Long-term prenatal effects of antidepressant use on the risk of affective disorders in the offspring: a register-based cohort study

Abstract

To investigate the association between intrauterine antidepressant exposure and offspring affective disorders over an 18-year follow-up period using Danish national registers. We included 42,988 singletons born during 1998-2011 and followed-up until 2016, death, emigration, or date of first affective disorder diagnosis. Children were categorised into two groups according to maternal antidepressant use within 2 years before and during pregnancy: continuation (use before and during pregnancy) or discontinuation (use before but not during pregnancy). The outcome was an affective disorders diagnosis in the offspring based on secondary/tertiary care records and primary care prescription data. Hazard ratios (HR) of affective disorders were estimated using Cox regression models. To consider confounding by shared environmental or genetic factors, we investigated the effect of paternal antidepressant use on the risk for affective disorders. Affective disorders were diagnosed in 1538 children. Children whose mothers continued antidepressants during pregnancy had an increased risk of affective disorders (HR = 1.20, 95% CI = 1.08-1.34), compared with children whose mothers discontinued before pregnancy. Similarly, continued paternal antidepressant use during pregnancy was associated with higher risk for offspring affective disorders (HR = 1.29, 95% CI = 1.12-1.49), compared to discontinuation. Based on data from primary and secondary/tertiary care, maternal antidepressant use during pregnancy was associated with an increased risk of affective disorders in the offspring. As similar associations were observed in children whose fathers continued antidepressant use across the pregnancy period, the observed association may be attributable to the underlying parental psychopathology, rather than the direct intrauterine exposure to antidepressants.

Prenatal Selective Serotonin Reuptake Inhibitor Exposure, Depression and Brain Morphology in Middle Childhood: Results from the ABCD Study

“…The initial link we observed between prenatal SSRI exposure and a small elevation in depressive symptoms in children was robust to the inclusion of lifetime history of maternal depression and depression density among first-degree relatives, but not recent (i.e., past-six-months) maternal depressive symptoms. Our observations contrast with large studies showing that prenatal SSRI exposure is associated with elevated risk for depression or internalizing symptoms ( Table 1 ; (6– 12)). Notably, over half of these studies did not explicitly model any form of maternal depression in analyses (8–10,12) and only a few (7,11) evaluated recent maternal depressive symptoms, though the children in these studies were younger than the current one.…”

“…Our observations contrast with large studies showing that prenatal SSRI exposure is associated with elevated risk for depression or internalizing symptoms ( Table 1 ; (6– 12)). Notably, over half of these studies did not explicitly model any form of maternal depression in analyses (8–10,12) and only a few (7,11) evaluated recent maternal depressive symptoms, though the children in these studies were younger than the current one. Along these lines, our observations mirror prior null associations observed for child internalizing symptoms at younger ages in studies that accounted for maternal depression during pregnancy and childhood ((13–17)).…”

“…Prenatal SSRI exposure has been associated with a host of adverse physical outcomes (e.g., diminished fetal growth, hypertension) (5), with mixed evidence that it may (e.g., (6–12)) or may not (e.g., (13–17)) be associated with depression-related phenotypes among offspring, even when considering maternal depression ( Table 1 ). Overall, larger studies have generally identified associations between prenatal SSRI exposure and depression-related outcomes, even when accounting for maternal depression and using concordant/discordant sibling designs (6,9–12), while the majority of null associations have arisen from relatively smaller samples (14,15,17).…”

“…Prenatal SSRI exposure has been associated with a host of adverse physical outcomes (e.g., diminished fetal growth, hypertension) (5), with mixed evidence that it may (e.g., (6–12)) or may not (e.g., (13–17)) be associated with depression-related phenotypes among offspring, even when considering maternal depression ( Table 1 ). Overall, larger studies have generally identified associations between prenatal SSRI exposure and depression-related outcomes, even when accounting for maternal depression and using concordant/discordant sibling designs (6,9–12), while the majority of null associations have arisen from relatively smaller samples (14,15,17). Contrasting a relatively sizable literature investigating prenatal SSRI exposure and depression-related outcomes in young children, there has been limited investigation of putative neural mechanisms through which risk may arise, despite evidence from non-human animal models that prenatal SSRI exposure may induce depression by altering brain development (e.g., (18)).…”

Treatment of Peripartum Depression with Antidepressants and Other Psychotropic Medications: A Synthesis of Clinical Practice Guidelines in Europe

“…However, only more recent studies have compared outcomes in offspring born to continuers versus discontinuers [ 61 ]. Antidepressant continuation in pregnancy was found to increase the risk of low birth weight, premature birth, or affective disorder diagnosis later in childhood [ 62 , 63 , 64 , 65 ]. Yet, the role of confounding by maternal disease severity remains an important concern in this research.…”