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Original Studies |
Department of Woman and Child Health, Pediatric Endocrinology Unit (S.L., E.M.R., M.H.), and the Department of Molecular Medicine, Clinical Genetics Unit (S.L., A.W., T.-H.B.), Karolinska Hospital, S-171 76 Stockholm, Sweden
Address all correspondence and requests for reprints to: Svetlana Lajic, M.D., Ph.D., Pediatric Endocrinology Unit (Q2:08), Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: svetlana.lajic{at}kbh.ki.se
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Abstract |
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Compared to their elder affected sisters, all 5 girls with severe congenital adrenal hyperplasia who were treated until term showed little virilization. Only 1 required surgery for labial fusion. The majority of the 44 dexamethasone-treated fetuses demonstrated normal pre- and postnatal growth compared to matched controls. However, several adverse events such as failure to thrive and delayed psychomotor development, were reported among the treated infants. In addition, treated mothers reported more side-effects during pregnancy than did controls. A significant increase in weight gain was observed during early pregnancy when treatment was initiated, but this initial rapid weight gain declined during late pregnancy or when treatment was terminated.
Thus, experience to date suggests that prenatal treatment of affected female fetuses is generally efficient in minimizing virilization of external genitalia. However, there is still a need to collect more data concerning possible rare unfavorable effects of this therapy on mother and child.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical symptoms of 21OHD demonstrate a wide spectrum of severity, with the most severe cases (three of four) diagnosed in the early neonatal period due to salt-wasting and prenatal virilization of affected females. Children with milder forms are diagnosed during childhood on the basis of growth acceleration and precocious pseudopuberty. The symptoms of the mildest forms of CAH can be so subtle that affected females are not diagnosed until adulthood on the basis of hirsutism and infertility.
During recent decades, several methods have been employed for prenatal diagnosis of 21OHD. Initially, 17-hydroxyprogesterone, 21-deoxycortisol, androstenedione, and testosterone levels were measured in amniotic fluid obtained by amniocentesis during midgestation (2, 3, 4, 5, 6). After mapping (7) and cloning of the gene encoding 21-hydroxylase (8), hormonal analyses were complemented by genetic linkage analysis using markers in the polymorphic human leukocyte antigen (HLA) loci (9, 10, 11, 12).
Hormonal analyses were, however, suboptimal for the detection of mild forms of CAH, and genetic linkage was not always informative, especially when the parents were HLA identical or if one parent was affected with CAH (13). In Sweden and Norway, prenatal diagnosis has been performed using allele-specific PCR on DNA from chorionic villous samples since 1990 (14). No false negative and only one false positive case has been detected, making this method very reliable.
Prenatal treatment was first introduced by David and Forest in 1984, when the first treatment with dexamethasone (DEX) to prevent virilization of a female fetus (15) was performed. Since 1984, several hundred at-risk pregnancies have been treated with DEX, and approximately 50 CAH-affected girls have benefited from this therapy (16, 17, 18, 19).
Prenatal treatment was started in Scandinavia in 1985. We report here the follow-up study of the outcome of all cases of prenatal diagnosis and treatment of CAH in Sweden and Norway during the years 1985–1995. Maternal tolerance of the treatment as well as pre- and postnatal growth and psychomotor development of the children are presented. All data have been compared with those obtained from matched, untreated controls.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In Sweden and Norway between the years 1985–1995, 43 fetuses at risk of being affected with severe CAH were treated with DEX to prevent prenatal virilization of affected females. As mutation analysis of 21OHD in Sweden and Norway is centralized to the Karolinska Hospital, we are certain that this cohort contains all cases of prenatal diagnosis and treatment in these countries during this period. In addition, 1 case was diagnosed and treated in Denmark.
One woman received treatment during 4 consecutive pregnancies, 1 during 3 pregnancies, and 3 women were treated twice. Of these 44 pregnancies, 37 were treated short term (approximately during the 6–12th weeks of pregnancy), because the fetus was either unaffected (n = 28) or an affected male (n = 9). Four pregnancies treated short term (unaffected fetuses) resulted in spontaneous abortions after chorionic villous sampling, and 1 pregnancy was terminated (an affected boy). Seven of the 44 cases were treated from the 6th week of pregnancy until term and resulted in 5 females with predicted severe CAH, 1 with mild CAH, and 1 unaffected female.
