Richard J. Derman

Oral misoprostol in preventing postpartum haemorrhage in resource-poor communities: a randomised controlled trial

BACKGROUND Postpartum haemorrhage is a major cause of maternal mortality in the developing world. Although effective methods for prevention and treatment of such haemorrhage exist--such as the uterotonic drug oxytocin--most are not feasible in resource-poor settings where many births occur at home. We aimed to investigate whether oral misoprostol, a potential alternative to oxytocin, could prevent postpartum haemorrhage in a community home-birth setting. METHODS In a placebo-controlled trial undertaken between September, 2002, and December, 2005, 1620 women in rural India were randomised to receive oral misoprostol (n=812) or placebo (n=808) after delivery. 25 auxiliary nurse midwives undertook the deliveries, administered the study drug, and measured blood loss. The primary outcome was the incidence of acute postpartum haemorrhage (defined as > or =500 mL bleeding) within 2 h of delivery. Analysis was by intention-to-treat. The trial was registered with the US clinical trials database (http://www. clinicaltrials.gov) as number NCT00097123. FINDINGS Oral misoprostol was associated with a significant reduction in the rate of acute postpartum haemorrhage (12.0% to 6.4%, p<0.0001; relative risk 0.53 [95% CI 0.39-0.74]) and acute severe postpartum haemorrhage (1.2% to 0.2%, p<0.0001; 0.20 [0.04-0.91]. One case of postpartum haemorrhage was prevented for every 18 women treated. Misoprostol was also associated with a decrease in mean postpartum blood loss (262.3 mL to 214.3 mL, p<0.0001). Postpartum haemorrhage rates fell over time in both groups but remained significantly higher in the placebo group. Women taking misoprostol had a higher rate of transitory symptoms of chills and fever than the control. INTERPRETATION Oral misoprostol was associated with significant decreases in the rate of acute postpartum haemorrhage and mean blood loss. The drugs low cost, ease of administration, stability, and a positive safety profile make it a good option in resource-poor settings.

Drape estimation vs. visual assessment for estimating postpartum hemorrhage

Objective: To compare (1) visual estimation of postpartum blood loss with estimation using a specifically designed blood collection drape and (2) the drape estimate with a measurement of blood loss by photospectrometry. Methods: A randomized controlled study was performed with 123 women delivered at the District Hospital, Belgaum, India. The women were randomized to visual or drape estimation of blood loss. A subsample of 10 drape estimates was compared with photospectrometry results. Results: The visual estimate of blood loss was 33% less than the drape estimate. The interclass correlation of the drape estimate to photospectrometry measurement was 0.92. Conclusion: Drape estimation of blood loss is more accurate than visual estimation and may have particular utility in the developing world. Prompt detection of postpartum hemorrhage may reduce maternal morbidity and mortality in low‐resource settings.

A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: The ACT cluster-randomised trial

BACKGROUND Antenatal corticosteroids for pregnant women at risk of preterm birth are among the most effective hospital-based interventions to reduce neonatal mortality. We aimed to assess the feasibility, effectiveness, and safety of a multifaceted intervention designed to increase the use of antenatal corticosteroids at all levels of health care in low-income and middle-income countries. METHODS In this 18-month, cluster-randomised trial, we randomly assigned (1:1) rural and semi-urban clusters within six countries (Argentina, Guatemala, India, Kenya, Pakistan, and Zambia) to standard care or a multifaceted intervention including components to improve identification of women at risk of preterm birth and to facilitate appropriate use of antenatal corticosteroids. The primary outcome was 28-day neonatal mortality among infants less than the 5th percentile for birthweight (a proxy for preterm birth) across the clusters. Use of antenatal corticosteroids and suspected maternal infection were additional main outcomes. This trial is registered with ClinicalTrials.gov, number NCT01084096. FINDINGS The ACT trial took place between October, 2011, and March, 2014 (start dates varied by site). 51 intervention clusters with 47,394 livebirths (2520 [5%] less than 5th percentile for birthweight) and 50 control clusters with 50,743 livebirths (2258 [4%] less than 5th percentile) completed follow-up. 1052 (45%) of 2327 women in intervention clusters who delivered less-than-5th-percentile infants received antenatal corticosteroids, compared with 215 (10%) of 2062 in control clusters (p<0·0001). Among the less-than-5th-percentile infants, 28-day neonatal mortality was 225 per 1000 livebirths for the intervention group and 232 per 1000 livebirths for the control group (relative risk [RR] 0·96, 95% CI 0·87-1·06, p=0·65) and suspected maternal infection was reported in 236 (10%) of 2361 women in the intervention group and 133 (6%) of 2094 in the control group (odds ratio [OR] 1·67, 1·33-2·09, p<0·0001). Among the whole population, 28-day neonatal mortality was 27·4 per 1000 livebirths for the intervention group and 23·9 per 1000 livebirths for the control group (RR 1·12, 1·02-1·22, p=0·0127) and suspected maternal infection was reported in 1207 (3%) of 48,219 women in the intervention group and 867 (2%) of 51,523 in the control group (OR 1·45, 1·33-1·58, p<0·0001). INTERPRETATION Despite increased use of antenatal corticosteroids in low-birthweight infants in the intervention groups, neonatal mortality did not decrease in this group, and increased in the population overall. For every 1000 women exposed to this strategy, an excess of 3·5 neonatal deaths occurred, and the risk of maternal infection seems to have been increased. FUNDING Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anemia: a randomized controlled clinical trial

