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ENDOCRINOLOGY AND GENDER
Year : 2013  |  Volume : 17  |  Issue : 3  |  Page : 373-375

Prenatal treatment of mothers with fetuses at risk for congenital adrenal hyperplasia: How relevant is it to Indian context?


Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication10-May-2013

Correspondence Address:
Ariachery C Ammini
Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2230-8210.111596

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   Abstract 

Management of congenital adrenal hyperplasia (CAH) from embryonic stage to adulthood is a critical challenge. We would like to comment on some of the practical difficulties in offering prenatal treatment for CAH-affected fetuses in Indian population. For initiating the prenatal dexamethasone (DEX) treatment, all members of the family need to be informed about the risks and benefits of the treatment to the mother and the fetus as well as about the available invasive diagnostic tests to determine the gender and genotype of the fetus. Prenatal sex disclosure is not routinely practiced in India due to high female feticide rate. The treatment has to be given to both unaffected and affected female fetuses until the determination of prenatal sex. Moreover, most of our populations reside in rural areas where the antenatal care is not adequate. Prenatal DEX treatment in India outruns the risks rather than the benefits, as evident from the literature on the safety of pregnant mothers and fetuses.

Keywords: Chorionic villus sampling, dexamethasone, genetic sex, virilization


How to cite this article:
Eunice M, Ammini AC. Prenatal treatment of mothers with fetuses at risk for congenital adrenal hyperplasia: How relevant is it to Indian context?. Indian J Endocr Metab 2013;17:373-5

How to cite this URL:
Eunice M, Ammini AC. Prenatal treatment of mothers with fetuses at risk for congenital adrenal hyperplasia: How relevant is it to Indian context?. Indian J Endocr Metab [serial online] 2013 [cited 2019 Nov 12];17:373-5. Available from: http://www.ijem.in/text.asp?2013/17/3/373/111596

In patients with congenital adrenal hyperplasia (CAH), the production of cortisol and aldosterone are diminished and adrenal androgen secretion is increased. This hyperandrogenism leads to varying degrees of virilization of external genitalia [1],[2] in 46, XX fetuses. In order to prevent this ambiguity, dexamethasone (DEX) treatment in CAH-risk pregnancies was introduced in France and in USA. [3],[4] Later, other groups also reported a reduction in the degree of virilization in affected female fetuses with DEX treatment. [5],[6] The treatment has been proven to be highly effective for the reduction of genital masculinization in 46, XX fetuses, if begun by the 8 th week postconception and used consistently throughout pregnancy. [7],[8] However, one study from Italy [9] stated that "to prevent truly the genital virilization, the treatment has to be started <8 weeks of gestational age." In which case, 7 out of 8 pregnancies have to be exposed to DEX treatment unnecessarily, albeit briefly (till the gender and genotype determination by invasive conventional chorionic villus sampling [CVS] at the gestational age between 10 and 11 weeks). Postnatal steroid therapy also improves the appearance of external genitalia during the first years of life. [10] A recent study [1] has captured all positive and negative outcomes of the CAH children on treatment and compared them with the control group. However, the authors summarized that "their studies do not replicate a previously reported adverse effect of short-term prenatal DEX exposure on working memory and on cognitive function in CAH girls with long-term DEX exposure contributing to concerns about potentially adverse cognitive after effects of such exposure."

Some animal studies on prenatal glucocorticoid therapy have raised concerns regarding the possible negative effects on behavioral and somatic development. [11],[12] Adult corticosteroid exposed rodent offspring are characterized by hypertension, hyperinsulinemia and hyperglycemia, fatty liver. Hyperactivity of the hypothalamic-pituitary adrenal axis and altered affective behavior, reminiscent of anxiety, as well as impaired learning and memory functions were also observed. [13] In the rhesus monkey, prenatal DEX during the last trimester resulted in offspring with elevated basal and stress-stimulated cortisol at the age of 10 months as well as smaller hippocampal volume. In the African vervet monkey, Chlorocebus aethiops, high-dose DEX exposure (120-200 g/kg) from midgestation until term resulted in offspring with an exaggerated cortisol response to stress in both prepubertal and in adult stages. These animals exhibited hypertension, impaired glucose tolerance, and hyperinsulinemia. [14]

A long-term follow-up of individuals treated prenatally with betamethasone due to a risk of preterm birth. The authors also noted that 30 years after the exposure, these individuals, particularly women, exhibited insulin resistance and 7% of the adults had elevated basal, morning cortisol levels. [15] Retrospective follow-up studies of mothers and 43 children treated from Sweden and Norway during 1985-1995 reported that some type of maternal discomforts could be attributed to DEX, and severe adverse events were also noted in the treated group compared with the control group. [16],[17],[18],[19] As a consequence of these findings, further recruitment of patients were put on hold for the ongoing prospective study of prenatal DEX treatment of CAH in Sweden until larger and more conclusive studies are published. [13] In another report, the authors reviewed the pathophysiology of CAH, the safety and ethical considerations of prenatal DEX treatment, and the views of multiple medical societies. They concluded that this experimental therapy should only be done in prospective trials approved by ethical review boards. [7],[20] The recent article on the use of DEX for the antenatal treatment for mothers with affected CAH fetuses stated that neither the FDA nor the EMA have granted a license and also suggested that the usefulness of fetal cells in the maternal circulation to karyotype the fetus should reduce the overall exposure time to DEX, but careful long-term follow-up is required. [21] Prenatal sex determination is prohibited in India due to high female feticide rate. The treatment has to be given to both unaffected as well as to the affected female fetuses until the determination of prenatal sex. For treating the affected female fetuses, both parents have to be informed about the risks, benefits, and uncertainties of the treatment and the gender of the fetus. Moreover, most of our populations reside in rural areas where the antenatal care is not adequate.

