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Background: Reducing deaths from hypertensive disorders of pregnancy is a global priority. Low dietary calcium might account for the high prevalence of pre-eclampsia and eclampsia in low-income countries. Calcium supplementation in the second half of pregnancy is known to reduce the serious consequences of pre-eclampsia; however, the effect of calcium supplementation during placentation is not known. We aimed to test the hypothesis that calcium supplementation before and in early pregnancy (up to 20 weeks' gestation) prevents the development of pre-eclampsia METHODS: We did a multicountry, parallel arm, double-blind, randomised, placebo-controlled trial in South Africa, Zimbabwe, and Argentina. Participants with previous pre-eclampsia and eclampsia received 500 mg calcium or placebo daily from enrolment prepregnancy until 20 weeks' gestation. Participants were parous women whose most recent pregnancy had been complicated by pre-eclampsia or eclampsia and who were intending to become pregnant. All participants received unblinded calcium 1·5 g daily after 20 weeks' gestation. The allocation sequence (1:1 ratio) used computer-generated random numbers in balanced blocks of variable size. The primary outcome was pre-eclampsia, defined as gestational hypertension and proteinuria. The trial is registered with the Pan-African Clinical Trials Registry, number PACTR201105000267371. The trial closed on Oct 31, 2017., Findings: Between July 12, 2011, and Sept 8, 2016, we randomly allocated 1355 women to receive calcium or placebo; 331 of 678 participants in the calcium group versus 320 of 677 in the placebo group became pregnant, and 298 of 678 versus 283 of 677 had pregnancies beyond 20 weeks' gestation. Pre-eclampsia occurred in 69 (23%) of 296 participants in the calcium group versus 82 (29%) of 283 participants in the placebo group with pregnancies beyond 20 weeks' gestation (risk ratio [RR] 0·80, 95% CI 0·61-1·06; p=0·121). For participants with compliance of more than 80% from the last visit before pregnancy to 20 weeks' gestation, the pre-eclampsia risk was 30 (21%) of 144 versus 47 (32%) of 149 (RR 0·66, CI 0·44-0·98; p=0·037). There were no serious adverse effects of calcium reported., Interpretation: Calcium supplementation that commenced before pregnancy until 20 weeks' gestation, compared with placebo, did not show a significant reduction in recurrent pre-eclampsia. As the trial was powered to detect a large effect size, we cannot rule out a small to moderate effect of this intervention., Funding: The University of British Columbia, a grantee of the Bill & Melinda Gates Foundation; UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO; the Argentina Fund for Horizontal Cooperation of the Argentinean Ministry of Foreign Affairs; and the Centre for Intervention Science in Maternal and Child Health., (© 2019 This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

INTRODUCTION Mortality analysis based on a single cause of death is not, in most cases, fully informative. There are several more illuminating procedures using a multiple cause of death approach; these are little known and rarely used in Cuba. The simplest of these methods, while methodologically limited, consists of summing all deaths from a specific cause mentioned on death certificates, regardless of whether the cause is listed as underlying or contributing. OBJECTIVE Using Cuban data, critically assess and implement two of the most recognized approaches to analyzing multiple causes of death. METHODS Multiple causes of death in Cuba were assessed for the years 2005, 2010 and 2015, employing death records from the National Medical Records and Health Statistics Bureau of Cuba's Ministry of Public Health. With the example of diabetes mellitus as underlying cause, we explored connections between underlying and associated (antecedent and contributing) causes on death certificates using two approaches from the international literature: the simple method and the cause-of-death association indicator. RESULTS The study identified main trends in multiple causes of death identified in 2005, 2010 and 2015, overall and by age group and sex. We observed a trend to increasing mean number of causes of death per death certificate between 2005 and 2015. The number of causes reported showed no substantial differences by age group or sex. Diseases of the arteries, arterioles and capillaries were by far the most frequently associated with diabetes mellitus as underlying cause. CONCLUSIONS The multiple causes of death approach affords more nuanced understanding of patterns of disease, comorbidity and death in the Cuban population. The indicators used fulfill different roles: the simple method brings to light the full range of ways in which a given cause contributes to mortality, and the cause-of-death association indicator enables exploration of links between different causes of death, not possible with the simple method. KEYWORDS Mortality, multifactorial causality, causes of death, diabetes mellitus, Cuba.

