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Reproduction and Fertility

Prenatal Treatment of Congenital Adrenal Hyperplasia

by Svetlana Lajic, MD, PhD

Ever since the first case was described, more than 20 years ago (1) , where prenatal virilization was prevented with dexamethasone (DEX) in a CAH affected female fetus, the treatment has been intensely debated. On the one hand, the treatment offers a means to prevent genital surgery in affected female infants, but in order to be fully effective it has to be initiated in the early first trimester before prenatal diagnosis with chorionic villous sampling is possible. Thus, a majority of treated fetuses (7 out of 8) will not benefit at all from the treatment, since CAH due to 21-hydroxylase deficiency is an autosomal recessive disorder. The question is whether early prenatal exposure to glucocorticoids such as dexamethasone may harm the developing fetus and lead to an increased risk of somatic (physical) and neuropsychological disease later in adult life.

The rationale for prenatal treatment is to treat the fetus with a glucocorticoid via the mother, in order to suppress the fetal adrenal androgen production that is increased in fetuses with severe forms of CAH (the salt-wasting and simple virilizing variants). Fetuses with mild non-classical CAH do not benefit from the treatment and it is therefore important that each family is genotyped prior to planning a second pregnancy, so that a correct genetic counseling can be offered. There are clear genotype-phenotype relationships in 21-hydroxylase deficiency and the degree of virilization can be predicted based on experience from previous cases. A mother that has previously given birth to a child with severe CAH can thus be offered treatment with DEX at 6-7th week of pregnancy in the next coming pregnancy. The dose given is 20 µg/kg body weight/day, based on pre-pregnancy weight and maximum 1.5 mg/day, in three divided doses. A few weeks later, around week 12, prenatal diagnosis is performed on fetal DNA obtained from a chorionic villous biopsy (CVS). In healthy fetuses and in CAH affected boys treatment will be stopped while affected girls will be treated until term.
The positive effects of the treatment in reducing or ameliorating genital virilization in affected girls are nowadays undisputable. However, should we be concerned whether DEX may have negative side-effects in the fetus, the growing child or later in adult life? The fact that only 1 out of 8 treated children will have a direct benefit of the treatment per se has added to these concerns. Treatment safety has been reported to be acceptable, at least in the short term perspective, based on findings of normal pre- and postnatal growth (2-5) and the reported side effects that have been observed do not appear to follow a particular pattern (2, 4, 6, 7). The treated children are not born premature and they do not present with an increased incidence of anomalies. In approximately 25 percent of treated mothers side effects can be observed, such as excessive weight gain during the first trimester of pregnancy, striae (stretch marks), mood swings, irritability, insomnia, oedema (swelling) and general discomfort (4). We have not seen an increased incidence of gestational diabetes mellitus or hypertension in treated mothers. Thus, the current follow-up studies on humans suggest that DEX treatment does not have major teratogenic effects (birth defects). Nevertheless, long-term effects are just starting to be addressed due to the fact that the oldest children treated are now reaching early adulthood. Results from experimental animal models have also raised concerns regarding the impact of the treatment on fetal programming and the possible effects on future metabolic and cognitive functions in adult life (8-10). Rats and monkeys exposed to prenatal corticosteroids have shown adverse effects both on somatic (physical) development, cognitive functions and behaviour. However, animal experiments aimed at identifying possible risks with prenatal glucocorticoid treatment have primarily been designed to mimic the treatment used for reducing the risk of respiratory distress syndrome in preterm infants and the glucocorticoid has thus been given late in the pregnancy. There is scarce clinical evidence concerning the effects of low-dose prenatal dexamethasone treatment as used in CAH.

Few follow-up studies on developmental outcome of the DEX-exposed children have been performed and only one has been based on direct assessment of the treated children (11). Direct assessment of treated children, that have reached school-age, using a wide range of neuropsychological tests in addition to child- and parent completed questionnaires will give valid data regarding cognitive functions, behaviour and prevalence of psychopathology. In our Swedish group of prenatally treated children (40 cases) and healthy non-treated controls (35 cases) we found that prenatal DEX treatment did not affect psychometric intelligence (IQ), short-term memory and long-term memory in treated cases. However, we could assess a negative effect on verbal working memory (sentence comprehension) and on children’s perceptions of their scholastic competence in addition to increased social anxiety. These effects were observed in short term treated, CAH unaffected children, when compared to healthy controls. Parents did not observe any negative effects on school performance. When long-term emotional and behavioural development of these children was assessed we could not observe any increase in psychopathology, but the parents of treated children reported that the children were more social compared to controls. We could not make any final conclusion regarding plausible negative effects in the CAH affected children, most probably due to a small study group.

In conclusion, this study indicates that prenatal DEX treatment has long-term effects on verbal working memory and on aspects of self-perception, both of which were previously not described, but no major behavioural problems or effects on long term memory or IQ have been found. An ethical dilemma regarding the future use of this treatment is opened-up because the ultimate clinical significance of our findings with increased sociability, social anxiety and affected verbal working memory among the healthy, CAH unaffected, short-term treated children, cannot yet be determined. It is therefore important that additional studies of larger cohorts are designed to make more decisive conclusions on the safety of this controversial treatment and preferably the treatment should only be given within the frames of a clinical study in order to ascertain accurate follow-up of the mother, the fetus and the growing child. A prospective, European, multi-centre study, PREDEX, is currently on-going (12). Until then, it is important that the parents are thoroughly informed about the potential risks and uncertainties as well as the benefits of the treatment.

