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Study Description


The purpose of this study is to perform the first long-term follow up study both of adolescents and young adults with a history of prenatal treatment with dexamethasone and of their mothers and to test for adverse medical or behavioral side effects. The emphasis will be on the outcome of this prenatal treatment in those fetuses who are not affected with steroid 21-hydroxylase deficiency (21OHD) form of congenital adrenal hyperplasia (CAH) and are either heterozygotes or homozygote-unaffected.

Prenatal treatment of 46,XX fetuses with 21OHD (via administration of dexamethasone to the pregnant mother) has been shown to reduce the masculinization of the genitalia and, thereby, the later need for 'corrective' feminizing genital surgery and potential impairment of sexual functioning. Along with the suppression of excess prenatal androgen production and reduction of prenatal masculinization of the genitalia in 46,XX fetuses with 21OHD, prenatal dexamethasone treatment may reduce the behavioral masculinization that is well documented in untreated 46, XX patients with 21OHD. Those fetuses who are partially treated until diagnosis of an unaffected status (heterozygous or homozygous-unaffected) will be studied as well. This latter group is of importance because these fetuses are being unnecessarily treated, but we have no way of diagnosing the unaffected status before the 8th week of gestation when treatment must begin for the female fetus who is affected. As treatment is necessary only until term in the female fetus affected with classical CAH, male fetuses and unaffected or heterozygous female fetuses do not require treatment. Thus, only one out of eight fetuses will require prenatal treatment until term. Findings of adverse effects of glucocorticoid treatment in non-human mammals [1, 2] have raised concerns among other clinicians and investigators about potential adverse side effects of such treatment on the developing human. Thus, this study will address this concern and investigate the potential adverse side effects of prenatal treatment.

Detailed Description

Females with classical CAH owing to 21-hydroxylase deficiency are born with ambiguous genitalia due to the production of excess androgens in utero. Prenatal treatment with dexamethasone was inaugurated in 1978 by Maguelone Forest and has been the standard of practice in the United States since 1986. Dexamethasone, which crosses the placental barrier, suppresses the fetal adrenal gland production of androgens, thus preventing ambiguous genitalia in the affected female. Children of both sexes are prenatally treated as soon as pregnancies at risk are confirmed. Treatment in females with 21OHD continues to term, but is discontinued in males and unaffected females. To date, 685 pregnancies have been diagnosed, of which 366 fetuses were treated. These investigators will study prenatally treated adolescents and adults 12 years and older with respect to medical and behavioral outcomes (see Table 5). In addition, mothers of children prenatally treated for varying periods of time for suspected 21OHD will be studied for long-term side effects of dexamethasone treatment administered during pregnancy. The long-term outcome in these children and their mothers has never before been studied.

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Study Inclusion/Exclusion Criteria

Inclusion Criteria:
For all participants:

  1. English-speaking
  2. Has undergone DNA testing for mutations in the CYP21A2 gene
  3. Ages 12 and older

For children who received prenatal dexamethasone treatment:

  1. Genetic confirmation of 21OHD diagnosis
  2. Received full or partial prenatal dexamethasone treatment

For children in the control group:

  1. Did not receive prenatal dexamethasone treatment

For mothers:

  1. History of at-risk pregnancy for a fetus affected with 21OHD
  2. Genetic confirmation of child's diagnosis

Exclusion Criteria:

  1. Any mental disorder that could prevent understanding of study materials
  2. Current or past steroid use for reasons other than CAH (i.e., asthma, lupus, rheumatoid arthritis)

Study History

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) refers to a family of inherited disorders of steroidogenesis. The most frequent form is 21-hydroxylase deficiency (21OHD), an autosomal recessive disorder which leads to cortisol deficiency and therefore to ACTH-driven excess production of adrenal androgens. In the classical form of 21OHD, prenatal androgen exposure causes external genital masculinization and ambiguity in newborn females and progressive postnatal virilization in either sex. Three-fourths of classical patients also have salt-wasting due to aldosterone deficiency. This is referred to as salt-wasting (SW) CAH, while the simple virilizing (SV) form preserves the ability to retain salt [3, 4]. In the milder nonclassical form of 21OHD, females are born with normal female genitalia, and are not routinely treated to term with dexamethasone [5].

