Hum. Reprod. Advance Access published online on April 16, 2008
Human Reproduction, doi:10.1093/humrep/den118
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Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
1 Department of Women and Child Health, Division of Obstetrics and Gynaecology, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden 2 Department of Obstetrics and Gynaecology, Sahlgrenska Academy, Sahlgrenska University Hospital, 413 45 Göteborg, Sweden 3 Department of Paediatric Surgery, Sahlgrenska Academy, Sahlgrenska University Hospital, 413 45 Göteborg, Sweden 4 Department of Endocrinology, Metabolism and Diabetes, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden 5 Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden 6 Department of Endocrinology, Sahlgrenska Academy, Sahlgrenska University Hospital, 41345 Göteborg, Sweden 7 Department of Clinical Sciences, Division of Psychiatry, Karolinska Institutet, Danderyd Hospital, 182 87 Stockholm, Sweden 8 Department of Pediatric Surgery, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden
9 Correspondence address. Fax: +46 8 517 73620; E-mail: agneta.nordenskjold{at}ki.se
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Abstract |
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BACKGROUND: Low pregnancy rate has been reported in women with congenital adrenal hyperplasia (CAH) and little information on pregnancy and children is known.
METHODS: In a Swedish study, 62 adult women with CAH, aged 18–63 years, and 62 age-matched controls were followed-up. Medical records, including those concerning pregnancies and deliveries, were examined and the 21-hydroxylase genotype of patients was noted. All women answered a questionnaire concerning sexual and reproductive health including health of the children.
RESULTS: Pregnancy and delivery rates were significantly lower in women with CAH (P < 0.001, P < 0.0056, respectively), and the severity of the 21-hydroxylase-mutation correlated with the reduced number of children born. More women with salt-wasting CAH were single and had not attempted pregnancy. Pregnancies were normal except for a significantly increased incidence of gestational diabetes in CAH patients (P < 0.0024). The children had normal birthweight and no malformations were observed. A later follow-up of the children showed a normal intellectual and social development. The sex ratio of the offspring differed significantly, with 25% boys in the CAH group compared with 56% among controls (P < 0.016). CAH women had more gynaecological morbidity during menopause.
CONCLUSIONS: Pregnancy and delivery rates are reduced in women with CAH mainly due to psychosocial reasons. The outcome of children did not differ from controls. The unexpected sex ratio in children born to mothers with CAH warrants further research.
Key words: congenital adrenal hyperplasia/21-hydroxylase mutation/pregnancy/sex ratio/gestational diabetes
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Introduction |
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Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is an autosomal recessive disorder characterized by impaired or total loss of activity in the enzyme required for the synthesis of cortisol and in
75% of cases also a failure to synthesise aldosterone. CAH is clinically divided into classic CAH that includes salt-wasting (SW), simple virilizing (SV) and non-classic (NC) disease. All three types are highly correlated with the spectrum of 21-hydroxylase mutations and to the severity of the disease (Wedell et al., 1994
; Pinto et al., 2003). In classic CAH, lifelong glucocorticoid and often also mineralocorticiod therapy are mandatory, whereas in the milder NC form, treatment is given when patients have symptoms such as hirsutism, oligo-amenorrhoea or infertility. If corticosteroid supplementation is insufficient, androgen production from the adrenals will increase and suppress gonadotrophin secretion from the pituitary that will lead to a disturbance of the ovarian cycle resulting in anovulation and infertility.
Until now, there has been a scarcity of reports on the outcome of pregnancies in women with CAH. Traditionally, low pregnancy rates have been reported especially in women with the SW form of classical CAH (Mulaikal et al., 1987; Jääskeläinen et al., 2000; Lo and Grumbach, 2001; Stikkelbroeck et al., 2003; Gastaud et al., 2007). The reasons for this low fertility in women with CAH have been discussed in several articles (Meyer-Bahlburg, 1999; Jääskeläinen et al., 2000; Otten el al., 2005). The literature on the outcome of pregnancies with regard to the progression of the pregnancies and the health of the children is even sparser. ‘Normal child’ is usually the only information given in most reports. More information is needed from long term follow-up studies where the outcomes of the pregnancies are related to the genotype and not only to the phenotype of women with CAH.