The pregnancy that produced a mildly affected female was treated before mutation detection had been introduced for prenatal diagnosis. After the birth of the child, it became evident that the mother was affected with mild CAH, and that three different mutations segregated in the family. The woman who gave birth to the unaffected girl treated until term refused chorionic villous sampling and amniocentesis and chose instead to receive treatment during the entire pregnancy. Of the entire cohort of 44 prenatally treated fetuses, there were two couples where the mother or the father was affected with mild, nonvirilizing CAH.
Treatment
In the event of a new pregnancy, women who had previously given birth to a child with a virilizing form of CAH were offered prenatal treatment with DEX. Treatment was initiated either by a local gynecologist or by a pediatric endocrinologist in collaboration with our unit. All families except one had previously been typed for the specific disease-causing mutations segregating in each family, which enables prediction of disease severity (20).
As suggested by David and Forest (15), treatment with DEX (20 µg/kg·day administered orally in three divided doses) was initiated before the 7th gestational week. Prenatal diagnosis of 21OHD was performed in all cases but four by allele-specific PCR (14) on DNA from chorionic villous samples. In one of these four cases (treated during 1985), prenatal diagnosis was based on HLA typing of amniotic cells obtained during the 15th week of pregnancy. In the remaining three cases (treated during 1986–1988), the prenatal diagnosis relied on HLA typing on DNA from chorionic villous samples.
The sex of the fetus was determined by karyotyping or analysis of sex chromosome markers using Y-specific DNA probes. If the fetus was unaffected or was an affected boy, treatment was interrupted approximately 3–4 weeks after the chorionic villous biopsy (CVB) was performed. If the fetus was an affected girl, treatment was continued until delivery.
During the pregnancy the mother was followed at the local maternity health care center. The efficacy of the treatment and the compliance of the mother were monitored using several parameters. Before treatment, a 24-h urinary cortisol (U-cortisol) sample was analyzed, and after the 12th gestational week 24-h U-estriol and U-cortisol samples were measured every second week. Both U-cortisol and U-estriol levels should be low, indicating suppression of both the maternal and fetal pituitary-adrenal axes. The diagnosis of the child was confirmed after birth by measuring 17-hydroxyprogesterone in serum or in capillary blood samples at the age of 72 h as a part of the general screening program for 21OHD.
Study design
A retrospective study of all cases treated prenatally in Sweden and Norway and of one case in Denmark during the years 1985–1995 was undertaken. The case files from the maternity health care centers were examined, and the development of the children’s linear growth, weight, and head circumference as well as developmental milestones were followed. One to 5 yr after delivery, each woman also answered a questionnaire about her well-being during the pregnancy. All but one of the mothers contacted replied.
The entire cohort was divided into 3 separate subgroups that were
compared to 3 separate control groups of untreated mothers and children
(see Table 1
). The healthy controls were
chosen from the same maternity health care centers that monitored the
treated mothers. Two consecutive pregnancies, matched for the sex of
the fetus and registered after the DEX-treated mother, were chosen at
each health care center. Our aim was to include controls from the same
environment and with a similar socio-economic background as the
DEX-treated mothers. In total, data from 49 control mothers and 44
control children were collected. The index cases (CAH-affected siblings
not treated prenatally) for each family were used as controls for the
subgroups of prenatally treated CAH fetuses regardless of the sex of
the index case.
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Statistical analysis
Student’s t test for independent (group A) or
dependent (groups B and C) samples was used for comparisons between
treated children and controls with regard to the following parameters:
change in body mass index (
BMI), maternal blood pressure during
pregnancy, placental weight, birth data, and postnatal growth of the
children. Maternal side-effects during pregnancy were compared using
Fisher’s test (two-tailed P value), whereas the rate of
weight gain during pregnancy (kilograms per week) was examined using
linear regression analysis and ANOVA. The log-rank test was used for
comparing the time of delivery (gestational week). The birth data (21)
and postnatal growth of the children were expressed as SD
scores based on to Swedish reference values for height and head
circumference (22) and British reference values for weight (23).
P = 0.05 was used to identify significance in all
analyses performed.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The complete cohort of 44 prenatally treated fetuses consisted of 28 unaffected fetuses treated short term, 9 CAH-affected males treated short term, 6 CAH-affected females treated full term, and 1 unaffected female treated full term. Two patients were not treated according to the recommended clinical protocol. The first of these was diagnosed by HLA typing before genotyping was available. This CAH-affected female fetus was treated until term, although she had the same mild, nonvirilizing form of CAH as her mother. This was the first fetus treated prenatally for CAH in Scandinavia. In the second of these cases, the mother refused chorionic villous sampling and chose to continue treatment throughout the entire pregnancy. She gave birth to an unaffected girl. Seven cases (of 44) were excluded from statistical analysis, including 4 spontaneous abortions (unaffected fetuses), 1 elective abortion (CAH-affected male), and 2 cases who were each the second treated child in their families (1 unaffected boy and 1 affected girl).