The adrenal gland is formed in the fourth week of gestation from coelemic epithelial mesoderm. By the sixth or seventh week of gestation, the functional adrenal cortex of the fetus [6] starts to secrete steroids. The critical time for sexual differentiation of the external genitalia is at 7-12 weeks of gestation. During this period, overexposure of the 46,XX female fetus to adrenal androgens causes masculinization of genitalia at birth. In affected fetuses with classical 21OHD, the steroidogenic pathway precursors are shuttled to the androgen pathway and the adrenal gland overproduces androgens prenatally. In females with the classical form of 21OHD (SW and SV), prenatal exposure to excessive androgens causes varying degrees of virilization evidenced as clitoral enlargement, labial fold fusion, and rostral migration of the urethral/vaginal perineal orifice. Masculinized external genitalia are classified into five Prader stages [7]:

Figure 1. Description of Prader score for genital ambiguity

  • Stage I: clitoromegaly without labial fusion
  • Stage II: clitoromegaly and posterior labial fusion
  • Stage III: greater degree of clitoromegaly, single perineal urogenital orifice, and almost complete labial fusion
  • Stage IV: increasingly phallic clitoris, urethra-like urogenital sinus at base of clitoris, and complete labial fusion
  • Stage V: penile clitoris, urethral meatus at tip of phallus, and scrotum-like labia (appear like males without palpable gonads)

Unlike the external genitalia, the internal female genitalia (uterus, fallopian tubes and ovaries) are normal, as the affected females do not have testes with Sertoli cells that secrete mullerian inhibiting hormone. Therefore, in affected females, the mullerian ducts do not regress, and the internal female genitalia develop normally.

Newborn males with the classical form of 21OHD (SW and SV) show no obvious signs of androgen excess, but they may demonstrate hyperpigmentation of the genitalia and/or an enlarged penis with relatively small testes. However, they may also look perfectly normal. They all have normally formed internal Wolffian ducts [8, 9].

Goto et al showed that the fetal hypothalamic-pituitary-adrenal axis is fully functional when the genitalia differentiate and administration of dexamethasone at the critical time for sexual differentiation suppresses the axis, reducing abnormal secretion of adrenal androgens. Their results also show that cortisol synthesis by the fetal adrenal decreases after this period, allowing the adrenal to secrete high levels of dehydroepiandrosterone, an androgen precursor. However, this does not masculinize female fetuses because androgens are aromatized to estrogens in the placenta. Thus normal sexual differentiation requires exquisite timing of fetal cortisol and androgen secretion versus placental capacity for aromatization [10].

Psychological effects of prenatal androgen excess

Masculinization of gender-related behavior (childhood play, peer association, career and leisure time preferences in adolescence and adulthood, maternalism, aggression, sexual orientation, etc.) has been documented in 46,XX girls and women with 21OHD and attributed to the effects of the excess prenatal androgen levels on the sexual differentiation of the brain and later behavior [11-13]. Increased rates of gender dysphoria and patient-initiated gender change above the rates of transsexualism in the general population have also been observed [14, 15], but may only be indirectly related to prenatal androgens [16]. Moreover, endocrine abnormalities, genital masculinization, and effects of corrective genital surgery appear to have adverse effects on sexual functioning, albeit with considerable variability [12].

Prenatal Diagnosis

In 1965, the first successful prenatal diagnosis of 21OHD was completed by Jeffcoate et al. [17] by measuring elevated 17-ketosteroids and pregnanetriol levels in the amniotic fluid obtained by amniocentesis. At present, hormonal diagnosis has been replaced by molecular genotyping of fetal cells obtained from chorionic villus sampling (CVS) or amniocentesis. CVS is preferred because it can be performed at the 9th - 11th week of gestation, while amniocentesis is usually performed at the 15th - 18th week of gestation.

DNA analysis of fetal cells is undertaken to identify any mutations in the CYP21A2 gene (OMIM number 201910), which encodes the enzyme 21-hydroxylase. The CYP21A2 gene and its pseudogene (CYP21A1P) are located in the HLA major histocompatibility complex on chromosome 6p21.3, each containing 10 exons spaced over 3.1 kb. Their nucleotide sequences are 98% identical in exons and approximately 96% identical in introns [18]. More than 100 mutations have been described including point mutations, small deletions, small insertions and complex rearrangement of the gene [19]. These mutations of the CYP21A2 gene can be characterized by in vitro expression studies and have been shown to have varying degrees of enzymatic activity that range from mild to severe. The CYP21A2 gene and common mutations are shown in Figure 2.

