The Effect of Calcium Supplementation on Body Weight Before and During Pregnancy in Women Enrolled in the WHO Calcium and Preeclampsia Trial.

INTRODUCTION: Obesity is a major and challenging public health problem. The aim of this substudy is to evaluate the effect of calcium supplementation on body weight in women recruited in the Calcium and Preeclampsia trial. METHODS: Women were recruited before pregnancy and randomized to receive a calcium supplement containing 500 mg of elemental calcium or placebo until 20 weeks' gestation; all women received 1.5 g from 20 weeks until delivery. RESULTS: A total of 630 women conceived during the study, 322 allocated to calcium and 308 to placebo. Among these, 230 allocated to calcium and 227 allocated to placebo had information on body weight at baseline and at 8 weeks' gestation. During the study period, women allocated to calcium had a mean weight increase of 1.1 (SD ±5.5) kg, whereas those allocated to placebo had a mean increase of 1.5 (SD ±6.1) kg, a mean difference of 0.4 kg (95% -0.4 (-1.4 to 0.6); P = .408). Women classified as obese at the start of the trial had a lower body weight gain at 8 weeks' gestation (1.0 kg; 95% CI: -3.2 to 1.2; P = .330) and at 32 weeks' gestation (2.1 kg; 95% CI: 5.6-1.3; P = .225) if they received calcium as compared to placebo. However, none of these differences were statistically significant. CONCLUSION: The smaller increase in body weight found in women supplemented with 500 mg elemental calcium daily is quantitatively consistent with previous studies. However, in this study, the difference was not statistically significant.

Critical barriers for preeclampsia diagnosis and treatment in low-resource settings: An example from Bolivia.

The goals of the United Nation's Millennium Summit for reducing maternal mortality have proven difficult to achieve. In Bolivia, where maternal mortality is twice the South American average, improving the diagnosis, treatment and ultimately prevention of preeclampsia is key for achieving targeted reductions. We held a workshop in La Paz, Bolivia to review recent revisions in the diagnosis and treatment of preeclampsia, barriers for their implementation, and means for overcoming them. While physicians are generally aware of current recommendations, substantial barriers exist for their implementation due to geographic factors increasing disease prevalence and limiting health-care access, cultural and economic factors affecting the care provided, and infrastructure deficits impeding diagnosis and treatment. Means for overcoming such barriers include changes in the culture of health care, use of standardized diagnostic protocols, the adoption of low-cost technologies for improving the diagnosis and referral of preeclamptic cases to specialized treatment centers, training programs to foster multidisciplinary team approaches, and efforts to enhance local research capacity. While challenging, the synergistic nature of current barriers for preeclampsia diagnosis and treatment also affords opportunities for making far-reaching improvements in maternal, infant and lifelong health.

Prepregnancy and early pregnancy calcium supplementation among women at high risk of pre-eclampsia: a multicentre, double-blind, randomised, placebo-controlled trial.

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.

Are women with history of pre-eclampsia starting a new pregnancy in good nutritional status in South Africa and Zimbabwe?

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.

Vascular Dysfunction in Mother and Offspring During Preeclampsia: Contributions from Latin-American Countries.

Pregnancy is a physiologically stressful condition that generates a series of functional adaptations by the cardiovascular system. The impact of pregnancy on this system persists from conception beyond birth. Recent evidence suggests that vascular changes associated with pregnancy complications, such as preeclampsia, affect the function of the maternal and offspring vascular systems, after delivery and into adult life. Since the vascular system contributes to systemic homeostasis, defective development or function of blood vessels predisposes both mother and infant to future risk for chronic disease. These alterations in later life range from fertility problems to alterations in the central nervous system or immune system, among others. It is important to note that rates of morbi-mortality due to pregnancy complications including preeclampsia, as well as cardiovascular diseases, have a higher incidence in Latin-American countries than in more developed countries. Nonetheless, there is a lack both in the amount and impact of research conducted in Latin America. An impact, although smaller, can be seen when research in vascular disorders related to problems during pregnancy is analyzed. Therefore, in this review, information about preeclampsia and endothelial dysfunction generated from research groups based in Latin-American countries will be highlighted. We relate the need, as present in many other countries in the world, for increased effective regional and international collaboration to generate new data specific to our region on this topic.

Role of Extracellular Vesicles and microRNAs on Dysfunctional Angiogenesis during Preeclamptic Pregnancies.

