Mariana Widmer

Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model

BACKGROUND Pre-eclampsia is a leading cause of maternal deaths. These deaths mainly result from eclampsia, uncontrolled hypertension, or systemic inflammation. We developed and validated the fullPIERS model with the aim of identifying the risk of fatal or life-threatening complications in women with pre-eclampsia within 48 h of hospital admission for the disorder. METHODS We developed and internally validated the fullPIERS model in a prospective, multicentre study in women who were admitted to tertiary obstetric centres with pre-eclampsia or who developed pre-eclampsia after admission. The outcome of interest was maternal mortality or other serious complications of pre-eclampsia. Routinely reported and informative variables were included in a stepwise backward elimination regression model to predict the adverse maternal outcome. We assessed performance using the area under the curve (AUC) of the receiver operating characteristic (ROC). Standard bootstrapping techniques were used to assess potential overfitting. FINDINGS 261 of 2023 women with pre-eclampsia had adverse outcomes at any time after hospital admission (106 [5%] within 48 h of admission). Predictors of adverse maternal outcome included gestational age, chest pain or dyspnoea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. The fullPIERS model predicted adverse maternal outcomes within 48 h of study eligibility (AUC ROC 0·88, 95% CI 0·84-0·92). There was no significant overfitting. fullPIERS performed well (AUC ROC >0·7) up to 7 days after eligibility. INTERPRETATION The fullPIERS model identifies women at increased risk of adverse outcomes up to 7 days before complications arise and can thereby modify direct patient care (eg, timing of delivery, place of care), improve the design of clinical trials, and inform biomedical investigations related to pre-eclampsia. FUNDING Canadian Institutes of Health Research; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction; Preeclampsia Foundation; International Federation of Obstetricians and Gynecologists; Michael Smith Foundation for Health Research; and Child and Family Research Institute.

Mapping the theories of preeclampsia and the role of angiogenic factors : A systematic review

OBJECTIVE: To evaluate claims that elevated soluble fms-like tyrosine kinase-1 receptor (sFlt-1) and decreased placental growth factor predict preeclampsia. DATA SOURCES: MEDLINE (1966–March 2006), EMBASE (1980–June 2006), POPLINE (1980–June 2006), CINAHL (1982–June 2006), and LILACS (1982–June 2006) were searched, and experts contacted. METHODS OF STUDY SELECTION: Studies identified and included were those reporting blood and urine levels of sFlt-1 or placental growth factor obtained before gestational week 30 or overt preeclampsia. TABULATION, INTEGRATION, AND RESULTS: Ten of 184 available studies analyzing sFlt-1 and 14 of 319 studies analyzing placental growth factor were included in this review. There was considerable interreport heterogeneity in methodology and results for sFlt-1 measured before gestational week 25. After week 25 placental growth factor and sFlt-1 levels varied consistently between the normal pregnancy group and women destined to develop preeclampsia, achieving significance in women who developed severe preeclampsia. CONCLUSION: Third-trimester increases in sFlt-1 and decreases in placental growth factor levels are associated with preeclampsia, specifically severe disease, based on retrospective data. The evidence is insufficient to recommend these markers to be used for screening, and prospective studies employing rigorous laboratory and study design criteria are needed to determine the clinical usefulness of these tests.

Classifications for Cesarean Section: A Systematic Review

Background Rising cesarean section (CS) rates are a major public health concern and cause worldwide debates. To propose and implement effective measures to reduce or increase CS rates where necessary requires an appropriate classification. Despite several existing CS classifications, there has not yet been a systematic review of these. This study aimed to 1) identify the main CS classifications used worldwide, 2) analyze advantages and deficiencies of each system. Methods and Findings Three electronic databases were searched for classifications published 1968–2008. Two reviewers independently assessed classifications using a form created based on items rated as important by international experts. Seven domains (ease, clarity, mutually exclusive categories, totally inclusive classification, prospective identification of categories, reproducibility, implementability) were assessed and graded. Classifications were tested in 12 hypothetical clinical case-scenarios. From a total of 2948 citations, 60 were selected for full-text evaluation and 27 classifications identified. Indications classifications present important limitations and their overall score ranged from 2–9 (maximum grade = 14). Degree of urgency classifications also had several drawbacks (overall scores 6–9). Woman-based classifications performed best (scores 5–14). Other types of classifications require data not routinely collected and may not be relevant in all settings (scores 3–8). Conclusions This review and critical appraisal of CS classifications is a methodologically sound contribution to establish the basis for the appropriate monitoring and rational use of CS. Results suggest that women-based classifications in general, and Robsons classification, in particular, would be in the best position to fulfill current international and local needs and that efforts to develop an internationally applicable CS classification would be most appropriately placed in building upon this classification. The use of a single CS classification will facilitate auditing, analyzing and comparing CS rates across different settings and help to create and implement effective strategies specifically targeted to optimize CS rates where necessary.