Figure 2. CYP21A2 gene and common mutations

Prenatal diagnosis is accurate in more than 95% of cases [20]; experience has helped to identify the inevitable pitfalls [21]. Determination of satellite markers may further increase the accuracy of molecular genetic analysis [22]. Masculinization of external genitalia in females affected with 21OHD is a potentially devastating condition, carrying the risk of wrong sex assignment at birth, difficult reconstructive surgery and subsequent long-term effects on quality of life.

Prenatal Treatment

In 1978, Maguelone Forest inaugurated prenatal treatment of the mother of potentially affected female fetuses to prevent or minimize masculinization of the genitalia. In 1986, Maria New became the only physician in the United States to routinely offer prenatal treatment of congenital adrenal hyperplasia. To date, Dr. New has prenatally diagnosed 685 pregnancies.

Prenatal treatment with dexamethasone (a glucocorticoid) has been shown to prevent or minimize the virilization of external genitalia in 21OHD affected females and thereby, the need for later 'corrective' feminizing genital surgery and its potential adverse side effects on sexual functioning by diminishment of sensation. Depending on the Prader score, corrective surgery may have both functional and cosmetic aspects to enable the affected female to experience intercourse, childbirth, and urination normal for her sex. Exogenous glucocorticoid replacement therapy targets the ACTH overproduction through negative feedback, and in turn reduces excessive adrenal androgens.

Institution of prenatal treatment before the 8th week of gestation effectively suppresses excessive adrenal androgens and prevents masculinization of female external genitalia. Dexamethasone is used because it binds minimally to cortisol binding globulin (CBG) in the maternal blood, and unlike hydrocortisone, which is often used to treat 21OHD in adults, escapes inactivation by the placental 11β-hydroxysteroid dehydrogenase type 2 enzyme. Thus, dexamethasone crosses the placenta from the mother to the fetus and suppresses ACTH secretion and thereby adrenal androgen oversecretion [23].

Figure 3. Algorithm of prenatal diagnosis and treatment in 21OHD

A simplified algorithm of management of potentially affected pregnancies is shown in Figure 3. According to the algorithm, in order to prevent masculinization of the external genitalia in an affected female fetus, dexamethasone administration must begin at or before the 8th week of gestation in pregnancies known to be at risk because of prior birth of a 21OHD-affected sibling or a positive family history. At the beginning of treatment, disease status and sex of the fetus are unknown. The molecular genetic diagnosis in the fetus makes prenatal diagnosis possible and reliable. If the fetus is later determined upon karyotype to be a male, or an unaffected female upon DNA analysis, treatment is discontinued. Otherwise, treatment is continued to term [24]. The optimal dosage and timing is 20 μg/kg/day of dexamethasone per maternal pre-pregnancy body weight, in three divided doses, starting as soon as pregnancy is confirmed and no later than 9 weeks after the last menstrual period [25, 26].

Preliminary Studies

Dexamethasone administered properly at or before the 8th week of gestation is effective in reducing genital masculinization as demonstrated by the difference in Prader score (Figure 1) of treated versus untreated affected females [24, 27, 28]. Of the 105 fetuses diagnosed with 21OHD, 61 were female; of these, 49 were treated prenatally with dexamethasone, but only 25 were treated before the 8th week of gestation. Prader score was 1-2, while those untreated, late-treated or partially-treated were born with a Prader score of 4 [23]. In Dr. Forest's experience in several European countries of 42 female fetuses with 21OHD, 38 had excellent results from dexamethasone treatment. Prader score was 1-2 and none required genital surgery [27]

In our extensive experience, mothers and fetuses did not have significant or enduring side effects of dexamethasone treatment [24, 27, 28]. Short-term clinical follow-up studies of mothers and fetuses treated with dexamethasone have been published by both investigators, and studies of psychological outcome in children under age 12 have been conducted by our group (see below).

