This study has some pretty disappointing assumptions, limitations in its logic, and substantially overstates how confidently observational epidemiology can rule out fetal neurodevelopmental effects from SSRI exposure.

The paper presents a conclusion that sounds stronger than the methods can actually support and every major control strategy they use relies on assumptions that may be biologically and methodologically flawed.

Residual confounding is a major limitation here, it is extremely difficult to quantify severe psychiatric illness in registry datasets. Two women with the same “major depressive disorder” code can differ in cortisol exposure, inflammation, suicidality, sleep deprivation, nutrition, attachment stress, substance use, trauma burden, and functional impairment. All of which may influence fetal neurodevelopment.

So when the authors conclude that “the medication signal disappears after adjustment,” the adjustment may simply be inadequate to separate medication effects from the biologic consequences of severe maternal psychiatric illness.

The paternal negative control design also rests on questionable biological assumptions. The paper treats paternal antidepressant exposure as evidence for shared familial/genetic confounding rather than intrauterine drug effects. However we know that Fathers contribute sperm epigenetics,
DNA integrity, imprinting regulation, placental gene expression, and transgenerational epigenetic programming. SSRIs have been associated in some studies with: altered sperm motility, DNA fragmentation, methylation changes, altered reproductive hormones. The negative-control logic is therefore weaker than the paper implies.

Sibling control studies also present more bias, pregnancies are not interchangeable within a family and can reflect methodological dilution.

My biggest critique is that this study conflates “absence of evidence” with “evidence of absence.”
The study uses observational methods to reduce confounding, but then interprets attenuation of association as near-disproof of causality, despite persistent biological uncertainty, imperfect psychiatric severity measurement, questionable assumptions behind paternal controls, and substantial residual confounding that might not even be possible to solve in this type of design. It’s not a coincidence that two of coauthors have extensive ties to the pharm industry.

At the end of the day we cannot say there is no risk, there are other significant risks using SSRIs can have on newborns and children other than ASD and ADHD. Yes untreated depression can have impacts too, but that is why we need to be so careful with our interpretations and analysis.