In this follow-up study from Sweden, 62 adult women with CAH due to 21-hydroxylase deficiency have been investigated to provide information on the influence of the genotype on menstrual pattern, fertility preferences and fertility and pregnancy outcome.
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Materials and Methods |
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The follow-up study was part of a collaborative project between Stockholm and Göteborg in Sweden to evaluate adult women with CAH from an endocrinological, gynaecological, psychosocial and psychosexual perspective. The performance of the study was as previously described (Falhammar et al., 2007a
). Sixty-two women, 18–63 years old, were recruited either by their physician or through the National CAH patient organization. An additional 17 CAH women were contacted, 4 declined to participate due to personal reasons and 13 could not take part because of different practical reasons. The proportion of different forms of the disease in these 17 women was similar to those followed-up. Sixty-two women born on the same day as the CAH patients were recruited as controls from the Swedish Population Registry. They were examined within 1 year from their age-matched CAH patients. All but two of the CAH women and the controls were of North-European, Caucasian ethnicity. Half of all women were younger than 30 years.
The women with CAH were analysed for mutations of the 21-hydroxylase gene with the mildest form of the two alleles as representative of the genotype. Fourteen women had a SW, potentially life-threatening form of CAH (corresponding to no enzyme activity, i.e. null/null), 15 had an I2splice-mutation (SW—a few percent of normal enzyme activity), 27 had mutations corresponding to the SV form of CAH and 6 had the NC form. Age of onset and initial symptoms varied with the severity of the mutations and has been previously described (Falhammar et al., 2007a).
All women gave their signed informed consent to participate in the study and were examined as outpatients between October 2002 and January 2005. The controls were seen within 1 year after the patients visit. A medical history was taken and all participants answered a semi-structured questionnaire (120 items) concerning treatment, earlier surgery, fertility, sexuality, pregnancies and social life. Only the women with CAH underwent a gynaecological examination to evaluate their present situation with regard to virilization and post-operative status as reported by us recently (Nordenskjöld et al., 2008). With the written permission of the CAH patients, all records of earlier treatment within the healthcare system were obtained and reviewed. Among women with a history of pregnancy, CAH and controls, the records from the antenatal clinic as well as records from the delivery wards were collected. The details of the outcome of the pregnancies were extracted from the records and compared with the information given by the women themselves. The process was facilitated by the fact that all antenatal clinics and delivery wards in Sweden have been using the same forms for more than three decades. In order to inform on the post-natal development of the children born to CAH mothers, one structured telephone or personal interview was performed 2–3 years after the first examination.
The Research Ethics Committee of Karolinska Institutet and of Göteborg University, Sweden, approved the study.
Statistical methods
The women with CAH were individually matched with the control women and thus data were considered as paired. In comparisons between the patients and their controls, McNemar test or the sign test was performed for categorical data and the Wilcoxon matched pair test for continuous data. For the outcome of term pregnancies, statistical methods for independent samples were used. The Chi-square test or Fisher's exact test was used for categorical data and the Mann–Whitney U-test for continuous data. A P-value of <0.05 was considered statistically significant.
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Menstrual pattern, social situation and fertility
There was no difference in age at menarche or first pregnancy between the women with CAH and their matched controls (Table I). However, significant differences were observed between age at sexual debut, number of women living in a steady heterosexual relationship and number of women who had attempted pregnancy—all factors having an influence on fertility outcome. Irregular menstruation, an indication of anovulatory cycles, was similar in women with CAH and controls; 28% of those women in whom the menstrual cycles could be assessed (Table I). The number of women experiencing menopause (five women) or secondary amenorrhoea (three women) was the same in the two groups. The use of hormonal contraceptives was similar among the patients and the controls, 17 and 24 women, respectively. Differences were observed among the women with CAH when their mutation status was taken into consideration (Table II). Notably, less than one-third of the women with the null/null mutation were living in heterosexual relations, whereas 81% of the women with the SV mutation were married or living in a steady heterosexual relationship. Bi/homosexuality was more common among the women with SW than among those with SV. Twenty-three of the 29 women with SW answered the questions on this issue and 8 considered themselves bi/homosexual. Twenty-three of the 27 women with SV answered the same questions and 2 considered themselves as bi/homosexual. However, most of these women were single without sexual partners. As was presented by us recently, 49 of the women with CAH had been corrected surgically with clitorido- and/or vaginoplasty. In the SW group, all 29 patients were operated, in the SV group 20/27 and none of the NC patients. Whether operated or not, the women with CAH were often less satisfied with the function and appearance of their genitals than their age-matched controls (Nordenskjöld et al., 2008
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When comparing pregnancy history, significantly fewer women with CAH had ever been pregnant, 16 compared with 41 in the control group (P < 0.0001) (Table III). A total of 31 pregnancies were seen among the 62 women with CAH compared with 76 among the 62 women in the control group (P < 0.0001). Only 25 children were born in the CAH group compared with 54 in the control group (P < 0.0056). The frequency of spontaneous abortions did not differ between the patients and the controls, but there were more induced abortions in the control group (P < 0.004). All induced abortions were performed on social grounds.