Background: Maternal nutritional status before and during pregnancy is an important contributor to pregnancy outcomes and early child health. The aim of this study was to describe the preconceptional nutritional status and dietary intake during pregnancy in high-risk women from South Africa and Zimbabwe., Methods: This is a prospective observational study, nested to the CAP trial. Anthropometric measurements before and during pregnancy and dietary intake using 24-h recall during pregnancy were assessed. The Intake Distribution Estimation software (PC-SIDE) was used to evaluate nutrient intake adequacy taking the Estimated Average Requirement (EAR) as a cut-off point., Results: Three hundred twelve women who had pre-eclampsia in their last pregnancy and delivered in hospitals from South Africa and Zimbabwe were assessed. 73.7 and 60.2% women in South Africa and Zimbabwe, respectively started their pregnancy with BMI above normal (BMI ≥ 25) whereas the prevalence of underweight was virtually non-existent. The majority of women had inadequate intakes of micronutrients. Considering food and beverage intake only, none of the micronutrients measured achieved the estimated average requirement. Around 60% of pregnant women reported taking folic acid or iron supplements in South Africa, but almost none did so in Zimbabwe., Conclusion: We found a high prevalence of overweight and obesity and high micronutrient intake inadequacy in pregnant women who had the previous pregnancy complicated with pre-eclampsia. The obesity figures and micronutrient inadequacy are issues of concern that need to be addressed. Pregnant women have regular contacts with the health system; these opportunities could be used to improve diet and nutrition., Trial Registration: PACTR201105000267371 . Registered 06 December 2010.

Background: The official WHO estimates of preterm birth are an essential global resource for assessing the burden of preterm birth and developing public health programmes and policies. This protocol describes the methods that will be used to identify, critically appraise and analyse all eligible preterm birth data, in order to develop global, regional and national level estimates of levels and trends in preterm birth rates for the period 1990 - 2014., Methods: We will conduct a systematic review of civil registration and vital statistics (CRVS) data on preterm birth for all WHO Member States, via national Ministries of Health and Statistics Offices. For Member States with absent, limited or lower-quality CRVS data, a systematic review of surveys and/or research studies will be conducted. Modelling will be used to develop country, regional and global rates for 2014, with time trends for Member States where sufficient data are available. Member States will be invited to review the methodology and provide additional eligible data via a country consultation before final estimates are developed and disseminated., Discussion: This research will be used to generate estimates on the burden of preterm birth globally for 1990 to 2014. We invite feedback on the methodology described, and call on the public health community to submit pertinent data for consideration., Trial Registration: Registered at PROSPERO CRD42015027439 CONTACT: pretermbirth@who.int.

Background: Fundal pressure (pushing on the upper part of the uterus in the direction of the birth canal) is often performed in routine practice, however the benefit and indications for its use are unclear and vigorous pressure is potentially harmful. There is some evidence that it may be applied routinely or to expedite delivery in some situations (e.g. fetal distress or maternal exhaustion), particularly in settings where other methods of achieving delivery (forceps, vacuum) are not available. Gentle assisted pushing (GAP) is an innovative method of applying gentle but steady pressure to the uterine fundus with the woman in an upright posture. This trial aims to evaluate the use of GAP in an upright posture, or upright posture alone, on reducing the mean time of delivery and the associated maternal and neonatal complications in women not having delivered following 15-30 min in the second stage of labour., Methods/design: We will conduct a multicentre, randomized, unblinded, controlled trial with three parallel arms (1:1:1). 1,145 women will be randomized at three hospitals in South Africa. Women will be eligible for inclusion if they are ≥18 years old, nulliparous, gestational age ≥ 35 weeks, have a singleton pregnancy in cephalic presentation and vaginal delivery anticipated. Women with chronic medical conditions or obstetric complications are not eligible. If eligible women are undelivered following 15-30 min in the second stage of labour, they will be randomly assigned to: 1) GAP in the upright posture, 2) upright posture only and 3) routine practice (recumbent/supine posture). The primary outcome is the mean time from randomization to complete delivery. Secondary outcomes include operative delivery, adverse neonatal outcomes, maternal adverse events and discomfort., Discussion: This trial will establish whether upright posture and/or a controlled method of applying fundal pressure (GAP) can improve labour outcomes for women and their babies. If fundal pressure is found to have a measurable beneficial effect, this gentle approach can be promoted as a replacement for the uncontrolled methods currently in use. If it is not found to be useful, fundal pressure can be discouraged.

