A. Pinol

WHO antenatal care randomised trial for the evaluation of a new model of routine antenatal care

BACKGROUND We undertook a multicentre randomised controlled trial that compared the standard model of antenatal care with a new model that emphasises actions known to be effective in improving maternal or neonatal outcomes and has fewer clinic visits. METHODS Clinics in Argentina, Cuba, Saudi Arabia, and Thailand were randomly allocated to provide either the new model (27 clinics) or the standard model currently in use (26 clinics). All women presenting for antenatal care at these clinics over an average of 18 months were enrolled. Women enrolled in clinics offering the new model were classified on the basis of history of obstetric and clinical conditions. Those who did not require further specific assessment or treatment were offered the basic component of the new model, and those deemed at higher risk received the usual care for their conditions; however, all were included in the new-model group for the analyses, which were by intention to treat. The primary outcomes were low birthweight (<2500 g), pre-eclampsia/eclampsia, severe postpartum anaemia (<90 g/L haemoglobin), and treated urinary-tract infection. There was an assessment of quality of care and an economic evaluation. FINDINGS Women attending clinics assigned the new model (n=12568) had a median of five visits compared with eight within the standard model (n=11958). More women in the new model than in the standard model were referred to higher levels of care (13.4% vs 7.3%), but rates of hospital admission, diagnosis, and length of stay were similar. The groups had similar rates of low birthweight (new model 7.68% vs standard model 7.14%; stratified rate difference 0.96 [95% CI -0.01 to 1.92]), postpartum anaemia (7.59% vs 8.67%; 0.32), and urinary-tract infection (5.95% vs 7.41%; -0.42 [-1.65 to 0.80]). For pre-eclampsia/eclampsia the rate was slightly higher in the new model (1.69% vs 1.38%; 0.21 [-0.25 to 0.67]). Adjustment by several confounding variables did not modify this pattern. There were negligible differences between groups for several secondary outcomes. Women and providers in both groups were, in general, satisfied with the care received, although some women assigned the new model expressed concern about the timing of visits. There was no cost increase, and in some settings the new model decreased cost. INTERPRETATIONS Provision of routine antenatal care by the new model seems not to affect maternal and perinatal outcomes. It could be implemented without major resistance from women and providers and may reduce cost.

Microdose intravaginal levonorgestrel contraception: A multicentre clinical trial

A multicentre clinical trial, including 19 centres in 13 countries, assessed the contraceptive efficacy and clinical acceptability of a Silastic 382 vaginal ring releasing 20 micrograms of levonorgestrel for at least 90 days. A total of 1005 women entered the study and 8176.74 woman-months of experience was gathered. The rate of intrauterine pregnancy at one year of use was 3.6 per 100 women (95% confidence interval 2.2-5.0), and of ectopic pregnancy, 0.2% (one case). The principal reasons for discontinuation were menstrual disturbances (17.2% at one year), vaginal symptoms (6.0%) and repeated expulsion of the ring (7.1%). The pregnancy rate with this 20 micrograms levonorgestrel-releasing vaginal ring compares favourably with that of a low estrogen combination oral contraceptive tested by WHO and is less than half that of a progestogen-only oral contraceptive in a WHO randomized study. It is concluded that the WHO intravaginal ring releasing an average of 20 micrograms of levonorgestrel per 24 hours is an effective method of contraception for at least one year of use.

Menstrual bleeding patterns in untreated women

Abstract Menstrual histories recorded by more than 1000 healthy, untreated women have been analyzed using the reference period method. Results were obtained for each year of age from 15 to 49. Between menarche and age 19, the most important feature of menstrual patterns is their variability. Within-woman mean segment (cycle) length then decreases slowly but steadily, from 29.0 days at age 20 to 26.7 days at age 40. The range of segment lengths over a year also falls, to a minimum of 7 days at age 38. During the 40s, mean segment length rises to 29 days at age 49, and there is a sharp increase in the range, to 28 days. The length and variability of bleeding episodes, however, changes little between the ages of 19 and 49. Modifications to the World Health Organization definitions of ‘clinically important’ bleeding patterns are proposed.

Effects of hormonal contraceptives on milk volume and infant growth: WHO Special Programme of Research and Development and Research Training in Human Reproduction

Abstract WHO conducted a three-centre study in Hungary and Thailand to evaluate the effects of hormonal contraception on lactation and infant growth. Women choosing oral contraceptives were randomly assigned to a combined oral contraceptive containing 30ug ethinyl estradiol and 150ug levonorgestrel ( N =86) or a progestin-only preparation containing 75ug dl-norgestrel ( N =85). Identical packaging and treatment schedules allowed double-blind observation. One-hundred-and-eleven women using no contraception or non-hormonal methods acted as controls. In the two Thai centres 59 women using depot-medroxyprogesterone acetate formed an additional comparison group. All subjects were healthy women with normal deliveries, whose infants had normal birth weights and satisfactory growth in the neonatal period. Breast milk volume was determined by pump expression using standardized procedures. Information was obtained on nursing frequency and supplementation, infant growth and morbidity. Pretreatment observations at 6 weeks post-partum were used as a baseline, and subjects were followed-up at 9, 12, 16, 20 and 24 weeks post-partum. Women using combined oral contraceptives had a decline in milk volume within 6 weeks of initiating treatment, whereas no significant decrease was observed in the other treatment groups. After 18 weeks of treatment, combined oral contraceptive users experienced a 41.9% decline in milk volume, compared to 12.0% with progestin-only minipills and 6.1% in the non-hormonal controls. The prevalence of complementary feeding and withdrawals due to inadequate milk supply were comparable in the four treatment groups. However, data were not available on the daily amounts of complementary feeds. There were no significant differences in growth of infants between treatment groups. Thus, women may have compensated for declines in milk volume by more supplementary feeding or by more prolonged and intense suckling episodes. We conclude that 30 ug estrogen-containing combined oral contraceptives impair milk secretion, but in the selected healthy group of mothers and children studied with the prevailing level of supplementary feeding, this did not adversely affect infant growth.

The relationship between the menstrual cycle and female sexual interest in women with PMS complaints and volunteers

This study assesses the influence of menstrual cycle phases and hormones on female sexual interest in both a nonclinical sample of volunteers (n = 18) and women who complained of premenstrual tension (n = 150). Women were assessed prospectively for two menstrual cycles with daily symptom charts. In addition mental status was assessed clinically and the Moos Menstrual Distress Questionnaire completed in the follicular and premenstrual phases. On the basis of these assessments women were assigned to subject groups. During the second cycle, daily 24-h urinary estrogens and urinary pregnanediol were determined. Sexual interest and feelings of well-being were recorded on a daily symptom rating chart. Sexual interest was found to be significantly higher in the follicular and ovulatory phases, than in the luteal, premenstrual, or menstrual phases. Sexual interest and feelings of well-being were correlated (R = 0.29). Sexual interest and feelings of well-being were not correlated with urinary estrogen or pregnanediol levels.

The epidemiology of syphilis in pregnancy.

This study evaluated the magnitude, risk factors and outcomes of syphilis in pregnancy in a large cohort of women in four countries participating in the World Health Organization (WHO) antenatal care trial. All women attending the first prenatal care at each selected clinic were enrolled. Screening at the first antenatal visit was routinely performed with either rapid plasma reagin or Venereal Disease Research Laboratory and confirmed by fluorescent treponemal antibody absorption. All women also had the same syphilis tests after delivery. The initial prevalence, the incidence during pregnancy and the overall prevalence of syphilis at delivery were 0.9%, 0.4% and 1.3% respectively. Risk factors for syphilis during pregnancy were younger age for the incidence and older age and a history of stillbirth for the prevalence. Women with syphilis during pregnancy had significantly more adverse outcomes. We support the recommendation that in addition to the initial testing, a second routine test for syphilis ought to be established early in the third trimester even in low prevalence areas.

A randomized, double-blind study of two combined and two progestogen-only oral contraceptives.