The incidence of affected female fetuses was 13.6% (6 of 44), whereas that of affected male fetuses was 20.5% (9 of 44). Apart from deletion of 1 or both alleles (50% mutation frequency), the most frequent mutation found in this population was the intron 2 splice (I2 splice) mutation (19% mutation frequency). This I2 splice mutation is the most common point mutation; it is found in approximately 27% of all affected alleles in the Scandinavian population (20). The other mutations involved were either one of the common mutations found in CAH populations all over the world or were unique to the individual family studied (24). All mutations were known to cause severe forms of CAH.
Maternal parameters monitored during pregnancy
Records from the maternity health care centers were studied, and weight gain, blood pressure, U-glucose, and U-protein were monitored during pregnancy. Information on placental weight and gross morphology were also obtained from the delivery health records.
Almost all of the treated women started DEX treatment before the seventh week of pregnancy (mean ± SEM, 6.3 ± 0.3 weeks). In the case of one woman treated full term, therapy was initiated later (week 11). CVB and prenatal diagnosis were performed during week 10 (9.7 ± 0.3), and treatment was terminated a few weeks later (at 13.5 ± 0.5 weeks) if the fetus was unaffected or was an affected male. The average dose of DEX administered to the women treated short term and carrying an unaffected fetus was 20.3 ± 0.6 µg/kg·day, and the corresponding value for mothers treated short term and carrying a CAH-affected male fetus was 21.9 ± 1.4 µg/kg·day. The initial dose for women treated full term was 22.9 ± 1.6 µg/kg·day, but the dose per kg BW decreased at the end of the pregnancy to 17.9 ± 1.1 µg/kg·day due to increased body weight.
The total increases in weight from the beginning to the end of
pregnancy for the different subgroups and their controls, calculated as
BMI, were compared. As shown in Table 1
, no significant differences
could be observed between the treated and untreated groups. However,
treated mothers often complained of rapid weight increase during early
pregnancy when treatment was initiated. Therefore, we analyzed the rate
of weight gain (kilograms per week) during the first trimester of
pregnancy and that during the entire pregnancy separately (Table 2).
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). No significant differences in blood pressure (P > 0.05, by t test) or in the incidence of glucosuria or proteinuria (data not shown) could be observed between treated mothers and their controls. The prenatally treated fetuses were not born prematurely compared to the untreated fetuses in each control group (P > 0.05, by log-rank test), nor was placental weight affected by DEX treatment (P > 0.05, by t test). The majority (32 of 37) of the prenatally treated children were delivered in a normal fashion, and the frequency of cesarean section or forceps delivery was not increased in this group.
Maternal side-effects and complications
A questionnaire concerning their well-being during pregnancy was
given to all women involved. In general, DEX-treated women reported
more complications, which could be either side-effects caused by DEX or
normal changes during pregnancy (Table 3). There was also a strong tendency for
mothers treated full term to report more side-effects than those
treated only during the first trimester of pregnancy. Approximately one
third of all DEX-treated women said that they would not undergo
treatment again.
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A total of 4 spontaneous abortions (of 44 pregnancies) occurred among the DEX-treated women. In none of these cases did the aborted fetus have CAH, and the mothers miscarried a few weeks after they had undergone CVB. The incidence of miscarriages among the treated women was thus 9%, similar to the incidence observed in other studies (17).
Prevention of virilization
In Table 4, the Prader status of the
treated girls and that of their elder, untreated siblings are listed.
Early initiation of treatment, i.e. before the seventh week
of gestation, and good compliance were necessary for optimal efficacy.
In four of five cases exhibiting severe CAH, the virilization of
external genitalia was significantly reduced compared to that in the
elder siblings. In one case (no. 2), the compliance of the mother was
poor, and the girl was born more virilized (Prader stage 2–3) than her
older well treated sister, but still less virilized than the index
case.
