This issue highlights Pediatric Endocrine Self Assessment Program. Test your clinical knowledge and prepare for your exam. Available on the online store.
You are seeing a 16-year-old girl who just learned that she is pregnant. She is upset because she recently had an allergic skin reaction for which she was given prescription-strength hydrocortisone cream. She used the ointment multiple times a day for several days while unknowingly pregnant. She understands that some hydrocortisone was systemically absorbed and is concerned that the medication has harmed the baby.
Regarding potential harm, you tell her that her fetus is at:
- Low risk because hydrocortisone is mostly metabolized by the placenta
- Low risk because the fetal ACTH level has been suppressed briefly and should recover quickly
- Low risk because the amount of hydrocortisone is insignificant compared with the high levels of maternal cortisol already crossing the placenta
- High risk because hydrocortisone crosses the placenta and adversely affects fetal adrenal development
- High risk because hydrocortisone crosses the placenta and adversely affects fetal growth
Low risk because hydrocortisone is mostly metabolized by the placenta
The fetus in the vignette was exposed to hydrocortisone, which is metabolized by the placental enzyme 11β-hydroxysteroid dehydrogenase isoenzyme 2. Therefore, the fetus is relatively protected from excessive glucocorticoid exposure (thus, Answer A is correct). Prednisone and prednisolone are only partially metabolized by this enzyme and partially cross the placenta, and dexamethasone crosses the placenta in larger concentrations. The corticosteroids that cross the placenta can be used therapeutically to treat the fetus. For example, dexamethasone has been used to improve fetal lung maturity in pregnancies at risk for preterm labor and, when administered before the ninth week of gestation, has also been successfully used to minimize masculinization of the genitalia in female fetuses affected with classic 21-hydroxylase deficiency (off-label use). Because hydrocortisone is mostly metabolized by the placenta, the fetal corticotropin-releasing hormone and ACTH levels have not been altered (thus, Answer B is incorrect). Although the maternal cortisol level increases up to 2- to 3-fold over the course of the pregnancy, it overall has a minimal effect on the fetus (thus, Answer C is incorrect). Because hydrocortisone is mostly metabolized by the placenta, it does not affect fetal growth (thus, Answer E is incorrect).
While hydrocortisone taken by the mother should not affect fetal adrenal gland development (Answer D), it is important to understand the embryologic development of the adrenal gland in general. The cells of the adrenal cortex are derived from the mesoderm, and the cells of the adrenal medulla are derived from the neuroectoderm. The adreno-gonadal progenitor cells first appear around the fourth week of gestation. The adrenal and gonadal cells then separate, and the adrenal cells migrate to the cranial pole of the mesonephros. By the end of the eighth week of gestation, the rudimentary adrenal gland has become clearly encapsulated and becomes associated with the upper pole of the kidney. The fetal adrenal cortex consists of the large and predominant inner “fetal” zone and the smaller outer “definitive” zone. The fetal zone makes the androgenic precursors DHEA and its sulfated form DHEA-S, which are synthesized to estriol by the placenta throughout pregnancy. The fetal zone rapidly involutes after birth and almost completely disappears by 6 to 12 months of life. The definitive zone is the main site of glucocorticoid and mineralocorticoid production. There is a “transitional” zone between the two main zones, but its function is not well understood. At birth, the adrenal glands are almost as large as adult adrenals, and following the involution of the “fetal” zone, the growth of the adrenals (primarily of the “definitive” zone) is relatively slow.
Describe the effects on the fetus when glucocorticoids are administered to a pregnant woman.
Ishimoto H, Jaffe RB. Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit. Endocr Rev. 2011;32(3):317-355.
Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocr Rev. 2005;26(6):775-799.