Naoko Kozuki

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

BackgroundPrevious 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).MethodsData 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.ResultsNulliparous, 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.ConclusionsNulliparous 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.FundingFunding 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.

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.

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

Summary 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. 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).

Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990

Background:Intrapartum hypoxic events (“birth asphyxia”) may result in stillbirth, neonatal or postneonatal mortality, and impairment. Systematic morbidity estimates for the burden of impairment outcomes are currently limited. Neonatal encephalopathy (NE) following an intrapartum hypoxic event is a strong predictor of long-term impairment.Methods:Linear regression modeling was conducted on data identified through systematic reviews to estimate NE incidence and time trends for 184 countries. Meta-analyses were undertaken to estimate the risk of NE by sex of the newborn, neonatal case fatality rate, and impairment risk. A compartmental model estimated postneonatal survivors of NE, depending on access to care, and then the proportion of survivors with impairment. Separate modeling for the Global Burden of Disease 2010 (GBD2010) study estimated disability adjusted life years (DALYs), years of life with disability (YLDs), and years of life lost (YLLs) attributed to intrapartum-related events.Results:In 2010, 1.15 million babies (uncertainty range: 0.89–1.60 million; 8.5 cases per 1,000 live births) were estimated to have developed NE associated with intrapartum events, with 96% born in low- and middle-income countries, as compared with 1.60 million in 1990 (11.7 cases per 1,000 live births). An estimated 287,000 (181,000–440,000) neonates with NE died in 2010; 233,000 (163,000–342,000) survived with moderate or severe neurodevelopmental impairment; and 181,000 (82,000–319,000) had mild impairment. In GBD2010, intrapartum-related conditions comprised 50.2 million DALYs (2.4% of total) and 6.1 million YLDs.Conclusion:Intrapartum-related conditions are a large global burden, mostly due to high mortality in low-income countries. Universal coverage of obstetric care and neonatal resuscitation would prevent most of these deaths and disabilities. Rates of impairment are highest in middle-income countries where neonatal intensive care was more recently introduced, but quality may be poor. In settings without neonatal intensive care, the impairment rate is low due to high mortality, which is relevant for the scale-up of basic neonatal resuscitation.

The associations of birth intervals with small-for-gestational-age, preterm, and neonatal and infant mortality: a meta-analysis

BackgroundShort and long birth intervals have previously been linked to adverse neonatal outcomes. However, much of the existing literature uses cross-sectional studies, from which deriving causal inference is complex. We examine the association between short/long birth intervals and adverse neonatal outcomes by calculating and meta-analyzing associations using original data from cohort studies conducted in low-and middle-income countries (LMIC).MethodsWe identified five cohort studies. Adjusted odds ratios (aOR) were calculated for each study, with birth interval as the exposure and small-for-gestational-age (SGA) and/or preterm birth, and neonatal and infant mortality as outcomes. The associations were controlled for potential confounders and meta-analyzed.ResultsBirth interval of shorter than 18 months had statistically significant increased odds of SGA (pooled aOR: 1.51, 95% CI: 1.31-1.75), preterm (pooled aOR: 1.58, 95% CI: 1.19-2.10) and infant mortality (pooled aOR: 1.83, 95% CI: 1.19-2.81) after controlling for potential confounding factors (reference 36-<60 months). It was also significantly associated with term-SGA, preterm-appropriate-for-gestational-age, and preterm-SGA. Birth interval over 60 months had increased risk of SGA (pooled aOR: 1.22, 95% CI: 1.07-1.39) and term-SGA (pooled aOR: 1.14, 95% CI: 1.03-1.27), but was not associated with other outcomes.ConclusionsBirth intervals shorter than 18 months are significantly associated with SGA, preterm birth and death in the first year of life. Lack of access to family planning interventions thus contributes to the burden of adverse birth outcomes and infant mortality in LMICs. Programs and policies must assess ways to provide equitable access to reproductive health interventions to mothers before or soon after delivering a child, but also address underlying socioeconomic factors that may modify and worsen the effect of short intervals.

