The use of selective serotonin reuptake inhibitors by women during pregnancy increases the risk of persistent pulmonary hypertension in newborns, with the risk doubling for use during late pregnancy.
The risk of persistent pulmonary hypertension of the newborn (PPHN) after exposure to any SSRI in late pregnancy was more than doubled (adjusted odds ratio, 2.1). The risk was slightly increased in association with exposure to SSRIs in early pregnancy (adjusted OR, 1.4). The combination of a previous admission to hospital for a psychiatric disorder and exposure to an SSRI in late pregnancy yielded an adjusted OR of 3.1. The findings – from a population-based cohort study of data from registries in five Nordic countries – were published Jan. 12 in BMJ (2011;344:d8012 [doi:10.1136/bmj.d8012]).
“As the risk in association with treatment in late pregnancy seems to be more than doubled, we recommend caution when treating pregnant women with SSRIs. It is essential to plan the treatment and to weigh the risks of persistent pulmonary hypertension of the newborn when treating women in late pregnancy with those of relapse of depression and neonatal abstinence syndrome if therapy is interrupted. For women where treatment with an SSRI is the only or best option, the choice of substance seems to be of minor importance,” said Dr. Helle Kieler, an ob.gyn. at the Centre for Pharmacoepidemiology at the Karolinska Institute in Stockholm, and her coinvestigators.
The researchers included women and their infants born in Denmark, Finland, Iceland, Norway, or Sweden between 1996 and 2007. Each of these countries has national registers with prospectively collected information on the health of all inhabitants. They obtained data from the medical birth registers, the prescription registers, and the cause of death registers from all five countries. Data on the mother’s previous psychiatric diseases and infant diagnoses were included for Denmark, Iceland, Sweden, and Finland and from the Danish Psychiatric Central Register.
The investigators included all singletons born after 33 weeks’ gestation between 1996 and 2007. Births were included only from the years when prescription data were available. They obtained information on PPHN, level of delivery hospital, maternal smoking, body mass index (BMI) in early pregnancy, year of birth, mode of delivery, gestational age at birth, birth weight, meconium aspiration, and maternal diseases recorded during pregnancy from the national registers.
The researchers also collected information about the mothers’ admissions to hospital for a psychiatric diagnosis during the 10 years before giving birth. In addition, they identified women who had filled prescriptions for antidepressants, antidiabetes drugs, or nonsteroidal anti-inflammatory drugs (NSAIDs) from 3 months before the start of pregnancy until delivery.
Dr. Kieler and her associates included six SSRIs in the analyses: fluoxetine, citalopram, paroxetine, sertraline, fluvoxamine, and escitalopram. They also performed subanalyses on whether other antidepressants with an effect on serotonin activity or norepinephrine activity would affect the risks of PPHN. Patient use was as “ever use” (3 months before the start of pregnancy until birth), as a filled prescription in late pregnancy (from 140 days after the start of pregnancy until birth), or in early pregnancy only (from 3 months before the start of pregnancy until a pregnancy length of 55 days).
Potential confounders included maternal smoking, age, BMI, purchased NSAIDs and antidiabetes drugs, diseases recorded during pregnancy, level of delivery hospital (university or nonuniversity hospital), and infants’ country of birth, birth year, and birth order.
In total, 1,618,255 singleton births were included. Of these, 0.7% of the mothers had filled a prescription for an SSRI during late pregnancy and 1.1% in early pregnancy only. The mothers with a filled prescription for an SSRI tended to be older and more often smokers than mothers not using SSRIs. Exposed infants had a lower gestational age at birth and were more often classified as small for gestational age. The absolute risk for PPHN for infants to mothers using SSRIs was as low as 3 infants per 1,000 exposed.
In late pregnancy, 627 women had filled a prescription for an antidepressant with an effect on serotonin activity or norepinephrine activity. The corresponding figure for early pregnancy only was 2,503. More than three-quarters (85%) of 63,615 women with a previous psychiatric diagnosis had not filled a prescription for any of the antidepressants during pregnancy.
Among the 11,014 infants exposed to an SSRI in late pregnancy, 33 (0.3%) had a diagnosis of PPHN – three of whom had meconium aspiration. Among 627 infants exposed to antidepressants with an effect on serotonin activity or norepinephrine activity, 3 (0.5%) had a diagnosis of PPHN. Of the 17,053 infants exposed to SSRIs only in early pregnancy, 32 (0.2%) had PPHN; 0.1% of the 1,588,140 infants never exposed to SSRIs were diagnosed with PPHN.
Of the infants with PPHN, 3 of the 33 infants (9%) who were exposed to SSRIs in late pregnancy died, as did 183 (9.5%) of the 1,935 who were never exposed to SSRIs. Among the 63,615 women with a previous admission to hospital for a psychiatric disorder, 114 (1.8%) infants had a diagnosis of PPHN.
The risk estimates of PPHN after exposure to fluoxetine, citalopram, sertraline, or paroxetine in late pregnancy ranged from 2 to 3. While the risk estimate for escitalopram was lower, this number was imprecise. No infants with PPHN had been exposed to fluvoxamine. “Exposure to the other antidepressants with an effect on serotonin activity or norepinephrine activity also generated increased risks,” Dr. Kieler and her associates wrote.
Risks for PPHN were only slightly increased in association with exposure to SSRI in early pregnancy only. Exposure to the other antidepressants with an effect on serotonin activity or norepinephrine activity did not increase the risk of PPHN in early pregnancy only.
After exclusion of infants with meconium aspiration, the risk estimates increased slightly, they said.
This study was funded by the Swedish Pharmacy Company. The authors reported that they had no relevant financial disclosures.
Additional Study Needed
In an accompanying editorial, Dr. Gideon Koren and Dr. Hevig Nordeng noted that “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” (BMJ 2011;343:d7642). Dr. Koren and Dr. Nordeng 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),” wrote Dr. Koren, who is director of the Motherisk Program at the Hospital for Sick Children in Toronto, and Dr. Nordeng, an associate professor of pharmacy at the University of Oslo.
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, they continued. “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 and Dr. Nordeng reported that they had no financial disclosures relevant to their editorial.
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