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When the number of children born is related to the mutation status of the women with CAH, the severity of the mutation clearly influenced the results. There were no children born from SW women with the null/null mutation, 3 children from 15 SW women carrying the I2splice mutation, 19 children from 27 women with SV and 3 children from 6 women with NC CAH. One pregnancy of a woman with the null/null mutations ended in a therapeutic abortion, another woman with the same mutation had a spontaneous abortion.
Nineteen patients had attempted pregnancy. Three of these belong to the oldest age group and only got superficial evaluation and treatment >20 years ago with Clomiphene without success. Two patients had unwanted pregnancies; one resulted in a spontaneous and the other one in a therapeutic abortion. Among the remaining 14 patients, four became pregnant spontaneously and did not need any evaluation. Five women had irregular menstruation and ovulation, an increase in the glucocorticosteroid dose or addition of fludrocortisone induced ovulation and pregnancy. No other evaluation or treatment was necessary. In five women, the pregnancies were the result of infertility investigation and relevant treatment. In this group no male factors were found, they all had normal sperm count. No further genetic or hormonal investigation was performed according to the clinical routine procedure. One woman with SV was treated with gonadotrophins and insemination with her husband’s sperm. The treatment resulted in two pregnancies, each with one child. Another woman with SV gave birth to two children, each after IVF treatment. Both these women had increased serum progesterone levels in the follicular phase and polycystic ovary syndrome (PCOS) like ovaries. Because of anovulation, PCO like ovaries and high progesterone levels, one woman (NC) underwent a period of infertility treatments including several cycles of gonadotrophin treatment and IVF, but without result. She finally got pregnant on her usual corticosteroid doses with metformin added to decrease insulin resistance (Falhammar et al., 2008). Another two CAH women, one SV and one NC, received treatment for moderate endometriosis. None of the control women had undergone infertility evaluation or treatment.
Outcome of the pregnancies
The length of pregnancy was significantly shorter in the women with CAH than in their age-matched healthy controls (P < 0.022) (Table IV). The reason for this is the high frequency of elective Caesarean section among the patients. Thus, 84% of the deliveries were elective or acute Caesarean sections in the women with CAH compared with only 9% in the control group. The main reason for a Caesarean section in the patient group was earlier genital surgery but in two non-operated patients, a cephalic-pelvic disproportion. The pregnancy length was normal in the four pregnancies that ended in a spontaneous vaginal delivery and in the three pregnancies that started with normal labour but ended in an acute Caesarean section. An unexpected finding was the incidence of gestational diabetes among the women with CAH. Three women experienced this complication during five pregnancies. The first woman (SV) developed gestational diabetes during each of her three pregnancies and received insulin treatment during the last two. Her corticosteroid dose before and during the pregnancies was moderate. The second woman (SV), while on a high prednisolone dose when pregnancy started, developed insulin dependent diabetes during the last trimester of her first pregnancy. Finally, the third woman (NC) was treated before the pregnancy with corticosteroids in a moderate dose with metformin added to decrease insulin resistance. She discontinued metformin in early pregnancy and developed mild gestational diabetes during the last part of the pregnancy and was treated with insulin (Falhammar et al., 2007c). All these three women had a normal BMI (20–24 kg/m2) before pregnancy and a normal weight increase during the pregnancy. There were no cases of diabetes in the control group. No cases of pre-eclampsia were registered among the women with CAH, but in almost 4% among the control women. The medications of the CAH mothers are presented in Table V. Nine of the 14 women received fludrocortisone in addition to their corticosteroid medication. Only 2 of the 14 women, one woman during two pregnancies, needed an increase in the corticosteroid dose during the last trimester of their pregnancies. In one woman, the prednisolone dose was decreased.