Maternal BMI and preterm birth: A systematic review of the literature with meta-analysis

Objectives. To examine the association between high prepregnancy maternal body mass index (BMI) and the risk of preterm birth (PTB). Methods. A systematic review of the literature. We included cohorts and case-control studies published since 1968 that examined the association between BMI and PTB of all types, spontaneous (s), elective and with ruptured membranes (PPROM) in three gestational age categories: general (<37 weeks), moderate (32–36 weeks) and very (<32 weeks) PTB. Results. 20,401 citations were screened and 39 studies (1,788,633 women) were included. Preobese (BMI, 25–29.9) and obese I (BMI, 30–34.9) women have a reduced risk for sPTB: AOR = 0.85 (95% CI: 0.80–0.92) and 0.83 (95% CI: 0.75–0.92), respectively. Their risk for moderate PTB was 1.20 (95% CI: 1.04–1.38) and 1.60 (95% CI: 1.32–1.94), respectively. Obese II women (BMI, 35–40) have an increased risk for PTB in general (AOR = 1.33, 95% CI: 1.12–1.57) moderate (AOR = 2.43, 95% CI: 1.46–4.05) and very PTB (AOR = 1.96, 95% CI: 1.66–2.31). Obese III women (BMI > 40) have an even higher risk for very PTB (AOR = 2.27, 95%CI: 1.76–2.94). High BMI does not modify the risk for PPROM and increases the risk for elective PTB. Conclusions. High maternal BMI may have different effects on different types of PTB.

Pre‐eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health

To assess the incidence of hypertensive disorders of pregnancy and related severe complications, identify other associated factors and compare maternal and perinatal outcomes in women with and without these conditions.

Active management of the third stage of labour with and without controlled cord traction: a randomised, controlled, non-inferiority trial

BACKGROUND Active management of the third stage of labour reduces the risk of post-partum haemorrhage. We aimed to assess whether controlled cord traction can be omitted from active management of this stage without increasing the risk of severe haemorrhage. METHODS We did a multicentre, non-inferiority, randomised controlled trial in 16 hospitals and two primary health-care centres in Argentina, Egypt, India, Kenya, the Philippines, South Africa, Thailand, and Uganda. Women expecting to deliver singleton babies vaginally (ie, not planned caesarean section) were randomly assigned (in a 1:1 ratio) with a centrally generated allocation sequence, stratified by country, to placental delivery with gravity and maternal effort (simplified package) or controlled cord traction applied immediately after uterine contraction and cord clamping (full package). After randomisation, allocation could not be concealed from investigators, participants, or assessors. Oxytocin 10 IU was administered immediately after birth with cord clamping after 1-3 min. Uterine massage was done after placental delivery according to local policy. The primary (non-inferiority) outcome was blood loss of 1000 mL or more (severe haemorrhage). The non-inferiority margin for the risk ratio was 1·3. Analysis was by modified intention-to-treat, excluding women who had emergency caesarean sections. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN 12608000434392. FINDINGS Between June 1, 2009, and Oct 30, 2010, 12,227 women were randomly assigned to the simplified package group and 12,163 to the full package group. After exclusion of women who had emergency caesarean sections, 11,861 were in the simplified package group and 11,820 were in the full package group. The primary outcome of blood loss of 1000 mL or more had a risk ratio of 1·09 (95% CI 0·91-1·31) and the upper 95% CI limit crossed the pre-stated non-inferiority margin. One case of uterine inversion occurred in the full package group. Other adverse events were haemorrhage-related. INTERPRETATION Although the hypothesis of non-inferiority was not met, omission of controlled cord traction has very little effect on the risk of severe haemorrhage. Scaling up of haemorrhage prevention programmes for non-hospital settings can safely focus on use of oxytocin. FUNDING United States Agency for International Development and UN Development Programme/UN Population Fund/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research.