A randomized double-blind study of two combined oral contraceptives and two progestogen-only oral contraceptives was conducted using the same protocol at WHO Collaborating Centres for Clinical Research in Human Reproduction in Bombay and Ljubljana of the 518 women admitted to the trial, 123 received mestranol 50 micrograms + norethisterone 1mg (MES 50 + NET 1); 137 received ethinyl estradiol 30 micrograms + levonorgestrel 150 micrograms (EE 30 + LNG 150); 130 received norethisterone 350 micrograms/NET 350); and 128 received levonorgestrel 30 micrograms (LNG 30). At one year, between 52.6 and 61.0 percent of those recruited had discontinued oral contraceptive use for all reasons, and by two years, between 70.5 and 76.5 percent had discontinued the treatment. These rates did not differ between the four treatment groups. However, discontinuation rates for all medical reasons at one and two years, and at two years pregnancy rates and discontinuation rates for bleeding disturbances, were significantly lower in the EE/LNG preparation. The groups receiving the MES/NET, LNG and NET had similar pregnancy rates, discontinuation rates for all medical reasons and all bleeding disturbances. There were two ectopic pregnancies among the 22 pregnancies in the progestogen-only groups. Discontinuation because of headache, dizziness and other central nervous system symptoms were significantly more common in those receiving MES/NET compared to EE/LNG. In contrast, discontinuation for gastro-intestinal disturbances were significantly higher in the EE/LNG combined preparation. Bleeding disturbances in the first few cycles tended to be higher in NET than in the LNG group. The data suggest that greater consideration be given to the benefits and risks of including progestogen-only oral contraceptives in the family planning programmes of some countries.

A multicentred phase III comparative study of two hormonal contraceptive preparations given once-a-month by intramuscular injection: II. The comparison of bleeding patterns

A multicentred Phase III clinical trial was conducted in 12 countries to compare HRP112 (depot-medroxyprogesterone acetate, 25 mg and estradiol cypionate, 5 mg) and HRP102 (norethisterone enantate, 50 mg and estradiol valerate, 5 mg) given every 28 days. Contraceptive efficacy and side-effects of both regimens were reported previously. Their effect on vaginal bleeding patterns is the object of this paper. A total of 2320 women were randomly assigned to each drug and 2000 of them provided a menstrual diary. The comparison of the bleeding patterns is made using a 90-day reference period approach and following the guidelines published by WHO. The analysis failed to identify any major difference in the vaginal bleeding patterns induced by both contraceptive preparations. For both drugs, the first bleeding episode following the first injection occurs early. For 70% of users, this is followed by a regular vaginal bleeding pattern similar to an untreated pattern. Others experience irregular bleeding and a few have either infrequent or frequent bleeding. The extremes of amenorrhea and prolonged bleeding are rare. There are no major trends in vaginal bleeding patterns with prolonged use of either preparation. Women with the worst vaginal bleeding patterns discontinue early in the clinical trial and the last three months of experience have the most influence in their decision to stop using the contraceptive method. The analysis suggests how the life-table analysis of discontinuation reasons underestimates the true incidence of vaginal bleeding irregularities in a clinical trial.

A randomized, double-blind study of six combined oral contraceptives

A randomized controlled clinical trial comparing six combined oral contraceptives with 50 micrograms or less of ethinyl estradiol was undertaken in 10 WHO Collaborating Centres for Clinical Research in Human Reproduction. A total of 2430 women entered the trial and were observed for 28,077 woman-cycles. All low-dose combined oral contraceptives demonstrated equivalent efficiency with one-year pregnancy rates of one to six percent. However, discontinuation rates for medical reasons differed significantly between the treatment groups, with the preparation containing 20 micrograms ethinyl estradiol and that containing 400 micrograms norethisterone acetate being associated with higher discontinuation rates due to bleeding disturbances. Even among the preparations which did not differ in discontinuation rates, the reasons for discontinuation did differ. Women receiving norethisterone preparations tended to discontinue because of bleeding disturbances while those receiving the levonorgestrel-containing preparations tended to discontinue because of complaints of nausea and vomiting.

Microdose intravaginal levonorgestrel contraception: A multicentre clinical trial: III. The relationship between pregnancy rate and body weight

This paper investigates the relationship between pregnancy rates and body weight of 1005 women using a vaginal ring releasing 20 micrograms levonorgestrel per 24 hours. While the overall pregnancy rate at one year was 3.7%, it was found that women have an increasing risk of pregnancy with increasing body weight. For example, a woman of 40 kg has an estimated pregnancy rate of 1.7% in contrast to 9.8% for a woman of 80 kg weight.