OBJECTIVE The objective of the study was to evaluate the efficacy, safety, and tolerability of intravenous ferric carboxymaltose, compared with oral ferrous sulfate in women with postpartum anemia. STUDY DESIGN In a multicenter, randomized, controlled study, 291 women less than 10 days after delivery with hemoglobin 10 g/dL or less were randomized to receive ferric carboxymaltose (n = 143) 1000 mg or less intravenously over 15 minutes or less, repeated weekly to a calculated replacement dose (maximum 2500 mg) or ferrous sulfate (n = 148) 325 mg orally thrice daily for 6 weeks. RESULTS Ferric carboxymaltose-treated subjects were significantly more likely to: (1) achieve a hemoglobin greater than 12 g/dL in a shorter time period with a sustained hemoglobin greater than 12 g/dL at day 42, (2) achieve hemoglobin rise 3 g/dL or greater more quickly, and (3) attain higher serum transferrin saturation and ferritin levels. Drug-related adverse events occurred less frequently with ferric carboxymaltose. CONCLUSION Intravenous ferric carboxymaltose was safe and well tolerated with an efficacy superior to oral ferrous sulfate in the treatment of postpartum iron deficiency anemia.

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.

The Maternal and Newborn Health Registry Study of the Global Network for Women's and Children's Health Research

To implement a vital statistics registry system to register pregnant women and document birth outcomes in the Global Network for Womens and Childrens Health Research sites in Asia, Africa, and Latin America.

Postpartum hemorrhage in resource-poor settings

Despite the strong interest of international health agencies, worldwide maternal mortality has not declined substantially over the past 10 years. Postpartum hemorrhage (PPH) is the most common cause of maternal death across the world, responsible for more than 25% of deaths annually. Although effective tools for prevention and treatment of PPH are available, most are not feasible or practical for use in the developing world where many births still occur at home with untrained birth attendants. Application of many available clinical solutions in rural areas would necessitate substantial changes in government infrastructure and in local culture and customs surrounding pregnancy and childbirth. Before treatment can be administered, prompt and accurate diagnosis must be made, which requires training and appropriate blood measurement tools. After diagnosis, appropriate interventions that can be applied in remote settings are needed. Many uterotonics known to be effective in reducing PPH in tertiary care settings may not be useful in community settings because they require refrigeration and/or skilled administration. Moreover, rapid transfer to a higher level of care must be available, a challenge in many settings because of distance and lack of transportation. In light of these barriers, low‐technological replacements for treatments commonly applied in the developed‐world must be utilized. Community education, improvements to emergency care systems, training for birth attendants, misoprostol, and Uniject™ have shown promise as potential solutions. In the short term, it is expedient to capitalize on practical opportunities that utilize the existing strengths and resources in each community or region in order to implement appropriate solutions to save the lives of women during childbirth.

A prospective study of maternal, fetal and neonatal deaths in low- and middle-income countries.

