Mom's SSRI Use Linked to Delayed Fetal Growth, Preterm Birth

Deborah Brauser

March 07, 2012

March 7, 2012 — Use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy may increase the risk for adverse fetal development and birth outcomes, new research suggests. However, untreated depression was also associated with delayed fetal growth.

In a population-based study of pregnant women, those who were depressed and who were treated with SSRIs showed fewer depressive symptoms than those who were not treated; but they also had a significantly higher risk of having fetuses with delayed head growth, and they were twice as likely to have preterm births as their healthy peers.

"We did not expect that any effect from SSRI use would be very selective, such as on head growth, although this is exactly what animal studies have predicted," coinvestigator Henning Tiemeier, MD, PhD, professor of psychiatric epidemiology in the Departments of Epidemiology and of Child and Adolescent Psychiatry at Erasmus Medical Center in Rotterdam, the Netherlands, told Medscape Medical News.

Dr. Henning Tiemeier

Dr. Tiemeier added that the study's takeaway message is that clinicians should "discuss and consider very carefully treatment alternatives to SSRIs with women who want to become pregnant."

The investigators note that the women in the study who were clinically depressed but did not receive any treatment for the disorder were also significantly more likely to have fetuses with reduced head growth as well as reduced body growth than their counterparts who were not depressed.

"Further research on the implications of these findings is needed," they write.

The study was published online March 5 in the Archives of General Psychiatry.

Open Debate

The researchers note that although treating depression during pregnancy is highly important, "high-quality studies with good controls" about the effect of SSRIs on an unborn child's health "are sparse."

"Thus, trying to balance the possible negative consequences of untreated maternal depression with the unknown potential negative consequences of SSRIs remains an open debate," they write.

"SSRIs are generally safe drugs, but animal studies have suggested that this may be different during pregnancy, when serotonin is a neurodevelopmental hormone," explained Dr. Tiemeier.

The investigators note that this is one of the first SSRI-assessing studies in humans to focus on head development during pregnancy.

The Generation R Study is an ongoing prospective trial of 9778 mothers in the Netherlands; it was designed to examine fetal life onward.

For this analysis, the researchers assessed data on 7696 women who were first enrolled in the Generation R Study during pregnancy.

Questionnaires were given to all of these participants during each trimester of pregnancy to assess SSRI use. The participants' responses were verified by pharmacy records. Women who used SSRIs before pregnancy were excluded from this analysis.

The Brief Symptom Inventory (BSI) was used to assess depressive symptoms at an average of 20.6 weeks of gestation. Each trimester, fetal ultrasonography was performed to determine head and body growth.

Adverse birth outcomes that were measured included preterm birth (before 37 weeks of gestation) and low birth weight (<2500 g).

Findings Not Conclusive

Results showed that 91.3% of the participants had no or low depressive symptoms, as shown on the BSI (considered the "healthy controls" group).

Of the remaining women, 7.4% had what were considered "clinically relevant depressive symptoms" (scores higher than 0.75) and did not use SSRIs during pregnancy. Only 1.3% (n = 99) had depressives symptoms and did use SSRIs.

The women using SSRIs during pregnancy had significantly lower symptom scores on the BSI than those who were considered depressive but who did not use SSRIs (P < .001).

However, prenatal SSRI use was associated with significantly reduced fetal head growth (−0.18 mm/wk; 95% confidence interval [CI], −0.32 to −0.07; P = .003) and a higher risk for preterm birth (odds ratio, 2.14; 95% CI, 1.08 - 4.25; P = .03) compared with the healthy control group.

Use of SSRIs during pregnancy was also associated with a lower birth weight, which "was explained by the shorter gestational duration and other covariates," and a significantly smaller head circumference at birth (P = .04), write the researchers.

