Effect of prenatal steroid treatment on the developing immune system

AbstractPrenatal steroids have an undisputed positive effect of de-creasingneonatalmorbidityandmortalitybyimprovingfetallung maturation. Some concerns have been raised on long-term consequences on the hypothalamic–pituitary–adrenalaxisandcognition,buttherearenostudiesaddressingeffectson the immune system. The thymus is an essential organ forthedevelopmentandselection ofTcells,andthymocytesareextremely sensitive to steroids. Using a mouse model for pre-natal steroid administration, we show here that betamethasonetreatment to the mother has a profound effect on the thymus ofthe offspring. We find the thym us volume reduced, affectingmostly the developing CD4+ CD8+ double-positive thymo-cytes and a compensatory accelera ted transition of the earlierstages to replenish the depleted compartment. This effect lastsfor at least 3 days, which correspond to a very relevant periodfortheselectionoftheTcellrepertoire.Moreover,weshowthatlow doses of betamethasone have similar effects on humanthymocytes in vitro. Therefore, further studies are needed toanalyze possible long-term consequences of this treatment onthe immune system of the offspring.Key message& Betamethasone administered to the mother before birthreaches the fetal thymus.& Prenatal betamethasone results in massive loss of devel-oping thymocytes.& The effects of betamethasone on thymus developmentare visible for several days.& Human thymocytes are also sensitive to low doses ofbetamethasone.& Altered thymocyte development around birth may havean effect on the immune system.Keywords Prenatalsteroids .Pregnancy .Betamethasone .Thymus .Apoptosis .ThymocytedevelopmentIntroductionWomen at risk of preterm birth before 34 weeks of gestationare routinely given a course of prenatal corticosteroids (ACS)to accelerate fetal lung maturation [1] in order to reduceneonatal mortality and respiratory distress syndrome. Knownsideeffectsofthistreatmentencompasslong-lastingeffectstothe hypothalamic–pituitary–adrenal (HPA) axis in children[2],andinmultiplecoursesofcorticosteroidtreatment,animalstudies have shown impaired brain growth [3, 4]. Until now,no studies have addressed the effect of prenatal steroid treat-ment on the immune system of the offspring, although corti-costeroids are known to promptly induce cell death of devel-oping thymocytes [5]. The thymus is an essential organ for Tcell production. Lymphoid precursors originating from thebone marrow migrate into the thymus, where they undergo