This makes the necessary follow-up care, which is essential for the regular monitoring of the patient on prenatal DEX treatment for the known side affects like maternal hypertension and edema. The benefits of DEX treatment outweigh the risks involved to the fetus and to the mother, when the follow-up care and monitoring facilities are inadequate.

 
   References Top

1.Meyer-Bahlburg HF, Dolezal C, Haggerty R, Silverman M, New MI. Cognitive outcome of offspring from dexamethasone-treated pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol 2012;167:103-10.  Back to cited text no. 1
    
2.Prader A. Genital findings in the female pseudo-hermaphroditism of the congenital adrenogenital syndrome; morphology, frequency, development and heredity of the different genital forms. Helv Paediatr Acta 1954;9:231-48.  Back to cited text no. 2
    
3.David M, Forest MG. Prenatal treatment of congenital adrenal hyperplasia resulting from 21-hydroxylase deficiency. J Pediatr 1984;105:799-803.  Back to cited text no. 3
    
4.New MI, Carlson A, Obeid J, Marshall I, Cabrera MS, Goseco A, et al. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 2001;86:5651-7.  Back to cited text no. 4
    
5.Forest MG. Recent advances in the diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Reprod Update 2004;10:469-85.  Back to cited text no. 5
    
6.Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003;349:776-88.  Back to cited text no. 6
    
7.Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2010;95:4133-60.  Back to cited text no. 7
    
8.Merce Fernandez-Balsells M, Muthusamy K, Smushkin G, Lampropulos JF, Elamin MB, Abu Elnour NO, 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-analysis. Clin Endocrinol (Oxf) 2010;73:436-44.  Back to cited text no. 8
    
9.Balsamo A, Baldazzi L, Menabò S, Cicognani A. Impact of molecular genetics on congenital adrenal hyperplasia management. Sex Dev 2010;4:233-48.  Back to cited text no. 9
    
10.Kulshreshtha B, Khadgawat R, Eunice M, Ammini AC. Congenital adrenal hyperplasia: Results of medical therapy on appearance of external genitalia. J Pediatr Urol 2010;6:555-9.  Back to cited text no. 10
    
11.Miller WL. Dexamethasone treatment of congenital adrenal hyperplasia in utero: An experimental therapy of unproven safety. J Urol 1999;162:537-40.  Back to cited text no. 11
    
12.Seckl JR. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol 2004;151:U49-62.  Back to cited text no. 12
    
13.Hirvikoski T, Nordenstrom A, Wedell A, Ritzen M, Lajic S. Prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia: The Swedish Experience and Standpoint. J Clin Endocrinol Metab 2012;97:1881-3.  Back to cited text no. 13
    
14.de Vries A, Holmes MC, Heijnis A, Seier JV, Heerden J, Louw J, et al. Prenatal dexamethasone exposure induces changes in nonhuman primate offspring cardiometabolic and hypothalamic-pituitary-adrenal axis function. J Clin Invest 2007;117:1058-67.  Back to cited text no. 14
    
15.Dalziel SR, Walker NK, Parag V, Mantell C, Rea HH, Rodgers A, et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet 2005;365:1856-62.  Back to cited text no. 15
    
16.Hirvikoski T, Nordenstrom A, Lindholm T, Lindblad F, Ritzen EM, Wedell A, et al. Cognitive functions in children at risk for congenital adrenal hyperplasia treated prenatally with dexamethasone. J Clin Endocrinol Metab 2007;92:542-8.  Back to cited text no. 16
    
17.Hirvikoski T, Nordenstrom A, Lindholm T, Lindblad F, Ritzen EM, Lajic S. Long-term follow-up of prenatally treated children at risk for congenital adrenal hyperplasia: Does dexamethasone cause behavioural problems? Eur J Endocrinol 2008;159:309-16.  Back to cited text no. 17
    
18.Hirvikoski T, Lindholm T, Lajic S, Nordenstrom A. Gender role behaviour in prenatally dexamethasone-treated children at risk for congenital adrenal hyperplasia-a pilot study. Acta Paediatr 2011;100:e112-9.  Back to cited text no. 18
    
19.Lajic S, Wedell A, Bui TH, Ritzen EM, Holst M. Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia. J Clin Endocrinol Metab 1998;83:3872-80.  Back to cited text no. 19
    
20.Witchel SF, Miller WL. Prenatal treatment of congenital adrenal hyperplasia-not standard of care. J Genet Couns 2012;21:615-24.  Back to cited text no. 20
    
21.Hindmarsh PC. Endocrine Society Congenital Adrenal Hyperplasia Guidelines: Great content but how to deliver? Clin Endocrinol (Oxf) 2012;76:465-6.  Back to cited text no. 21
    



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