The fetuses of women who took SSRIs during pregnancy showed reduced growth of the head but not the body in a study published online March 5 in Archives of General Psychiatry.

In contrast, the fetuses of women who had depressive symptoms but did not take SSRIs during pregnancy showed growth restriction of the entire body, including the head. "Our results indicate a rather specific effect of SSRI use during pregnancy, which differs from [the effect of] depressive symptoms on the fetus," said Hanan El Marroun, Ph.D., of the department of child and adolescent psychiatry, Sophia Children’s Hospital, Rotterdam, the Netherlands, and associates.

A study of the offspring of nearly 10,000 women showed that the fetuses of women who took SSRIs during pregnancy showed reduced growth of the head and were twice as likely to be born preterm.

Fetal head growth is "one of the best prenatal markers of brain volume," and reduced head growth has been linked to poor cognitive performance, behavioral problems, and psychiatric disorders later in life. "Nonetheless, we must be careful not to infer an association of SSRI use in pregnancy with future developmental problems. ... [M]ore long-term drug safety studies are needed before evidence-based recommendations can be derived," the investigators noted.

"Our findings further raise the question whether maternal SSRI treatment during pregnancy is better or worse for the fetus than untreated maternal depression, "they added.

Dr. El Marroun and colleagues studied the relationship between depression and fetal growth using data from the Generation R Study, a population-based prospective cohort study of the offspring of nearly 10,000 women who gave birth in Rotterdam between 2002 and 2006. The children were studied from early fetal life (by means of detailed ultrasonography) through birth and infancy.

For their analysis, Dr. El Marroun and associates assessed 7,696 mother-infant pairs. Most of the mothers (7,027, or 91.3%), who had few depressive symptoms and did not use SSRIs, formed the control group. Another 570 mothers (7.4%) had clinically relevant depressive symptoms but did not use SSRIs, while the remaining 99 mothers (1.3%) used SSRIs during pregnancy.

Mean depression scores on the depression scale of the Brief Symptom Inventory were 0.10 in the control group, 1.45 in the women with depressive symptoms but no SSRIs, and 0.74 for the women taking SSRIs.

Fetuses of women who were depressed but not taking SSRIs showed a slower rate of weight gain, approximately 4.4 g/wk less than the control group. Fetuses of women in the SSRI group showed no such reduction in overall growth.

Fetuses of women who were depressed but not taking SSRIs also showed a reduced head circumference, which was in line with their generally slower weight gain. However, fetuses of mothers using SSRIs showed a much more pronounced reduction in head circumference that was not in line with their normal weight gain.

This link between maternal SSRI use and reduced fetal head circumference remained robust through a series of analyses that adjusted for potentially confounding factors such as maternal ethnicity, smoking status, use of benzodiazepines, and severity of depressive symptoms. However, the effect of maternal SSRI use on head growth was characterized as "rather small," with reductions of only 4 mm or less, the investigators said (Arch. Gen. Psychiatry 2012 March 5 [doi:10.1001/archgenpsychiatry.2011.2333]).

In addition, children born to women using SSRIs were twice as likely to be born preterm as were controls. The absolute rates of preterm birth were 5.1% in the control group, 6.3% in the mothers with depressive symptoms who weren’t taking SSRIs, and 10.1% in the mothers taking SSRIs.

The reason why SSRIs might restrict fetal head growth is not known.

It is possible that treated women had more severe depression than untreated women, or that they had experienced previous bouts of depression. Either scenario could affect maternal physiology, and thus fetal development, the researchers said.

It also is possible that manipulating serotonin levels with SSRIs could directly affect fetal brain growth, as serotonin is known to play an important role in prenatal brain development.

A third possibility is that "epiphenomena of SSRI use" such as smoking, drinking, low socioeconomic status, family stress, malnutrition, or genetic susceptibility could affect fetal head growth. However, when epiphenomena compromise fetal growth, they typically impair head growth last of all, which is known as the brain-sparing effect, Dr. El Marroun and colleagues said.

The study results reinforce that "clinicians must carefully weigh the known risks of untreated depression during pregnancy and the possible adverse effects of SSRIs," they said.

This study was supported by the Sophia Children’s Hospital Foundation and the Netherlands Organization for Health Research and Development (NOHRD). The Generation R Study was supported by Erasmus Medical Centre Rotterdam, Erasmus University Rotterdam, the Netherlands Organization for Scientific Research, and NOHRD. The authors reported no relevant financial disclosures.

SSRIs During Pregnancy May Restrict Fetal Head Growth