Use of antidepressants during pregnancy is associated with adverse outcomes in infants, according to results of two separate studies. Both trials highlight the importance of assessing the risk-benefit ratio of treatment with antidepressant medication in women who are pregnant.

In the February Archives of Pediatrics and Adolescent Medicine, Rachel Levinson-Castiel, MD, and colleagues reported that use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy was associated with an increased risk of neonatal abstinence syndrome, a type of withdrawal with symptoms that include high-pitched crying, tremors, and disturbed sleep. The researchers found that 30% of infants exposed to SSRIs in utero had symptoms of neonatal abstinence syndrome; 13% of those exposed had severe symptoms of this syndrome.

The study included 120 infants born in Israel between January 1, 2002, and August 31, 2004. Sixty infants had prolonged exposure to SSRIs in utero, especially during the third trimester. Thirty-seven were exposed to paroxetine hydrochloride, 12 to fluoxetine, eight to citalopram hydrobromide, two to venlafaxine hydrochloride, and one to sertraline hydrochloride. Neonatal abstinence syndrome was assessed using the Finnegan score.

SYMPTOMS OF NEONATAL ABSTINENCE SYNDROME

The researchers found that three infants who were exposed to SSRIs for the complete pregnancy duration had major congenital anomalies—ventricular septal defect with or without cleft palate and hydronephrosis with ureterocele. One infant in the control group had hydronephrosis. None of the infants with major congenital anomalies had any other serious medical complications.

Dr. Levinson-Castiel and her colleagues observed symptoms of neonatal abstinence syndrome in 18 of the 60 SSRI-exposed infants versus none of the 60 control infants. Of those 18 infants, eight had a severe neonatal abstinence syndrome (Finnegan score greater than or equal to 8), and 10 had mild neonatal abstinence syndrome (Finnegan score, 4 to 7). Of the eight infants with severe neonatal abstinence syndrome, six had been exposed to paroxetine, one to fluoxetine, and one to citalopram. None of the infants with neonatal abstinence syndrome symptoms required treatment.

According to the investigators, maximum Finnegan scores were recorded for as long as four days following birth. They advised that SSRI-exposed infants be monitored for at least 48 hours after birth and noted that the long-term effects of in utero exposure to SSRIs have not been determined.

"The high prevalence of neonatal abstinence syndrome in infants exposed to SSRIs in utero should be brought to the attention of family physicians, psychiatrists, gynecologists, pediatricians, and mothers. Because maternal depression during pregnancy also entails a risk to the newborn, the risk-benefit ratio of continuing SSRI treatment should be assessed," concluded the researchers.

RISK OF PERSISTENT PULMONARY HYPERTENSION

In the February 9 New England Journal of Medicine, Christina D. Chambers, PhD, MPH, and colleagues found that use of SSRIs during late pregnancy was associated with persistent pulmonary hypertension in newborns. Neither the use of SSRIs during early pregnancy nor the use of non-SSRI antidepressant drugs was associated with an increased risk of persistent pulmonary hypertension.

A total of 377 infants with persistent pulmonary hypertension and 836 control infants were included in the study. Maternal interviews were conducted regarding medication use in pregnancy and potential confounders, including demographic variables and health history. Among mothers taking antidepressants, the following SSRI medications were used: citalopram, fluoxetine, paroxetine, and sertraline. In addition, mothers reported using the following non-SSRIs: tricyclic antidepressant medications (ie, amitriptyline, imipramine, and nortriptyline), bupropion, venlafaxine, and trazodone.

Dr. Chambers’ team found that 14 infants with persistent pulmonary hypertension had been exposed to an SSRI after the 20th week of gestation, compared with six control infants. "The frequency of infant death up to the time of maternal interview was 3% in the persistent pulmonary hypertension group and 0% in the control group," noted the researchers.

They also reported that the risk of persistent pulmonary hypertension was not associated with exposure to any antidepressant medication at any time during pregnancy, nor was risk associated with exposure to SSRIs alone at any time during pregnancy. However, further analysis revealed that exposure to SSRIs after the 20th week of gestation was associated with an increased risk of persistent pulmonary hypertension. "There was no increased risk of persistent pulmonary hypertension when SSRI use was restricted to the first half of the pregnancy," stated the researchers.

"Further research should assess the relationship of different types and dosages of SSRIs with persistent pulmonary hypertension and with milder respiratory complications in newborns," suggested Dr. Chambers and her colleagues. "Studies should also be undertaken to investigate whether there is any association between SSRIs and persistent pulmonary hypertension in the offspring of women who discontinue SSRI use late in pregnancy. Furthermore, to better identify patients who may be at risk, investigations should explore interactions between environmental and genetic factors."

The researchers concluded that "clinicians and their patients must consider both the benefits of SSRIs in the treatment of depression and the potential risk of persistent pulmonary hypertension relative to the risks and benefits of alternative treatments or nontreatment."

—Karen L. Spittler

Suggested Reading
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.
Levinson-Castiel R, Merlob P, Linder N, et al. Neonatal abstinence syndrome after in utero exposure to selective serotonin reuptake inhibitors in term infants. Arch Pediatr Adolesc Med. 2006;160:173-176.

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