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Outcome of the children
There were no differences concerning the outcome of the children born to mothers with different mutations. Thus, the birthweight and the future development did not differ between children born to mothers with SW, SV or NC. Furthermore, the weights of the first-born child, the weight of the girls and the boys were similar among children born to mothers with CAH or to the control women (Table VI). All children with the exception of one in the CAH group and one in the control group had an Apgar score of 10 at 5 min. None of the children were small for gestational age (SGA). One child from a mother with CAH was prematurely born in the 34 week, weighed 2270 g, and developed infant respiratory distress syndrome, which warranted a 3 weeks stay in the neonatal intensive care unit. This boy was diagnosed as having classical CAH at the age of four and has since developed normally on corticosteroid treatment. Two children in the control group were born before 37 full weeks, weighing 2270 and 2790 g, both of them developed normally post-natally. There were no malformations among the children of the CAH mothers; none of the girls had any signs of virilization. One child in the control group had a small ventricular septum defect.
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An unexpected finding was the difference in the sex ratio among the children with significantly fewer boys than girls, being born to CAH mothers than to their age-matched controls (Table VI).
Later follow-up of the children
The results of the structured personal or telephone interview with the 14 women with CAH who had born children (n = 25) are presented in Table VII. With few exceptions, all children were healthy and had remained so since the post-natal period. One boy of a SV mother was diagnosed at the age of 4 with CAH, I173N/I2splice, and developed well on treatment. All other children had normal growth according to their growth channel. Two girls were dyslectic; one of these had results above average in school and was now a university undergraduate, whereas the other girl performed less than average in school. All other children had normal intellectual development and school performance. Three children had allergic problems, childhood eczema or bronchial asthma.
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Other gynaecologic morbidity
Three women with CAH, all SW with the null/null mutation, had long standing secondary amenorrhoea, probably due to inadequate compliance with their corticosteroid medication as they all had high serum levels of 17-OH-progesterone and testosterone (Falhammar et al., 2007a
). Three of the control women also had secondary amenorrhoea, one due to ongoing breastfeeding, and one as a result of treatment for Mb Hodgkin 10 years earlier and one due to PCOS. Of the seven women with CAH in the perimenopausal and menopausal age group, three had spontaneous menopause without any major problems. Four had uterine fibroids and menometrorraghia that resulted in hysterectomy, endometrial ablation or treatment with high doses of Depot-ProveraR or use of a Levo-Norgestrel device prior to the menopause. All of the control women in the same age group reported having had a spontaneous menopause or perimenopause without any problems.
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Discussion |
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The low frequency of pregnancies among women with CAH compared with their age-matched controls is consistent with other previous reports (Mulaikal et al., 1987
; Jääskeläinen et al., 2000; Krone et al., 2001; Lo and Grumbach, 2001; Stikkelbroeck et al., 2003; Gastaud et al., 2007). There were no differences in spontaneous abortions between the patients and the control women, but significantly more therapeutic abortions among the control women. The number of term pregnancies among the CAH women was clearly related to the severity of the mutation. In the group with the most severe mutation, there was no term pregnancy, and in the women with the SV and NC mutation, the fertility was almost normal. These findings are also consistent with the literature. Lo and Grumbach (2001) reviewed the literature published 1956–2000 and reported on 105 pregnancies resulting in the birth of 73 children in women with virilizing adrenal hyperplasia. Of the 20 women with a clinically diagnosed SW disease, only a few had delivered children. Additionally, Krone et al. (2001) reported on 18 of 119 CAH women who had given birth to 31 children, of which only one by a woman with SW. That report also included a mutational analysis of the 18 women who became pregnant (one SW (null/null), 12 SV and 5 NC). Moreover, Dumic et al. (2005) reported on three women, one SV and two carrying an I2splice mutation, giving birth to four children. Hoepffner et al. described nine pregnancies in six women with classic CAH, also including the mutation status of the subjects. Two women with null/null mutations became pregnant and each delivered one child. One woman with the I2splice mutation gave birth to two, and three women with a SV mutation gave birth to four children (Hoepffner et al., 2004). These reports are in accordance with our findings of a lower pregnancy rate among the CAH women with the most severe mutations in the 21-hydroxylase gene.