The fetuses from mothers who reported prenatal depressive symptoms but who had not used SSRIs had significantly reduced head growth (−0.08 mm/wk; 95% CI, −0.14 to −0.03; P = .003) as well as reduced body growth/weight gain (−4.4 g/wk; 95% CI, −6.3 to −2.4; P < .001) compared with the healthy control participants.

"Our results indicate a rather specific effect of SSRI use during pregnancy, which differs from depressive symptoms on the fetus," write the investigators.

"Although our findings add to current knowledge about the consequences of SSRI use (or nonuse)..., they are not conclusive."

The researchers cite several possible explanations for the reduced head growth finding, including serotonin's prominent role in prenatal brain development. So "manipulation of serotonin levels with SSRIs in utero may directly affect fetal brain growth."

Smoking and/or drinking during pregnancy has also been shown to affect fetal growth. Although the investigators tried to adjust for these risk factors, they admit that some "unmeasured residual confounding" could still be present.

Dr. Tiemeier reported that the investigators plan to continue following the children from this study to assess future behavioral problems and possible autistic traits.

Consistent Findings

"I think this study is pretty consistent with what the rest of the literature has shown. So I don't think it was surprising," Kimberly A. Yonkers, MD, professor in the Departments of Psychiatry, Obstetrics/Gynecology/Reproductive Sciences, and Epidemiology/Public Health at Yale School of Medicine in New Haven, Connecticut, told Medscape Medical News.

Dr. Kimberly Yonkers

"Other registry data suggest that SSRIs are associated with preterm birth," added Dr. Yonkers.

One concern she noted with the study is that it used the self-reported BSI to assess depressive symptoms.

"This isn't a diagnostic questionnaire; it's a measure of distress. So it doesn't enable researchers to really look at psychological factors except in very broad and superficial terms," said Dr. Yonkers. "Here, they suggest that severity of underlying illness may also contribute to adverse birth outcomes. But what that really means is difficult to delineate in this dataset."

Dr. Yonkers, who was not involved with this research, was lead author for a report jointly released in 2009 by the American Psychiatric Association (APA) and the American College of Obstetricians and Gynecologists (ACOG) on treatment options for pregnant women with or at risk for major depressive disorder.

"We took the position that nothing substitutes for the individual assessment of a given person. So one has to take into consideration what her illness is, what her risk of relapse is, what medications she has responded to, and what her preferences are, as well as what risks are associated with the use of medication," she explained.

Another concern she voiced about the current study was the small sample size of women who were considered to be depressed and using SSRIs, "which means the confidence intervals were pretty wide when they tried to show effects." She also noted that the odds ratio of 2.14 found for preterm birth was very high.

"That was certainly higher than what we see in our data, which are currently in press in the Journal of Epidemiology," she added.

She noted that the finding of decreased fetal head growth was interesting, "but there's nothing in the literature that suggests that there are cognitive effects from SSRI use during pregnancy."

"So fetal head growth may be important if it's an index of cognitive problems, but that hasn't been shown to be the case. Having said that, this is really an under-studied area," said Dr. Yonkers. "But at this point, we don't know if it has clinical significance."

Overall, Dr. Yonkers said that the recommendations from the APA/ACOG report "haven't substantially changed."

"Without further longitudinal follow-up, I don't see that the findings from this study really suggest any risk beyond what we currently have concerns about, which are an increased risk of delivering early, possible persistent pulmonary hypertension, and that fluoxetine use during the first trimester might be associated with a higher risk of some congenital heart malformations," she said.

"Still, in terms of their effects on birth outcomes, SSRI use is probably not as serious as smoking and certainly not as serious as alcohol."

The study was supported by the Erasmus Medical Center Rotterdam and the Erasmus University Rotterdam and by grants from the Netherlands Organization for Health Research and Development, the Netherlands Organization for Scientific Research, and the Sophia Children's Hospital Foundation. The study authors and Dr. Yonkers have disclosed no relevant financial relationships.

Arch Gen Psychiatry. Published online March 5, 2012. Abstract

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