Reconsidering the association between maternal Crohn's disease and offspring psychiatric outcomes

Abstract

I am writing to express concerns regarding the conclusions of the article by Skott et al., titled “Offspring exposure to Crohn's disease during pregnancy and association with psychiatric regulatory disturbances in childhood,” published in your esteemed journal.¹ While the study provides valuable insights into the potential impacts of maternal Crohn's disease (CD) on offspring psychiatric health, several critical issues challenge the robustness of its conclusions.

The confounding influence of maternal use of medication may not have been completely adjusted in the study, especially corticosteroids. The standard treatment of CD exacerbations is corticosteroids, which have been shown to cross the placenta and have been linked to an elevated risk of mental and behavioral disorders in children.² Even though Skott et al. controlled anti-CD drugs, the exact effect of corticosteroids might not have been sufficiently separated, and the observed relationships might be overstated.

The literature is characterized by significant inconsistency when it comes to the relationship between maternal CD and the particular psychiatric conditions in offspring. According to Skott et al., there is no collaboration with autism spectrum disorders (ASD), but a recent study in Nature Medicine discovered a correlation between parental inflammatory bowel disease (IBD) and childhood autism.³ This inconsistency unlocks the possibility that genetic mechanisms are at work, rather than in-utero exposure, making it difficult to render a causal conclusion as done by Skott et al.

Genetic overlap between neuropsychiatric diseases and IBD has been thoroughly established. That statement is strongly supported by a 2023 genome-wide association study (GWAS) published in Med.⁴ In this investigation, which was conducted as a part of the Human Phenotype Project, the analysis of more than 8700 individuals revealed strong associations between Crohn's disease (CD) polygenic risk scores (PRS) and genes related to sleep regulation, feeding behavior, and metabolic properties. Interestingly, some of the CD-risk loci were shared with genes that control circadian rhythm, appetite, and hypothalamic signaling pathways—implicating a common genetic basis between immune dysregulation and neurobehavioral phenotypes. The fact that the authors did not control the psychiatric histories of parents or the genetic information of offspring makes it possible that the observed relationships may be due to inherited vulnerability as opposed to prenatal exposure.

Other cohort studies have reported no increased risk of long-term morbidities in the offspring of mothers with IBD. For instance, Jølving et al. (2017) found no elevated risk for various diseases.⁵ Although these studies may not have specifically targeted the same psychiatric outcomes, they collectively question the generalizability of Skott et al.'s findings.

In light of these concerns, I urge the authors to reconsider their data in the context of these limitations and inconsistencies. Future research should focus on disentangling the effects of maternal disease activity, medication use, and genetic predispositions on offspring psychiatric health. Such studies are essential for providing accurate guidance to clinicians and patients managing CD during pregnancy.

No funding was received for the preparation or submission of this letter.

The authors declare no conflicts of interest related to this letter.