Several authors have discussed the reasons for the low fertility among women with CAH (Meyer-Bahlburg, 1999; Jääskeläinen et al., 2000; Otten et al., 2005). A number of factors have been suggested such as delayed psychosexual development, low sexual activity, adrenal overproduction of androgens and progestins, PCOS, neuro-endocrine factors and genital surgery. Some of these factors are obviously interrelated. In the present study, the age of sexual debut was significantly later among the women with CAH than in their age-matched controls. A majority of the CAH women had undergone genital surgery and many were dissatisfied with their genitals (Nordenskjöld et al., 2008). Irregular menstruation as an indication of anovulation was of the same frequency in patients and controls, 28%. This is lower than the 61% reported among CAH women in a recent study (Bachelot et al., 2006). The number of women living in a steady heterosexual relationship was also significantly lower. Thus, among the women with SW (null/null and I2splice), 71% and 53%, respectively, were singles when compared with 19% in the SV group. A low interest for getting married and performing the traditional child care role, especially among CAH women with SW, has been discussed by Meyer-Bahlburg (1999). This is probably one important factor contributing to the low pregnancy rate. It should also be pointed out that half of the CAH patients with severe mutations were <30 years old. Thus, they may not yet have made a decision with regard to their reproductive future. In Sweden, the mother’s average age at the birth of the first child is 30 years (Medical Birth Registry of Sweden, 2007). Hence, the most plausible explanation for the observed low fertility among the women with CAH presented here is probably that 70% of them had not yet tried to get pregnant. All the women with CAH, who had tried and had experienced difficulties, had all been successfully treated, with the exception of the three women in the oldest age group. This concurs with the recent report from Hoepffner et al. (2004) indicating a good fertility outcome also in SW women when adequately treated. Furthermore, modern methods of assisted reproduction technologies are now available also to women living in a lesbian relationship. Thus, women with CAH who wish to have children should have better prospects today, than during earlier decades.
The progress and outcome of the pregnancies with regard to the women’s health were normal except in five cases of gestational diabetes among three women—20% of all pregnancies—while none of the control pregnancies were complicated with diabetes. The frequency of gestational diabetes is related to the stringency of screening for diabetes during pregnancy. It should be equivalent in patients and controls in this study because they all attended public antenatal care clinics in Sweden that use the same guidelines for care. Gestational diabetes in this study is more frequent than reported from the Swedish Medical Birth Registry, 1.4–4% (Medical Birth Registry of Sweden, 2007). The explanation may be found in the glucocorticoid medication. Earlier reports on our data of non-pregnant women with CAH indicated that many of them were receiving glucocorticoids in doses higher than recommended (LWPES/ESPE, 2002). This is supported by the findings of the extensively suppressed androgen levels and high frequency of osteopenia/osteoporosis among women with CAH (Falhammar et al., 2007a,b). One of the three women who developed gestational diabetes was treated with a high dose of prednisolone (17 mg daily) when conceiving and a second one was treated with metformin for PCOS and insulin resistance before pregnancy. The only other case of gestational diabetes in a woman with CAH was reported by Zacharin. This woman was severely obese before pregnancy (BMI 38 kg/m2) and on a high glucocorticosteroid dose (Zacharin, 1999). All of our three women who developed diabetes had a normal BMI. Gestational diabetes was not seen among any of the 18 women with CAH giving birth to 31 children in Krone's report, although the doses of glucocorticoids are comparable. There was however no information on diabetes screening procedures in that report (Krone et al., 2001). No case of pre-eclampsia was observed among our pregnant CAH women as opposed to findings in earlier studies (Lo et al., 1999; Dumic et al., 2005).