1. David, M., and Forest, M. G. (1984) Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. Journal of Pediatrics 105, 799-803
2. Forest, M. G., and Dörr, H. G. (1993) Prenatal treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: European experience in 223 pregnancies at risk. Pediatric Research 33, S3
3. Mercado, A. B., Wilson, R. C., Cheng, K. C., Wei, J.-Q., and New, M. I. (1995) Prenatal Treatment and Diagnosis of Congenital Adrenal Hyperplasia Owing to Steroid 21-Hydroxylase Deficiency. Journal of Clinical Endocrinology and Metabolism 80, 2014-2020
4. Lajic, S., Wedell, A., Bui, T. H., Ritzen, E. M., and Holst, M. (1998) Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 83, 3872-3880
5. New, M. I., Carlson, A., Obeid, J., Marshall, I., Cabrera, M. S., Goseco, A., Lin-Su, K., Putnam, A. S., Wei, J. Q., and Wilson, R. C. (2001) Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 86, 5651-5657
6. Haan, E. A., Serjeantson, S. W., Norman, R., Rollond, A. K., Antonis, P., Richards, R. I., and Penfold, J. L. (1992) Prenatal diagnosis and successful intrauterine treatment of a female fetus with 21-hydroxylase deficiency. Med J Aust 156, 132-135
7. Couper, J. J., Hutson, J. M., and Warne, G. L. (1993) Hydrometrocolpos following prenatal dexamethasone treatment for congenital adrenal hyperplasia (21-hydroxylase deficiency). Eur J Pediatr 152, 9-11
8. Seckl, J. R., and Miller, W. L. (1997) How safe is long-term prenatal glucocorticoid treatment? Jama 277, 1077-1079
9. Seckl, J. R., and Meaney, M. J. (2004) Glucocorticoid programming. Ann N Y Acad Sci 1032, 63-84
10. Miller, W. L. (1999) Dexamethasone treatment of congenital adrenal hyperplasia in utero: an experimental therapy of unproven safety. J Urol 162, 537-540
11. Hirvikoski, T., Nordenstrom, A., Lindholm, T., Lindblad, F., Ritzen, E. M., Wedell, A., and Lajic, S. (2007) Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. J Clin Endocrinol Metab 92, 542-548
12. Lajic, S., Nordenstrom, A., Ritzen, E. M., and Wedell, A. (2004) Prenatal treatment of congenital adrenal hyperplasia. Eur J Endocrinol 151 Suppl 3, U63-69

Misconceptions Surrounding Prenatal Dexamethasone Treatment in CAH

Prenatal dexamethasone is used for the sole purpose of preventing fusion of the vaginal and urethral openings, commonly referred to as ambiguous genitalia in females affected with the classical form of CAH [1-2]. It is unknown whether or not prenatal dexamethasone has any effect on sexual orientation. While some women affected by CAH may identify as bisexual or homosexual, the vast majority of women with CAH consider themselves to be heterosexual. The percentage of women who identify as bisexual or homosexual among women with CAH is only slightly higher than the general population [3-4].
While dexamethasone taken by a mother will cross the placenta and effectively replace the insufficient cortisol made by the fetus, it is not a cure for CAH. After birth, an affected individual will continue to require lifelong replacement with glucocorticoid treatment.
Thalidomide was an anti-emetic used by pregnant women in the 1950’s. It was quickly apparent that the use of thalidomide during pregnancy caused severe congenital limb deformities in the offspring [5]. Thalidomide is classified as an FDA Pregnancy Category “X” medication (Physician Desk Reference, PDR.net), a medication where the risks clearly outweigh the benefits, and it is absolutely contraindicated during pregnancy. Unlike thalidomide, dexamethasone is used to treat the fetus, not the mother (see question #2). Dexamethasone (as are all steroids, including topical creams) is an FDA Pregnancy Category “C” medication (Physician Desk Reference, PDR.net), which refers to medications for which there are no adequate and well-controlled safety studies in humans, but potential benefits may warrant use of the drug despite potential risks. Steroids have been prescribed for pregnant women since the 1970’s for various reasons [6]. While the long-term safety of dexamethasone during pregnancy is still unclear, it does not fall into the same category as thalidomide.
1. Forest, M.G., M. David, and Y. Morel, Prenatal diagnosis and treatment of 21-hydroxylase deficiency. J Steroid Biochem Mol Biol, 1993. 45(1-3): p. 75-82.

2. Fernandez-Balsells, M.M., et al., Prenatal Dexamethasone Use For The Prevention Of Virilization In Pregnancies At Risk For Classical Congenital Adrenal Hyperplasia due to 21 hydroxylase (CYP21A2) deficiency: A Systematic Review And Meta-Analyses. Clin Endocrinol (Oxf), 2010.

3. Meyer-Bahlburg, H.F., Late diagnosed 46,XX child with congenital adrenal hyperplasia (CAH): deciding the gender of rearing. J Natl Med Assoc, 2008. 100(6): p. 759-60.

4. Hines, M., C. Brook, and G.S. Conway, Androgen and psychosexual development: core gender identity, sexual orientation and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH). J Sex Res, 2004. 41(1): p. 75-81.

5. Millen, J.W., Thalidomide and limb deformities. Lancet, 1962. 2(7256): p. 599-600.

6. Liggins, G.C. and R.N. Howie, A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics, 1972. 50(4): p. 515-25.

 

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