Category 1 (Fetal/Offspring outcome)

In published studies by Dr. New and Dr. Forest, birth length and head circumferences were not different between the treated and untreated groups [24, 25, 28]. Although birth weight in affected infants treated with dexamethasone was statistically lower than affected infants not prenatally treated with dexamethasone, it is unlikely that there is any clinical significance between the birth weights of the treated (mean weight 3.28 kg) and untreated affected (mean weight 3.60 kg) groups [24]. The period of gestation and rate of fetal wasting did not differ between these groups. Moreover, the incidence of fetal deaths in treated pregnancies does not exceed that predicted for the general population [29]. Postnatal growth has also been normal in studies published to date, including our own data and that of Lajic et al, in which 44 children treated prenatally had normal pre- and postnatal growth compared to matched controls [30]. Preliminary data suggest that proper prenatal treatment of fetuses at risk for 21OHD is effective and safe. However, long-term outcome data are needed.

Treatment failures

Although great success with prenatal treatment has been reported, rare treatment failures occur [27]. These failures have been attributed to the cessation of therapy in midgestation, noncompliance or suboptimal dosing; however, some reports from other groups provide no ready explanation [9, 31]. Studies before 1993 must be viewed with caution, as it was common practice then to discontinue dexamethasone treatment to obtain hormonal values in amniotic fluid, and because protocols varied among institutions [23]. Discontinuing dexamethasone treatment for even a short period during sexual differentiation increases the likelihood of genital masculinization in affected female newborns.

Adverse effects reported by others

The basis for concern for long term adverse effects of prenatal dexamethasone partially arises from animal studies. Most of the studies investigating the influence of prenatal glucocorticoids were performed in rodents, mainly rats [32, 33]. Many animal studies used a considerably higher dosage per kilogram of body weight than is used for prenatal dexamethasone treatment in the human. In rats, dexamethasone at the dose of 100 μg/kg daily throughout pregnancy led to low birth weight, low kidney weight, nephron deficit, sodium retention and hypertension in offspring [34]. When dexamethasone was administered at this dose or higher to rats late in pregnancy, dexamethasone led to adult hypertensive offspring [35-37] and low birth weight [38]. Dexamethasone exerts its effects through impairing maternal food intake and weight gain in the rodent, rather than through direct pharmacological effects [39].

Similar prenatal glucocorticoid-induced fetal growth restriction was observed in sheep in association with reduced postnatal arterial pressure, instead of hypertension as in rats. [40] Prenatal dexamethasone treatment in guinea pigs did not cause decreased birth weight [41]. Treatment of pregnant mothers with 20 μg/kg per day of dexamethasone throughout pregnancy was associated with decreased birth weight and adult hypertension in rats[42], but not in sheep [43]. Early in rat pregnancy, dexamethasone treatment failed to program for offspring hypertension [35, 44], whereas in sheep short term dexamethasone exposure very early in pregnancy programmed the offspring for hypertension in adulthood [45]. Thus, the stage of gestation in which exposure occurs is crucial in the outcome of animal studies. Proposed mechanisms of this prenatal programming in offspring include an increase in proximal tubule Na+/H+ exchanger activity [46], altered vascular contractility as shown in sheep [47] and in rats [48],and glucocorticoid receptor (GR) activation [49].

In animal studies, among the reported adverse effects are those on the developing hippocampus, which may result in poor memory and cognitive functioning [50-53]. High dose prenatal dexamethasone given to marmosets gave rise to impaired proliferation of dentate gyrus in the newborn [54]. When rhesus monkeys were studied, the high dose of prenatal dexamethasone produced a modestly decreased hippocampal volume in the neonatal monkeys [55, 56]. If these findings are transferable to the human condition, there may be poor educational and occupational outcome in humans. Translation of primate research to human knowledge requires precautions because the primate studies have used various designs, thereby making comparison difficult. [57] Relative glucocorticoid resistance (GR) observed in new world primates such as the common marmoset mandated a higher dose of dexamethasone compared to old world primates (rhesus, baboon and human). Despite the significant difference in receptor ligand systems, marmoset monkeys demonstrated high GR expression in dentate gyrus [58], similar to humans [59]. In contrast, the GR in the rhesus monkey is weakly expressed in the dentate gyrus, but is more abundant in the hypothalamus, cerebellum and cerebral cortex [60].