Moderate to Severe, but Not Mild, Maternal Anemia Is Associated with Increased Risk of Small-for-Gestational-Age Outcomes

Anemia is highly prevalent globally, estimated at 40-50% in women of reproductive age. Prior studies have produced inconclusive evidence as to the association between maternal anemia and intrauterine growth restriction (IUGR). We conducted a systematic review of the literature containing associations between maternal anemia and small for gestational age (SGA) outcomes (as a proxy for IUGR). A meta-analysis was performed to pool associations, categorized by the hemoglobin cutoffs presented by the authors. We identified 12 studies reporting associations between maternal anemia and SGA. For the meta-analysis, there were 7 associations with a hemoglobin cutoff <110 g/L, 7 with a cutoff <100 g/L, and 5 with a cutoff <90 or <80 g/L. Although the <110- and <100-g/L categories showed no significant relationship with SGA, the <90- or <80-g/L category was associated with a 53% increase in risk of the newborn being SGA [pooled OR = 1.53 (95% CI: 1.24-1.87); P < 0.001]. Moderate to severe, but not mild, maternal anemia appears to have an association with SGA outcomes, but the findings must be viewed with caution due to the great heterogeneity of the studies. Further examination should be conducted using datasets with better standardized definitions and measurements of exposure and outcome.

Short Maternal Stature Increases Risk of Small-for-Gestational-Age and Preterm Births in Low- and Middle-Income Countries: Individual Participant Data Meta-Analysis and Population Attributable Fraction

BACKGROUND Small-for-gestational-age (SGA) and preterm births are associated with adverse health consequences, including neonatal and infant mortality, childhood undernutrition, and adulthood chronic disease. OBJECTIVES The specific aims of this study were to estimate the association between short maternal stature and outcomes of SGA alone, preterm birth alone, or both, and to calculate the population attributable fraction of SGA and preterm birth associated with short maternal stature. METHODS We conducted an individual participant data meta-analysis with the use of data sets from 12 population-based cohort studies and the WHO Global Survey on Maternal and Perinatal Health (13 of 24 available data sets used) from low- and middle-income countries (LMIC). We included those with weight taken within 72 h of birth, gestational age, and maternal height data (n = 177,000). For each of these studies, we individually calculated RRs between height exposure categories of < 145 cm, 145 to < 150 cm, and 150 to < 155 cm (reference: ≥ 155 cm) and outcomes of SGA, preterm birth, and their combination categories. SGA was defined with the use of both the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) birth weight standard and the 1991 US birth weight reference. The associations were then meta-analyzed. RESULTS All short stature categories were statistically significantly associated with term SGA, preterm appropriate-for-gestational-age (AGA), and preterm SGA births (reference: term AGA). When using the INTERGROWTH-21st standard to define SGA, women < 145 cm had the highest adjusted risk ratios (aRRs) (term SGA-aRR: 2.03; 95% CI: 1.76, 2.35; preterm AGA-aRR: 1.45; 95% CI: 1.26, 1.66; preterm SGA-aRR: 2.13; 95% CI: 1.42, 3.21). Similar associations were seen for SGA defined by the US reference. Annually, 5.5 million term SGA (18.6% of the global total), 550,800 preterm AGA (5.0% of the global total), and 458,000 preterm SGA (16.5% of the global total) births may be associated with maternal short stature. CONCLUSIONS Approximately 6.5 million SGA and/or preterm births in LMIC may be associated with short maternal stature annually. A reduction in this burden requires primary prevention of SGA, improvement in postnatal growth through early childhood, and possibly further intervention in late childhood and adolescence. It is vital for researchers to broaden the evidence base for addressing chronic malnutrition through multiple life stages, and for program implementers to explore effective, sustainable ways of reaching the most vulnerable populations.

Exploring the association between short/long preceding birth intervals and child mortality: using reference birth interval children of the same mother as comparison.

