Is It Time to Alter the Standard of Care for Iron Deficiency/Iron Deficiency Anemia in Reproductive-Age Women?

Two billion people worldwide suffer from anemia, with reproductive-age women being disproportionately affected. Iron plays a crucial role in cellular function and impacts cognition, physical function, and quality of life. Iron deficiency (ID) and iron deficiency anemia (IDA) are associated with adverse effects on pregnancy and fetal development. Oral iron supplementation has been the standard treatment for decades, often producing sub-optimal outcomes. Many babies are still being born with ID and suffer adverse sequelae due to inadequate iron levels in the mothers. Is it time to consider a broad scale-up of parenteral iron as a new standard of care?

Overview of iron deficiency and iron deficiency anemia in women and girls of reproductive age.

Over 50% of pregnant women are anemic and the majority of these are iron deficient. Micronutrient deficiency, the symptom of heavy menstrual bleeding in nonpregnant individuals, and loss of blood associated with pregnancy and obstetric delivery contribute to iron deficiency (ID). Poor outcomes with low maternal iron can affect not only the pregnancy but can also have major bearings on the offspring. Correction of ID and iron deficiency anemia (IDA) in pregnant and prepregnant populations with single-dose intravenous iron supplementation may offer improved outcomes. A harmonization process that incorporates all major randomized controlled trials studying the use of single-dose IV iron compared with oral iron may suggest actions for changing the global trajectory of ID/IDA for women and girls of reproductive age.

Neurodevelopment, vision and auditory outcomes at age 2 years in offspring of participants in the 'Women First' maternal preconception nutrition randomised controlled trial.

BACKGROUND: Maternal nutrition in preconception and early pregnancy influences fetal growth. Evidence for effects of prenatal maternal nutrition on early child development (ECD) in low-income and middle-income countries is limited. OBJECTIVES: To examine impact of maternal nutrition supplementation initiated prior to or during pregnancy on ECD, and to examine potential association of postnatal growth with ECD domains. DESIGN: Secondary analysis regarding the offspring of participants of a maternal multicountry, individually randomised trial. SETTING: Rural Democratic Republic of the Congo, Guatemala, India and Pakistan. PARTICIPANTS: 667 offspring of Women First trial participants, aged 24 months. INTERVENTION: Maternal lipid-based nutrient supplement initiated preconceptionally (arm 1, n=217), 12 weeks gestation (arm 2, n=230) or not (arm 3, n=220); intervention stopped at delivery. MAIN OUTCOME MEASURES: The INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) cognitive, language, gross motor, fine motor, positive and negative behaviour scores; visual acuity and contrast sensitivity scores and auditory evoked response potentials (ERP). Anthropometric z-scores, family care indicators (FCI) and sociodemographic variables were examined as covariates. RESULTS: No significant differences were detected among the intervention arms for any INTER-NDA scores across domains, vision scores or ERP potentials. After adjusting for covariates, length-for-age z-score at 24 months (LAZ24), socio-economic status, maternal education and FCI significantly predicted vision and INTER-NDA scores (R2=0.11-0.38, p<0.01). CONCLUSIONS: Prenatal maternal nutrition supplementation was not associated with any neurodevelopmental outcomes at age 2 years. Maternal education, family environment and LAZ24 predicted ECD. Interventions addressing multiple components of the nurturing care model may offer greatest impact on children's developmental potential. TRIAL REGISTRATION NUMBER: NCT01883193.

Birth length is the strongest predictor of linear growth status and stunting in the first 2 years of life after a preconception maternal nutrition intervention: the children of the Women First trial.

