"Pharmacoepidemiological studies can show an association but cannot prove causation, yet the authors state that SSRI use in late pregnancy increased the risk of this syndrome, implying causation," Dr. Gideon Koren and Dr. Hevig Nordeng noted in an accompanying editorial. They pointed out several problems that are inherent in this type of study and problems with this particular study.
"A major challenge in prescription database studies is to prove exposure. The fact that the drug was prescribed does not mean that it was taken. In this study, the timing of exposure was based on the pharmacies’ date of dispensing and defined daily dosages (which may differ from the prescribed doses), but they did not mention the uncertainty around the timing of exposure and how it was calculated," they wrote.
"In addition, without having validated the diagnosis or reviewed the medical charts of each case, it is difficult to estimate the quality of Kieler and colleagues’ definition of pulmonary hypertension in the newborn. In [a] 2006 case-control study, 40% of the potential cases were rejected after a neonatologist reviewed the medical records (N. Engl. J. Med. 2006;354:579-87)."
Surprisingly, Kieler et al. excluded neonates with one cause of pulmonary hypertension in the newborn, meconium aspiration, but did not do so with other known causes. "This decision is not justified, especially when the registries available to the authors included clinical details on all other known causes of the syndrome. By not controlling for these confounding or modifying conditions, the authors have missed an opportunity to calculate the attributable risk of SSRIs in causing pulmonary hypertension in the newborn," wrote Dr. Koren and Dr. Nordeng.
In addition, "although the authors argue against confounding by indication, their analyses clearly show that women who did not use antidepressants in pregnancy but who had been admitted to hospital for psychiatric reasons were more likely to give birth to infants with pulmonary hypertension in the newborn (OR 1.3)."
Lastly, "an important question is not the relative risk of an SSRI causing the syndrome, but rather absolute attributable risk. As estimated previously, this syndrome may occur in less than one in 100 pregnant women treated with an SSRI. If the infant has no life-threatening known causes of pulmonary hypertension in the newborn – such as meconium aspiration, sepsis, congenital heart disease, or diaphragmatic hernia – the chance of a full recovery is high. Future studies, or additional analyses of Kieler and colleagues’ large cohort, may be able to quantify this risk, or the lack of one," they wrote.
Dr. Koren is director of the Motherisk Program at the Hospital for Sick Children in Toronto. Dr. Nordeng is an associate professor of pharmacy at the University of Oslo. Both reported that they had no financial disclosures relevant to this accompanying editorial (BMJ 2011;343:d7642).