It has been debated whether corticosteroid doses should be increased during pregnancy. (Garner, 1998; Amadori, 2006). In our data, the dose was increased in only 3 out of 25 pregnancies. In comparison, in the data presented by Krone et al. (2001), the doses were increased in one-third of the pregnancies. The decision to do this or not should always be based on the individual needs of the women, and hence it can differ between different patient groups (Lo et al., 1999). All women, who had undergone genital surgery one or several times, were offered elective Caesarean section hence the rate of Caesarean section was higher than in controls. Altogether, only four CAH women were delivered vaginally, none had had genital surgery. The rate of Caesarean section is thus higher than previously reported (Krone et al., 2001; Lo and Grumbach, 2001).
The outcome of the children born to the 14 women with CAH was excellent; the mean birthweight of both boys and girls were equal to the birthweight of the children among the control women. None of the 19 girls in our study were observed with any signs of virilization and there were no malformations. Only one child was born prematurely, and there were no children that were SGA. This is in contrast to the only other report on this issue describing five SGA children among 31 term pregnancies of CAH women (Krone et al., 2001).
The most unexpected finding was the significant difference in the sex ratio of the children. In the group of children born to the control women, there were 56% boys compared with 25% boys born to the women with CAH. It is possible that this is a chance finding due to the fewer pregnancies in the patient group. However, when looking into data available in the literature, the same tendency is observed. In the paper by Lo and Grumbach (2001) concerning 74 children, the sex was not reported in 41 of them. However, among 33 children, there were 22 girls and 11 boys. Furthermore, in three recent publications, another 26 girls and 17 boys were described (Krone et al., 2001; Hoepffner et al., 2004; Dumic et al., 2005). If these figures are combined with our data, the sex ratio of all children born to CAH mothers so far published in the literature will be 68 girls to 34 boys. The finding is intriguing and the explanation for this is not clear. One hypothesis is that the hormonal status of the CAH mothers at the time of implantation may have an impact on the uterine milieu that favours female sex in the offspring.
The late follow-up of the children was consistent with the report by Krone et al. (2001), i.e. a normal postnatal development. One of 25 children in the present study was diagnosed with CAH of the SV type.
Finally, few of our women had reached the age of perimenopause or menopause. It was however obvious that among them there was a high rate of gynaecological morbidity in comparison with their age-matched controls. This has not been observed in other clinical reports, mainly due to the fact that women with CAH in these age groups have not been followed-up before. The low number of cases makes it impossible to hypothesise on the reasons for this difference but the finding needs to be kept in mind in future follow-up studies.
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Conclusions |
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In this large follow-up study of 62 women with CAH, only 14 women had given birth to 25 children compared with 54 children born to 41 age-matched control women. The reduced fertility in the women with CAH is clearly related to the severity of the mutation. The main reason may be that fewer patients than controls are living in a heterosexual relationship and fewer have tried to get pregnant. Another factor could be that the women in our study with the more severe mutations are still rather young and may not have reached a decision with regard to their reproductive future. However, all pregnancies that occurred were normal except for an increase in gestational diabetes among the CAH patients, a finding that calls for screening of this complication during a CAH pregnancy. The outcome of the children was excellent and did not differ from that of the control children. An unexpected finding was the uneven sex ratio between the children of mothers with CAH with significantly fewer boys than girls, an observation with some support in the literature. A late follow-up of the children indicated a normal development. The high frequency of gynaecological morbidity among perimenopausal and menopausal women with CAH need further attention in the future.
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Funding |
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The Swedish Research Council; HRH Crown Princess Lovisa Foundation; Foundation Frimurarna; the Samariten Foundation, Sven Jerring Foundation and Göteborg Medical Society.
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Acknowledgements |
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The authors wish to acknowledge the excellent help from Anette Härström RN and Ingrid Hansson RN for practical assistance and Elisabeth Berg BSc, Department of Learning, Informatics, Management and Ethics, Karolinska Institutet for statistical support.
Conflict of interest: none declared.
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Submitted on October 11, 2007; resubmitted on March 9, 2008; accepted on March 12, 2008.
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