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Division of Pediatrics (S.G., A.N.), Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, SE-141 86 Stockholm, Sweden; and Department of Molecular Medicine and Surgery (A.W.), Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden
Address all correspondence and requests for reprints to: Sebastian Gidlöf, Centre for Inherited Metabolic Diseases, CMMS C2 71, Karolinska University Hospital Huddinge, SE-141 86 Huddinge, Sweden. E-mail: sebastian.gidlof.616{at}student.ki.se.
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Abstract |
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Objective: The objective of the study was to investigate whether severity of 21-hydroxylase gene (CYP21) deficiency in fetuses with congenital adrenal hyperplasia (CAH) correlates with length of pregnancy.
Design and Subjects: The gestational age (GA) of a cohort of CAH patients born between 1978 and 2004 was studied retrospectively. The GA was correlated to the severity of disease indicated by CYP21 genotype in 114 patients. The results were compared with respect to sex and the normal Swedish population data.
Results: In female fetuses with CAH, we found a correlation between GA and CYP21 genotype. Females with the most severe form of the disease, null mutation, had the longest GA and differed significantly from the normal population. No difference between the sexes was detected for fetuses with CAH as a group. There were no significant differences between CYP21 genotype groups for males.
Conclusions: Female patients with severe CYP21 deficiency had longer GA than patients with the milder form of the disease, indicating that androgen excess, increased 17-hydroxyprogesterone levels, or cortisol deficiency or a combination of these factors is of importance for prolongation of pregnancy. The same correlation was not observed for male patients. The results of this study support the notion that steroid hormones affect the prolongation of pregnancy or onset of labor or both.
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Introduction |
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17-hydroxyprogesterone (17-OHP), a naturally occurring reduced metabolite of progesterone, has in clinical trials been shown to prevent preterm delivery in women with recurring preterm delivery (4, 5). However, it has been shown to be effective only when used as a long-term prophylactic. Whether its function is on the genomic or structural level is unknown.
Progesterone is a substrate for the production of several metabolites in steroid hormone biosynthesis. Experimental studies have indicated that 5ß-dihydroprogesterone, a metabolite of progesterone, can inhibit oxytocin-induced contractions in intact human uterine tissue, which would suggest that it can inhibit the onset of labor (6). It is not known whether the physiological effect is mediated via other steroids or receptors.
Divon et al. (7) showed that male fetuses have longer pregnancies than females in normal pregnancies, the difference being 0.8 d. This may suggest that fetal androgens, i.e. testosterone, another possible product of progesterone metabolism, can influence the onset of labor.
We investigated the length of pregnancy for mothers giving birth to children with congenital adrenal hyperplasia (CAH). CAH is a group of autosomal recessive disorders caused by deficiencies in one of the enzymes in the adrenal steroid hormone synthesis. The most commonly affected gene is 21-hydroxylase gene (CYP21) (>95%), coding for 21-hydroxylase (8). CYP21 deficiency results in deficient production of cortisol and aldosterone. The cortisol deficiency gives rise to an increased ACTH production, resulting in synthesis of the precursors before the enzyme block, including 17-OHP, and in increased production of androgens. The genetics of 21-hydroxylase deficiency is well known. Nine mutations and a gene deletion make up for about 95% of all affected alleles in the Swedish population. There is a spectrum of severity of the disease (9) with a good correlation between genotype and clinical manifestations, i.e. degree of cortisol and aldosterone deficiency as well as amount of androgen production. The enzyme deficiency is present already in fetal life, resulting in an inability of the fetus and placenta to metabolize progesterone and 17-OHP, leading to accumulation of these precursors as well as androgens. We have previously shown that the17-OHP level in the neonatal period correlates well with the CYP21 genotype (10).
The objective of this study was to investigate whether CAH predisposes to prolongation of pregnancy and whether this could be correlated to sex and to severity of disease indicated by CYP21 genotype.
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Subjects and Methods |
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A cohort of pregnancies that had lead to the birth of children with CAH between 1978–2004 (n = 165) was studied retrospectively. Data on gestational age and sex were collected from the Guthrie cards of the national neonatal screening program in Sweden. The information on the cards was given by the midwife collecting the screening samples. The Swedish screening for CAH started in 1986. For children born earlier, medical records were obtained. CYP21 genotyping is carried out routinely in most parts of Sweden in children with positive screening results. Children with no information about gestational age (n = 9), sex (n = 1), or for whom the CYP21 genotype was not performed (n = 21) were not included in the study. The four girls that had received prenatal dexamethasone treatment, to decrease the virilization of external genitalia, were also excluded. CYP21 mutation analysis was performed for 144 children. Patients for whom the CYP21 mutation was not possible to classify in genotype groups according to severity were not included (n = 12). Preterm children were not included in the statistical analysis (n = 8). One child was delivered by elective cesarean section and was therefore excluded. A total of 109 subjects met the criteria for inclusion in the study.
Determination of gestational age
In Sweden gestational age is initially estimated through last menstrual period (LMP). In the 16th gestational week, all women are offered an examination for sonographic determination of gestational age (GA). Ultrasonography has been used for determination of GA by most units since 1982 (11). In this study only one pregnancy was before 1982.
Davis et al. (12) compared LMP and sonographic determination and found that male fetuses had a longer GA when measured with sonography than LMP. However, sex-related differences in this method of determining gestational age cannot be the only explanation because probability of postterm fetuses to be of male sex increases in a linear fashion for each postterm week (7).