Preeclampsia is a syndrome characterized by hypertension during pregnancy, which is a leading cause of morbidity and mortality in both mother and newborn in developing countries. Some advances have increased the understanding of pathophysiology of this disease. For example, reduced utero-placental blood flow associated with impaired trophoblast invasion may lead to a hypoxic placenta that releases harmful materials into the maternal and feto-placental circulation and impairs endothelial function. Identification of these harmful materials is one of the hot topics in the literature, since these provide potential biomarkers. Certainty, such knowledge will help us to understand the miscommunication between mother and fetus. In this review we highlight how placental extracellular vesicles and their cargo, such as small RNAs (i.e., microRNAs), might be involved in endothelial dysfunction, and then in the angiogenesis process, during preeclampsia. Currently only a few reports have addressed the potential role of endothelial regulatory miRNA in the impaired angiogenesis in preeclampsia. One of the main limitations in this area is the variability of the analyses performed in the current literature. This includes variability in the size of the particles analyzed, and broad variation in the exosomes considered. The quantity of microRNA targets genes suggest that practically all endothelial cell metabolic functions might be impaired. More studies are required to investigate mechanisms underlying miRNA released from placenta upon endothelial function involved in the angiogenenic process.

Early-pregnancy percent body fat in relation to preeclampsia risk in obese women.

OBJECTIVE: The purpose of this study was to identify differences of early-pregnancy body fat percentage and body mass index (BMI) between obese women that experienced preeclampsia and those who did not. STUDY DESIGN: We performed an analysis of the Prenatal Exposures and Preeclampsia Prevention 3 longitudinal cohort study of preeclampsia mechanisms in obese and overweight women. Women completed questionnaires regarding their health behaviors; had hematocrit level, weight and height, and waist and hip circumferences measured, and had resistance and reactance measured by bioelectric impedance analysis machine during the first, second, and third trimesters. Total body water, fat mass, and percent body fat were calculated with the use of pregnancy-specific formulas. Preeclampsia was assessed with the clinical definition and a research definition (clinical preeclampsia plus hyperuricemia). Logistic regression models were constructed to analyze early-pregnancy BMI and body fat percentage (measured at 10.2 ± 3.0 weeks of gestation) as predictors of preeclampsia outcomes. RESULTS: Three hundred seventy-three women were included in the analysis: 30 women had preeclampsia by clinical definition (8.0%), and 14 women had preeclampsia by the research definition (3.8%). There was no relationship between BMI and preeclampsia risk in obese women; however, body fat percentage was associated significantly with increased risk of both the clinical definition of preeclampsia and the research definition. In 239 obese women, a 1% increase in body fat was associated with approximately 12% increased odds of clinical preeclampsia and 24% increased risk of preeclampsia by the research definition. CONCLUSION: Early-pregnancy body fat appears to be important in the pathophysiologic condition of preeclampsia in obese women.

Impaired adenosine-mediated angiogenesis in preeclampsia: potential implications for fetal programming.

Preeclampsia is a pregnancy-specific syndrome, defined by such clinical hallmarks as the onset of maternal hypertension and proteinuria after 20 weeks of gestation. The syndrome is also characterized by impaired blood flow through the utero-placental circulation and relative placental ischemia, which in turn, may generate feto-placental endothelial dysfunction. Endothelial dysfunction in offspring born from preeclamptic pregnancies has been associated with an increased risk of cardiovascular disease, including hypertension, later in life. Interestingly, diminished endothelial function, manifested by low angiogenic capacity, leads to hypertension in animal studies. Recently, we have shown that the adenosine receptor A2A/nitric oxide/vascular endothelial growth factor axis is reduced in human umbilical vein endothelial cells derived from preeclamptic pregnancies, an effect correlated with gestational age at onset of preeclampsia. We and others suggested that impaired vascular function might be associated with high cardiovascular risk in offspring exposed to pregnancy diseases. However, we are not aware of any studies that examine impaired adenosine-mediated angiogenesis as a possible link to hypertension in offspring born from preeclamptic pregnancies. In this review, we present evidence supporting the hypothesis that reduced adenosine-mediated angiogenesis during preeclamptic pregnancies might be associated with development of hypertension in the offspring.

[Uric acid and purine plasma levels as plausible markers for placental dysfunction in pre-eclampsia]. / Purinas y ácido úrico en pre-eclampsia: interacciones fisiopatológicas y proyecciones en investigación.

Uric acid is the final metabolite of purine break down, such as ATP, ADP, AMP, adenosine, inosine and hypoxanthine. The metabolite has been used broadly as a renal failure marker, as well as a risk factor for maternal and neonatal morbidity during pre-eclamptic pregnancies. High purine levels are observed in pre-eclamptic pregnancies, but the sources of these purines are unknown. However, there is evidence that pre-eclampsia (mainly severe pre-eclampsia) is associated with an increased release of cellular fragments (or microparticles) from the placenta to the maternal circulation. These in fact could be the substrate for purine metabolism. Considering this background, we propose that purines and uric acid are part of the same physiopathological phenomenon in pre-eclampsia (i.e., placental dysfunction) and could become biomarkers for placental dysfunction and postnatal adverse events.

Prenatal Chlamydia trachomatis infection increases the risk of preeclampsia.

