Aust NZ J Obstet Gynaecol 1992; 32: 3: 233

Norethisterone and Gestational Diabetes Norman A. Beischer’, MD, MGO, FRACOG, FRACS, Toni Cookson’, SEN, Mary Sheedy’, BAppSc and Peter Wein4, FRACOG Mercy Hospital for Women and Department of Obstetrics and Gynaecology, University of Melbourne

Summary: In a single practice during the 21 years 1971-1991, the incidence of gestational diabetes in pregnancies in which norethisterone was prescribed was 32.4% (22 of 69) in comparison with 7.1% in pregnancies in which the women did not take norethisterone (137 of 1,684) (p < 0.001). Gestational diabetes was no less severe (degree of hyperglycaemia, need for insulin therapy) when associated with norethisterone. However, follow-up revealed that gestational diabetes when associated with norethisterone had a lesser risk of emerging diabetes mellitus and impaired glucose tolerance. Masculinization of a female fetus occurred in 5 of 39 (12.8%) exposed to norethisterone; all were cases of clitoral hypertrophy not requiring surgical treatment. Norethisterone in these 69 pregnanices accounted for 33.3% (5 of 15) cases of clitoral hypertrophy diagnosed in 100,756 consecutive.births. Although the use of progestogen therapy is now generally considered to be contraindicated, because of the risk of masculinization of the female fetus, norethisterone was commonly prescribed 20-30 years ago in this community for women from the time of the first antenatal visit if they had a past history of habitual abortion and/or recurrent intrauterine fetal death, and particularly those previously treated unsuccessfully by cervical ligation for cervical incompetence. The senior author has prescribed norethisterone for a high proportion of such women for many years and continues to do so. At the Mercy Hospital for Women it has been the policy since 1971 to perform a 50 g oral glucose tolerance test at 26-30 weeks’ gestation in all patients after an overnight fast. Over the years it became our impression that there was an increased prevalence of gestational diabetes in women receiving norethisterone. Accordingly we reviewed the case notes of all private patients of the senior author managed since 1971 to examine the relationship between gestational diabetes and norethisterone; we also sought to determine if the risk of emerging permanent diabetes was different in women whose gestational diabetes was associated with norethisterone therapy than in all other women with gestational diabetes. We also analyzed these data to see the risk of norethisterone causing masculinization of the female fetus. 1. 2. 3. 4.

Professor. Private practice nurse. Research administrator. Senior lecturer.

Address for correspondence: Professor N.A. Beischer, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Clarendon Street, East Melbourne, Victoria 3002.

SUBJECTS AND METHODS Since coding of norethisterone therapy was likely to be incomplete in the total hospital population, the records of all private practice patients delivered by NA Beischer at the Mercy Maternity Hospital for Women since 1971 were reviewed to identify those who were prescribed norethisterone during pregnancy. These records were analyzed to assess the incidence and severity of gestational diabetes, dose of norethisterone, clinical complications and perinatal results including presence of signs of masculinization in female infants. Glucose tolerance testing was performed following a 10-12 hour overnight fast by measuring capillary plasma glucose at fasting and at 1 and 2 hours after a 50 g glucose load. Glucose measurements were performed using the Beckman Autonanalyser. Gestational diabetes was diagnosed by the combination of a 1-hour glucose level of 9.0 mmol/l or more and a 2-hour glucose level of 7.0 mmol/l or more. Patients with gestational diabetes were enrolled in a follow-up programme and a postnatal glucose tolerance test was performed 4 to 6 weeks after delivery to establish whether or not glucose tolerance had returned to normal. A 75 g oral glucose load was given to comply with the WHO criteria for nonpregnant subjects (1). Capillary plasma glucose was measured after fasting and 1 and 2 hours after the glucose load. Results were interpreted according to the WHO criteria for capillary plasma as normal, impaired glucose tolerance (IGT = fasting < 7.8 mmol/l and 2-hour 8.9-12.1 mmol/l) or diabetes (fasting 27. 8 mmol/l or 2-hour 212.2 mmol/l). The follow-up programme of women with gestational diabetes was initiated in 1981; the time lapse from the initial diagnosis provided considerable difficulties with enrolment which since 1981 has been managed prospectively beginning at the time of the postnatal visit.

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We also reviewed the case notes of all patients in the total hospital population delivered since 1971 in which the neonate was noted to have clitoral hypertrophy, masculinization of the genitalia or genitourinary abnormalities, to assess the association with norethisterone therapy. Statistical analysis was performed using the Xz test or Fisher’s exact test for categorical data as appropriate. Risk ratio and 95% confidence limits (CI) were calculated according to the method of Katz et a1 (1).

RESULTS During the 21 years 1971-1991there were available for study 1,683 pregnancies in which glucose tolerance testing was performed including 69 in which the patient was prescribed norethisterone usually from the time of the first consultation at which pregnancy was confirmed. In all cases the norethisterone was continued until delivery. The dose was one 5 mg tablet per day in 42 pregnancies, one tablet twice daily in 18 and one tablet 3 times daily in 9 pregnancies. The overall incidence of gestational diabetes was 8.1% (137 of 1,684 pregnancies), and was 7.1% in pregnancies in which the women did not take norethisterone and 32.4% in those pregnanices in which this drug was prescribed (table 1) (p

Norethisterone and gestational diabetes.

In a single practice during the 21 years 1971-1991, the incidence of gestational diabetes in pregnancies in which norethisterone was prescribed was 32...
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