SSRI Exposure In Utero Alters Neurobehavioral Development

But Clinical Implications, If Any, Are Unclear

Megan Brooks

August 22, 2011

August 22, 2011 — In utero exposure to selective serotonin reuptake inhibitors (SSRIs) appears to alter neurobehavioral development in the fetus, results of a study published online in Neuropsychopharmacology suggest.

In the study, fetuses exposed to standard and high doses of SSRIs exhibited disrupted emergence of quiet, non–rapid eye movement (non-REM) sleep during the third trimester, "characterized by continual bodily activity and, thus, poor inhibitory motor control during this sleep state near term."

Although the clinical significance of this observation for postnatal development is unclear, it could predict sleep problems in children down the road, Eduard J. Mulder, PhD, and colleagues from University Medical Centre, Utrecht, the Netherlands, note in their article.

However, Tim Oberlander, MD, FRCP, of The Child and Family Research Institute, University of British Columbia in Vancouver, Canada, who was not involved in the study, cautioned against reading too much into this finding, for now.

"This is one step in a long series of human studies to figure out what is happening at a neurobehavioral, biologic, and molecular level," with these medications, he noted in a telephone interview with Medscape Medical News.

"At the macro level, it's important to recognize that mother's mental health is really the critical issue here and, there are downstream effects of the mood disturbances themselves that need to be carefully considered," he added.

Abnormal Phenomenon

In their prospective, observational study, Dr. Mulder and colleagues examined developmental milestones of fetal behavior during pregnancy in 3 groups of women:

96 women with psychiatric disorders who took SSRIs throughout gestation (medicated group);

37 women who had discontinued SSRI therapy in gestation or before conception (unmedicated group); and

130 healthy women without mental disorders who never took SSRIs (control group).

The researchers assessed fetal behavior using ultrasonography 3 times during pregnancy (between 15 and 19 weeks, 27 and 29 weeks, and 37 and 39 weeks of gestation). They studied the effects of SSRIs over a wide range of doses (low, standard, or high) and for different drug types. All of the medicated women were undergoing SSRI monotherapy, most often paroxetine (44%), fluoxetine (21%), and citalopram (20%).

According to the researchers, fetuses exposed to standard or high doses of an SSRI, irrespective of type, showed significantly increased motor activity at the beginning and the end of the second trimester, relative to control, unmedicated, or low-medicated fetuses.

"Most strikingly," note Dr. Mulder and colleagues, was a lack of inhibitory control of motor output at times the fetuses are supposed to be at rest or in quiet non-REM sleep. "Bodily activity at high rate during non-REM sleep in SSRI-exposed fetuses is an abnormal phenomenon," they point out.

They also note that the fetal effects of standard to high SSRI doses were seen throughout pregnancy but were "most prominent on the architecture of non-REM sleep near term."

Neurobehavioral development in fetuses of low-medicated and unmedicated women with psychiatric disorders was indistinguishable from development in healthy control fetuses, the researchers say.

Long-Term Follow-Up Critical

In a recent study, Dr. Oberlander and colleagues found changes in brain blood flow and heart rate variability at 36 weeks in SSRI-exposed fetuses, both before and after an acute dose of the drug.

The findings by Dr. Mulder's group "take it to the next step by showing behavioral differences (differences in body movement) that occur earlier than 36 weeks," Dr. Oberlander noted.

"The researchers have done one other thing that is absolutely critical in this area of research and that is try to tease apart the effect of mother's mood from the drug itself," he added.

The next critical question, said Dr. Oberlander, is to determine what these findings mean in terms of newborn and child behavior and to understand the areas of the brain that are influenced by changes in serotonin and related neurotransmitters."

In adults, he explained, serotonin plays a critical role in regulating mood, appetite, blood pressure, and other key functions.

"But long before it becomes a neurotransmitter, serotonin directs the development of its own system and other related systems that become important to regulating stress and thinking, learning, and memory," he said.

Therefore, changing levels of serotonin in the developing brain related to prenatal SSRI exposure "could have an impact that only appears later in development, making long-term follow-up really critical."

Population-Based Perspective Needed

In their paper, Dr. Mulder and colleagues note that studies have shown that neonatal problems seen after prenatal exposure to SSRIs are "time limited and usually resolve within a couple of weeks, although exposed infants appear to have increased health utilization in the first year of life."

They also point out that follow-up studies up to 5 years of age are "presently reassuring" as to the safety of SSRIs. Apart from subtle motor deficits in prenatally exposed infants, no major effects have been found on cognition, temperament, or internalizing and externalizing behaviors.

However, "from a neurodevelopmental view, the signs of non-REM sleep disruption may pose the SSRI-exposed fetus to future risks," Dr. Mulder and colleagues note. They conclude that use of higher-than-standard doses of SSRIs in pregnancy "may be discouraged, if possible and safe."

"We need to take a population-level perspective on this," said Dr. Oberlander.

"Between 15% and 20% of women experience mood disturbances during pregnancy that bring them to their clinician and impact everyday functioning. But rather than trying to think only about whether drug exposure is good or bad, we need to ask about the context that brings the fetus into contact with the drug and with mother's mood," he added.

It's clearly a "risk-benefit calculation that puts many women and their clinicians in a very difficult spot, and we have to recognize that there is no one-size-fits-all."

Dr. Mulder and colleagues and Dr. Oberlander have disclosed no relevant financial relationships.

Neuropsychopharmacology. 2011;36:1961-1971. Text

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