CYP21 genotyping
CYP21 mutation analysis was carried out on genomic DNA prepared from venous blood samples using allele-specific PCR and DNA sequencing (13). The patients were divided into four groups, depending on the severity of the mutation on the mildest allele, Null, I2 splice, Ile172Asn (I172N), and Val281Leu (V281L).
Statistical analysis
The SPSS computer program 14.0 (SPSS, Inc., Chicago, IL) was used for all the statistical analyses. The alpha level was set to 0.05. The differences between the groups were calculated using GA age and genotype group was analyzed by means of the Spearman rank order correlation coefficient. The student’s t test was used for comparison between the normal population data and CAH study population. The study was approved by the ethical committee of the Karolinska Institutet in Stockholm.
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Results |
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A total of 28 pregnancies (10 male, 18 female) belonged to the null genotype group. The fetuses in this group had a mutation of CYP21 on both alleles causing completely abolished CYP21 activity. The I2 splice genotype group consisted of 36 pregnancies (21 male, 15 female) carrying children with either I2 splice/null genotypes or homozygosity for the I2 splice mutation. The I172N genotype group consisted of 35 pregnancies (13 male and 22 female fetuses) with genotypes: I172N/Null, I172N/I2 splice, or I172N/I172N. The genotype group leading to the mildest form of CAH was genetically characterized by compound heterozygosity or homozygosity for V281L. This group comprised 10 pregnancies (three male and seven female).
The exact number of gestational days, full weeks plus days, was known for 66 patients (29 male, 37 female). Their genotype groups were: null (six male, 14 female), I2 splice (13 male, eight female), I172N (10 male, nine female), and V281L (no male, six female). Statistical analysis was performed for this group separately and for the whole group including the patients for which only full gestational week at parturition was given.
The mean GA at delivery for children with CAH and information about gestational week and day at parturition was 282.2 ± 10.4. There was no statistically significant difference between the sexes (Table 1
; P = 0,13). This finding differs from the reported difference in the general population in which male fetuses were born 0.8 d later than females (280.6 ± 8.9 vs. 279.8 ± 8.6 d) (7).
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The gestational age was significantly different among the different genotype groups for the whole study population (P = 0.002). Analysis of differences in GA for female infants alone showed a significant difference among the genotype groups (P = 0.002) (Fig. 1). The difference between genotype groups when analyzed for female infants with exact GA given was also significant (P = 0.008). Post hoc analysis showed a difference between the null and I172N groups (P = 0.003) and the V281L group (P = 0.04). I2 splice and I172N differed (P = 0.011) as well as I2 splice and V281L (P = 0.043). The differences between null and I2 splice or I172N and V281L were not significant. There was no statistical difference in GA between the genotype groups for male infants.
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Four female fetuses with prenatal dexamethasone treatment were not included in the calculations. Their GA was 278.0 ± 5.6 SD (null and I2 splice genotype).
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Discussion |
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In girls with CAH, there was a significant correlation between length of gestation and severity of CYP21 deficiency as measured by CYP21 genotype group. Female patients in the most severely affected group, the null genotype group, had the longest gestation. Patients with the more severe mutations have a more pronounced cortisol deficiency as well as androgen excess.
It has been shown that cortisol increases toward the end of the normal pregnancy, and it has been postulated that the switch from cortisone to cortisol in amnion fluid is related to the termination of pregnancy (1). Male and female fetuses in the same CYP21 genotype group can be assumed to have the same cortisol deficiency. The difference in GA between males and females with CAH as a group did not reach significance (male 284.8 ± 10.7 vs. female 280.8 ± 10.0, P = 0.13). The GA of the boys in the normal population was 280.6 ± 8.9 d, compared with 284.8 ± 10.7 for CAH boys; this difference was statistically significant. Obviously we cannot rule out that cortisol deficiency contributes to our findings.
Female patients with severe CYP21 deficiency had longer GA than patients with the milder form of the disease, indicating that androgen excess, increased 17-OHP levels, or cortisol deficiency or a combination of these factors are of importance for prolongation of pregnancy. The same correlation was not observed for male patients. Male fetuses with CAH have androgens, 17-OHP, and testosterone of adrenal as well as testicular origin (14). These testicular steroid hormones may minimize differences between the genotype groups in males with respect to androgen concentration in amnion fluid. It may also contribute to the prolongation of GA, compared with normal males. There were no males in the mildest genotype group, possibly increasing the difference in androgen levels further.
The fact that there was no statistically significant difference in GA between males and females among the CAH patients may reflect the fact that there is a smaller than normal difference in androgen concentration between the sexes due to adrenal androgen production in this patient group.
The mean differences in GA between males and females in the normal population are significant but not large. Hence, a large difference between the genotype groups cannot be expected. Although a definite answer to which factors are involved in prolongation of pregnancy and induction of labor cannot be given by our results, the observed significant difference in the limited number of infants in this study is still of interest. The results of this study support the notion that steroid hormones affect the prolongation of pregnancy or onset of labor or both.
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Footnotes |
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Disclosure Statement: The authors have nothing to disclose.
First Published Online October 17, 2006
Abbreviations: CAH, Congenital adrenal hyperplasia; CYP21, 21-hydroxylase gene; GA, gestational age; LMP, last menstrual period; 17-OHP, 17-hydroxyprogesterone.
Received June 26, 2006.
Accepted October 6, 2006.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-hydroxyprogesterone caproate. N Engl J Med 348:2379–2385This article has been cited by other articles:
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  J. O'Sullivan, S. Iyer, N. Taylor, and T. Cheetham Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is associated with a prolonged gestational age Arch. Dis. Child., August 1, 2007; 92(8): 690 - 692. [Abstract] [Full Text] [PDF]
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