BACKGROUND: The multicountry Women First trial demonstrated that nutritional supplementation initiated prior to conception (arm 1) or early pregnancy (arm 2) and continued until delivery resulted in significantly greater length at birth and 6 mo compared with infants in the control arm (arm 3). OBJECTIVES: We evaluated intervention effects on infants' longitudinal growth trajectory from birth through 24 mo and identified predictors of length status and stunting at 24 mo. METHODS: Infants' anthropometry was obtained at 6, 12, 18, and 24 mo after the Women First trial (registered at clinicaltrials.gov as NCT01883193), which was conducted in low-resource settings: Democratic Republic of Congo, Guatemala, India, and Pakistan. Longitudinal models evaluated intervention effects on infants' growth trajectory from birth to 24 mo, with additional modeling used to identify adjusted predictors for growth trajectories and outcomes at 24 mo. RESULTS: Data for 2337 (95% of original live births) infants were evaluated. At 24 mo, stunting rates were 62.8%, 64.8%, and 66.3% for arms 1, 2, and 3, respectively (NS). For the length-for-age z-score (LAZ) trajectory, treatment arm was a significant predictor, with adjusted mean differences of 0.19 SD (95% CI: 0.08, 0.30; P < 0.001) and 0.17 SD (95% CI: 0.07, 0.27; P < 0.001) for arms 1 and 2, respectively. The strongest predictors of LAZ at 24 mo were birth LAZ <-2 and <-1 to ≥-2, with adjusted mean differences of -0.76 SD (95% CI: -0.93, -0.58; P < 0.001) and -0.47 SD (95% CI: -0.56, -0.38; P < 0.001), respectively. For infants with ultrasound-determined gestational age (n = 1329), the strongest predictors of stunting were birth LAZ <-2 and <-1 to ≥- 2: adjusted relative risk of 1.62 (95% CI: 1.39, 1.88; P < 0.001) and 1.46 (95% CI: 1.31, 1.62; P < 0.001), respectively. CONCLUSIONS: Substantial improvements in postnatal growth are likely to depend on improved intrauterine growth, especially during early pregnancy.

Anemia and adverse outcomes in pregnancy: subgroup analysis of the CLIP cluster-randomized trial in India.

BACKGROUND: Iron-deficiency anemia is a known risk factor for several adverse perinatal outcomes, but data on its impact on specific maternal morbidities is less robust. Further, information on associations between anemia in early pregnancy and subsequent outcomes are understudied. METHODS: The study population was derived from the Community Level Interventions for Pre-eclampsia (CLIP) trial in Karnataka State, India (NCT01911494). Included were women who were enrolled in either trial arm, delivered by trial end date, and had a baseline measure of hemoglobin (Hb). Anemia was classified by WHO standards into four groups: none (Hb ≥ 11 g/dL), mild (10.0 g/dL ≤ Hb < 11.0 g/dL), moderate (7.0 g/dL ≤ Hb < 10.0 g/dL) and severe (Hb < 7.0 g/dL). Targeted maximum likelihood estimation was used to estimate confounder-adjusted associations between anemia and a composite (and its components) of adverse maternal outcomes, including pregnancy hypertension. E-values were calculated to assess robustness to unmeasured confounding. RESULTS: Of 11,370 women included, 10,066 (88.5%) had anemia, that was mild (3690, 32.5%), moderate (6023, 53.0%), or severe (68, 0.6%). Almost all women (> 99%) reported taking iron supplements during pregnancy. Blood transfusions was more often administered to those with anemia that was mild (risk ratio [RR] 2.16, 95% confidence interval [CI] 1.31-3.56), moderate (RR 2.37, 95% CI 1.56-3.59), and severe (RR 5.70, 95% CI 3.00-10.85). No significant association was evident between anemia severity and haemorrhage (antepartum or postpartum) or sepsis, but there was a U-shaped association between anemia severity and pregnancy hypertension and pre-eclampsia specifically, with the lowest risk seen among those with mild or moderate anemia. CONCLUSION: In Karnataka State, India, current management strategies for mild-moderate anemia in early pregnancy are associated with similar rates of adverse maternal or perinatal outcomes, and a lower risk of pregnancy hypertension and preeclampsia, compared with no anemia in early pregnancy. Future research should focus on risk mitigation for women with severe anemia, and the potential effect of iron supplementation for women with normal Hb in early pregnancy.

Growth from Birth Through Six Months for Infants of Mothers in the "Women First" Preconception Maternal Nutrition Trial.

