Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis.

BACKGROUND: Babies with low birthweight (<2500 g) are at increased risk of early mortality. However, low birthweight includes babies born preterm and with fetal growth restriction, and not all these infants have a birthweight less than 2500 g. We estimated the neonatal and infant mortality associated with these two characteristics in low-income and middle-income countries. METHODS: For this pooled analysis, we searched all available studies and identified 20 cohorts (providing data for 2,015,019 livebirths) from Asia, Africa, and Latin America that recorded data for birthweight, gestational age, and vital statistics through 28 days of life. Study dates ranged from 1982 through to 2010. We calculated relative risks (RR) and risk differences (RD) for mortality associated with preterm birth (<32 weeks, 32 weeks to <34 weeks, 34 weeks to <37 weeks), small-for-gestational-age (SGA; babies with birthweight in the lowest third percentile and between the third and tenth percentile of a US reference population), and preterm and SGA combinations. FINDINGS: Pooled overall RRs for preterm were 6·82 (95% CI 3·56-13·07) for neonatal mortality and 2·50 (1·48-4·22) for post-neonatal mortality. Pooled RRs for babies who were SGA (with birthweight in the lowest tenth percentile of the reference population) were 1·83 (95% CI 1·34-2·50) for neonatal mortality and 1·90 (1·32-2·73) for post-neonatal mortality. The neonatal mortality risk of babies who were both preterm and SGA was higher than that of babies with either characteristic alone (15·42; 9·11-26·12). INTERPRETATION: Many babies in low-income and middle-income countries are SGA. Preterm birth affects a smaller number of neonates than does SGA, but is associated with a higher mortality risk. The mortality risks associated with both characteristics extend beyond the neonatal period. Differentiation of the burden and risk of babies born preterm and SGA rather than with low birthweight could guide prevention and management strategies to speed progress towards Millennium Development Goal 4--the reduction of child mortality. FUNDING: Bill & Melinda Gates Foundation.

The associations of parity and maternal age with small-for-gestational-age, preterm, and neonatal and infant mortality: a meta-analysis.

BACKGROUND: Previous studies have reported on adverse neonatal outcomes associated with parity and maternal age. Many of these studies have relied on cross-sectional data, from which drawing causal inference is complex. We explore the associations between parity/maternal age and adverse neonatal outcomes using data from cohort studies conducted in low- and middle-income countries (LMIC). METHODS: Data from 14 cohort studies were included. Parity (nulliparous, parity 1-2, parity ≥ 3) and maternal age (<18 years, 18-<35 years, ≥ 35 years) categories were matched with each other to create exposure categories, with those who are parity 1-2 and age 18-<35 years as the reference. Outcomes included small-for-gestational-age (SGA), preterm, neonatal and infant mortality. Adjusted odds ratios (aOR) were calculated per study and meta-analyzed. RESULTS: Nulliparous, age <18 year women, compared with women who were parity 1-2 and age 18-<35 years had the highest odds of SGA (pooled adjusted OR: 1.80), preterm (pooled aOR: 1.52), neonatal mortality (pooled aOR: 2.07), and infant mortality (pooled aOR: 1.49). Increased odds were also noted for SGA and neonatal mortality for nulliparous/age 18-<35 years, preterm, neonatal, and infant mortality for parity ≥ 3/age 18-<35 years, and preterm and neonatal mortality for parity ≥ 3/≥ 35 years. CONCLUSIONS: Nulliparous women <18 years of age have the highest odds of adverse neonatal outcomes. Family planning has traditionally been the least successful in addressing young age as a risk factor; a renewed focus must be placed on finding effective interventions that delay age at first birth. Higher odds of adverse outcomes are also seen among parity ≥ 3 / age ≥ 35 mothers, suggesting that reproductive health interventions need to address the entirety of a woman's reproductive period. FUNDING: Funding was provided by the Bill & Melinda Gates Foundation (810-2054) by a grant to the US Fund for UNICEF to support the activities of the Child Health Epidemiology Reference Group.

Effects of antenatal multiple micronutrient supplementation on children's weight and size at 2 years of age in Nepal: follow-up of a double-blind randomised controlled trial.

BACKGROUND: The negative effects of low birthweight on the later health of children in developing countries have been well studied. However, undertaking programmes to address this issue can be difficult since there is no simple correlation between increasing birthweight and improving child health. In 2005, we published results of a randomised controlled trial in Nepal, in which 1200 women received either iron and folic acid or a supplement that provided the recommended daily allowance of 15 vitamins and minerals, over the second and third trimesters of pregnancy. Here, we report on 2-3 years' follow-up of children born during the trial. METHODS: We visited children at home and obtained data for the primary outcomes of weight and height, for childhood illnesses, and maternal blood haemoglobin. The study is registered as an International Standard Randomised Controlled Trial, number ISRCTN88625934. FINDINGS: Between December, 2005, and December, 2006, we assessed 917 children (455 controls, 462 intervention) at a mean age of 2.5 years. Mean birthweight had been 77 g (95% CI 24-130) greater in the micronutrient group than in controls. At 2.5 years old, controls weighed a mean of 10.7 kg (SD 1.38), and those in the intervention group 10.9 kg (SD 1.54). Children of women who had taken multiple micronutrient supplements during pregnancy were a mean 204 g (95% CI 27-381) heavier than controls. They also had greater measurements than controls in the circumference of the head (2.4 mm [95% CI 0.6-4.3]), chest (3.2 mm [0.4-6.0]), and mid-upper arm (2.4 mm [1.1-3.7]), and in triceps skinfold thickness (2.0 mm [0.0-0.4]). Systolic blood pressure was slightly lower in the intervention group (2.5 mm Hg [0.5-4.6]). INTERPRETATION: In a poor population, the effects of maternal multiple micronutrient supplementation on the fetus persisted into childhood, with increases in both weight and body size. These increases were small, however, since those exposed to micronutrients had an average of 2% higher weight than controls. The public-health implications of changes in weight and blood pressure need to be clarified through further follow-up.

