Jain D*, Warke HS**.
(* First Year Resident, ** Associate Professor. Department of Obstetrics and Gynaecology, Seth G.S Medical College and KEM Hospital, Mumbai, India.)
Congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder, the most common cause of which is 21 hydroxylase enzyme deficiency. Fertility in women with congenital adrenal hyperplasia is decreased due to various reasons. We present a case of a woman with a diagnosed case of CAH who had undergone genitoplasty surgery in childhood, but conceived spontaneously without any assisted reproductive technique and gave birth to three consecutive healthy female children.
CAH is a group of inherited disorders characterised by inability to synthesise cortisol. More than 90% of the cases are due to 21 hydroxylase deficiency. Other deficiencies could affect genes coding for 11-beta-hydroxylase, 17-alpha-hydroxylase, 3-beta-hydroxysteroid dehydrogenase, aldosterone synthase and steroid acute regulatory protein (STAR); and these deficiencies have varied presentations. The gene encoding 21 hydroxylase enzymes is CYP21, and in classical CAH the production of cortisol and aldosterone is decreased or absent, which results in excessive production of pituitary ACTH. This in turn leads to excessive production of adrenal androgens and progesterone, including 17-hydroxy-progesterone.
A 30 year old woman, G3P2L2 with previous two lower segment caesarean sections, a diagnosed case of 21- hydroxylase deficiency (simple virilising variant of CAH) presented to the antenatal outpatient department at 15 weeks of gestation. She had been diagnosed as CAH at 5 years of age with ambiguous genitalia, raised 17- hydoxyprogesterone level, enlarged clitoris and normal karyotype (46, XX).
At the age of 7 years, she underwent reduction clitoroplasty and vaginoscopy. On vaginoscopy normal vagina and cervix was visualised. Urethral and anal orifices were normal. Ultrasonography showed a hypoplastic uterus with normal bilateral ovaries. She was started on tablet prednisolone 5 mg daily. She had regular follow up with endocrinologists at our institute.
Menarche was attained at the age of 13 years, but cycles were irregular. She developed salt craving. Her blood pressure was normal (110/70 mm of Hg). Endocrinologist changed her medications from tablet prednisolone to tablet dexamethasone 0.5 mg at bed time.
She got married at the age of 18 years. She had spontaneous conception after 1 year of marriage and a second conception after two years. During both the pregnancies she was registered at our hospital and tablet dexamethasone 0.5 mg once a day was continued throughout the pregnancies. Both previous pregnancies resulted in healthy female children delivered by lower segment cesarean sections (first for breech 6 years back and second for failure of induction of labor 4 years back). Postoperatively she was continued on tablet prednisolone 5mg once a day. Both the children had normal karyotype and a normal growth pattern.
She again conceived spontaneously and came for registration at 15 weeks of gestation at our hospital. The development of fetus was appropriate for the gestational age. Tablet dexamethasone 0.5 mg once a day was continued in consultation with endocrinologist. Antenatal course was otherwise uneventful. Elective cesarean section was performed at 39 weeks gestation in view of previous two lower segment cesarean sections. She delivered a healthy female child with normal appearing genitalia weighing 2.99 kgs with normal Apgar score. Perioperatively injection hydrocortisone 100 mg was administered intravenously. Postoperatively she was started on tablet prednisolone 5 mg OD which was continued in the postpartum period.
CAH was first described by De Crecchio in 1865 and academically confirmed by Wilkins et al. Congenital adrenal hyperplasia is a rare congenital disorder acquired by autosomal recessive inheritance. It is known that 21- hydroxylase deficiency is the main cause of CAH in 90% to 95% cases. Our patient had classical type of CAH.
The classical form is diagnosed with early clitoromegaly necessitating surgical correction, as was done in our patient. Internal reproductive organs, ovaries, uterus, fallopian tubes, upper vagina and mullerian structures are normal, as was seen in our patient.
Due to genetic deficiency of 21 hydroxylase, synthesis of cortisol is decreased and secretion of ACTH is increased as the hypothalamus-pituitary reacts to low levels of cortisol. It induces hyperplasia of adrenal cortex, resulting in increased precursors of cortisol and testosterone and distinctive clinical symptoms, with a wide spectrum of severity. The cornerstone of the management of CAH is suppression of ACTH with orally administered steroids.
The dose of steroids should be carefully adjusted in order to protect external genitalia of the fetus and at the same time to avoid cushingoid features in the mother. Dexamethasone (20 μg/kg/day) should be instituted before the ninth week of gestation and continued throughout pregnancy. The fetal hypothalamic-pituitary-adrenal axis gets inhibited and the excess androgen secretion from the adrenal is reduced which prevents virilization in affected females. Dexamethasone is preferred due to its propensity to cross the placenta and reach the fetal circulation.
An increased incidence of cesarean section has been reported in females with CAH. This is due to cephalopelvic disproportion in these females because of android nature of the pelvis due to excess of androgens. It can also be due to reconstructive surgeries done on the genitalia.
All three pregnancies in our patient resulted in female babies. There is an increased propensity of female infants in those with classic congenital adrenal hyperplasia. Among children born to women with congenital adrenal hyperplasia, it was found that only 25% were boys as compared to 55% in control population. This uneven sex ratio can be due to feminine environment in these mothers during the time of implantation due to steroid administration.
To summarize, the goals of therapy in a pregnancy with CAH include prevention of adrenal insufficiency, reduction of fetal exposure to androgens by use of glucocorticoids and avoidance of damage to reconstructed genitalia. Prenatal glucocorticoid therapy is key to management.
Women with congenital adrenal hyperplasia have lower rates of conception. They should regularly receive glucocorticoid therapy in order to prevent the occurrence of ambiguous genitalia in the fetus. With a multidisciplinary approach involving endocrinologists, successful pregnancy outcomes are possible.
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Jain D, Warke HS. Pregnancy In A Patient With Congenital Adrenal Hyperplasia. JPGO 2018. Volume 5 No.3. Available from: http://www.jpgo.org/2018/03/pregnancy-in-patient-with-congenital.html