OBJECTIVE: To evaluate whether the fetal linear growth effects of maternal nutrition supplementation would be maintained through 6 months postnatal age. STUDY DESIGN: The Women First trial was a multicountry, individually randomized clinical trial that compared the impact of maternal nutrition supplementation initiated preconception (Arm 1) vs at ∼11 weeks of gestation (Arm 2), vs no supplement (Arm 3); the intervention was discontinued at delivery. Trial sites were in Democratic Republic of Congo, Guatemala, India, and Pakistan. Analysis includes 2421 infants born to 2408 randomized women. Primary outcome was the trajectory of length-for-age z scores (LAZ) by arm, based on assessments at birth and 1, 3, and 6 months. We fitted longitudinal models on growth from birth to 6 months using generalized estimating equations; maternal intervention effects were evaluated, adjusting for site and baseline maternal covariates. RESULTS: Linear growth for Arms 1 and 2 was statistically greater than for Arm 3 in 3 of the 4 countries, with average pairwise mean differences in LAZ of 0.25 (95% CI 0.15-0.35; P < .001) and 0.19 (95% CI 0.09-0.28; P < .001), respectively. Compared with Arm 3, average overall adjusted relative risks (95% CI) for stunting (LAZ <-2) were lower for Arms 1 and 2: 0.76 (0.66-0.87; P < .001) and 0.77 (0.67-0.88; P < .001), respectively. CONCLUSIONS: Improved linear growth in early infancy observed for the 2 intervention arms supports the critical importance of maternal nutrition before conception and in the early phase of gestation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01883193.

Prevalence of iron deficiency in first trimester, nonanemic pregnant women.

Despite a high frequency of iron deficiency in pregnancy, the United States Preventative Services Task Force (USPSTF) stated: "there is inconclusive evidence routine supplementation for iron deficiency anemia improves maternal or infant clinical health outcomes." In contradistinction, high-quality epidemiologic studies report long lasting deficits in infants diagnosed with iron deficiency in the first 6 months of life compared with infants who were not, with specific deficits in cognition, memory, executive function and electrophysiology documented up to 19 years of age. Infants are not routinely screened for iron deficiency. United Kingdom guidelines differ and recommend screening high-risk infants who are preterm, of diabetic, underweight, obese, or vegetarian mothers, those born to anemic or iron deficient mothers, of smokers, those with inflammatory bowel disease or abnormal uterine bleeding, and from pregnancies in which the intergravid period is <6 months. Iron parameters are not routinely drawn unless anemia is present and in some cases only if microcytic. In that iron deficiency precedes the development of anemia, and waiting for its development misses a large number of overtly iron deficient gravidas. Iron parameters were measured in 102 consecutive, nonselected, nonanemic, first trimester women presenting to their obstetricians. Using standard cutoffs of percent transferrin saturation and/or serum ferritin, 42% were observed to be iron deficient. Given the lack of harm of testing for iron deficiency, it appears prudent to err on the side of caution and screen all presenting pregnant mothers until properly powered outcome data become available. The current recommendations of the USPSTF may need to be revisited.

Preconception nutrition intervention improved birth length and reduced stunting and wasting in newborns in South Asia: The Women First Randomized Controlled Trial.