Additional adverse effects on prenatal growth and development in general have been predicted to lead to development of hypertension in later adolescence and adulthood [34, 42, 61]. Further, deranged glucose tolerance was demonstrated in rodents [33, 62]. Dexamethasone administration to pregnant sows during the last 24 hours of prenatal life decreased bone mineral density, content and geometric and mechanical parameters of humeri in the newborns. A link between early fetal GR activation and postnatal development of some characteristics typifying metabolic syndrome was found in a marmoset monkey study [63].

Because of the physiological differences between animals and humans, significances of these studies in the human are unknown. The safety of human versus rodent treatment may be explained by the fact that rodent glucocorticoid receptor ligand systems are different from that of the human, primarily due to lack of 17-hydroxylation in the adrenals and receptor differences. In contrast to marmosets, gene expression levels of steroid hormone receptors in rodents change with age [58]. It was shown that ontogeny of hippocampal GR and the effects of prenatal dexamethasone treatment differed between human and mouse [64].

Human studies of other conditions
Concerns about the effect of glucocorticoids on the fetal brain arise from studies of other conditions where much higher dosage was used in patients at risk for co-morbidities which may have an impact on neurodevelopmental outcome. Yeh et al showed that school-aged children who had received early postnatal dexamethasone for the prevention of chronic lung disease of prematurity suffered from impaired motor and cognitive function [65]. This increased risk of neurodevelopmental sequelae may be directly related to the risk of developing chronic lung disease among the infants being treated. [66] Subsequent studies did not succeed in replicating these results [67, 68].

Published data from Forest and Dorr [27] from several European countries indicate a small number of fetal side effects from dexamethasone treatment, either partial or until term (see Table 1).

Table 1. Fetal Side Effects

Fetal Side Effects Fetuses with partial
treatment (174 total)
Fetuses with treatment
until term (64 total)
Intrauterine death 3 0
Fetal distress 0 1
Hydrocephalus 1 0
IUGR 2 0
Malformations 0 0

Long-term effects of prenatal dexamethasone exposure on offspring (Category 1)

In order to make prenatal treatment of 21OHD widely available to female fetuses at risk, it is essential to discover if there are any long-term adverse effects of prenatal treatment with steroids. There was a consensus conference of the Lawson Wilkins Pediatric Society in March 2002 to assess the best methods of treating 21OHD. The conclusion on prenatal treatment reads as follows:

"Study protocols should consider all psychological/behavioral and somatic effects of excess prenatal glucocorticoids and androgens that have been observed in animal experiments or in human studies. Long-term follow-up into late adolescence is mandatory. Relevant control populations should be identified. These studies should also include the partially treated fetuses. Funding agencies, such as the National Institutes of Health or the European Commission, should be encouraged to support such long term studies." [69, 70]

Although no adverse effects are clearly attributable to prenatal treatment, the effects of such treatment cannot yet be ruled out. There is concern that exposure of the developing fetus to dexamethasone may have harmful effects. The basis for this concern, which has been a subject of intense debate, is the absence to date of long-term follow-up studies on treated fetuses. Given the need for initiation of prenatal dexamethasone treatment before sex chromosomes and 21OHD status of the fetus can be determined, early prenatal dexamethasone exposure also occurs in 21OHD-unaffected male and female fetuses, and the concerns regarding adverse side effects apply to these individuals as well.

Therefore, long-term follow-up studies that include a large body of data are needed to address a variety of somatic and psychological outcomes [27]. Some known complications of the medical disorder Cushing Syndrome (excess cortisol) include hypertension, overweight, Type 2 diabetes mellitus, and decrease in bone mineral density. These conditions are largely reversible when the source of excess cortisol is removed. However, animal studies have raised concerns about potential long-term side effects even with prenatal exposure to glucocorticoids (dexamethasone), even though that exposure is limited to pregnancy or only a part of it. Therefore, adequate extended follow-up studies must be conducted in order to investigate analagous long-term adverse side effects of prenatal dexamethasone exposure in humans. Hence, we propose to compare the prevalence of hypertension and obesity in subjects who received prenatal dexamethasone with control subjects who did not receive prenatal treatment, and to collect descriptive data on the rarer adverse conditions type 2 diabetes mellitus and fracture rate as an indicator of bone fragility, for which our sample sizes will not be sufficient to perform prevalence comparisons with adequate statistical power (see below). Table 2 lists the prevalence of these conditions in the general population, with which we will contrast the prevalence in our control subjects.