Obstetric transition: the pathway towards ending preventable maternal deaths

ending preventable maternal deaths JP Souza, € O Tunc alp, JP Vogel, M Bohren, M Widmer, OT Oladapo, L Say, AM G€ ulmezoglu, M Temmerman a UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland b Department of Social Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil c Glide Technical Cooperation and Research, Ribeirao Preto, Sao Paulo, Brazil d Johns Hopkins Bloomberg School of Public Health, Baltimore, ML, USA Correspondence: JP Souza, Department of Social Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Avenida Bandeirantes, 3900, Ribeirao Preto, Sao Paulo, Brazil 14049-900 Email jpsouza@fmrp.usp.br

Biomarkers of Spontaneous Preterm Birth: An Overview of The Literature in the Last Four Decades

Background: Understanding spontaneous preterm birth ([PTB] < 37 weeks) is difficult due to heterogeneities associated with multitudes of risk factors and pathophysiological pathways. Several biomarkers are routinely used clinically for predicting preterm labor; however, these factors are either nonspecific or detected too late. Objective: Systematic review of literature on PTB biomarkers in the last 40 years to map out the existing knowledge and gaps in understanding PTB biomarkers. Search strategies: Five electronic databases were searched for human studies on PTB biomarkers published in any language between 1965 and 2008. Selection criteria: The phenotype of interest for final data extraction was exclusively spontaneous PTB with no rupture of membranes. Data extraction included (a) general characteristics of the study (clinical setting, period, and study design), (b) study/participant characteristics (inclusion and exclusion criteria, race/ethnicity, number of participants, gestational age at sampling, (c) characteristics of the biomarker (type, rationale for its selection, type of biological sample, and assay used, and (d) concentration of biomarkers in cases and controls. Data collection and analysis: The search yielded 7255 citations and data were extracted from 217 articles which met our inclusion and exclusion criteria. Main results: A total of 116 different biomarkers were reported and these were assayed 578 times in the 217 included studies. Over two thirds of the 217 studies were performed on North American or European populations. No reliable biomarkers emerged as a risk predictor of PTB. Conclusions: Identifying similar studies on biomarkers for the prediction of PTB was a very challenging task due heterogeneities in study design, sampling issues (types, timing and processing), assay methods, and analyses. Major areas of concern identified in this review include poor phenotype definition, nonideal study designs and poor rationale for biomarker selection and assays and population stratification issues.

The World Health Organization Fetal Growth Charts: A Multinational Longitudinal Study of Ultrasound Biometric Measurements and Estimated Fetal Weight.