South Asia has >50% of the global burden of low birth weight (LBW). The objective was to determine the extent to which maternal nutrition interventions commenced before conception or in the 1st trimester improved fetal growth in this region. This was a secondary analysis of combined newborn anthropometric data for the South Asian sites (India and Pakistan) in the Women First Preconception Maternal Nutrition Trial. Participants were 972 newborn of mothers who were poor, rural, unselected on basis of nutritional status, and had been randomized to receive a daily lipid-based micronutrient supplement commencing ≥3 months prior to conception (Arm 1), in the 1st trimester (Arm 2), or not at all (Arm 3). An additional protein-energy supplement was provided if BMI <20 kg/m2 or gestational weight gain was less than guidelines. Gestational age was established in the 1st trimester and newborn anthropometry obtained <48-hours post-delivery. Mean differences at birth between Arm 1 vs. 3 were length +5.3mm and weight +89g. Effect sizes (ES) and relative risks (RR) with 95% CI for Arm 1 vs. 3 were: length-for-age Z-score (LAZ) +0.29 (0.11-0.46, p = 0.0011); weight-for-age Z-score (WAZ) +0.22 (0.07-0.37, p = 0.0043); weight-to-length-ratio-for-age Z-score (WLRAZ) +0.27 (0.06-0.48, p = 0.0133); LAZ<-2, 0.56 (0.38-0.82, p = 0.0032); WAZ <-2, 0.68 (0.53-0.88, p = 0.0028); WLRAZ <-2, 0.76 (0.64-0.89, p = 0.0011); small-for-gestational-age (SGA), 0.74 (0.66-0.83, p<0.0001); low birth weight 0.81 (0.66-1.00, p = 0.0461). For Arm 2 vs. 3, LAZ, 0.21 (0.04-0.38); WAZ <-2, 0.70 (0.53-0.92); and SGA, 0.88 (0.79-0.97) were only marginally different. ES or RR did not differ for preterm birth for either Arm 1 vs. 3 or 2 vs. 3. In conclusion, point estimates for both continuous and binary anthropometric outcomes were consistently more favorable when maternal nutrition supplements were commenced ≥3 months prior to conception indicating benefits to fetal growth of improving women's nutrition in this population.

Maternal Characteristics Affect Fetal Growth Response in the Women First Preconception Nutrition Trial.

The objective of this secondary analysis was to identify maternal characteristics that modified the effect of maternal supplements on newborn size. Participants included 1465 maternal-newborn dyads in Guatemala, India, and Pakistan. Supplementation commenced before conception (Arm 1) or late 1st trimester (Arm 2); Arm 3 received usual care. Characteristics included body mass index (BMI), stature, anemia, age, education, socio-economic status (SES), parity, and newborn sex. Newborn outcomes were z-scores for length (LAZ), weight (WAZ), and weight to length ratio-for-age (WLRAZ). Mixed-effect regression models included treatment arm, effect modifier, and arm * effect modifier interaction as predictors, controlling for site, characteristics, and sex. Parity (para-0 vs. para ≥1), anemia (anemia/no anemia), and sex were significant effect modifiers. Effect size (95% CI) for Arm 1 vs. 3 was larger for para-0 vs. ≥1 for all outcomes (LAZ 0.56 (0.28, 0.84, p < 0.001); WAZ 0.45 (0.20, 0.07, p < 0.001); WLRAZ 0.52 (0.17, 0.88, p < 0.01) but only length for Arm 2 vs. 3. Corresponding effects for para ≥1 were >0.02. Arm 3 z-scores were all very low for para-0, but not para ≥1. Para-0 and anemia effect sizes for Arm 1 were > Arm 2 for WAZ and WLRAZ, but not LAZ. Arm 1 and 2 had higher WAZ for newborn boys vs. girls. Maternal nulliparity and anemia were associated with impaired fetal growth that was substantially improved by nutrition intervention, especially when commenced prior to conception.

A prospective, multi-center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON-IDA trial.

Iron deficiency anemia (IDA) is prevalent, and intravenous iron, especially if given in a single dose, may result in better adherence compared with oral iron. The present trial (FERWON-IDA) is part of the FERWON program with iron isomaltoside 1000/ferric derisomaltose (IIM), evaluating safety and efficacy of high dose IIM in IDA patients of mixed etiologies. This was a randomized, open-label, comparative, multi-center trial conducted in the USA. The IDA patients were randomized 2:1 to a single dose of 1000 mg IIM, or iron sucrose (IS) administered as 200 mg intravenous injections, up to five times. The co-primary endpoints were adjudicated serious or severe hypersensitivity reactions, and change in hemoglobin from baseline to week eight. A total of 1512 patients were enrolled. The frequency of patients with serious or severe hypersensitivity reactions was 0.3% (95% confidence interval: 0.06;0.88) vs 0.4% (0.05;1.45) in the IIM and IS group, respectively. The co-primary safety objective was met, and no risk difference was observed between groups. The co-primary efficacy endpoint of non-inferiority in hemoglobin change was met, and IIM led to a significantly more rapid hematological response in the first two weeks. The frequency of cardiovascular events was 0.8% and 1.2% in the IIM and IS group, respectively (P = .570). The frequency of hypophosphatemia was low in both groups. Iron isomaltoside administered as 1000 mg resulted in a more rapid and more pronounced hematological response, compared with IS, which required multiple visits. The safety profile was similar with a low frequency of hypersensitivity reactions and cardiovascular events.

