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Published:March 14, 2020DOI:https://doi.org/10.1016/j.ajog.2020.03.014
      We thank Dr Jobe for making the point that fetal neurodevelopment is susceptible to a range of insults, which may include exposure to antenatal corticosteroids that are widely accepted as having no adverse effects on the fetus. We share your view that animal studies compellingly suggest that corticosteroids alter developmental programming that can lead to physiologic or anatomic changes, which may not manifest clinically for decades.
      • Jobe A.H.
      Antenatal corticosteroids: a concern for lifelong outcomes.
      Addressing this question is challenging on 2 levels: (1) we cannot perform a clinical trial that randomizes pregnant women to receive or not receive corticosteroids without compromising neonatal survival, and (2) studying long-term health outcomes after birth requires decades of data in very large cohorts with appropriate methods to address the most common threats to causal inference that include confounding, effect modification, and bias on multiple levels.
      Few places in the world have the healthcare and medical record infrastructure to enable the epidemiologic investigation of the developmental origins of neuropsychiatric disorders. Scandinavia and a few other European countries are ideal places to study these questions because their perinatal databases can be linked to outcomes in children over many decades. As we demonstrated in a Swedish cohort
      • Al-Haddad B.J.S.
      • Jacobsson B.
      • Chabra S.
      • et al.
      Long-term risk of neuropsychiatric disease after exposure to infection in utero.
      of pregnant women with an inpatient diagnosis of infection, children must be followed for at least 7 years to capture a substantial proportion of autism spectrum disorder diagnoses; for depression, >21 years of follow up was necessary. We are intrigued by the findings of a recent Finnish study of 4708 pregnant women and their children followed for 6–10 years after birth; betamethasone exposure was associated with a significantly higher odds ratio of “any mental and behavioral disorder” (ICD-10 coding: F00-F99; odds ratio, 2.76; 95% confidence interval, 1.76–4.32).
      • Wolford E.
      • Lahti-Pulkkinen M.
      • Girchenko P.
      • et al.
      Associations of antenatal glucocorticoid exposure with mental health in children.
      Interestingly, this association was independent of whether the child was born preterm or at term.
      Investigation of the link between antenatal corticosteroids and the long-term risk for neuropsychiatric disorders in children is critical given the recent expansion in obstetric practice for administering corticosteroids to pregnant women. We see an important role for epidemiologic studies using models with causal frameworks of the complex variables programming neurodevelopmental outcome. Although we focused on the link between infectious diseases in pregnancy and neuropsychiatric outcomes in our review,
      • Al-Haddad B.J.S.
      • Oler E.
      • Armistead B.
      • et al.
      The fetal origins of mental illness.
      we concur that the impact of corticosteroid use in pregnancy is understudied and concerning on a population level.

      References

        • Jobe A.H.
        Antenatal corticosteroids: a concern for lifelong outcomes.
        J Pediatr. 2020; 217: 184-188
        • Al-Haddad B.J.S.
        • Jacobsson B.
        • Chabra S.
        • et al.
        Long-term risk of neuropsychiatric disease after exposure to infection in utero.
        JAMA Psychiatry. 2019; 76: 294-602
        • Wolford E.
        • Lahti-Pulkkinen M.
        • Girchenko P.
        • et al.
        Associations of antenatal glucocorticoid exposure with mental health in children.
        Psychol Med. 2020; 50: 247-257
        • Al-Haddad B.J.S.
        • Oler E.
        • Armistead B.
        • et al.
        The fetal origins of mental illness.
        Am J Obstet Gynecol. 2019; 221: 549-562

      Linked Article

      • Other causes of fetal brain injury
        American Journal of Obstetrics & GynecologyVol. 223Issue 2
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          Your recent publication from Al-Haddad et al1 struck a cord with me as I read the print copy, old fashioned I know. The Al-Haddad et al article about fetal origins focused only on infections; however, in the same issue there is a very good clinical opinion from Caritis and Panigrahy2 about maternal opioids and fetal brain development. Another interest of mine, antenatal corticosteroids, also has increasing literature about fetal brain effects.3,4 It is not all just infection that may be causing mental illness in later life.
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