Effect of multiple micronutrient supplementation during pregnancy on inflammatory markers in Nepalese women.

BACKGROUND: Multiple micronutrient supplementation of Nepalese women during pregnancy is associated with a significant increase in birth weight. OBJECTIVE: We tested the hypothesis that improved birth weight in infants of mothers supplemented with micronutrients is associated with a decrease in inflammatory responses and an increase in the production of T helper 1 cells and T helper 2 cells. DESIGN: The study was embedded in a randomized controlled trial of 15 micronutrients, compared with iron-folate supplementation (control), given during pregnancy with the aim of increasing birth weight. Blood samples were collected at 32 wk of gestation, 12-20 wk after supplementation began, for the measurement of inflammatory markers. Breast-milk samples were collected 1 mo after delivery for the measurement of the ratio of milk sodium to potassium (milk Na:K). In an opportunistically selected subgroup of 70 women, mitogen-stimulated cytokine production was measured ex vivo in whole blood. RESULTS: Blood eosinophils; plasma concentrations of the acute phase reactants C-reactive protein, alpha(1)-acid glycoprotein (AGP), neopterin, and ferritin; milk Na:K; and the production of interleukin (IL) 10, IL-4, interferon gamma, and tumor necrosis factor alpha in whole blood did not differ significantly between the supplemented and control groups. Plasma C-reactive protein and AGP were higher in women who had a preterm delivery, and AGP was higher in women who delivered a low-birth-weight term infant than in women who delivered a normal-birth-weight term infant. CONCLUSIONS: The results indicate an association between systemic inflammation in late pregnancy and compromised delivery outcome in Nepalese women but do not support the hypothesis that multiple micronutrient supplementation changes cytokine production or inflammatory markers.

Effects of antenatal multiple micronutrient supplementation on birthweight and gestational duration in Nepal: double-blind, randomised controlled trial.

BACKGROUND: Neonatal mortality is the biggest contributor to global mortality of children younger than 5 years, and low birthweight is a crucial underlying factor. We tested the hypotheses that antenatal multiple micronutrient supplementation would increase infant birthweight and gestational duration. METHODS: We did a double-blind, randomised controlled trial in Dhanusha district, Nepal. Women attending for antenatal care with singleton pregnancies at up to 20 weeks' gestation were invited to participate. Participants were randomly allocated either routine iron and folic acid supplements (control; n=600) or a multiple micronutrient supplement providing a recommended daily allowance of 15 vitamins and minerals (intervention; n=600). Supplementation began at a minimum of 12 weeks' gestation and continued until delivery. Primary outcome measures were birthweight and gestational duration. Analysis was by intention to treat. The study is registered as an International Standard Randomised Controlled Trial, number ISRCTN88625934. FINDINGS: Birthweight was available for 523/600 infants in the control group and 529/600 in the intervention group. Mean birthweight was 2733 g (SD 422) in the control group and 2810 g (453) in the intervention group, representing a mean difference of 77 g (95% CI 24-130; p=0.004) and a relative fall in the proportion of low birthweight by 25%. No difference was recorded in the duration of gestation (0.2 weeks [-0.1 to 0.4]; p=0.12), infant length (0.3 cm [-0.1 to 0.6]; p=0.16), or head circumference (0.2 cm [-0.1 to 0.4]; p=0.18). INTERPRETATION: In a poor community in Nepal, consumption of a daily supplement containing a recommended daily allowance of 15 micronutrients in the second and third trimesters of pregnancy was associated with increased birthweight when compared with a standard iron and folic acid preparation. The effects on perinatal morbidity and mortality need further comparisons between studies. Published online March 3, 2005 http://image.thelancet.com/extras/04art11045web.pdf.

National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010.

BACKGROUND: National estimates for the numbers of babies born small for gestational age and the comorbidity with preterm birth are unavailable. We aimed to estimate the prevalence of term and preterm babies born small for gestational age (term-SGA and preterm-SGA), and the relation to low birthweight (<2500 g), in 138 countries of low and middle income in 2010. METHODS: Small for gestational age was defined as lower than the 10th centile for fetal growth from the 1991 US national reference population. Data from 22 birth cohort studies (14 low-income and middle-income countries) and from the WHO Global Survey on Maternal and Perinatal Health (23 countries) were used to model the prevalence of term-SGA births. Prevalence of preterm-SGA infants was calculated from meta-analyses. FINDINGS: In 2010, an estimated 32·4 million infants were born small for gestational age in low-income and middle-income countries (27% of livebirths), of whom 10·6 million infants were born at term and low birthweight. The prevalence of term-SGA babies ranged from 5·3% of livebirths in east Asia to 41·5% in south Asia, and the prevalence of preterm-SGA infants ranged from 1·2% in north Africa to 3·0% in southeast Asia. Of 18 million low-birthweight babies, 59% were term-SGA and 41% were preterm-SGA. Two-thirds of small-for-gestational-age infants were born in Asia (17·4 million in south Asia). Preterm-SGA babies totalled 2·8 million births in low-income and middle-income countries. Most small-for-gestational-age infants were born in India, Pakistan, Nigeria, and Bangladesh. INTERPRETATION: The burden of small-for-gestational-age births is very high in countries of low and middle income and is concentrated in south Asia. Implementation of effective interventions for babies born too small or too soon is an urgent priority to increase survival and reduce disability, stunting, and non-communicable diseases. FUNDING: Bill & Melinda Gates Foundation by a grant to the US Fund for UNICEF to support the activities of the Child Health Epidemiology Reference Group (CHERG).