Trends of antenatal care during pregnancy in low- and middle-income countries: Findings from the global network maternal and newborn health registry.

BACKGROUND: Antenatal care (ANC) is an important opportunity to diagnose and treat pregnancy-related complications and to deliver interventions aimed at improving health and survival of both mother and the infant. Multiple individual studies and national surveys have assessed antenatal care utilization at a single point in time across different countries, but ANC trends have not often been studied in rural areas of low-middle income countries (LMICs). The objective of this analysis was to study the trends of antenatal care use in LMICs over a seven-year period. METHODS: Using a prospective maternal and newborn health registry study, we analyzed data collected from 2011 to 2017 across five countries (Guatemala, India [2 sites], Kenya, Pakistan, and Zambia). Utilization of any ANC along with use of select services, including vitamins/iron, tetanus toxoid vaccine and HIV testing, were assessed. We used a generalized linear regression model to examine the trends of women receiving at least one and at least four antenatal care visits by site and year, controlling for maternal age, education and parity. RESULTS: Between January 2011 and December 2017, 313,663 women were enrolled and included in the analysis. For all six sites, a high proportion of women received at least one ANC visit across this period. Over the years, there was a trend for an increasing proportion of women receiving at least one and at least four ANC visits in all sites, except for Guatemala where a decline in ANC was observed. Regarding utilization of specific services, in India almost 100% of women reported receiving tetanus toxoid vaccine, vitamins/iron supplementation and HIV testing services for all study years. In Kenya, a small increase in the proportion of women receiving tetanus toxoid vaccine was observed, while for Zambia, tetanus toxoid use declined from 97% in 2011 to 89% in 2017. No trends for tetanus toxoid use were observed for Pakistan and Guatemala. Across all countries an increasing trend was observed for use of vitamins/iron and HIV testing. However, HIV testing remained very low (<0.1%) for Pakistan. CONCLUSION: In a range of LMICs, from 2011 to 2017 nearly all women received at least one ANC visit, and a significant increase in the proportion of women who received at least four ANC visits was observed across all sites except Guatemala. Moreover, there were variations regarding the utilization of preventive care services across all sites except for India where rates were generally high. More research is required to understand the quality and influences of ANC.

A multicountry randomized controlled trial of comprehensive maternal nutrition supplementation initiated before conception: the Women First trial.

Background: Reported benefits of maternal nutrition supplements commenced during pregnancy in low-resource populations have typically been quite limited. Objectives: This study tested the effects on newborn size, especially length, of commencing nutrition supplements for women in low-resource populations ≥3 mo before conception (Arm 1), compared with the same supplement commenced late in the first trimester of pregnancy (Arm 2) or not at all (control Arm 3). Methods: Women First was a 3-arm individualized randomized controlled trial (RCT). The intervention was a lipid-based micronutrient supplement; a protein-energy supplement was also provided if maternal body mass index (kg/m2) was <20 or gestational weight gain was less than recommendations. Study sites were in rural locations of the Democratic Republic of the Congo (DRC), Guatemala, India, and Pakistan. The primary outcome was length-for-age z score (LAZ), with all anthropometry obtained <48 h post delivery. Because gestational ages were unavailable in DRC, outcomes were determined for all 4 sites from WHO newborn standards (non-gestational-age-adjusted, NGAA) as well as INTERGROWTH-21st fetal standards (3 sites, gestational age-adjusted, GAA). Results: A total of 7387 nonpregnant women were randomly assigned, yielding 2451 births with NGAA primary outcomes and 1465 with GAA outcomes. Mean LAZ and other outcomes did not differ between Arm 1 and Arm 2 using either NGAA or GAA. Mean LAZ (NGAA) for Arm 1 was greater than for Arm 3 (effect size: +0.19; 95% CI: 0.08, 0.30, P = 0.0008). For GAA outcomes, rates of stunting and small-for-gestational-age were lower in Arm 1 than in Arm 3 (RR: 0.69; 95% CI: 0.49, 0.98, P = 0.0361 and RR: 0.78; 95% CI: 0.70, 0.88, P < 0.001, respectively). Rates of preterm birth did not differ among arms. Conclusions: In low-resource populations, benefits on fetal growth-related birth outcomes were derived from nutrition supplements commenced before conception or late in the first trimester. This trial was registered at clinicaltrials.gov as NCT01883193.

Community health worker knowledge and management of pre-eclampsia in rural Karnataka State, India.

BACKGROUND: In India, the hypertensive disorders of pregnancy and postpartum haemorrhage are responsible for nearly 40 % of all maternal deaths. Most of these deaths occur in primary health settings which frequently lack essential equipment and medication, are understaffed, and have limited or no access to specialist care. Community health care workers are regarded as essential providers of basic maternity care; and the quality of care they provide is dependent on the level of knowledge and skills they possess. However, there is limited research regarding their ability to manage pregnancy complications. This study aims to describe the current state of knowledge regarding pre-eclampsia and eclampsia among community health care workers (auxiliary nurse midwives, accredited social health activists, staff nurses) in northern Karnataka, India. Furthermore, this study describes the treatment approaches used by various cadres of community health workers for these conditions. The findings of this study can help plan focussed training sessions to build upon their strengths and to address the identified gaps. METHODS: Data were collected as part of a larger study aimed at assessing the feasibility of community-based treatment for pre-eclampsia. Eight focus group discussions were conducted in 2012-2013 in northern Karnataka State: four with staff nurses and auxiliary nurse midwives and four with accredited social health activists. In addition, twelve auxiliary nurse midwives and staff nurses completed questionnaires to explore their competence and self-efficacy in managing pre-eclampsia. Qualitative data were audio-recorded, transcribed verbatim and translated for thematic analysis using NVivo 10. RESULTS: Community health workers described their understanding of the origins of hypertension and seizures in pregnancy. Psychological explanations of hypertension were most commonly reported: stress, tension, and fear. The most common explanation for eclampsia was not receiving a tetanus vaccination. Despite some common misperceptions regarding aetiology, these community health workers demonstrated a good grasp of the potential consequences of hypertension in pregnancy. According to auxiliary nurse midwives and staff nurses, if hypertension was detected they encouraged rest, decreased salt intake, iron supplementation and tetanus vaccination. In addition, some staff nurses administered antihypertensives, MgSO4, or other anticonvulsants. All auxiliary nurse midwives had some awareness of MgSO4, but none had administered it themselves. CONCLUSIONS: This study showed that knowledge regarding the aetiology of pre-eclampsia was limited. Nevertheless, their basic knowledge and skills could be strengthened to more effectively manage the hypertensive disorders of pregnancy in their communities. TRIAL REGISTRATION: NCT01911494.

A pre-post study of a multi-country scale up of resuscitation training of facility birth attendants: does Helping Babies Breathe training save lives?

BACKGROUND: Whether facility-based implementation of Helping Babies Breathe (HBB) reduces neonatal mortality at a population level in low and middle income countries (LMIC) has not been studied. Therefore, we evaluated HBB implementation in this context where our study team has ongoing prospective outcome data on all pregnancies regardless of place of delivery. METHODS: We compared outcomes of birth cohorts in three sites in India and Kenya pre-post implementation of a facility-based intervention, using a prospective, population-based registry in 52 geographic clusters. Our hypothesis was that HBB implementation would result in a 20 % decrease in the perinatal mortality rate (PMR) among births ≥1500 g. RESULTS: We enrolled 70,704 births during two 12-month study periods. Births within each site did not differ pre-post intervention, except for an increased proportion of <2500 g newborns and deliveries by caesarean section in the post period. There were no significant differences in PMR among all registry births; however, a post-hoc analysis stratified by birthweight documented improvement in <2500 g mortality in Belgaum in both registry and in HBB-trained facility births. No improvement in <2500 g mortality measures was noted in Nagpur or Kenya and there was no improvement in normal birth weight survival. CONCLUSIONS: Rapid scale up of HBB training of facility birth attendants in three diverse sites in India and Kenya was not associated with consistent improvements in mortality among all neonates ≥1500 g; however, differential improvements in <2500 g survival in Belgaum suggest the need for careful implementation of HBB training with attention to the target population, data collection, and ongoing quality monitoring activities. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov: NCT01681017 .

Community perceptions of pre-eclampsia in rural Karnataka State, India: a qualitative study.

BACKGROUND: Maternal deaths have been attributed in large part to delays in recognition of illness, timely transport to facility, and timely treatment once there. As community perceptions of pregnancy and their complications are critical to averting maternal morbidity and mortality, this study sought to contribute to the literature and explore community-based understandings of pre-eclampsia and eclampsia. METHODS: The study was conducted in rural Karnataka State, India, in 2012-2013. Fourteen focus groups were held with the following community stakeholders: three with community leaders (n = 27), two with male decision-makers (n = 19), three with female decision-makers (n = 41), and six with reproductive age women (n = 132). Focus groups were facilitated by local researchers with clinical and research expertise. Discussions were audio-recorded, transcribed verbatim and translated to English for thematic analysis using NVivo 10. RESULTS: Terminology exists in the local language (Kannada) to describe convulsions and hypertension, but there were no terms that are specific to pregnancy. Community participants perceived stress, tension and poor diet to be precipitants of hypertension in pregnancy. Seizures in pregnancy were thought to be brought on by anaemia, poor medical adherence, lack of tetanus toxoid immunization, and exposure in pregnancy to fire or water. Sweating, fatigue, dizziness-unsteadiness, swelling, and irritability were perceived to be signs of hypertension, which was recognized to have the potential to lead to eclampsia or death. Home remedies, such as providing the smell of onion, placing an iron object in the hands, or squeezing the fingers and toes, were all used regularly to treat seizures prior to accessing facility-based care although transport is not delayed. CONCLUSIONS: It is evident that 'pre-eclampsia' and 'eclampsia' are not well-known; instead hypertension and seizures are perceived as conditions that may occur during or outside pregnancy. Improving community knowledge about, and modifying attitudes towards, hypertension in pregnancy and its complications (including eclampsia) has the potential to address community-based delays in disease recognition and delays in treatment that contribute to maternal and perinatal morbidity and mortality. Advocacy and educational initiatives should be designed to target knowledge gaps and potentially harmful practices, and respond to cultural understandings of disease. TRIAL REGISTRATION: NCT01911494.

Safety and efficacy of rapid (1,000 mg in 1 hr) intravenous iron dextran for treatment of maternal iron deficient anemia of pregnancy.

Maternal iron deficiency anemia (IDA) is associated with risk of adverse perinatal outcomes. Oral iron is recommended to reverse anemia, but has gastrointestinal toxicity and frequent non-adherence. Intravenous (IV) iron is reserved for intolerance of, or unresponsiveness to, oral therapy, malabsorption, and severe anemia (1% with hemoglobin [Hgb] levels <7 g/dL). With rare (<100 per one million) adverse events (AEs) ability to infuse a sufficient dose of low molecular weight iron dextran (LMWID) over 60 min, LMWID is an attractive option. This study demonstrated safety and efficacy of rapid IV infusion of 1,000 mg LMWID to gravidas with moderate to severe IDA. An observational treatment study of 1,000 mg LMWID administered over 1 hr for IDA in 189 consecutive, unselected second and third trimester gravidas after oral iron failure was conducted. All received a test dose of 25 mg LMWID and were monitored for AEs during the 60-min infusion. No premedication was administered unless more than one drug allergy or asthma was present in which case IV methylprednisolone was administered. All were followed through pregnancy and delivery. Monitored parameters included Hgb, mean corpuscular volume, serum ferritin, and percent transferrin saturation. About 189 subjects received 1,000 mg LMWID. No serious AEs occurred. About 2% experienced transient infusion reactions. Hgb improved by 1-1.9 g/dL in 82% and ≥2 g/dL in 24%. Second trimester treatment was not associated with greater Hgb improvement than third trimester treatment. Anemia resolved in 95%. Administration of a single large dose of IV LMWID was effective, safe, and convenient. Am. J. Hematol. 91:590-593, 2016. © 2016 Wiley Periodicals, Inc.

Implementation and evaluation of the Helping Babies Breathe curriculum in three resource limited settings: does Helping Babies Breathe save lives? A study protocol.

BACKGROUND: Neonatal deaths account for over 40% of all under-5 year deaths; their reduction is increasingly critical for achieving Millennium Development Goal 4. An estimated 3 million newborns die annually during their first month of life; half of these deaths occur during delivery or within 24 hours. Every year, 6 million babies require help to breathe immediately after birth. Resuscitation training to help babies breathe and prevent/manage birth asphyxia is not routine in low-middle income facility settings. Helping Babies Breathe (HBB), a simulation-training program for babies wherever they are born, was developed for use in low-middle income countries. We evaluated whether HBB training of facility birth attendants reduces perinatal mortality in the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Global Network research sites. METHODS/DESIGN: We hypothesize that a two-year prospective pre-post study to evaluate the impact of a facility-based training package, including HBB and essential newborn care, will reduce all perinatal mortality (fresh stillbirth or neonatal death prior to 7 days) among the Global Network's Maternal Neonatal Health Registry births ≥1500 grams in the study clusters served by the facilities. We will also evaluate the effectiveness of the HBB training program changing on facility-based perinatal mortality and resuscitation practices. Seventy-one health facilities serving 52 geographically-defined study clusters in Belgaum and Nagpur, India, and Eldoret, Kenya, and 30,000 women will be included. Primary outcome data will be collected by staff not involved in the HBB intervention. Additional data on resuscitations, resuscitation debriefings, death audits, quality monitoring and improvement will be collected. HBB training will include training of MTs, facility level birth attendants, and quality monitoring and improvement activities. DISCUSSION: Our study will evaluate the effect of a HBB/ENC training and quality monitoring and improvement package on perinatal mortality using a large multicenter design and approach in 71 resource-limited health facilities, leveraging an existing birth registry to provide neonatal outcomes through day 7. The study will provide the evidence base, lessons learned, and best practices that will be essential to guiding future policy and investment in neonatal resuscitation. TRIAL REGISTRATION: Trial registration ClinicalTrials.gov Identifier: NCT01681017.

ENC training reduces perinatal mortality in Karnataka, India.

OBJECTIVE: To evaluate the effect of World Health Organization Essential Newborn Care course and the American Academy of Pediatrics Neonatal Resuscitation Program training on perinatal mortality in rural India. METHODS: This study was part of a multi-country prospective, community-based cluster randomized controlled trial. Birth, 7-day and 28-day neonatal outcomes for all women with pregnancies greater than 28 weeks in the 26 study communities in Karnataka, India were included. Mortality rates pre- and post-Essential Newborn Care training were collected prospectively and then communities randomized to either receive neonatal resuscitation or refresher newborn care training in the control clusters. RESULTS: Consent was obtained on 99% of the 25,096 births. Perinatal mortality for infants ≥500 g decreased from 52 to 36/1000 after newborn care training (RR 0.7; 95% CI 0.5, 0.9); stillbirth decreased from 23 to 14/1000 (RR 0.62; 95% CI 0.46, 0.83) and early neonatal mortality decreased from 29 to 22/1000 (RR 0.74; 95% CI 0.53, 1.03). Mortality was not reduced further with resuscitation training. CONCLUSIONS: Using a pre-post design, World Health Organization Essential Newborn Care community birth attendant training resulted in a significant reduction in perinatal mortality. In low-resource settings, the newborn care training package appears to be an effective intervention to decrease perinatal 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 2,500 g 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 2,500 g. 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).

BACKGROUND: Maternal 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/DESIGN: We 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 Women's and Children's 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. DISCUSSION: In 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 REGISTRATION: ClinicalTrials.gov NCT01073488.