The management of congenital adrenal hyperplasia during preconception, pregnancy, and postpartum

Abstract

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders of steroidogenesis of the adrenal cortex, most commonly due to 21-hydroxylase deficiency caused by mutations in the CYP21A2 gene. Although women with CAH have decreased fecundity, they are able to conceive; thus, if pregnancy is not desired, contraception options should be offered. If fertility is desired, women with classic CAH should first optimize glucocorticoid treatment, followed by ovulation induction medications and gonadotropins if needed. Due to the possible pregnancy complications and implications on the offspring, preconception genetic testing and counseling with a high-risk obstetrics specialist is recommended. For couples trying to avoid having a child with CAH, care with a reproductive endocrinology and infertility specialist to utilize in vitro fertilization can be offered, with or without preimplantation genetic testing for monogenic disorders. Prenatal screening and diagnosis options during pregnancy include maternal serum cell free-DNA for sex of the baby, and chorionic villus sampling and amniocentesis for diagnosis of CAH. Pregnant women with classic CAH need glucocorticoids to be adjusted during the pregnancy, at the time of delivery, and postpartum, and should be monitored for adrenal crisis. Maternal and fetal risks may include chorioamnionitis, maternal hypertension, gestational diabetes, cesarean section, and small for gestational age infants. This review on CAH due to 21-hydroxylase deficiency highlights reproductive health including genetic transmission, contraception options, glucocorticoid management, fertility treatments, as well as testing, antenatal monitoring, and management during pregnancy, delivery, and postpartum.

Keywords: 21-hydroxylase deficiency; Congenital adrenal hyperplasia; Contraception; Fertility; Pregnancy.

Fig. 1

The genetics of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The most commonly found mutations are shown in relation to the phenotypic spectrum. Mutations range from complete loss of function of the 21-hydroxylase enzyme associated with the classic salt-wasting type to mild impairment with 30 to 50 percent of enzyme activity associated with the nonclassic type. Overall, there is a continuum of disease severity with clinical overlap of these categories, good correlation between genotype and phenotype for severe mutations (residual 21-hydroxylase function 0–1%) and greater phenotype variability amongst intermediate and less severe genotypes. Adapted from Merke et al. N Engl J Med 2020

Fig. 2

Genetic risk of a patient with CAH having a child with CAH. The majority of patients with CAH are compound heterozygotes with different mutations on each allele and a phenotype corresponding to the milder gene defect. (A) If the partner of a patient with CAH is not a carrier, then all offspring will be carriers. (B) If the partner of a patient with CAH is a carrier of CAH, then there is a 50 percent risk of CAH in the offspring. Based on the incidence of classic CAH, approximately 1 in 60 individuals carry an allele that causes classic CAH. Therefore, the probability that a patient with classic CAH will have a child with classic CAH is 1 in 120 (1/60 x ½) if the genotype of the partner is unknown. Genetic counseling and genotyping are recommended prior to conception

Fig. 3

Genetic risk of a patient with nonclassic CAH (NCCAH) having a child with classic CAH. (A) Approximately two-thirds of patients with NCCAH carry an allele that causes classic CAH. Therefore, half of all children might be carriers of a classic gene. (B) If the partner of a patient with NCCAH is a carrier of classic CAH and the patient with NCCAH carries an allele that causes classic CAH, then there is a 25 percent risk of classic CAH and 25 percent risk of NC CAH in offspring. If the genotypes are unknown, the risk of a patient with NCCAH having a child with classic CAH is approximately 1 in 350 (2/3 × 1/2 × 1/60 × 1/2), but a higher prevalence up to 2.3% has been shown in retrospective cohort studies [21, 22]

Fig. 4

Preconception and infertility management for couples who desire fertility. Many patients with CAH may only have a clinical diagnosis. In order to identify and minimize the risk of having a child affected with CAH, partner genetic testing is recommended, especially if the partner is from the same family or ethnicity. Green boxes show treatment for the female patient with CAH. ¹Approximately two-thirds of patients with NCCAH carry an allele that causes classic CAH (see Fig. 3). Both alleles of patients with classic CAH carry mutations that cause classic CAH. ²Glucocorticoid therapy is recommended for patients with NC CAH and infertility (no conception after 12 months) or history of miscarriage. ³Ovarian reserve testing, semen analysis, hysterosalpingogram/sonohystogram