Paternal Depression as a Risk Factor for Neurodevelopmental Disorders in Offspring: Implications for Maternal Depression and Its Treatment During Pregnancy

A great deal of research has been conducted on the risk of autism spectrum disorder (ASD) and attention-deficit/
hyperactivity disorder (ADHD) in offspring after maternal exposure to antidepressant drugs during pregnancy.1-3 However, there is no clarity, yet, on whether antidepressants contribute to the risk or whether the risk is driven primarily by variables related to maternal depression, the commonest indication for antidepressant use during pregnancy. Interestingly, research has shown that paternal antidepressant use during pregnancy is also associated with an increased risk of ASD in offspring, though the evidence is not consistent.4,5 A recent study6 that focused on paternal depression in relation to pregnancy and subsequent risk of ASD and ADHD in offspring is therefore of interest.

Parental Depression and Neurodevelopmental Outcomes in Offspring

Chen et al6 studied a birth cohort of children (n = 708,515; 52% male) born in Taiwan during 2001-2008 and followed to the end of 2011. The data were drawn from the Taiwan National Health Insurance Research Database, which contains health care data of > 99% of the population of the country. Data were extracted for ASD and ADHD in children and depression in parents; diagnoses were based on ICD-9 codes. Using Cox regression, the authors studied the effects of paternal and maternal depression on the risk of ASD and ADHD in the offspring, with exposure to parental depression recorded as present before pregnancy, during pregnancy, and < 1, 1-3, and > 3 years after birth. These analyses were adjusted for family income, degree of family urbanization, parental ages, and offspring sex.

The mean age of the mothers was 29 years, and that of the fathers was 32 years. The prevalence of depression before pregnancy was 2.2% in mothers and 1.2% in fathers; these figures were 0.5% and 0.6%, respectively, during pregnancy, and 1.4%-6.6% and 0.8%-3.6%, respectively, in the different time intervals after birth. ASD was diagnosed in 0.6% of the children at a mean age of 4.6 years, and ADHD was diagnosed in 4.0% at a mean age of 6.3 years.

Important findings from the study6 are presented in Table 1. In summary, maternal and paternal depression were each associated with a statistically significant increase in the risk of each disorder (ASD and ADHD), and in each of the 5 exposure windows studied (before, during, and after pregnancy). When adjacent exposure windows were clubbed together to capture possible increased risks associated with chronic depression, for maternal as well as paternal depression the risks were generally similar for ASD but slightly raised for ADHD, suggesting that chronicity of exposure to depression may be important for the risk of ADHD only. Combined maternal and paternal depression was also associated with generally (modestly) higher values for risk.

Critical Appraisal

In general, studies examining neurodevelopmental outcomes after antidepressant exposure during pregnancy adjust analyses for many, even dozens of, confounding variables. In contrast, the study by Chen et al6 adjusted for very few confounds. As examples, there was no adjustment for maternal comorbidities; maternal medication exposure during pregnancy; maternal use of tobacco, alcohol, and other substances; and exposures to environmental adversities before or after birth, all of which could potentially influence the risk of adverse neurodevelopmental outcomes. However, the authors6 examined risks associated with exposure to depression in each parent separately and in the context of exposure during different time windows before as well as after birth; the study findings can therefore guide hypotheses on what may drive the risk. In this context, the finding of increased risk associated with paternal depression for each disorder (ASD and ADHD) in each window of exposure assumes importance.

A large number of observational studies have examined the association between antidepressant exposure during pregnancy and the risk of neurodevelopmental disorders, especially ASD, in offspring. Many but not all studies have found that antidepressant exposure is associated with an increase in risk. However, studies specifically with ASD as the outcome of interest have also found increased risks associated with antidepressant exposure limited to the pre-pregnancy period, and studies have found increased risks in gestationally antidepressant-unexposed siblings, as well. The findings of Chen et al6 are therefore important because if paternal depression is associated with increased risk of ASD and ADHD in offspring, the spotlight moves away from maternal depression and antidepressant use during pregnancy and shifts to unknown and unmeasured confounds.

If paternal as well as maternal depression, occurring in any time window, can increase the risk of ASD and ADHD in offspring, genetic factors are important candidates for the unknown and unmeasured confounds. In this context, a recent, very large genetic study found 20 loci common to major depression and ASD and 10 loci common to major depression and ADHD.7,8 Besides genetic factors, environmental adversities can also be unknown and unmeasured confounds. For example, behaviors associated with paternal depression may compromise maternal physical and mental health and thereby compromise the future health of an unborn child. Similarly, such behaviors may create environmental adversities during infancy and early childhood, and exposure to these adversities may compromise the health of the developing child.

This does not mean that the experience of maternal depression and gestational exposure to antidepressants are not risk factors; it merely means that the roles of maternal depression and antidepressants, if any, may be even smaller than previously believed. This conclusion is important because health care providers may be reluctant to prescribe an antidepressant during pregnancy because of the studies associating gestational antidepressant exposure with neurodevelopmental risks, and depressed pregnant mothers may be reluctant to use antidepressants, if advised, for the same reason. The understanding that genetic variables or environmental adversity may drive the risk could reduce the guilt associated with the use of antidepressants during pregnancy and reduce the suffering of mothers who respond after initiating the antidepressant. In fact, an expectant mother who is less depressed because she has responded to an antidepressant may have a healthier internal and external environment, and healthier behaviors, than an expectant mother who suffers through her depression out of fear of risks associated with antidepressant use.

Final Notes

The discussion presented in the previous section is not intended to imply that antidepressants are safe during pregnancy; there are many other antenatal, perinatal, and postnatal risks that have been associated with gestational exposure to these drugs, though a causal role can never be established in observational research.9-15 All decision-making regarding treatment during pregnancy therefore needs to be shared between the health care provider and the expectant mother. Last, but not least, the findings of studies of outcomes in antidepressant-exposed pregnancies should be considered possibly suspect if they have not been adjusted for exposure to paternal depression.

Published online: December 1, 2020.

Each month in his online column, Dr Andrade considers theoretical and practical ideas in clinical psychopharmacology with a view to update the knowledge and skills of medical practitioners who treat patients with psychiatric conditions.

Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences, Bangalore, India ([email protected]).
Financial disclosure and more about Dr Andrade.

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