed to SSRIs in utero. Thus many women with more severe or recurrent illness may elect to continue treatment with SSRIs during pregnancy, acknowledging that the risks associated with untreated depression are greater than the risks of SSRI use.
Ruta Nonacs, MD, PhD
Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, et al. Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New England Journal of Medicine 2006; 354(6):579-87.
Van Marter LJ, Leviton A, Allred EN, et al. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal anti-inflammatory drug consumption during pregnancy. Pediatrics 1996;97:658-63.