Prenatal Treatment Of Congenital Adrenal Hyperplasia Research Articles

Prenatal diagnosis and in utero treatment of congenital adrenal hyperplasia: An up-to-date comprehensive review.

Congenital adrenal hyperplasia (CAH) is a term that encompasses a wide range of conditions that affect the adrenals. Diagnosis and treatment before birth are important as irreparable birth defects can be avoided, decreasing the need for surgical intervention later in life, especially regarding genitalia anomalies. Although early implementation of dexamethasone in the prenatal treatment of CAH has been controversial, there is recent evidence that this treatment can reduce long-term complications.

Prenatal Dexamethasone Treatment of Children at Risk for Congenital Adrenal Hyperplasia: The Swedish Experience and Standpoint

Congenital adrenal hyperplasia (CAH) refers to rare ( 1:10,000), recessively inherited disorders of adrenal steroidogenesis. 21-Hydroxylase deficiency, the most common form, results in virilization of external genitalia in severely affected female fetuses. Prenatal treatment of CAH with dexamethasone (DEX) has been administered since the mid-1980s and is effective in reducing virilization in CAH-affected girls (1). The treatment has to be initiated early in pregnancy, before prenatal testing is possible. Consequently, seven of eight fetuses (all boys and CAH-unaffected girls) are treated in early pregnancy without any benefit of the treatment per se, until prenatal testing can determine the sex and diagnostic status at the end of the first trimester. CAH-affected girls are treated until term. Prenatal DEX treatment of fetuses at risk for CAH is controversial. Results from animal studies, as well as studies on prenatal glucocorticoid therapy in other contexts, have raised concerns regarding possible negative effects on behavioral and somatic development (2, 3). Adult corticosteroid-exposed rodent offspring are characterized by hypertension (via reduced nephron number); hyperinsulinemia and hyperglycemia (via permanently increased levels of the hepatic enzyme phosphoenolpyruvate carboxylase); fatty liver but not obesity when given a high-fat diet; and hyperactivity of the hypothalamic-pituitaryadrenal axis and altered affective behavior, reminiscent of anxiety, as well as impaired learning and memory functions. In the rhesus monkey, prenatal DEX during the last trimester resulted in offspring with elevated basaland stress-stimulated cortisol at the age of 10 months as well as smaller hippocampal volume. In the African vervet monkey, high-dose DEX exposure (120–200 g/kg) from midgestation until term resulted in offspring with an exaggerated cortisol response to stress already prepubertally, and adult animals exhibited hypertension, impaired glucose tolerance, and hyperinsulinemia (4). A long-term follow-up of individuals treated prenatally with betamethasone due to a risk of preterm birth shows that 30 yr after exposure the individuals exhibit insulin resistance, particularly in women, and 7% of the adults had elevated basal, morning cortisol levels (5). Other authors consider the prenatal treatment of CAH to be safe (1), but the recent Endocrine Society Guidelines state that such treatment should only be done within the frames of ethically approved clinical studies (6). The prenatal treatment of CAH is considered to be safe in the short-term perspective, although there are few longterm follow-up studies. In Sweden, prenatal treatment of CAH has been administered within the frameworks of a clinical study since 1999. The study, which is ongoing, is designed as a prospective, nonrandomized, multicenter trial in several participating European countries, including both follow-up of the mothers and long-term follow-up of the children. In Sweden, 31 cases have been enrolled during the last 10 yr. Hence, it will take several years before the first results from the long-term follow-up assessments will be available. We have also conducted retrospective follow-up studies of mothers and 43 children treated in Sweden and Nor-

An Update of Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders caused by mutations that encode for enzymes involved in one of the various steps of adrenal steroid synthesis. These defects result in the absence or the decreased synthesis of cortisol from its cholesterol precursor. The anterior pituitary secretes excess adrenocorticotrophic hormone (ACTH) via feedback regulation by cortisol, which results in overstimulation of the adrenals and causes hyperplasia. Symptoms due to CAH can vary from mild to severe depending on the degree of ensymatic defect. In the classical form of CAH, there is a severe enzymatic defect owing to mutations in the CYP21 gene. Classically affected female fetuses undergo virilization of the genitalia prenatally and present with genital ambiguity at birth; however, prenatal treatment of CAH with dexamethasone to prevent ambiguity has been successfully utilized for over a decade. In the less severe, late-onset form of CAH, prenatal virilization does not occur. The milder enzyme deficiency was termed nonclassical 21-hydroxylase deficiency (NC21OHD) in 1979 and was later found to be the most common autosomal recessive disorder in humans. Disease frequency of NC21OHD varies between ethnic groups with the highest ethnic-specific disease frequency in Ashkenazi Jews at 1/27. NC21OHD is diagnosed by serum elevations of 17-OHP that plot on a nomogram between the range for unaffected individuals and levels observed for classical CAH and is typically confirmed with molecular genetic analysis. Similar to classical CAH, nonclassical 21-hydroxylase deficiency may cause premature development of pubic hair, advanced bone age, accelerated linear growth velocity and diminished final height in both males and females. Severe cystic acne has also been attributed to nonclassical CAH. Women may present with symptoms of androgen excess, including hirsutism, temporal baldness, and infertility. Menarche in females may be normal or delayed and secondary amenorrhea is a frequent occurrence. Polycystic ovary syndrome may also be seen in these patients. In males, early beard growth, acne, and growth spurt may prompt the diagnosis of NC21OHD. Although many males appear to be asymptomatic, they may present with oligozoospermia or diminished fertility. Individuals presenting to dermatology and infertility clinics with symptoms of hyperandrogenemia are rarely screened for NC21OHD. However, with hormonal and molecular genetic screening, previously undiagnosed patients may be identified and can therefore receive glucocorticoid treatment, which has been shown to reverse symptoms within 3 months.