Hypertension is defined as BP >140/90 in an adult (or >95th % for age, height, and sex in a child <18 years) on three separate occasions. Overweight is defined as BMI >85th % for sex and age in a child or BMI >25.0 kg/m2 in an adult (age >18 years). Type 2 diabetes mellitus is defined as a fasting glucose >126 mg/dL or a 2 hour glucose level >200 mg/dL following a 75 gram glucose load. Clinically significant fractures will be ascertained by an increased incidence of fractures other than of the ribs, sternum, skull or face, fingers, toes, and cervical vertebrae. Use of fracture incidence as a primary endpoint for ascertaining bone density has been widely used in the bone density literature, including the Women's Health Initiative and bisphosphonate trials [71-79]. As recommended by our consultant Henry Bone, MD the question to be answered by the pertinent physician is: "Did this patient suffer fractures of a type or frequency that suggests unusually fragile bones?" (Appendices H and I) Due to our small sample size and the low prevalence of fractures in these age groups, however, we will not be able to perform adequate statistical analysis, so this endpoint will be descriptive only.

Table 2. Prevalence in the general population of the United States (12 - 34 years of age)*

Condition Prevalence in general
population(age 12-19 yrs)
Prevalence in general
population (age 20-34 yrs)
Hypertension(BP >95th %) 5% 3.1%
Overweight (BMI >85th % based on 2000 CDC curve) 17% 47% (20-39)
Diabetes Mellitus Type 2 022% 2.2% (20-39)
Osteoporosis <1% <1%

*MMWR: Racial/Ethnic Disparities in Prevalence, Treatment, and Control of Hypertension - United States, 1999-2002. Centers for Disease Control (Jan14, 2005).
Prevalence of Overweight and Obesity Among Adults: United States, 2003-2004. Department of Health and Human Services, National Center for Health Statistics.
National Diabetes Fact Sheet: National Center for Chronic Disease Prevention and Health Promotion (2002). Osteoporosis: National Health and Nutrition Examination Survey, Department of Health and Human Services, National Center for Health Statistics.

Psychological effects on offspring of prenatal dexamethasone exposure

Given the genital and behavioral effects of prenatal exposure to excess androgens in 46,XX CAH, the question arises whether prenatal dexamethasone treatment reduces not only genital masculinization, but also behavioral masculinization in 46,XX CAH. In addition, the concerns of some investigators regarding potential long-term behavioral side effects in terms of cognitive function, and, by implication, educational and occupational outcome need to be addressed.

Our group has studied developmental outcomes in children up to the age of 12 who were treated prenatally with dexamethasone. Our published findings from these studies are as follows:

  1. In a pilot study, we examined cognitive and behavioral development, behavior problems, and temperament in 26 consecutively identified, prenatally dexamethasone-exposed children aged 6 months to 5 1/2 years, and compared them to 14 dexamethasone-unexposed children [80]. Both groups came from pregnancies at risk for 21OHD, and three children in each group were 21OHD-affected. Assessments were performed by way of mother-completed standard questionnaires. No significant differences were found in cognitive abilities. On temperament questionnaires, dexamethasone-exposed children showed significantly more Shyness, greater Emotionality, less Sociability, and (marginally) greater Avoidance than unexposed children. Dexamethasone-exposed children also had significantly higher Internalizing and Total Problem scores on the behavior problem measure for 2-3 year olds.
  2. In the second phase of the study, 174 prenatally dexamethasone-exposed children compared to 313 dexamethasone-unexposed children, aged 1 month to 12 years, were assessed for developmental outcomes through four standardized questionnaires administered to their mothers [80]. None of the developmental domains, including cognitive, motor, language, social, self-help skills, differed between the two groups, or between (usually small) subgroups formed by age, gender, and CAH status. Duration of prenatal dexamethasone exposure was not correlated with cognitive function.
  3. The third phase of the study used a comprehensive face-to-face evaluation of behavioral development of 140 children aged 5-12 years (about one third 21OHD- affected and one half dexamethasone-exposed). Again, no significant adverse cognitive effects of prenatal dexamethasone exposure were found [81]. Gender role behavior blindly assessed by interview and observation showed the expected masculinization of 21OHD-affected dexamethasone-unexposed girls, albeit without effects on gender identity (dimensionally assessed) [16]. Prenatally dexamethasone-exposed 21OHD girls appeared behaviorally less masculinized, but this finding was not significant when controlled for age differences (Meyer-Bahlburg et al., manuscript in preparation). However, given the subsample sizes, the statistical power of phase 3 was quite limited.