The relationship between Chlamydia trachomatis (CT) and preeclampsia was examined longitudinally among 205 cases and 423 normotensive controls nested within the Collaborative Perinatal Project. Antibodies were analyzed at a first prenatal visit (mean 14.2 weeks) and at delivery. Prenatal infections were identified as IgG/IgM seroconversion or a four-fold rise in IgG antibody titers. Although serological evidence of incident prenatal CT infection was uncommon (n=9, 1.4%) in this general pregnant population, infected women were more likely to develop preeclampsia, after adjustment for maternal age, body mass index, smoking status, race and time between blood draws (ORadj 7.2, 95% CI 1.3 - 39.7).

Purinas y ácido úrico en pre-eclampsia: interacciones fisiopatológicas y proyecciones en investigación / Uric acid and purine plasma levels as plausible markers for placental dysfunction in pre-eclampsia

Uric acid is the final metabolite of purine break down, such as ATP, ADP, AMP, adenosine, inosine and hypoxanthine. The metabolite has been used broadly as a renal failure marker, as well as a risk factor for maternal and neonatal morbidity during pre-eclamptic pregnancies. High purine levels are observed in pre-eclamptic pregnancies, but the sources of these purines are unknown. However, there is evidence that pre-eclampsia (mainly severe pre-eclampsia) is associated with an increased release of cellular fragments (or microparticles) from the placenta to the maternal circulation. These in fact could be the substrate for purine metabolism. Considering this background, we propose that purines and uric acid are part of the same physiopathological phenomenon in pre-eclampsia (i.e., placental dysfunction) and could become biomarkers for placental dysfunction and postnatal adverse events.

The uriscreen test to detect significant asymptomatic bacteriuria during pregnancy.

BACKGROUND: Asymptomatic bacteriuria (ASB) occurs in 2-11% of pregnancies and it is a clear predisposition to the development of acute pyelonephritis, which, in turn, poses risk to mother and fetus. Treatment of bacteriuria during pregnancy reduces the incidence of pyelonephritis. Therefore, it is recommended to screen for ASB at the first prenatal visit. The gold standard for detection of bacteriuria during pregnancy is urine culture, but this test is expensive, time-consuming, and labor-intensive. OBJECTIVE: To determine the reliability of an enzymatic urine screening test (Uriscreen; Savyon Diagnostics, Ashdod, Israel) for detecting ASB in pregnancy. METHODS: Catheterized urine samples were collected from 150 women who had routine prenatal screening for ASB. Patients with urinary symptoms, active vaginal bleeding, or who were previously on antibiotics therapy were excluded from the study. Sensitivity, specificity, and the positive and negative predictive values for the Uriscreen were estimated using urine culture as the criterion standard. Urine cultures were considered positive if they grew >10(5) colony-forming units of a single uropathogen. RESULTS: Twenty-eight women (18.7%) had urine culture results indicating significant bacteriuria, and 17 of these 28 specimens had positive enzyme activity. Of 122 samples with no growth, 109 had negative enzyme activity. Sensitivity, specificity, and positive and negative predictive values for the Uriscreen test were 60.7% (+/-18.1), 89.3% (+/-5.6), 56.6%, and 90.8%, respectively. CONCLUSION: The Uriscreen test had inadequate sensitivity for rapid screening of bacteriuria in pregnancy.

Critical pathways for the management of preeclampsia and severe preeclampsia in institutionalised health care settings.

BACKGROUND: Preeclampsia is a complex disease in which several providers should interact continuously and in a coordinated manner to provide proper health care. However, standardizing criteria to treat patients with preeclampsia is problematical and severe flaws have been observed in the management of the disease. This paper describes a set of critical pathways (CPs) designed to provide uniform criteria for clinical decision-making at different levels of care of pregnant patients with preeclampsia or severe preeclampsia. METHODS: Clinicians and researchers from different countries participated in the construction of the CPs. The CPs were developed using the following steps: a) Definition of the conceptual framework; b) Identification of potential users: primary care physicians and maternal and child health nurses in ambulatory settings; ob/gyn and intensive care physicians in secondary and tertiary care levels. c) Structural development. RESULTS: The CPs address the following care processes: 1. Screening for preeclampsia, risk assessment and classification according to the level of risk. 2. Management of preeclampsia at primary care clinics. 3. Evaluation and management of preeclampsia at secondary and tertiary care hospitals: 4. Criteria for clinical decision-making between conservative management and expedited delivery of patients with severe preeclampsia. CONCLUSION: Since preeclampsia continues to be one of the primary causes of maternal deaths and morbidity worldwide, the expected impact of these CPs is the contribution to improving health care quality in both developed and developing countries. The CPs are designed to be applied in a complex health care system, where different physicians and health providers at different levels of care should interact continuously and in a coordinated manner to provide care to all preeclamptic women. Although the CPs were developed using evidence-based criteria, they could require careful evaluation and remodelling according to each system's demands. Additionally, the CPs need to be tested in large-scale, multi-level studies in order to thoroughly examine and evaluate their efficacy and effectiveness.