Challenges in Prenatal Treatment with Dexamethasone (original) (raw)
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Prenatal Dexamethasone for Congenital Adrenal Hyperplasia
Journal of Bioethical Inquiry, 2012
Following extensive examination of published and unpublished materials, we provide a history of the use of dexamethasone in pregnant women at risk of carrying a female fetus affected by congenital adrenal hyperplasia (CAH). This intervention has been aimed at preventing development of ambiguous genitalia, the urogenital sinus, tomboyism, and lesbianism. We map out ethical problems in this history, including: misleading promotion to physicians and CAH-affected families; de facto experimentation without the necessary protections of approved research; troubling parallels to the history of prenatal use of diethylstilbestrol (DES); and the use of medicine and public monies to attempt prevention of benign behavioral sex variations. Critical attention is directed at recent investigations by the U.S. Food and Drug Administration (FDA) and Office of Human Research Protections (OHRP); we argue that the weak and unsupported conclusions of these investigations indicate major gaps in the systems meant to protect subjects of high-risk medical research.
Clinical Endocrinology, 2010
Context Prenatal treatment with dexamethasone to prevent virilization in pregnancies at risk for classical congenital adrenal hyperplasia (CAH) remains controversial. Objective To conduct a systematic review and meta-analyses of studies that evaluated the effects of dexamethasone administration during pregnancies at risk for classical CAH because of 21-hydroxylase deficiency (CYP21A2). Data Sources We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception through August 2009. Review of reference lists and contact with CAH experts further identified candidate studies. Study Selection Reviewers working independently and in duplicate determined trial eligibility. Eligible studies reported the effects on either foetal or maternal outcomes of dexamethasone administered during pregnancy compared to a control group that did not receive any treatment. Data Extraction Reviewers working independently and in duplicate determined the methodological quality of studies and collected data on patient characteristics, interventions, and outcomes. Data Synthesis We identified only four eligible observational studies (325 pregnancies treated with dexamethasone). The methodological quality of the included studies was overall low. Metaanalysis demonstrates a reduction in foetus virilization measured by Prader score in female foetuses treated with dexamethasone initiated early during pregnancy (weighted mean difference, )2AE33, 95% CI, )3AE38, )1AE27). No deleterious effects of dexamethasone on stillbirths, spontaneous abortions, foetal malformations, neuropsy-chological or developmental outcomes were found although these data are quite sparse. There was increased oedema and striae in the mothers treated with dexamethasone. There were no data on longterm follow-up of physical and metabolic outcomes in children exposed to dexamethasone. Conclusions The observational nature of the available evidence and the overall small sample size of the whole body of the literature significantly weaken inferences about the benefits and harms of dexamethasone in this setting. Dexamethasone seems to be associated with reduction in foetus virilization without significant maternal or foetal adverse effects. However, this review underscores the current uncertainty and further investigation is clearly needed. The decision about initiating treatment should be based on patients' values and preferences and requires fully informed and consenting parents.
Following extensive examination of published and unpublished materials, we provide a history of the use of dexamethasone in pregnant women at risk of carrying a female fetus affected by congenital adrenal hyperplasia (CAH). This intervention has been aimed at preventing development of ambiguous genitalia, the urogenital sinus, tomboyism, and lesbianism. We map out ethical problems in this history, including: misleading promotion to physicians and CAH-affected families; de facto experimentation without the necessary protections of approved research; troubling parallels to the history of prenatal use of diethylstilbestrol (DES); and the use of medicine and public monies to attempt prevention of benign behavioral sex variations. Critical attention is directed at recent investigations by the U.S. Food and Drug Administration (FDA) and Office of Human Research Protections (OHRP); we argue that the weak and unsupported conclusions of these investigations indicate major gaps in the systems meant to protect subjects of high-risk medical research.
Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia
Hormone Research, 2007
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.
Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment
Journal of Steroid Biochemistry and Molecular Biology, 1999
The diagnostic term congenital adrenal hyperplasia (CAH) applies to a family of inherited disorders of steroidogenesis caused by an abnormality in one of the five enzymatic steps necessary in the conversion of cholesterol to cortisol. The enzyme defects are translated as autosomal recessive traits, with the enzyme deficient in more than 90% of CAH cases being 21-hydroxylase. In the classical forms of CAH (simple virilizing and salt wasting), owing to 21-hydroxylase deficiency (21-OHD), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Non-classical 21-OHD (NC21OHD) refers to the condition in which partial deficiencies of 21-hydroxylation produce less extreme hyperandrogenemia and milder symptoms. Females do not demonstrate genital ambiguity at birth.The gene for adrenal 21-hydroxylase, CYP21, is located on chromosome 6p in the area of HLA genes. Specific mutations may be correlated with a given degree of enzymatic compromise and the clinical form of 21-OHD. NC21OHD patients are predicted to have mild mutations on both alleles or one severe and one mild mutation of the 21-OH locus (compound heterozygote). In most cases the mutation groups represent one diagnosis (e.g., Del/Del with SW CAH), however we have found several non-correlations of genotype to phenotype. Non-classical and classical patients were found within the same mutation group. Phenotypic variability within each mutation group has important implications for prenatal diagnosis and treatment.Prenatal treatment of 21-OHD with dexamethasone has been utilized for a decade. An algorithm has been developed for prenatal diagnosis and treatment, which, when followed closely, has been safe for both the mother and the fetus, and has been effective in preventing ambiguous genitalia in the affected female newborn. This is an instance of an inborn metabolic error successfully treated prenatally.Since 1986, prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) has been carried out in 403 pregnancies in The New York Hospital–Cornell Medical Center. In 280, diagnoses were made by amniocentesis, while 123 were diagnosed using chorionic villus sampling. Of the 403 pregnancies evaluated, 84 babies were affected with classical 21-OHD. Of these, 52 were females, 36 of whom were treated prenatally with dexamethasone. Dexamethasone administered at or before 10 weeks of gestation (23 affected female fetuses) was effective in reducing virilization. Thirteen cases had affected female sibs (Prader stages 1–4); 6 of these fetuses were born with entirely normal female genitalia, while 6 were significantly less virilized (Prader stages 1–2) than their sibs, and one was Prader stage 3. Eight newborns had male sibs; 4 were born with normal genitalia, 3 were Prader stages 1–2, and 3 were born Prader stages 3–4. No significant or enduring side effects were noted in either the mothers or the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight, length, or head circumference from untreated, unaffected newborns.Based on our experience, proper prenatal diagnosis and treatment of 21-OHD is effective in significantly reducing or eliminating virilization in the newborn female. This spares the affected female the consequences of genital ambiguity of genital surgery, sex misassignment, and gender confusion.
Long-Term Somatic Follow-Up of Prenatally Treated Children with Congenital Adrenal Hyperplasia 1
The Journal of Clinical Endocrinology & Metabolism, 1998
Prenatal virilization of female fetuses is a serious symptom associated with severe congenital adrenal hyperplasia. In attempt to avoid sexual ambiguity, prenatal treatment of 21-hydroxylase deficiency was initiated in 1984, with the first Scandinavian case treated in 1985. Here we have studied the outcome of prenatal diagnosis and therapy of 44 at-risk pregnancies monitored during the years 1985-1995 in Scandinavia. Treated mothers and children were compared with matched controls.
Successful Pregnancy Outcome in Patient with Congenital Adrenal Hyperplasia
Journal of Morphological Sciences, 2018
The term congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive disorders, which involves a deficiency of an enzyme involved in the synthesis of cortisol, aldosterone, or both. There are two forms of CAH: classic, devided into salt-waisting and simple virilizing, and nonclasic form. Fertility is relative in CAH, but the incidence of spontaneous miscarriage is higher. We present а patient with simple virilising form of CAH and pregnancy. Our patient was admitted in the hospital in 2014 when we diagnosed simple virilisng form of CAH. She came with history of two unsuccesfull IVF's, in 2013 and 2014. Dexamethason therapy was introduced. In preparation for conception, the steroid replacement was changed to Prednisolon. There was one more IVF performed, in 2016, again without succes. Our patient concieved naturally in august 2017. The screening conducted at the first visit of 14 weeks of gestation was normal and further tests conducted at gynaecologist were also normal. During pregnancy, she continued to take prednisolone (minimum dose 7.5 mg/day to maximum dose 20 mg/day). Check ups were done each two months. She delivered female, weighs 2.9 kg by elective cesarean section at 38+1 week of gestation. The baby exhibited normal Apgar score. The external genitalia were normal. After the delivery, the patient had taken prednisolone (15 mg/day) consistently for theCAH. Choosing the appropriate type and dose of steroid replacement is quite challenging in the treatment of women with classical CAH desiring pregnancy.Succesfull management of CAH in pregnancy requires a firm knowledge of endocrine changes that occur during gestation. From a fetal and neonatal standpoint, accurate prenatal diagnosis alows good prenatal treatment in an attept to minimize clinical problems in the neonates.
The Journal of Clinical Endocrinology & Metabolism, 2004
Dexamethasone (DEX) administration to the pregnant woman has become the treatment of choice for the prevention of genital masculinization in female fetuses affected with congenital adrenal hyperplasia (CAH). Although no somatic teratological side effects have been found to date, recent animal research has shown adverse effects of glucocorticoids on brain structures such as the hippocampus, raising concerns about possible functional side effects of DEX on human development. The current survey of 487 children, 1 month to 12 yr of age, focused on cognitive and motor development. The mothers of 174 prenatally DEX-exposed children (including 48 with CAH) and 313 unexposed children (including 195 with CAH) completed four standardized developmental questionnaires about their children. None of the comparisons of prenatally DEX-exposed children and unexposed controls was significant. Among the DEX-exposed children, increased duration of DEX exposure was correlated with significantly fewer developmental delays on three variables of one of the questionnaires, but none of the correlations reached significance, when Bonferroni corrections for multiple correlations were used. With the methods used, we were unable to document any adverse effects of early-prenatal DEX treatment in the doses recommended for the treatment of pregnancies at risk for CAH on motor and cognitive development. (J Clin