Category 2 (Maternal outcome)
Some potential pregnancy complications of dexamethasone treatment that have been brought into question include an increased incidence of hypertension, gestational diabetes, striae, excessive weight gain, and post-partum depression. There were no significant enduring side effects. In Dr. New's experience (685 pregnancies), maternal complications were not different in the mothers treated with dexamethasone compared to untreated mothers. Table 3 lists the incidence of each of these complications during pregnancy found in the general population. We expect to find similar incidence rates in our control subjects. Normal weight gain for a singleton pregnancy in the United States is 15-40 pounds (See Table 3).

The same potential long-term complications of prenatal dexamethasone listed above for offspring are present for the mothers as well. Again therefore, adequate extended follow-up studies must be conducted on the mothers. Table 4 lists the prevalence rate of each condition in the general population for various adult age groups, which we expect will be comparable in our control group.

Table 3. Prevalence of Complications During Pregnancy in the General Population of the United States*

Condition Incidence in general population
Striae 52%
Severe striae 12%
Excessive weight
gain (>40 lbs for singleton)
Gestational diabetes 3-5%
Hypertension (BP >140/90) 6%
Post-partum depression 13%

*Atwal et al (2006). Striae gravidarum in primiparae. British Journal of Dermatology pp 1-5. Solomon et al (1997). A prospective study of pregravid determinants of gestational diabetes mellitus. JAMA 278 (13) 1078-83.
Rhodes et al (2003). Contribution of excess weight gain during pregnancy and macrosomia to the caesarean delivery rate, 1990-2000. Pediatrics 111(5 Part 2): 1181-5.
Zhang et al (2003). Severe morbidity associated with hypertensive disorders in pregnancy in the United States. Hypertens Pregnancy 22 (2):203-12.

Table 4. Prevalence in General Population of the United States of Various Adverse Effects, Divided by Age Groups*

Condition Prevalence in general population
20-34 yrs 35-44 yrs 45-54 yrs 55-64 yrs
Hypertension(BP >140/90) 3.1% 18.6% 33.4% 57.9%
Overweight (BMI >25) 47% (20-39) 56% (40-59) 56% (40-59) 65% (60-74)
Diabetes Mellitus Type 2 2.2% (20-39) 9.7% (40-59) 9.7% (40-59) 18.3% (>60)
Osteoporosis <1% 5.7% (30-50) 16% (>50) 29.5% (≥65)

*See references in Table 3.

In conjunction with a psychological pilot follow-up study of prenatally dexamethasone-exposed children, we conducted a small retrospective survey of 38 mothers' attitudes toward and experiences of CVS, amniocentesis, and dexamethasone diagnostic procedures. The results of this study showed that these procedures were well tolerated, and almost every woman said that the anxiety or discomfort associated with the procedure was far outweighed by the value of knowing whether or not the fetus was affected. The earlier diagnostic information provided by CVS was highly valued. Maternal side effects of dexamethasone were common (75%) and more than one third of the women rated one or more side effects as "quite a bit" or "very much" (weight gain, fatigue, stomach pain, irritability, facial hair growth). Many women expressed anxiety about possible short- and long-term side effects of dexamethasone on their unborn children and themselves, but all except one said they would undergo dexamethasone treatment again to prevent a 21OHD girl*#39;s genital masculinization [82].


Despite reassuring data on efficacy of prenatal treatment in 21OHD, concerns about the long-term risks of this treatment must be addressed. The first prenatal treatment occurred in 1986 in New York. We are now able to assess the long-term effects of prenatal dexamethasone treatment in these patients. To date, long-term medical and behavioral side effects of prenatal treatment with dexamethasone have not been sufficiently studied. A systematic long-term follow up of individuals now over the age of 12 will enhance our understanding of prenatal steroid exposure in humans [24, 69].

  • Study Activated January 4, 2008
  • First Accrual March 21, 2008
  • Study closed August 01, 2009

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