November 11, 2015
Over the last 2 decades, the medical community has accumulated more information regarding fetal exposure to selective serotonin reuptake inhibitors than almost any medicine that women take during pregnancy.
Data on the risks for major congenital malformations and even specific malformations, such as cardiac defects, are so vast that they can be confusing for clinicians and researchers alike to digest. Yet the consensus among experts in reproductive safety is that the risk of teratogenesis following fetal exposure to SSRIs is small in terms of absolute risks (N Engl J Med. 2007;356:2732-3.).
But women and their partners are worried about more than the risk of malformations. They also are concerned about how fetal exposure to SSRIs will impact long-term neurobehavioral sequelae. It turns out that is a much more challenging question, and the data available to inform our answers still are relatively sparse.
There have been several reports in the literature that suggest there are modest effects on motor function in children whose mothers used SSRIs during pregnancy, but these reports have not been particularly systematic and have excluded some relevant variables, such as the presence or absence of a psychiatric disorder during pregnancy.
In what is considered a seminal examination of this topic performed more than a decade ago, Dr. Irena Nulman and her colleagues at the Motherisk program in Toronto demonstrated the importance of accounting for postpartum maternal depression and mood. Among a group of children exposed to fluoxetine (Prozac) or tricyclic antidepressants throughout pregnancy, there were no differences in IQ or language development, compared with unexposed children between 15 and 71 months of age. However, children with lower cognitive and language achievement were more likely to have mothers with higher ratings of postpartum mood disturbance (Am J Psychiatry. 2002 Nov;159:1889-95.).
The charge to the field is to tackle this next clinical research frontier: the longer-term effects of fetal exposure to antidepressants and maternal psychiatric illness. Only by factoring in both of these important variables will we be able to get a true model of risk for this very critical issue of longer-term behavioral function.
Recently, researchers attempted to look at this question using data from the Norwegian Mother and Child Cohort study, a large population-based, prospective pregnancy cohort study. Children were assessed at age 3 years and motor development was assessed by maternal reports of fine and gross motor development using items from the Ages and Stages Questionnaire (ASQ). Maternal ASQ scores were compared with data from another Norwegian study in which clinicians assessed motor development using the gross and fine motor Mullen Scales of Early Learning (MSEL).
The strength of the study is that it included a very large number of children – more than 50,000 – although it is noteworthy that only a small percentage of women actually used SSRIs during pregnancy. A total of 381 women reported the use of SSRIs during pregnancy, with about half of the women reporting prolonged use (defined as exposure at two points of observation in the study).
The findings are noteworthy. The study showed that children with prolonged SSRI exposure were more likely to exhibit delays in fine motor development, compared with children with no fetal exposure to SSRIs (odds ratio, 1.42; 95% confidence interval, 1.07-1.87). The association persisted even after adjusting for symptoms of anxiety and depression before and during pregnancy. The severity of maternal depression provided only a partial explanation for the association, and depression after pregnancy appeared to have no impact on the estimated effect of SSRIs during pregnancy (BJOG. 2015 Sep 15. doi: 10.1111/1471-0528.13582).
So how does the clinician translate these findings into practice? While the study indicates that prolonged prenatal exposure to SSRIs was associated with delayed motor development at age 3 years, the association was very weak, and only a few children had clinically significant impairment in motor development. The finding should be reassuring to many women who are faced with this decision.
The researchers should be commended for trying to at least begin to tackle this critical frontier with respect to the risk-benefit decision in using these medicines during pregnancy. The problem is that in the absence of robust data quantifying the exposure to maternal psychiatric illness, the quality of the data still is somewhat limited.
So far the data indicate that there is not a major signal for neurobehavioral dysregulation associated with fetal exposure to SSRIs. That being said, to adequately answer the question for the field it will be important to conduct a single, prospective study where we can accurately quantify exposure to medicine and exposure to maternal psychiatric illness during pregnancy. That type of study will allow us to assess the relative exposures and come up with a much more refined risk estimate. We also will be able to fold in a critical piece – the role of genomics.
Genomics will play a significant role in determining risk because vulnerability to potential disruption in central nervous system development may be a factor in determining the development of the brain in utero. We know, for example, that prenatal stress affects neuromodulation in the brain, and that vulnerability to disruption will be variable from patient to patient. Prospective studies where we not only quantify what medicines women are taking and the severity of psychiatric illness, but also vulnerability to central nervous system disruption, if any, at the level of the genome will be a critical missing piece for future investigators.
Even similar exposure to medicine and psychiatric disorders may have variable effects on the developing brain. If we can identify that variability at the level of the genome, then we will be able to create a refined model of risk that will dictate personalized medicine with respect to reproductive psychopharmacology.
Dr. Cohen is the director of the Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. To comment, email him at email@example.com.