Prevention of ambiguous genitalia by prenatal treatment with dexamethasone in pregnancies at risk for congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) refers to a family of monogenic inherited disorders of adrenal steroidogenesis most often caused by a deficiency of the 21-hydroxylase enzyme. In the classic forms of CAH (simple virilizing and salt-wasting), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Prenatal treatment of CAH with dexamethasone has been successfully utilized for over a decade. This article reports on 595 pregnancies prenatally diagnosed using amniocentesis or chorionic villus sampling between 1978 and 2002 at the New York Presbyterian Hospital-Weill Medical College of Cornell University. No significant or enduring side effects were noted in the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight from untreated, unaffected newborns. Based on our experience, prenatal diagnosis and treatment of 21-hydroxylase deficiency is effective in significantly reducing or eliminating virilization in the newborn female. Prevention of genital virilization in female newborns with classic CAH avoids the risk of sex misassignment and diminishes the need for corrective surgery and the resulting psychological impact that may extend into adulthood.

EXTENSIVE PERSONAL EXPERIENCE: Prenatal Diagnosis for Congenital Adrenal Hyperplasia in 532 Pregnancies

Congenital adrenal hyperplasia (CAH) refers to a family of monogenic inherited disorders of adrenal steroidogenesis most often caused by enzyme 21-hydroxylase deficiency (21-OHD). In the classic forms of CAH (simple virilizing and salt wasting), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Prenatal treatment of CAH with dexamethasone has been successfully used for over a decade. This article serves as an update on 532 pregnancies prenatally diagnosed using amniocentesis or chorionic villus sampling between 1978 and 2001 at New York Presbyterian Hospital-Weill Medical College of Cornell University. Of the 532 pregnancies, 281 were prenatally treated for CAH due to the risk of 21-hydroxylase deficiency. Follow-up telephone interviews with mothers, genetic counselors, endocrinologists, pediatricians, and obstetricians were performed in all cases. Of the pregnancies evaluated, 116 babies were affected with classic 21-OHD. Of these, 61 were female, 49 of whom were treated prenatally with dexamethasone. Dexamethasone administered at or before 9 wk gestation (in proper doses) was effective in reducing virilization. There were no statistical differences in the symptoms during pregnancy between mothers treated with dexamethasone and those not treated with dexamethasone, except for weight gain, edema, and striae, which were greater in the treated group. No significant or enduring side-effects were noted in the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight from untreated, unaffected newborns. Based on our experience, prenatal diagnosis and proper prenatal treatment of 21-OHD are effective in significantly reducing or eliminating virilization in the newborn female. This spares the affected female the consequences of genital ambiguity, genital surgery, and possible sex misassignment.

EXTENSIVE PERSONAL EXPERIENCE: Prenatal Diagnosis for Congenital Adrenal Hyperplasia in 532 Pregnancies

Congenital adrenal hyperplasia (CAH) refers to a family of monogenic inherited disorders of adrenal steroidogenesis most often caused by enzyme 21-hydroxylase deficiency (21-OHD). In the classic forms of CAH (simple virilizing and salt wasting), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Prenatal treatment of CAH with dexamethasone has been successfully used for over a decade. This article serves as an update on 532 pregnancies prenatally diagnosed using amniocentesis or chorionic villus sampling between 1978 and 2001 at New York Presbyterian Hospital-Weill Medical College of Cornell University. Of the 532 pregnancies, 281 were prenatally treated for CAH due to the risk of 21-hydroxylase deficiency. Follow-up telephone interviews with mothers, genetic counselors, endocrinologists, pediatricians, and obstetricians were performed in all cases. Of the pregnancies evaluated, 116 babies were affected with classic 21-OHD. Of these, 61 were female, 49 of whom were treated prenatally with dexamethasone. Dexamethasone administered at or before 9 wk gestation (in proper doses) was effective in reducing virilization. There were no statistical differences in the symptoms during pregnancy between mothers treated with dexamethasone and those not treated with dexamethasone, except for weight gain, edema, and striae, which were greater in the treated group. No significant or enduring side-effects were noted in the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight from untreated, unaffected newborns. Based on our experience, prenatal diagnosis and proper prenatal treatment of 21-OHD are effective in significantly reducing or eliminating virilization in the newborn female. This spares the affected female the consequences of genital ambiguity, genital surgery, and possible sex misassignment.

Prenatal diagnosis and treatment of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is associated with hormonal imbalance which predisposes affected females to prenatal development of genital ambiguity. Because the disease is usually not lethal and can be treated with glucocorticoids, affected pregnancies are seldom terminated. Dexamethasone can be administered to the pregnant mother and is effective in correcting the fetus's adrenal hormone imbalance during gestation. Nearly a decade's experience with prenatal treatment of CAH indicates that the risk-benefit ratio is favorable for mother and fetus with careful medical supervision of gestationally administered dexamethasone.