Thus far, most studies assessing outcomes in children prenatally exposed to antidepressants have focused on risk for congenital malformations. In this context, there is ample evidence to support the reproductive safety of commonly used antidepressants. Over the last decade, we have seen an increasing number of studies examining long-term outcomes in children exposed to antidepressants, including neurodevelopmental outcomes. These studies have focused on the prevalence of developmental disorders, such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and, less commonly, performance on standardized tests of cognitive and motor development.
Determining the long-term neurobehavioral sequelae of fetal exposure to a particular medication presents many challenges. Prospective observational studies have yielded the richest data but are small and therefore underpowered in terms of estimating risk, especially when looking at more subtle outcomes. Larger studies using medical databases offer statistical power; however, studies including larger sample sizes are typically not able to consider confounding factors that may impact outcomes, including adherence to the treatment regimen, medication dosage and duration, quality of prenatal care, symptom burden during pregnancy, and exposure to tobacco and other substances.
The most recent review looking at long-term outcomes is from Rommel and colleagues (2020), presenting a systematic review of studies examining the long-term effects of prenatal exposure to antidepressants on physical, neurodevelopmental, and psychiatric outcomes in children 4 years of age or older.
The researchers identified original research articles in the medical literature which included information on the long-term outcomes of prenatal antidepressant exposure. After screening and removal of duplicate studies, a total of 34 studies were included in the analysis. Methodologies varied considerably across the studies. About 40% of the studies were prospective; the remainder were retrospective studies relying on large medical databases. Sample sizes ranged from 36 to over 1.5 million. Because of the significant heterogeneity of the studies, the authors were not able to perform a formal meta-analysis of the data. The quality of the evidence for the examined outcomes was rated as low to very low (per GRADE guidelines).
PHYSICAL OUTCOMES: Five studies investigated physical outcomes: asthma, cancer, body mass index (BMI), and epilepsy. There was no association between exposure and outcomes, except for conflicting results for BMI.
NEURODEVELOPMENTAL OUTCOMES: Eighteen studies examined an array of neurodevelopmental outcomes, including cognition, behavior, IQ, motor development, speech, language, and scholastic outcomes. Although some studies observed worse outcomes in children with prenatal exposure to antidepressants, they found no consistent associations with antidepressant exposure after taking potential confounders into account.
PSYCHIATRIC OUTCOMES: Eleven studies investigated psychiatric outcomes. After adjusting for confounders, prenatal antidepressant exposure was associated with affective disorders but not with childhood psychiatric outcomes, including autism spectrum disorders or attention-deficit/hyperactivity disorder.
Although previous studies have reported associations between in utero exposure to antidepressants and physical, neurodevelopmental, and psychiatric outcomes, this analysis indicates that these associations seem to reflect the underlying maternal psychiatric disorder, as opposed to prenatal exposure to a particular medication. When analysis controlled for confounding by indication, prenatal exposure to antidepressants was associated only with offspring BMI (conflicting results) and affective disorders.
When we look at outcomes in children with prenatal exposure to antidepressants, it is difficult, if not impossible, to account for all of the many factors that may impact outcomes. Given that maternal depression (in the absence of antidepressant exposure) has been associated with developmental delays and worse school performance in offspring, it is challenging to disentangle the effects of maternal depression from the effects of the medication used to treat this disorder. Furthermore, our studies are not randomized controlled trials, and there are important differences in women choosing to continue antidepressants during pregnancy versus those deciding to discontinue treatment. It is likely that women who continue treatment have more severe illness or psychiatric comorbidity. While smaller prospective studies may be able to measure depressive symptoms in mothers, larger databases do not contain this information.
In addition, it is very difficult to factor in the genetic and environmental factors associated with maternal psychiatric illness. More recent studies have used sibling pairs to control for genetic and environmental factors, comparing outcomes in exposed and unexposed siblings. While using this type of analysis decreases this type of confounding, it cannot totally eliminate it. For one, siblings, unless they are identical twins, share only 50% of their genetic material. Second, siblings are similar but not identical in terms of intrauterine exposures, parenting, exposure to adversity, educational experiences, and other important environmental factors which may affect long-term outcomes.
The importance of identifying and controlling for residual confounding factors is highlighted by the fact that while many studies show worse neurodevelopmental outcomes in children with prenatal exposure to antidepressants, the differences between exposed and unexposed children are attenuated or disappear after controlling for potential confounding factors. While questions and controversies remain, the information we have gathered on long-term outcomes is largely reassuring.
You can find the full (and free) text of our commentary on this study HERE.
Ruta Nonacs, MD PhD
Nonacs RM, Cohen LS. Challenges in Determining Outcomes of Prenatal Exposure to Antidepressants. J Clin Psychiatry. 2020 May 12. Free Article
Rommel AS, Bergink V, Liu X, Munk-Olsen T, Molenaar NM. Long-Term Effects of Intrauterine Exposure to Antidepressants on Physical, Neurodevelopmental, and Psychiatric Outcomes: A Systematic Review. J Clin Psychiatry. 2020 May 12;81(3):19r12965.