OBJECTIVE To quantify maternal, fetal and neonatal mortality in low- and middle-income countries, to identify when deaths occur and to identify relationships between maternal deaths and stillbirths and neonatal deaths. METHODS A prospective study of pregnancy outcomes was performed in 106 communities at seven sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. Pregnant women were enrolled and followed until six weeks postpartum. FINDINGS Between 2010 and 2012, 214,070 of 220,235 enrolled women (97.2%) completed follow-up. The maternal mortality ratio was 168 per 100,000 live births, ranging from 69 per 100,000 in Argentina to 316 per 100,000 in Pakistan. Overall, 29% (98/336) of maternal deaths occurred around the time of delivery: most were attributed to haemorrhage (86/336), pre-eclampsia or eclampsia (55/336) or sepsis (39/336). Around 70% (4349/6213) of stillbirths were probably intrapartum; 34% (1804/5230) of neonates died on the day of delivery and 14% (755/5230) died the day after. Stillbirths were more common in women who died than in those alive six weeks postpartum (risk ratio, RR: 9.48; 95% confidence interval, CI: 7.97-11.27), as were perinatal deaths (RR: 4.30; 95% CI: 3.26-5.67) and 7-day (RR: 3.94; 95% CI: 2.74-5.65) and 28-day neonatal deaths (RR: 7.36; 95% CI: 5.54-9.77). CONCLUSION Most maternal, fetal and neonatal deaths occurred at or around delivery and were attributed to preventable causes. Maternal death increased the risk of perinatal and neonatal death. Improving obstetric and neonatal care around the time of birth offers the greatest chance of reducing mortality.

Epidemiology of stillbirth in low-middle income countries: A Global Network Study

Objective. To determine population‐based stillbirth rates and to determine whether the timing and maturity of the stillbirths suggest a high proportion of potentially preventable deaths. Design. Prospective observational study. Setting. Communities in six low‐income countries (Democratic Republic of Congo, Kenya, Zambia, Guatemala, India, and Pakistan) and one site in a mid‐income country (Argentina). Population. Pregnant women residing in the study communities. Methods. Over a five‐year period, in selected catchment areas, using multiple methodologies, trained study staff obtained pregnancy outcomes on each delivery in their area. Main outcome measures. Pregnancy outcome, stillbirth characteristics. Results. Outcomes of 195 400 deliveries were included. Stillbirth rates ranged from 32 per 1 000 in Pakistan to 8 per 1 000 births in Argentina. Three‐fourths (76%) of stillbirth offspring were not macerated, 63% were ≥37 weeks and 48% weighed 2 500g or more. Across all sites, women with no education, of high and low parity, of older age, and without access to antenatal care were at significantly greater risk for stillbirth (p<0.001). Compared to those delivered by a physician, women delivered by nurses and traditional birth attendants had a lower risk of stillbirth. Conclusions. In these low‐middle income countries, most stillbirth offspring were not macerated, were reported as ≥37 weeks’ gestation, and almost half weighed at least 2 500g. With access to better medical care, especially in the intrapartum period, many of these stillbirths could likely be prevented.

Communities, birth attendants and health facilities: a continuum of emergency maternal and newborn care (the global network's EmONC trial)

BackgroundMaternal and newborn mortality rates remain unacceptably high, especially where the majority of births occur in home settings or in facilities with inadequate resources. The introduction of emergency obstetric and newborn care services has been proposed by several organizations in order to improve pregnancy outcomes. However, the effectiveness of emergency obstetric and neonatal care services has never been proven. Also unproven is the effectiveness of community mobilization and community birth attendant training to improve pregnancy outcomes.Methods/DesignWe have developed a cluster-randomized controlled trial to evaluate the impact of a comprehensive intervention of community mobilization, birth attendant training and improvement of quality of care in health facilities on perinatal mortality in low and middle-income countries where the majority of births take place in homes or first level care facilities. This trial will take place in 106 clusters (300-500 deliveries per year each) across 7 sites of the Global Network for Womens and Childrens Health Research in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. The trial intervention has three key elements, community mobilization, home-based life saving skills for communities and birth attendants, and training of providers at obstetric facilities to improve quality of care. The primary outcome of the trial is perinatal mortality. Secondary outcomes include rates of stillbirth, 7-day neonatal mortality, maternal death or severe morbidity (including obstetric fistula, eclampsia and obstetrical sepsis) and 28-day neonatal mortality.DiscussionIn this trial, we are evaluating a combination of interventions including community mobilization and facility training in an attempt to improve pregnancy outcomes. If successful, the results of this trial will provide important information for policy makers and clinicians as they attempt to improve delivery services for pregnant women and newborns in low-income countries.Trial RegistrationClinicalTrials.gov NCT01073488