Background: The assessment of treatment success in clinical trials when multiple (repeated) doses (courses) are involved is quite common, for example, in the case of infertility treatment with assisted reproductive technology (ART), and medical abortion using misoprostol alone or in combination with mifepristone. Under these or similar circumstances, most researchers assess success using binomial proportions after a certain number of consecutive doses, and some have used survival analysis. In this paper we discuss the main problems in using binomial proportions to summarize (the overall) efficacy after two or more consecutive doses of the relevant treatment, particularly for the case of misoprostol in medical abortion studies. We later discuss why the survival analysis is best suited under these circumstances, and illustrate this by using simulated data., Methods: The formulas required for the binomial proportion and survival analysis (without and with competing risks) approaches are summarized and analytically compared. Additionally, numerical results are computed and compared between the two approaches, for several theoretical scenarios., Results: The main conceptual limitations of the binomial proportion approach are identified and discussed, caused mainly by the presence of censoring and competing risks, and it is demonstrated how survival analysis can solve these problems. In general, the binomial proportion approach tends to underestimate the "real" success rate, and tends to overestimate the corresponding standard error., Conclusions: Depending on the rates of censored observations or competing events between repeated doses of the treatment, the bias of the binomial proportion approach as compared to the survival analysis approaches varies; however, the use of the binomial approach is unjustified as the survival analysis options are well known and available in multiple statistical packages. Our conclusions also apply to other situations where success is estimated after multiple (repeated) doses (courses) of the treatment.

Objective: The aim of this study was to estimate the age at natural menopause in women with SLE., Methods: One thousand and thirty-nine consecutive SLE patients <60 years of age were surveyed. Demographic and clinical data were queried by a single investigator. SLE characteristics and co-morbidities were retrieved from their medical records. Natural menopause was defined as amenorrhoea ≥12 months in the absence of previous hysterectomy, CYC exposure and severe chronic kidney disease (SCKD). Pregnant women and those with menses during the 12 months prior to interview were considered premenopausal. Median age at menopause was estimated by both logit and survival analyses. In addition, mean age at menopause was calculated for patients aged ≥40 years. Factors associated with age at natural menopause were assessed by Cox regression analysis., Results: A total of 961 SLE women were analysed. At interview, most patients (81.6%) were premenopausal, 7.9% had natural menopause, 6.3% were postmenopausal previously exposed to CYC, 4.1% had undergone hysterectomy before menopause and 0.1% presented with SCKD and amenorrhoea. The mean age at interview was 35.2 years (s.d. 10.1), the mean age at SLE diagnosis was 26.9 years (s.d. 8.6) and the mean duration of disease was 8.2 years (s.d. 7.1). The mean recalled age at menopause was 46.4 years (s.d. 4.7). Median age at menopause estimated by logit and survival analyses were 50.7 and 50.8 years, respectively. Only the age at SLE diagnosis was associated with age at natural menopause., Conclusion: Median age at natural menopause in women with lupus is 50 years. This is consistent with the age at menopause reported in the general population., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To assess the side effects unrelated to disease activity and the acceptability of combined oral contraceptives (COCs), progestin-only pills (POPs) and copper-releasing intrauterine devices (IUDs) in women with systemic lupus erythematosus (SLE)., Study Design: A randomized clinical trial including 162 women with SLE, assigned to COC (n=54), POP (n=54) or IUD (n=54). Follow-up visits were conducted after 1, 2, 3, 6, 9 and 12 months of treatment to monitor the presence of symptoms, changes in body weight and blood pressure as well as the development of health problems other than those relating to lupus. Reasons for discontinuation and satisfaction with the use of the assigned method were recorded at the end of treatment. Statistical analysis included descriptive statistics, repeated measure analyses and Kaplan-Meier curves., Results: Significantly different discontinuation rates due to any reason [35%, 55%, 29% (p<0.01)] or nonmedical reasons [(11%, 31%, 4% (p<0.05)] were observed among the COC, POP and IUD groups. Nausea was most frequent among COC users, dysmenorrhea among IUD users and acne and hirsutism among POP users. Mean blood pressures remained unchanged. Mild increases in body weight were observed over time in all treatment groups. Most women were satisfied with the use of the assigned contraceptive method., Conclusions: Oral contraceptives and IUD are acceptable birth control methods for patients with lupus, when counseling and specialized health attention are provided; however, the acceptability of POP appears to be inferior. Side effects unrelated to lupus disease activity are not frequent reasons to discontinue the contraceptive methods., Implications: This study delves into an area that has not been explored among patients with lupus. Our findings on the associated side effects and reasons for discontinuing COCs, POPs or copper-bearing IUDs may be useful in improving contraceptive counseling for women with lupus. Furthermore, they also heighten our knowledge on the reasons that may preclude the widespread use of effective contraceptives among lupus patients., (Copyright © 2014. Published by Elsevier Inc.)