Background Perinatal mortality and morbidity continue to be major global health challenges strongly associated with prematurity and reduced fetal growth, an issue of further interest given the mounting evidence that fetal growth in general is linked to degrees of risk of common noncommunicable diseases in adulthood. Against this background, WHO made it a high priority to provide the present fetal growth charts for estimated fetal weight (EFW) and common ultrasound biometric measurements intended for worldwide use. Methods and Findings We conducted a multinational prospective observational longitudinal study of fetal growth in low-risk singleton pregnancies of women of high or middle socioeconomic status and without known environmental constraints on fetal growth. Centers in ten countries (Argentina, Brazil, Democratic Republic of the Congo, Denmark, Egypt, France, Germany, India, Norway, and Thailand) recruited participants who had reliable information on last menstrual period and gestational age confirmed by crown–rump length measured at 8–13 wk of gestation. Participants had anthropometric and nutritional assessments and seven scheduled ultrasound examinations during pregnancy. Fifty-two participants withdrew consent, and 1,387 participated in the study. At study entry, median maternal age was 28 y (interquartile range [IQR] 25–31), median height was 162 cm (IQR 157–168), median weight was 61 kg (IQR 55–68), 58% of the women were nulliparous, and median daily caloric intake was 1,840 cal (IQR 1,487–2,222). The median pregnancy duration was 39 wk (IQR 38–40) although there were significant differences between countries, the largest difference being 12 d (95% CI 8–16). The median birthweight was 3,300 g (IQR 2,980–3,615). There were differences in birthweight between countries, e.g., India had significantly smaller neonates than the other countries, even after adjusting for gestational age. Thirty-one women had a miscarriage, and three fetuses had intrauterine death. The 8,203 sets of ultrasound measurements were scrutinized for outliers and leverage points, and those measurements taken at 14 to 40 wk were selected for analysis. A total of 7,924 sets of ultrasound measurements were analyzed by quantile regression to establish longitudinal reference intervals for fetal head circumference, biparietal diameter, humerus length, abdominal circumference, femur length and its ratio with head circumference and with biparietal diameter, and EFW. There was asymmetric distribution of growth of EFW: a slightly wider distribution among the lower percentiles during early weeks shifted to a notably expanded distribution of the higher percentiles in late pregnancy. Male fetuses were larger than female fetuses as measured by EFW, but the disparity was smaller in the lower quantiles of the distribution (3.5%) and larger in the upper quantiles (4.5%). Maternal age and maternal height were associated with a positive effect on EFW, particularly in the lower tail of the distribution, of the order of 2% to 3% for each additional 10 y of age of the mother and 1% to 2% for each additional 10 cm of height. Maternal weight was associated with a small positive effect on EFW, especially in the higher tail of the distribution, of the order of 1.0% to 1.5% for each additional 10 kg of bodyweight of the mother. Parous women had heavier fetuses than nulliparous women, with the disparity being greater in the lower quantiles of the distribution, of the order of 1% to 1.5%, and diminishing in the upper quantiles. There were also significant differences in growth of EFW between countries. In spite of the multinational nature of the study, sample size is a limiting factor for generalization of the charts. Conclusions This study provides WHO fetal growth charts for EFW and common ultrasound biometric measurements, and shows variation between different parts of the world.

Misoprostol as an adjunct to standard uterotonics for treatment of post-partum haemorrhage: a multicentre, double-blind randomised trial

BACKGROUND Post-partum haemorrhage is a leading cause of global maternal morbidity and mortality. Misoprostol, a prostaglandin analogue with uterotonic activity, is an attractive option for treatment because it is stable, active orally, and inexpensive. We aimed to assess the effectiveness of misoprostol as an adjunct to standard uterotonics compared with standard uterotonics alone for treatment of post-partum haemorrhage. METHODS Women delivering vaginally who had clinically diagnosed post-partum haemorrhage due to uterine atony were enrolled from participating hospitals in Argentina, Egypt, South Africa, Thailand, and Vietnam between July, 2005, and August, 2008. Computer-generated randomisation was used to assign women to receive 600 microg misoprostol or matching placebo sublingually; both groups were also given routine injectable uterotonics. Allocation was concealed by distribution of sealed and sequentially numbered treatment packs in the order that women were enrolled. Providers and women were masked to treatment assignment. The primary outcome was blood loss of 500 mL or more within 60 min after randomisation. Analysis was by intention to treat. This study is registered, number ISRCTN34455240. FINDINGS 1422 women were assigned to receive misoprostol (n=705) or placebo (n=717). The proportion of women with blood loss of 500 mL or more within 60 min was similar between the misoprostol group (100 [14%]) and the placebo group (100 [14%]; relative risk 1.02, 95% CI 0.79-1.32). In the first 60 min, an increased proportion of women on misoprostol versus placebo, had shivering (455/704 [65%] vs 230/717 [32%]; 2.01, 1.79-2.27) and body temperature of 38 degrees C or higher (303/704 [43%] vs 107/717 [15%]; 2.88, 2.37-2.50). INTERPRETATION Findings from this study do not support clinical use of 600 microg sublingual misoprostol in addition to standard injectable uterotonics for treatment of post-partum haemorrhage. FUNDING Bill & Melinda Gates Foundation, and UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction.