Zinc Supplementation Initiated Prior to or During Pregnancy Modestly Impacted Maternal Status and High Prevalence of Hypozincemia in Pregnancy and Lactation: The Women First Preconception Maternal Nutrition Trial.

BACKGROUND: Data regarding effects of small-quantity-lipid-based nutrient supplements (SQ-LNS) on maternal serum zinc concentrations (SZC) in pregnancy and lactation are limited. OBJECTIVES: The objectives of this study were to evaluate the effect of preconception compared with prenatal zinc supplementation (compared with control) on maternal SZC and hypozincemia during pregnancy and early lactation in women in low-resource settings, and assess associations with birth anthropometry. METHODS: From ∼100 women/arm at each of 3 sites (Guatemala, India, and Pakistan) of the Women First Preconception Maternal Nutrition trial, we compared SZC at 12- and 34-wk gestation (n = 651 and 838, respectively) and 3-mo postpartum (n = 742) in women randomly assigned to daily SQ-LNS containing 15 mg zinc from ≥3 mo before conception (preconception, arm 1), from ∼12 wk gestation through delivery (early pregnancy, arm 2) or not at all (control, arm 3). Birth anthropometry was examined for newborns with ultrasound-determined gestational age. Statistical analyses were performed separately for each time point. RESULTS: At 12-wk gestation and 3-mo postpartum, no statistical differences in mean SZC were observed among arms. At 34-wk, mean SZC for arms 1 and 2 were significantly higher than for arm 3 (50.3, 50.8, 47.8 µg/dL, respectively; P = 0.005). Results were not impacted by correction for inflammation or albumin concentrations. Prevalence of hypozincemia at 12-wk (<56 µg/dL) was 23% in Guatemala, 26% in India, and 65% in Pakistan; at 34 wk (<50 µg/dL), 36% in Guatemala, 48% in India, and 74% in Pakistan; and at 3-mo postpartum (<66 µg/dL) 79% in Guatemala, 91% in India, and 92% in Pakistan. Maternal hypozincemia at 34-wk was associated with lower birth length-for-age Z-scores (all sites P = 0.013, Pakistan P = 0.008) and weight-for-age Z-scores (all sites P = 0.017, Pakistan P = 0.022). CONCLUSIONS: Despite daily zinc supplementation for ≥7 mo, high rates of maternal hypozincemia were observed. The association of hypozincemia with impaired fetal growth suggests widespread zinc deficiency in these settings. This trial is registered at clinicaltrials.gov as #NCT01883193.

Infant and young child feeding indicators are positively associated with length and family care indicators in the children of the Women First trial participants.

This research describes the proportion of children in four low- and middle-income countries with adequate dietary practices at 6, 12, 18 and 24 months of age and how these practices changed over time using the World Health Organisation and UNICEF's infant young child feeding (IYCF) indicators. The associations between the IYCF indicators and anthropometric z-scores from 6 to 24 months, and between the IYCF indicators and the family care indicators (FCIs) at 24 months are described. This was a longitudinal study of offspring from participants in the Women First Preconception Maternal Nutrition Trial conducted in Sud-Ubangi, Democratic Republic of Congo; Chimaltenango, Guatemala; Belagavi, North Karnataka, India; and Thatta, Sindh Province, Pakistan. The frequency of the minimum dietary diversity (MDD), minimum meal frequency (MMF), and minimum adequate diet (MAD) increased between 6 and 24 months, but even at 24 months MAD remained below 50% at all sites. MDD (ß = 0.12; 95% CI = 0.04-0.22) and MMF (ß = 0.10; 95% CI = 0.03-0.17) were positively associated with length-for-age z-score at 24 months. All IYCF indicators were positively associated with mean total FCI score: MDD (proportion ratio [PR] = 1.04; 95% CI = 1.02-1.07), MMF (PR = 1.02; 95% CI = 1.01-1.04), MAD (PR = 1.05; 95% CI = 1.02-1.08). Although there are multiple barriers to young children having an adequate diet, our results support a positive association between familial interactions and improved IYCF feeding practices.

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.

Preconceptional Lipid-Based Nutrient Supplementation in 2 Low-Resource Countries Results in Distinctly Different IGF-1/mTOR Placental Responses.

BACKGROUND: Preconceptional maternal small-quantity lipid-based nutrient supplementation (SQLNS) improved intrauterine linear growth in low-resource countries as demonstrated by the Women First Preconception Maternal Nutrition Trial (WF). Fetal growth is dependent on nutrient availability and regulated by insulin-like growth factor 1 (IGF-1) through changes in placental transfer capacity, mediated by the mechanistic target of rapamycin (mTOR) pathway. OBJECTIVES: Our objective was to evaluate the role of placental mTOR and IGF-1 signaling on fetal growth in women from 2 low-resource countries with high rates of stunting after they received preconceptional SQLNS. METHODS: We studied 48 women from preconception through delivery who were from Guatemala and Pakistan and received SQLNS or not, as part of the WF study. Placental samples were obtained at delivery (control, n = 24; SQLNS, n = 24). Placental protein or mRNA expression of eukaryotic translation initiation factor binding protein-1 (4E-BP1), ribosomal protein S6 (rpS6), AMP-activated protein kinase α (AMPKA), IGF-1, insulin-like growth factor receptor (IGF-1R), and pregnancy associated plasma protein (PAPP)-A, and DNA methylation of the IGF1 promoter were determined. Maternal serum IGF-1, insulin-like growth factor binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, PAPP-A, PAPP-A2, and zinc were measured. RESULTS: Mean ± SEM maternal prepregnancy BMI differed between participants in Guatemala (26.5 ± 1.3) and Pakistan (19.8 ± 0.7) (P < 0.001). In Pakistani participants, SQLNS increased the placental rpS6(T37/46):rpS6 ratio (1.5-fold) and decreased the AMPKA(T172):AMPKA ratio. Placental IGF1 mRNA expression was positively correlated with birth length and birth weight z-scores. Placental PAPP-A (30-fold) and maternal serum zinc (1.2-fold) increased with SQLNS. In Guatemalan participants SQLNS did not influence placental mTOR signaling. Placental IGF-1R protein expression was positively associated with birth length and birth weight z-scores. SQLNS increased placental PAPP-A (40-fold) and maternal serum IGFBP-4 (1.6-fold). CONCLUSIONS: In Pakistani pregnant women with poor nutritional status, preconceptional SQLNS activated placental mTOR and IGF-1 signaling and was associated with improved fetal growth. In contrast, in Guatemalan women SQLNS did not activate placental nutrient-sensing pathways. In populations experiencing childhood stunting, preconceptional SQLNS improves placental function and fetal growth only in the context of poor maternal nutrition. This trial was registered at clinicaltrials.gov as NCT01883193.

Use of Smokeless Tobacco Before Conception and Its Relationship With Maternal and Fetal Outcomes of Pregnancy in Thatta, Pakistan: Findings From Women First Study.

INTRODUCTION: Smokeless tobacco (SLT) consumption during pregnancy has adverse consequences for the mother and fetus. We aimed to investigate the effects of maternal pre-pregnancy SLT consumption on maternal and fetal outcomes in the district of Thatta, Pakistan. AIMS AND METHODS: We conducted a secondary data analysis of an individual randomized controlled trial of preconception maternal nutrition. Study participants were women of reproductive age (WRA) residing in the district of Thatta, Pakistan. Participants were asked questions regarding the usage of commonly consumed SLT known as gutka (exposure variable). Study outcomes included maternal anemia, miscarriage, preterm births, stillbirths, and low birth weight. We performed a cox-regression analysis by controlling for confounders such as maternal age, education, parity, working status, body mass index, and geographic clusters. RESULTS: The study revealed that 71.5% of the women reported using gutka, with a higher proportion residing in rural areas as compared with urban areas in the district of Thatta, Pakistan. In the multivariable analysis, we did not find a statistically significant association between gutka usage and anemia [(relative risk, RR: 1.04, 95% confidence interval, CI (0.92 to 1.16)], miscarriage [(RR: 1.08, 95% CI (0.75 to 1.54)], preterm birth [(RR: 1.37, 95% CI (0.64 to 2.93)], stillbirth [(RR: 1.02, 95% CI (0.39 to 2.61)], and low birth weight [(RR: 0.96, 95% CI (0.72 to 1.28)]. CONCLUSIONS: The study did not find an association between gutka usage before pregnancy and adverse maternal and fetal outcomes. In the future, robust epidemiological studies are required to detect true differences with a dose-response relationship between gutka usage both before and during pregnancy and adverse fetomaternal outcomes. IMPLICATIONS: While most epidemiological studies conducted in Pakistan have focused on smoking and its adverse outcomes among males, none of the studies have measured the burden of SLT among WRA and its associated adverse outcomes. In addition, previously conducted studies have primarily assessed the effect of SLT usage during pregnancy rather than before pregnancy on adverse fetal and maternal outcomes. The current study is unique because it provides an insight into the usage of SLT among WRA before pregnancy and investigates the association between pre-pregnancy SLT usage and its adverse fetomaternal outcomes in rural Pakistan.

Improved first trimester maternal iodine status with preconception supplementation: The Women First Trial.

Maternal iodine (I) status is critical in embryonic and foetal development. We examined the effect of preconception iodine supplementation on maternal iodine status and on birth outcomes. Non-pregnant women in Guatemala, India and Pakistan (n ~ 100 per arm per site) were randomized ≥ 3 months prior to conception to one of three intervention arms: a multimicronutrient-fortified lipid-based nutrient supplement containing 250-µg I per day started immediately after randomization (Arm 1), the same supplement started at ~12 weeks gestation (Arm 2) and no intervention supplement (Arm 3). Urinary I (µg/L) to creatinine (mg/dl) ratios (I/Cr) were determined at 12 weeks for Arm 1 versus Arm 2 (before supplement started) and 34 weeks for all arms. Generalized linear models were used to assess the relationship of I/Cr with arm and with newborn anthropometry. At 12 weeks gestation, adjusted mean I/Cr (µg/g) for all sites combined was significantly higher for Arm 1 versus Arm 2: (203 [95% CI: 189, 217] vs. 163 [95% CI: 152, 175], p < 0.0001). Overall adjusted prevalence of I/Cr < 150 µg/g was also lower in Arm 1 versus Arm 2: 32% (95% CI: 26%, 38%) versus 43% (95% CI: 37%, 49%) (p = 0.0052). At 34 weeks, adjusted mean I/Cr for Arm 1 (235, 95% CI: 220, 252) and Arm 2 (254, 95% CI: 238, 272) did not differ significantly but were significantly higher than Arm 3 (200, 95% CI: 184, 218) (p < 0.0001). Nominally significant positive associations were observed between I/Cr at 12 weeks and birth length and head circumference z-scores (p = 0.028 and p = 0.005, respectively). These findings support the importance of first trimester iodine status and suggest need for preconception supplementation beyond salt iodization alone.

Prevalence of clinically-evident congenital anomalies in the Western highlands of Guatemala.

BACKGROUND: Congenital anomalies are a significant cause of death and disability for infants, especially in low and middle-income countries (LMIC), where 95% of all deaths due to anomalies occur. Limited data on the prevalence and survival of infants with congenital anomalies are available from Central America. Estimates have indicated that 53 of every 10,000 live births in Guatemala are associated with a congenital anomaly. We aim to report on the incidence and survival of infants with congenital anomalies from a population-based registry and classify the anomalies according to the International Classification of Disease, Tenth Revision (ICD-10). METHODS: We conducted a planned secondary analysis of data from the Maternal Newborn Health Registry (MNHR), a prospective, population-based study carried out by the Global Network for Women's and Children's Health Research in seven research sites. We included all deliveries between 2014 and 2018 in urban and rural settings in Chimaltenango, in the Western Highlands of Guatemala. These cases of clinically evident anomalies were reported by field staff and reviewed by medically trained staff, who classified them according to ICD - 10 categories. The incidence of congenital anomalies and associated stillbirth, neonatal mortality, and survival rates were determined for up to 42 days. RESULTS: Out of 60,142 births, 384 infants were found to have a clinically evident congenital anomaly (63.8 per 10,000 births). The most common were anomalies of the nervous system (28.8 per 10,000), malformations and deformations of the musculoskeletal system (10.8 per 10,000), and cleft lip and palate (10.0 per 10,000). Infants born with nervous system anomalies had the highest stillbirth and neonatal mortality rates (14.6 and 9.0 per 10,000, respectively). CONCLUSIONS: This is the first population-based report on congenital anomalies in Guatemala. The rates we found of overall anomalies are higher than previously reported estimates. These data will be useful to increase the focus on congenital anomalies and hopefully increase the use of interventions of proven benefit. TRIAL REGISTRATION: ClinalTrial.gov ID: NCT01073475 .

Association of parity with birthweight and neonatal death in five sites: The Global Network's Maternal Newborn Health Registry study.

BACKGROUND: Nulliparity has been associated with lower birth weight (BW) and other adverse pregnancy outcomes, with most of the data coming from high-income countries. In this study, we examined birth weight for gestational age z-scores and neonatal (28-day) mortality in a large prospective cohort of women dated by first trimester ultrasound from multiple sites in low and middle-income countries. METHODS: Pregnant women were recruited during the first trimester of pregnancy and followed through 6 weeks postpartum from Maternal Newborn Health Registry (MNHR) sites in the Democratic Republic of Congo (DRC), Guatemala, Belagavi and Nagpur, India, and Pakistan from 2017 and 2018. Data related to the pregnancy and its outcomes were collected prospectively. First trimester ultrasound was used for determination of gestational age; (BW) was obtained in grams within 48 h of delivery and later transformed to weight for age z-scores (WAZ) adjusted for gestational age using the INTERGROWTH-21st standards. RESULTS: 15,121 women were eligible and included. Infants of nulliparous women had lower mean BWs (males: 2676 gr, females: 2587 gr, total: 2634 gr) and gestational age adjusted weight for age z-scores (males: - 0.73, females: - 0.77, total: - 0.75,) than women with one or more previous pregnancies. The largest differences were between zero and one previous pregnancies among female infants. The associations of parity with BW and z-scores remained even after adjustment for maternal age, maternal height, maternal education, antenatal care visits, hypertensive disorders, and socioeconomic status. Nulliparous women also had a significantly higher < 28-day neonatal mortality rate (27.7 per 1,000 live births) than parous women (17.2 and 20.7 for parity of 1-3 and ≥ 4 respectively). Risk of preterm birth was higher among women with ≥ 4 previous pregnancies (15.5%) compared to 11.3% for the nulliparous group and 11.8% for women with one to three previous pregnancies (p = 0.0072). CONCLUSIONS: In this large sample from diverse settings, nulliparity was independently associated with both lower BW and WAZ scores as well as higher neonatal mortality compared to multiparity.

Oligohydramnios: a prospective study of fetal, neonatal and maternal outcomes in low-middle income countries.

BACKGROUND: Oligohydramnios is a condition of abnormally low amniotic fluid volume that has been associated with poor pregnancy outcomes. To date, the prevalence of this condition and its outcomes has not been well described in low and low-middle income countries (LMIC) where ultrasound use to diagnose this condition in pregnancy is limited. As part of a prospective trial of ultrasound at antenatal care in LMICs, we sought to evaluate the incidence of and the adverse maternal, fetal and neonatal outcomes associated with oligohydramnios. METHODS: We included data in this report from all pregnant women in community settings in Guatemala, Pakistan, Zambia and the Democratic Republic of Congo (DRC) who received a third trimester ultrasound as part of the First Look Study, a randomized trial to assess the value of ultrasound at antenatal care. Using these data, we conducted a planned secondary analysis to compare pregnancy outcomes of women with to those without oligohydramnios. Oligohydramnios was defined as measurement of an Amniotic Fluid Index less than 5 cm in at least one ultrasound in the third trimester. The outcomes assessed included maternal morbidity and fetal and neonatal mortality, preterm birth and low-birthweight. We used pairwise site comparisons with Tukey-Kramer adjustment and multivariable logistic models using general estimating equations to account for the correlation of outcomes within cluster. RESULTS: Of 12,940 women enrolled in the clusters in Guatemala, Pakistan, Zambia and the DRC in the First Look Study who had a third trimester ultrasound examination, 87 women were diagnosed with oligohydramnios, equivalent to 0.7% of those studied. Prevalence of detected oligohydramnios varied among study sites; from the lowest of 0.2% in Zambia and the DRC to the highest of 1.5% in Pakistan. Women diagnosed with oligohydramnios had higher rates of hemorrhage, fetal malposition, and cesarean delivery than women without oligohydramnios. We also found unfavorable fetal and neonatal outcomes associated with oligohydramnios including stillbirths (OR 5.16, 95%CI 2.07, 12.85), neonatal deaths < 28 days (OR 3.18, 95% CI 1.18, 8.57), low birth weight (OR 2.10, 95% CI 1.44, 3.07) and preterm births (OR 2.73, 95%CI 1.76, 4.23). The mean birth weight was 162 g less (95% CI -288.6, - 35.9) with oligohydramnios. CONCLUSIONS: Oligohydramnos was associated with worse neonatal, fetal and maternal outcomes in LMIC. Further research is needed to assess effective interventions to diagnose and ultimately to reduce poor outcomes in these settings. TRIAL REGISTRATION: NCT01990625.

Malpresentation in low- and middle-income countries: Associations with perinatal and maternal outcomes in the Global Network.

INTRODUCTION: Uncertainty exists regarding the impact of malpresentation on pregnancy outcomes and the optimal mode of delivery in low- and middle-income countries. We sought to compare outcomes between cephalic and non-cephalic pregnancies. MATERIAL AND METHODS: Using the NICHD Global Network's prospective, population-based registry of pregnancy outcomes from 2010 to 2016, we studied outcomes in 436 112 singleton pregnancies. Robust Poisson regressions were used to estimate the risk of adverse outcomes associated with malpresentation. We examined rates of cesarean delivery for malpresentation and compared outcomes between cesarean and vaginal delivery by region. RESULTS: Across all regions, stillbirth and neonatal mortality rates were higher among deliveries with malpresentation. In adjusted analysis, malpresentation was significantly associated with stillbirth (adjusted relative risk [aRR] 4.0, 95% confidence interval [CI] 3.7-4.5) and neonatal mortality (aRR 2.3, 95% CI 2.1-2.6). Women with deliveries complicated by malpresentation had higher rates of morbidity and mortality. Rates of cesarean delivery for malpresentation ranged from 27% to 87% among regions. Compared with cesarean delivery, vaginal delivery for malpresentation was associated with increased maternal risk, especially postpartum hemorrhage (aRR 5.0, 95% CI; 3.6-7.1). CONCLUSIONS: In a cohort of deliveries in low- and middle-income countries, malpresentation was associated with increased perinatal and maternal risk. Further research is needed to determine the best management of these pregnancies.

Correction to: International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol.

Following publication of the original article [1], the author mentioned that two additional NIH staff were involved in the development of the protocol who did not receive recognition in the Acknowledgments section in their published article.

International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol.

BACKGROUND: Until recently, Zika virus (ZIKV) infections were considered mild and self-limiting. Since 2015, they have been associated with an increase in microcephaly and other birth defects in newborns. While this association has been observed in case reports and epidemiological studies, the nature and extent of the relationship between ZIKV and adverse pregnancy and pediatric health outcomes is not well understood. With the unique opportunity to prospectively explore the full spectrum of issues related to ZIKV exposure during pregnancy, we undertook a multi-country, prospective cohort study to evaluate the association between ZIKV and pregnancy, neonatal, and infant outcomes. METHODS: At research sites in ZIKV endemic regions of Brazil (4 sites), Colombia, Guatemala, Nicaragua, Puerto Rico (2 sites), and Peru, up to 10,000 pregnant women will be recruited and consented in the first and early second trimesters of pregnancy and then followed through delivery up to 6 weeks post-partum; their infants will be followed until at least 1 year of age. Pregnant women with symptomatic ZIKV infection confirmed by presence of ZIKV RNA and/or IgM for ZIKV will also be enrolled, regardless of gestational age. Participants will be tested monthly for ZIKV infection; additional demographic, physical, laboratory and environmental data will be collected to assess the potential interaction of these variables with ZIKV infection. Delivery outcomes and detailed infant assessments, including physical and neurological outcomes, will be obtained. DISCUSSION: With the emergence of ZIKV in the Americas and its association with adverse pregnancy outcomes in this region, a much better understanding of the spectrum of clinical outcomes associated with exposure to ZIKV during pregnancy is needed. This cohort study will provide information about maternal, fetal, and infant outcomes related to ZIKV infection, including congenital ZIKV syndrome, and manifestations that are not detectable at birth but may appear during the first year of life. In addition, the flexibility of the study design has provided an opportunity to modify study parameters in real time to provide rigorous research data to answer the most critical questions about the impact of congenital ZIKV exposure. TRIAL REGISTRATION: NCT02856984 . Registered August 5, 2016. Retrospectively registered.

Factors associated with anemia among women of the reproductive age group in Thatta district: study protocol.

BACKGROUND: Maternal anemia is a leading public health issue placing pregnant women at higher risk of low birth weight, preterm birth, perinatal mortality, and neonatal mortality. Women in developing countries are at higher risk of anemia which could be either due to micronutrient deficiencies, hemoglobinopathies, infections or other socio-demographic factors. Thus, it is highly essential to explore the factors of anemia among women of the reproductive age group in order to design suitable interventions. The primary objective of this study is to assess the biological and socio-demographic factors that are associated with anemia among the women of the reproductive age group in Thatta district. METHODS: An exploratory mixed method study using quantitative and qualitative approaches will be conducted in district Thatta Pakistan from September 2018 to January 2019. In the qualitative phase, data will be collected through focus group discussions and key informant interviews to understand the perceptions of women, their husbands and healthcare providers about anemia. In addition, a quantitative approach using cross-sectional study will be conducted to determine biological and socio-demographic factors associated with anemia. Approximately 150 non-pregnant women and their spouses will be included in the quantitative component of the study. In addition to thematic analysis for the qualitative component, Logistic regression will be done to calculate adjusted Odds ratios with their respective 95% CIs to assess the factors associated with anemia. DISCUSSION: The better understanding of biological, socio-demographic factors and community perceptions of anemia will help us to design strategies and interventions to better address anemia during the reproductive cycle in rural areas of Pakistan. This will help the researchers and policymakers to take the appropriate action accordingly by designing suitable approaches to address the specific type of anemia in the rural population of Pakistan. This will, in turn, reduce the chances of adverse maternal and fetal outcomes associated with anemia.

A Prospective, Population-Based Study of Trends in Operative Vaginal Delivery Compared to Cesarean Delivery Rates in Low- and Middle-Income Countries, 2010-2016.

OBJECTIVE: Few data are available on cesarean delivery and operative vaginal delivery trends in low- and middle-income countries. Our objective was to analyze a prospective population-based registry including eight sites in seven low- and middle-income countries to observe trends in operative vaginal delivery versus cesarean delivery rates over time, across sites. STUDY DESIGN: A prospective population-based study, including home and facility births among women enrolled from 2010 to 2016, was performed in communities in Argentina, Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, and Zambia. Women were enrolled during pregnancy and delivery outcome data were collected. RESULTS: We analyzed 354,287 women; 4,119 (1.2%) underwent an operative vaginal delivery and 45,032 (11.2%) delivered by cesarean. Across all sites with data for 7 years, rates of operative vaginal delivery decreased from 1.6 to 0.3%, while cesarean delivery increased from 6.4 to 14.4%. Similar trends were seen when individual country data were analyzed. Operative vaginal delivery rates decreased in both hospitals and clinics, except in the hospital setting at one of the Indian sites. CONCLUSION: In low- and middle-income countries, operative vaginal delivery is becoming less utilized while cesarean delivery is becoming an increasingly common mode of delivery.

Strategies for optimizing maternal nutrition to promote infant development.

BACKGROUND: The growing appreciation of the multi-faceted importance of optimal maternal nutrition to the health and development of the infant and young child is tempered by incompletely resolved strategies for combatting challenges. OBJECTIVE: To review the importance of maternal nutrition and strategies being employed to optimize outcomes. METHODS: Selected data from recent literature with special focus on rationale for and currently published results of maternal nutrition supplements, including lipid based nutrition supplements. RESULTS: 1) An impelling rationale for improving the maternal and in utero environment of low resource populations has emerged to achieve improved fetal and post-natal growth and development. 2) Based partly on population increases in adult height over one-two generations, much can be achieved by reducing poverty. 3) Maternal, newborn and infant characteristics associated with low resource environments include evidence of undernutrition, manifested by underweight and impaired linear growth. 4) Apart from broad public health and educational initiatives, to date, most specific efforts to improve fetal growth and development have included maternal nutrition interventions during gestation. 5) The relatively limited but real benefits of both iron/folic acid (IFA) and multiple micronutrient (MMN) maternal supplements during gestation have now been reasonably defined. 6) Recent investigations of a maternal lipid-based primarily micronutrient supplement (LNS) have not demonstrated a consistent benefit beyond MMN alone. 7) However, effects of both MMN and LNS appear to be enhanced by commencing early in gestation. CONCLUSIONS: Poor maternal nutritional status is one of a very few specific factors in the human that not only contributes to impaired fetal and early post-natal growth but for which maternal interventions have demonstrated improved in utero development, documented primarily by both improvements in low birth weights and by partial corrections of impaired birth length. A clearer definition of the benefits achievable by interventions specifically focused on correcting maternal nutrition deficits should not be limited to improvements in the quality of maternal nutrition supplements, but on the cumulative quantity and timing of interventions (also recognizing the heterogeneity between populations). Finally, in an ideal world these steps are only a prelude to improvements in the total environment in which optimal nutrition and other health determinants can be achieved.

Predictors of the Size of the Exchangeable Zinc Pool Differ between Children and Adults.

BACKGROUND: The size of the rapidly exchanging pool of body zinc has been suggested as having potential utility as a biomarker of zinc status. Knowledge of the relations of exchangeable zinc pool (EZP) size to relevant variables is necessary to adequately evaluate its use as a biomarker. OBJECTIVE: We used regression analysis to investigate associations of EZP with age, sex, body size, and zinc nutrition variables. METHODS: Data were compiled from 18 isotope tracer studies of zinc absorption in 247 children and adults (248 observations) in which EZP and relevant variables (e.g., weight, age, absorbed zinc) were measured. Linear regression analyses were performed separately on data from adults and children. RESULTS: In children, EZP was most strongly associated with weight (r = 0.78). The best-fitting regression models of EZP (R2 ≥ 0.68) had weight or age and weight-for-age z score as predictors. Other variables had little effect on EZP when controlling for weight. Absorbed zinc was observed to be a predictor of EZP only in zinc intervention trials of infants. The mean EZP/wt was 4 mg/kg between 8 and 120 mo of age. In adults, EZP was observed to vary in a complex manner with (in order of importance) age, absorbed zinc, weight, sex, and plasma zinc concentration. EZP data from zinc-deprived subjects were lower than the 95% prediction interval of a model of normative data. CONCLUSIONS: EZP was observed to maintain a constant size relative to weight and was influenced only slightly by other factors in children. In contrast, EZP in adults varied with several factors, including absorbed zinc, and was statistically smaller in zinc-deprived individuals. The findings suggest that EZP may have utility as an indicator of zinc status in adults, but there is less evidence for this in children. Additional data are needed to reach a definitive conclusion.

Upregulation of Zinc Absorption Matches Increases in Physiologic Requirements for Zinc in Women Consuming High- or Moderate-Phytate Diets during Late Pregnancy and Early Lactation.

Background: Estimated physiologic requirements (PRs) for zinc increase in late pregnancy and early lactation, but the effect on dietary zinc requirements is uncertain.Objective: The aim of this study was to determine changes in daily fractional absorbed zinc and total absorbed zinc (TAZ) from ad libitum diets of differing phytate contents in relation to physiologic zinc requirements during pregnancy and lactation.Methods: This was a prospective observational study of zinc absorption at 8 (phase 1) and 34 (phase 2) wk of gestation and 2 (phase 3) and 6 (phase 4) mo of lactation. Participants were indigenous Guatemalan women of childbearing age whose major food staple was maize and who had been randomly assigned in a larger study to either of 2 ad libitum feeding groups: low-phytate maize (LP; 1.6 mg/g; n = 14) or control maize (C; 7.1 mg/g; n = 8). Total dietary zinc (milligrams per day, TDZ) and phytate (milligrams per day) were determined from duplicate diets and fractional absorption (FAZ) by dual isotope ratio technique (TAZ = TDZ × FAZ). All variables were examined longitudinally and by group and compared with PRs. TAZ values at later phases were compared with phase 1. Measured TAZ was compared with predicted TAZ for nonpregnant, nonlactating (NPNL) women.Results: TAZ was greater in the LP group than in the C group at all phases. All variables increased from phase 1 to phases 2 and 3 and declined at phase 4. TAZ increased by 1.25 mg/d (P = 0.045) in the C group and by 0.81 mg/d (P = 0.058) in the LP group at phase 2. At phase 3, the increases were 2.66 mg/d (P = 0.002) in the C group and 2.28 mg/d (P = 0.0004) in the LP group, compared with a 1.37-mg/d increase in PR. Measured TAZ was greater than predicted values in phases 2-4.Conclusions: Upregulation of zinc absorption in late pregnancy and early lactation matches increases in PRs of pregnant and lactating women, regardless of dietary phytate, which has implications for dietary zinc requirements of pregnant and lactating women.

A description of the methods of the aspirin supplementation for pregnancy indicated risk reduction in nulliparas (ASPIRIN) study.

BACKGROUND: Preterm birth (PTB) remains the leading cause of neonatal mortality and long term disability throughout the world. Though complex in its origins, a growing body of evidence suggests that first trimester administration of low dose aspirin (LDA) may substantially reduce the rate of PTB. METHODS: Hypothesis: LDA initiated in the first trimester reduces the risk of preterm birth. Study Design Type: Prospective randomized, placebo-controlled, double-blinded multi-national clinical trial conducted in seven low and middle income countries. Trial will be individually randomized with one-to-one ratio (intervention/control) Population: Nulliparous women between the ages of 14 and 40, with a singleton pregnancy between 6 0/7 weeks and 13 6/7 weeks gestational age (GA) confirmed by ultrasound prior to enrollment, no more than two previous first trimester pregnancy losses, and no contraindications to aspirin. INTERVENTION: Daily administration of low dose (81 mg) aspirin, initiated between 6 0/7 weeks and 13 6/7 weeks GA and continued to 36 0/7 weeks GA, compared to an identical appearing placebo. Compliance and outcomes will be assessed biweekly. OUTCOMES: Primary outcome: Incidence of PTB (birth prior to 37 0/7 weeks GA). Secondary outcomes Incidence of preeclampsia/eclampsia, small for gestational age and perinatal mortality. DISCUSSION: This study is unique as it will examine the impact of LDA early in pregnancy in low-middle income countries with preterm birth as a primary outcome. The importance of developing low-cost, high impact interventions in low-middle income countries is magnified as they are often unable to bear the financial costs of treating illness. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02409680 Date: March 30, 2015.

A prospective study of maternal, fetal and neonatal outcomes in the setting of cesarean section in low- and middle-income countries.

INTRODUCTION: Cesarean section (CS) rates are increasing globally with an unclear effect on pregnancy outcomes. The study objective was to quantify maternal and perinatal morbidity and mortality associated with CS compared with vaginal delivery (VD) both within and across sites in low- and middle-income countries. MATERIAL AND METHODS: A prospective population-based study including home and facility births in 337 153 women with a VD and 47 308 women with a CS from 2010 to 2015 was performed in Guatemala, India, Kenya, Pakistan, Zambia and Democratic Republic of Congo. Women were enrolled during pregnancy; delivery and 6-week follow-up data were collected. RESULTS: Across all sites, CS rates increased from 8.6% to 15.2%, but remained low in African sites. Younger, nulliparous women were more likely to have a CS, as were women with higher education and those delivering an infant weighing 1500-2499 g. Across all sites, maternal and neonatal mortality was higher, and stillbirths were lower, in pregnancies delivered by CS. Antepartum and postpartum complications as well as obstetric interventions and treatments were more common among women who underwent CS. In stratified analyses, all outcomes were worse in women with a CS compared with VD in African compared to non-African sites. CONCLUSIONS: CS rates increased across all sites during the study period, but at more pronounced rates in the non-African sites. CS was associated with reduced postpartum hemorrhage and lower rates of stillbirths in the non-African sites. In the African sites, CS was associated with an increase in all adverse outcomes. Further studies are necessary to better understand the increase in adverse outcomes with CS in the African sites.

Anthropometric indices for non-pregnant women of childbearing age differ widely among four low-middle income populations.

BACKGROUND: Maternal stature and body mass indices (BMI) of non-pregnant women (NPW) of child bearing age are relevant to maternal and offspring health. The objective was to compare anthropometric indices of NPW in four rural communities in low- to low-middle income countries (LMIC). METHODS: Anthropometry and maternal characteristics/household wealth questionnaires were obtained for NPW enrolled in the Women First Preconception Maternal Nutrition Trial. Body mass index (BMI, kg/m2) was calculated. Z-scores were determined using WHO reference data. RESULTS: A total of 7268 NPW participated in Equateur, DRC (n = 1741); Chimaltenango, Guatemala (n = 1695); North Karnataka, India (n = 1823); and Thatta, Sindh, Pakistan (n = 2009). Mean age was 23 y and mean parity 1.5. Median (P25-P75) height (cm) ranged from 145.5 (142.2-148.9) in Guatemala to 156.0 (152.0-160.0) in DRC. Median weight (kg) ranged from 44.7 (39.9-50.3) in India to 52.7 (46.9-59.8) in Guatemala. Median BMI ranged from 19.4 (17.6-21.9) in India to 24.9 (22.3-28.0) in Guatemala. Percent stunted (<-2SD height for age z-score) ranged from 13.9% in DRC to 80.5% in Guatemala; % underweight (BMI <18.5) ranged from 1.2% in Guatemala to 37.1% in India; % overweight/obese (OW, BMI ≥25.0) ranged from 5.7% in DRC to 49.3% in Guatemala. For all sites, indicators for higher SES and higher age were associated with BMI. Lower SES women were underweight more frequently and higher SES women were OW more frequently at all sites. Younger women tended to be underweight, while older women tended to be OW. CONCLUSIONS: Anthropometric data for NPW varied widely among low-income rural populations in four countries located on three different continents. Global comparisons of anthropometric measurements across sites using standard reference data serve to highlight major differences among populations of low-income rural NPW and assist in evaluating the rationale for and the design of optimal intervention trials. TRIAL REGISTRATION: ClinicalTrials.gov # NCT01883193 (18 June 2013, retrospectively registered).