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In Table 5, birth weight, length, and head
circumference (SD scores) are presented for treated and
untreated children. DEX treatment did not have any negative effect on
fetal growth, as treated children were born normal in size compared to
the matched controls. It should be noted that, surprisingly, treated
CAH-affected boys demonstrated increased birth lengths compared to
untreated siblings.
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. Data for both treated
and untreated boys lie within ±2 SD for all parameters, as
was also the case for the unaffected girls. The birth data related to
gestational age followed the same pattern for the CAH-affected boys
(data not shown) and girls (Fig. 2) as
for their controls, except for one girl who was born growth retarded;
her mother had preeclampsia (see above).
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. As shown, these
children grew as well as their untreated peers, as no significant
differences could be observed at the ages of 3 months, 1 yr, and 4 yr,
nor did comparison of the latest measurements (data collected at the
latest visit at the well-baby clinic; Fig. 4) for treated vs. untreated
children reveal any significant differences (P > 0.05,
by t test). The oldest treated boy has been followed for 8
yr now, and the oldest girl has been followed for 6.5 yr. Similarly,
the more recently recorded heights and weights for prenatally treated
CAH-affected boys and girls and their untreated siblings did not differ
significantly (P > 0.05, by t test),
although among the girls there are two cases (aged 5.5 and 7 yr) whose
growth is 2 SD below the mean (Fig. 5). The mildly CAH-affected girl that was
treated during the entire fetal period has been followed for 9 yr now
and has developed very well.
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Developmental milestones were normal for the majority of the prenatally treated children. However, some adverse events were observed among cases treated both short term and full term. One unaffected boy who was treated for 7 weeks was born with severe hydrocephalus and agenesis of the corpus callosum. Another unaffected boy was born large for gestational age, and at birth the obstetrician observed a broad neck and hypospadias with unilateral cryptorchidism. At 9 months of age this boy had developed baby-talk. Today, at 2 yr of age, his motor skills are undeveloped, his head circumference is unusually small, and he does not talk. The parents of this boy are first cousins.
Adverse events have also been noted in the case of three unaffected girls. At 2 weeks of age, one of these girls developed severe episodic vomiting that persisted for several months. Her serum concentrations of liver enzymes were elevated, and she developed liver steatosis. This girl was suspected of having a metabolic disease, but this was never confirmed. Today, at 3 yr of age, she is doing fine, and her growth is normal, as is her psychomotor development. Her problems during early life were suspected to be due to an adenovirus infection.
Another unaffected girl stopped gaining weight adequately after 6 months of age. At 20 months of age, her weight was 3 SD below the mean, and her height was 1.5 SD below the mean. She was admitted to the pediatric ward and investigated for celiac disease, which has not yet been confirmed.
Another unaffected girl treated during her entire fetal life had two episodes of pneumonia at 9 months of age. She recovered from these infections, but according to her mother this child developed extreme fluctuations in mood and aggressiveness and was therefore examined, by electroencephalogram and psychological development tests. The explanation for her behavior is still unknown.
In the group of CAH-affected girls treated during the entire fetal period, three cases have to be considered as involving adverse events. The full term treated girl with mild CAH, mentioned previously, was delivered by cesarean section during the 37th gestational week because of maternal preeclampsia. She was growth retarded at birth (-4 SD) but later recovered, and at 9 yr of age, she was doing very well with normal growth and psychomotor development.
Two affected sisters have had developmental problems. The older sister was born normal in size for gestational age, but gained weight poorly during the first year of life. At the age of 1 yr her weight and height were 5 SD below the mean. After 2 yr of age, she started to catch-up and at the age of 6 yr her height was only 1.5 SD below the mean.
Her younger sister was more virilized at birth due to poor maternal compliance. Labor was induced during the 38th gestational week because of decreased fetal growth and maternal hypertension. This girl was born growth retarded, and at 1 month of age she developed seizures. Soon after that, she developed severe vomiting and episodes of metabolic acidosis with hypoglycemia and was diagnosed as having a mitochondrial disease (complex I defect). Her psychomotor development is delayed, and today at 2.5 yr of age this girl has percutaneous gastrostomy. She communicates with her mother only through signs, but has normal hearing and motor functions. She still has occasional seizures, and her head circumference has dropped from 1 to 3 SD below the mean.
In the control groups one child with trisomy 21 was reported. No other chromosomal aberrations or abnormalities were observed.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This is the first report on an extensive long term somatic follow-up of children treated prenatally with DEX. Their growth data were compared with data for untreated matched controls. Gross developmental milestones were recorded, but no specific psychological tests were applied. The oldest treated child has now been followed for more than 9 yr.
Prenatal treatment of 21OHD with DEX was effective in preventing virilization of external genitalia in affected females, provided that treatment was begun before the seventh week of gestation and was continued without interruption until term. One affected female in our study was not treated in an optimal fashion due to poor maternal compliance. This girl was born more virilized (Prader stage 2–3) than her older sister, who had normal external genitalia, but was less virilized than her untreated sister (Prader stage 4). Similar observations have been reported from other studies where treatment was started around the 10th week of gestation and was interrupted during the late second or early third trimester of pregnancy (19, 26). These findings clearly demonstrate the importance of early initiation and continuation of treatment until term. It is also crucial that the mother is carefully informed about possible maternal side-effects and provided with support and follow-up during the treatment.
The maternal side-effects and adverse events in this study are similar to those that could be expected in connection with glucocorticoid (GC) treatment as well as during normal pregnancy. Previously reported data on normal weight gain during pregnancy concern mostly the second and third trimesters, and only very limited data are available on average weight gain during early pregnancy. The mothers treated with DEX reported that they gained weight rapidly when treatment was initiated. We confirmed that DEX-treated mothers do indeed gain weight more rapidly than untreated controls during the first trimester of pregnancy, but that the total weight gain during pregnancy is not affected by the treatment.
The incidence of spontaneous abortions (9%) observed in this study is in line with that observed in the general population. During the first trimester of pregnancy fetal loss is approximately 7%, and after the ninth gestational week this incidence drops to 2% (27).
Pre- and postnatal growth and psychomotor development of treated children must be followed carefully; in particular, the development of the unaffected children treated short term should be monitored, because these children receive no benefit from the treatment. GC administered in high doses during fetal life do not seem to be teratogenic in primates, but have been shown to be neurotoxic to the primate brain. Administration of DEX in high doses to pregnant rhesus monkeys during the period corresponding to the early third trimester of human pregnancy induced degeneration and depletion of the hippocampal pyramidal and dentate granular neurons in the fetal brain (28). The doses administered to these monkeys were 16 times higher than the doses recommended for antenatal steroid therapy designed to induce fetal lung maturation in pregnancies at risk of preterm delivery, and 200 times higher than the doses recommended for prenatal treatment of CAH.
We did not observe any elevated incidence of fetal abnormalities or fetal death, although a larger number of abnormalities in postnatal growth and behavior were seen in the treated groups. Whether this difference is caused by DEX is, of course, very difficult to determine. However, overall the treated children seem to grow normally compared to untreated peers and siblings. The increased birth length of the treated CAH boys should be interpreted with caution due to the small sample size.
Rats exposed to GC in utero demonstrated an increased incidence of hypertension later in life (29). Pups of mice treated with extremely high doses of GC also showed more aggressive behavior (30). We have not monitored the blood pressure of prenatally treated infants, but the results obtained in animal studies raise important questions concerning interactions between the in utero environment and common adult diseases.
Recent psychological studies of prenatally treated children, based on parental questionnaires, suggest that the DEX-treated children are more shy and emotional and less social than their unexposed peers (31). Cognitive development was normal, as no developmental delay was observed. These investigators state that their results should be considered preliminary, because many of their statistical comparisons were performed on small sample sizes, and that direct examination of children should be performed. More detailed studies on the psychological performance of Swedish DEX-treated children are also presently in progress.
Another important aspect of prenatal treatment of CAH is the possibility of avoiding the traumatic experience of a child born with ambiguous genitalia. The gender identity of virilized CAH girls may be affected, as high levels of androgens may virilize not only the body, but also the brain (32, 33). Prenatal treatment will eliminate or reduce traumatic surgical interventions and may also reduce the risk of future psychological problems associated with gender identity.
In conclusion, although in our experience prenatal treatment with dexamethasone is effective in preventing virilization of girls with severe 21OHD, several adverse events have been noted in treated infants. As it is not known yet whether these events were attributable to DEX, the treatment must still be regarded as experimental until more experience has accumulated. The treatment and monitoring of mothers and infants should therefore be centralized. In addition, prospective international, multicenter studies should be organized.
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Acknowledgments |
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Footnotes |
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Received May 15, 1998.
Revised July 17, 1998.
Accepted July 21, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-hydroxyprogesterone
in congenital adrenal hyperplasia [Letter]. J Pediatr. 86:310–312.[Medline]
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