Interpretation
In line with prior studies showing HR of magnitude
0.75-0.9836,37 with 1.20 as upper bound of the pooled
95% CI,38 we found no substantial difference in ADHD
risk between prenatally SSRI/SNRI exposed children and children born to
non-medicated women. Albeit with some uncertainty, the averaged hazard
for ADHD with SSRI/SNRI exposure at any time during pregnancy was
elevated (53% increased risk) when comparing to discontinuers, and
likewise following 9-20 weeks exposure duration (2.1-fold increase).
These contrasting results across comparisons may be in part due to lower
impulsive traits and thereby lower ADHD risk in discontinuers than in
the other groups; however they do also suggest that antenatal
depression/anxiety is possibly a key confounder. While confounding by
indication was limited in the comparison with non-medicated, by
restriction, discontinuers had no active psychiatric illness in
pregnancy.16 This risk of confounding did not emerge
in the timing analysis, possibly because we fit methods able to account
for time-varying depression symptom severity in
pregnancy.30
Causal interpretation of HR is however risky, and effect estimates
averaged over the duration of study’s follow-up may not be
informative.39 In this study, the HRs changed over
time and this was not due to a cohort effect or to sex-specific
differences. We observed lower or at least equal ADHD risk in SSRI/SNRI
exposed children compared with unexposed in early childhood. Yet, an
increased risk emerged in mid childhood (7-9 years). This temporal trend
was apparent across all the window of exposures, except for SSRI/SNRI in
late pregnancy, which partly aligns with the result of Boukhris et
al .40 Further comparison with prior research is
difficult since adjusted survival curves are often not presented, the
follow-up time is too short, or it is unclear whether the HRs were
constant over time.36,39,41-43
The observed ADHD risk reduction at early childhood aligns with our
analysis by child age 5 years; nevertheless, the effect sizes were small
and unlikely to reach clinical relevance. This absence of risk aligns
with results of prior studies that controlled for maternal mood
disorders, genetic liability or familial
environment.44 Alternative explanations are however
possible: chance, few ADHD cases in early childhood, or distorted
maternal report on child ADHD symptoms.45
The apparent elevated risk for ADHD observed in mid childhood, at age
7-9 years, needs careful interpretation. We found some evidence for an
association between SSRI/SNRI ever exposure (93% increased hazard) or
for 9-20 weeks duration (2.8-fold increased hazard), relative to
non-medicated in this age band. Evidence was weak for longer duration of
exposure, and there were no substantial timing associations. Inattention
symptoms are more easily detected as children grow
older.46 Our age-specific results may then be
explained by measurement issues, but bias due to frailty, small sample
size, or competing risks cannot be ruled out. If the former explanation
holds true, the question remains as to why measurement bias would be
differential across the exposure groups. It could be argued that
children prenatally exposed to an active, non-medicated depression are
more susceptible to the combined type of ADHD,46 often
detected in earlier childhood. This would reduce the number of
susceptible children in this group over time, and in turn produce a
fictitious increased hazard for the
SSRI/SNRI-exposed.39 At the same time, an age-specific
association between prenatal SSRI/SNRI and predominantly inattentive
ADHD subtype,46 cannot be completely ruled out. The
pathophysiology of ADHD involves multiple neuronal circuits, and
serotonin has been shown to modulate the default mode
network.47,48 Yet, the role of age-specific genetic
influences, or the importance of the environmental exposure to
depression or SSRI/SNRI on ADHD across ages, remains untestable in the
current study.49
Our results document the confounding role of maternal pre-existing
clinical depression/anxiety, yielding a risk attenuation of 18-20% in
the weighted effect estimates. This factor was independently associated
with child ADHD (34% increased risk), which replicates prior
research.40 It is reasonable that maternal psychiatric
status prior to pregnancy confound the antidepressant-ADHD association
via unfavorable health behaviors, poor nutrition, or genetic make-up.