INTRODUCTION Disability-adjusted life years is a composite measure that integrates the components of mortality and morbidity. It is a useful indicator of overall disease burden and is particularly useful for evaluating health intervention outcomes. In the cases of breast and reproductive system cancers, these can also negatively affect childbearing opportunities for young women. OBJECTIVE Determine disability-adjusted life years for breast and reproductive system cancers in Cuban women aged 15-44 years during the period 1990-2006. METHODS A national epidemiological study was conducted using Cuba's disease and vital statistics registry data for 1990, 1995, 2000 and 2006. Disability-adjusted life years in women aged 15-44 years were calculated for breast cancer and three female reproductive system cancers (cervical, endometrial and ovarian), by summing years of life lost due to premature mortality and years lived with disability. Years of life lost due to premature mortality were determined based on age-specific estimates of life expectancy. Years lived with disability were calculated as the product of severities (provided by the 1990 Global Burden of Disease study) and incidence and average duration, both obtained via the DISMOD II program. Data entered in the program include national statistics on incidence, prevalence, and mortality. RESULTS Breast cancer and cervical cancer proved to have the highest rates of potential years of life lost due to premature mortality, with the sharpest increases in the period (from 139 to 206.5 and 114.7 to 215.2 per 100,000, respectively). Endometrial and ovarian neoplasms crept up more slowly. An increase in years lived with disability was seen in three of these four types of cancer; only cervical cancer saw a decline (from 12.7 to 9 per 100,000). Breast cancer and cervical cancer presented the highest levels of disability-adjusted life years for all four years studied, rising from 146.9 to 227.8 and 127.4 to 224.2 per 100,000, respectively between 1990 and 2006. CONCLUSIONS An unfavorable trend in disability-adjusted life years was seen for breast and cervical cancer between 1990 and 2006 in Cuban women of childbearing age.

Background: Intermediate outcomes are common and typically on the causal pathway to the final outcome. Some examples include noncompliance, missing data, and truncation by death like pregnancy (e.g. when the trial intervention is given to non-pregnant women and the final outcome is preeclampsia, defined only on pregnant women). The intention-to-treat approach does not account properly for them, and more appropriate alternative approaches like principal stratification are not yet widely known. The purposes of this study are to inform researchers that the intention-to-treat approach unfortunately does not fit all problems we face in experimental research, to introduce the principal stratification approach for dealing with intermediate outcomes, and to illustrate its application to a trial of long term calcium supplementation in women at high risk of preeclampsia., Methods: Principal stratification and related concepts are introduced. Two ways for estimating causal effects are discussed and their application is illustrated using the calcium trial, where noncompliance and pregnancy are considered as intermediate outcomes, and preeclampsia is the main final outcome., Results: The limitations of traditional approaches and methods for dealing with intermediate outcomes are demonstrated. The steps, assumptions and required calculations involved in the application of the principal stratification approach are discussed in detail in the case of our calcium trial., Conclusions: The intention-to-treat approach is a very sound one but unfortunately it does not fit all problems we find in randomized clinical trials; this is particularly the case for intermediate outcomes, where alternative approaches like principal stratification should be considered.

