ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This systematic review examined the impact of at least one trimester of pregnancy glucocorticoid treatment on pregnancy, neonatal and child outcomes. It included human studies published after 2000 (to 2022) to avoid earlier work where maternal and newborn care may have been outdated. It identified 23 eligible papers, most described cohort studies (not all had control groups), 3 case reports or series and one meta-analysis of dexamethasone (DEX) to prevent virilisation in CAH¹. The glucocorticoids of interest were predniso(lo)ne (10 studies), DEX (11 studies) or both (2 studies).

Antenatal prednisone up to 60 mg/d and prednisolone up to 40 mg/d did not increase risk of miscarriage, stillbirth or neonatal death, there was no evidence of harmful effects on congenital abnormalities, birth weight, blood pressure, hypoglycemia or hypocortisolemia. In children followed until age 7y, (methyl)predniso(lo)ne was not associated with altered body composition, bone mass, or BMI. These somewhat reassuring results for pregnant women treated for a wide number of conditions (such as anti-SSA/Ro antibodies, rheumatoid arthritis, inflammatory bowel disease, lupus). Although monitoring of offspring is still short term, it must be remembered that these synthetic glucocorticoids can be inactivated by placental 1β-hydroxysteroid dehydrogenase type 2, unlike DEX.

For antenatal DEX, the commonly used dose 20 mcg/kg/day showed no association with lower birth weight, preterm birth or altered childhood body composition. There was a higher incidence of miscarriages and stillbirths with DEX ≥ 4 mg/d in early pregnancy, but it is difficult to infer causality due to prescription indication bias. Mild adrenal insufficiency was reported in 2 newborns. In longer term follow-up, antenatal DEX (1-1.5 mg/d) was associated with lower insulin secretion, and at ages ≥ 16y, higher plasma glucose, total cholesterol and LDL-cholesterol were noted in offspring exposed to 20 mcg/kg/d.

This systematic review concludes that girls exposed to antenatal DEX 20 mcg/kg/d had lower scores of both verbal and non-verbal intelligence, as well as verbal working memory tasks at age 7-17y. Visual spatial working memory was also negatively affected. Another excellent but non-systematic review summarised CAH diagnosis and treatment in animal and human studies with prenatal DEX exposure, including cognitive and behavioral effects². Clearly more longitudinal studies are needed. Until then, updated Endocrine Society guidelines recommend antenatal DEX only for CAH and only within approved studies, and when possible, to use cell-free fetal DNA testing from as early as 6-7 weeks to avoid exposure to male fetuses³.

References: 1. Fernández-Balsells MM, Muthusamy K, Smushkin G, et al. Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: a systematic review and meta-analyses. Clin Endocrinol (Oxf). 2010;73(4):436-444. doi: 10.1111/j.1365-2265.2010.03826.x.2. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia-current insights in pathophysiology diagnostics management. Endocr Rev. 2022;43(1):91-159. doi: 10.1210/endrev/bnab016.3. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2018; 103(11):4043-4088. doi: 10.1210/jc.2018-01865.