Objective: To define the effects of continuous sequential estrogen plus progestin therapy on menopausal symptoms in women with systemic lupus erythematosus (SLE)., Methods: We performed a randomized, double-blind, 24-month clinical trial involving 106 women with SLE who were in the menopausal transition or early or late postmenopause. Patients received continuous sequential estrogen plus progestin (n = 52) or placebo (n = 54). Menopausal symptoms were assessed using the Greene Climacteric Scale at 0, 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months. A new factor analysis of the scale reduced 21 items to 5 factors. The primary outcome was improvement of menopausal symptoms throughout the followup period. Results were analyzed by the intent-to-treat principle., Results: At baseline, demographic and disease characteristics were similar in both groups. Fifteen of 21 menopausal symptoms had a prevalence of ≥50%, with a similar distribution between groups. Vasomotor factor scores decreased over time in both groups (P = 0.002), but in the estrogen plus progestin group the reduction was more pronounced than in the placebo group (1.5-2.0 versus 0.35-0.8 points on a scale of 0-6; P = 0.03). Maximum effects were observed among the most symptomatic women. Psychological, subjective-somatic, and organic-somatic factors scores also improved along time (P < 0.001), but the treatment and placebo arms improved to a similar degree. Thromboses occurred in 3 patients receiving estrogen plus progestin and in 1 patient receiving placebo., Conclusion: Menopausal symptoms are highly prevalent in peri- and postmenopausal lupus patients. Estrogen plus progestin improved vasomotor symptoms at a clinically significant level, but not other menopausal symptoms. Given the thrombotic risks of menopausal hormone therapy, this should be used only in women with significant vasomotor symptoms., (Copyright © 2011 by the American College of Rheumatology.)

The objective of this study was to estimate the evolution of the burden of disease in Cuba for 20 major causes at five year intervals from 1990 to 2005, in terms of mortality and years of life lost due to premature death (YLL), using national mortality registries. Six summary measures were computed for each of the 20 major causes of death which characterized the evolution of the disease burden over the period studied. The 20 causes were then grouped according to their behaviour in these summary measures; hierarchical cluster analysis was used to support this grouping process. We compute YLL results with and without age-weighting and time discounting (3%). The 20 major causes were grouped into 12 subgroups, each with a particular pattern. The burden of disease in Cuba during the period 1990-2005 has a peculiar pattern that does not reproduce the one characteristic of other low- and middle-income countries. The approach used in this study supports a better description of mortality and YLL trends for major causes, for identifying possible explanations, and for supporting public health policy making. It seems convenient to reproduce this analysis using shorter time intervals, e.g. annually.

Background: The effects of estrogen-containing contraceptives on disease activity in women with systemic lupus erythematosus have not been determined., Methods: We conducted a single-blind clinical trial involving 162 women with systemic lupus erythematosus who were randomly assigned to combined oral contraceptives, a progestin-only pill, or a copper intrauterine device (IUD). Disease activity was assessed at 0, 1, 2, 3, 6, 9, and 12 months according to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). The primary outcome was global disease activity, which we estimated by measuring the area under the SLEDAI curve. Secondary outcomes included the maximum SLEDAI score, change in SLEDAI score, incidence of lupus flares, median time to first flare, systemic lupus erythematosus treatment, and adverse events. The results were analyzed by the intention-to-treat method., Results: At baseline, all demographic features and disease characteristics were similar in the three groups. The mean (+/-SD) SLEDAI score was 6.1+/-5.6 in the group assigned to combined oral contraceptives, 6.4+/-4.6 in the group assigned to the progestin-only pill, and 5.0+/-5.3 in the group assigned to the IUD (54 patients in each group) (P=0.36). Disease activity remained mild and stable in all groups throughout the trial. There were no significant differences among the groups during the trial in global or maximum disease activity, incidence or probability of flares, or medication use. The median time to the first flare was three months in all groups. Thromboses occurred in four patients (two in each of the two groups receiving hormones), and severe infections were more frequent in the IUD group. One patient receiving combined oral contraceptives died from amoxicillin-related severe neutropenia., Conclusions: Global disease activity, maximum SLEDAI score, incidence of flares, time to first flare, and incidence of adverse events were similar among women with systemic lupus erythematosus, irrespective of the type of contraceptive they were using., (Copyright 2005 Massachusetts Medical Society.)