BackgroundThis study used data from recent Demographic and Health Surveys (DHS) to examine the impact of short or long preceding birth intervals on neonatal and under-five mortality. In order to minimize the effect of selection issues, we examined child mortality outcomes of the same mother, comparing short or long interval births against births with what had previously been considered optimal intervals.MethodsWe analyzed 47 DHS datasets from low- and middle-income countries. For each dataset, we compared neonatal and under-five mortality of short preceding interval births (<18 months, <24 months) to reference interval births (24-<60 months) of a mother, using conditional logistic regression matching on the mother. We also conducted the same matched analysis for long (≥60 months, ≥72 months) preceding interval births. These associations were then meta-analyzed. We also stratified the analyses by mothers’ completed fertility (fertility at end of reproductive period) to assess whether maternal characteristics highly correlated with completed fertility modify the association between birth interval and child mortality.ResultsChildren with shorter preceding intervals had increased odds of both neonatal (<24 months, OR: 1.61, 95% CI: 1.52-1.70) and under-five mortality (<24 months, OR: 1.48, 95% CI: 1.40-1.56). When the associations were stratified by the mothers’ completed fertility, the impact of short intervals was greatly reduced or eliminated for low fertility mothers. In contrast, mortality associations became stronger for children of high fertility mothers. However, when the births of high fertility mothers were limited to birth orders 2-4, the associations were comparable to those of low fertility mothers. Longer preceding birth intervals had lower odds of mortality than reference intervals (i.e. under-5 mortality for ≥60 months, OR 0.59, 95% CI: 0.52-0.67). This effect was also mediated by mothers’ completed fertility; there was a strong protective effect of longer birth intervals for the high fertility mothers but not for low fertility mothers.ConclusionsThese analyses reproduced findings reported in previous literature that shorter birth intervals are associated with higher child mortality. However the negative impact of short birth intervals may only occur in high parity births. Reproductive health interventions that seek to lengthen birth intervals may have larger impact by targeting women with high parity. This finding is consistent with the concept of maternal depletion as the underlying cause of increased adverse child outcomes associated with shorter birth intervals.

Prevalence of Small-for-Gestational-Age and Its Mortality Risk Varies by Choice of Birth-Weight-for-Gestation Reference Population

Background We use data from rural Nepal and South India to compare the prevalence of small-for-gestational-age (SGA) and neonatal mortality risk associated with SGA using different birth-weight-for-gestation reference populations. Methods We identified 46 reference populations in low-, middle-, and high-income countries, of which 26 met the inclusion criteria of being commonly cited and having numeric 10th percentile cut points published. Those reference populations were then applied to populations from two community-based studies to determine SGA prevalence and its relative risk of neonatal mortality. Results The prevalence of SGA ranged from 10.5% to 72.5% in Nepal, and 12.0% to 78.4% in India, depending on the reference population. Females had higher rates of SGA than males using reference populations that were not sex specific. SGA prevalence was lowest when using reference populations from low-income countries. Infants who were both preterm and SGA had much higher mortality risk than those who were term and appropriate-for-gestational-age. Risk ratios for those who are both preterm and SGA ranged from 7.34–17.98 in Nepal and 5.29–11.98 in India, depending on the reference population. Conclusions These results demonstrate the value of a common birth-weight-for-gestation reference population that will facilitate comparisons of SGA prevalence and mortality risk across research studies.

Estimates of burden and consequences of infants born small for gestational age in low and middle income countries with INTERGROWTH-21(st) standard: analysis of CHERG datasets.

Objectives To estimate small for gestational age birth prevalence and attributable neonatal mortality in low and middle income countries with the INTERGROWTH-21st birth weight standard. Design Secondary analysis of data from the Child Health Epidemiology Reference Group (CHERG), including 14 birth cohorts with gestational age, birth weight, and neonatal follow-up. Small for gestational age was defined as infants weighing less than the 10th centile birth weight for gestational age and sex with the multiethnic, INTERGROWTH-21st birth weight standard. Prevalence of small for gestational age and neonatal mortality risk ratios were calculated and pooled among these datasets at the regional level. With available national level data, prevalence of small for gestational age and population attributable fractions of neonatal mortality attributable to small for gestational age were estimated. Setting CHERG birth cohorts from 14 population based sites in low and middle income countries. Main outcome measures In low and middle income countries in the year 2012, the number and proportion of infants born small for gestational age; number and proportion of neonatal deaths attributable to small for gestational age; the number and proportion of neonatal deaths that could be prevented by reducing the prevalence of small for gestational age to 10%. Results In 2012, an estimated 23.3 million infants (uncertainty range 17.6 to 31.9; 19.3% of live births) were born small for gestational age in low and middle income countries. Among these, 11.2 million (0.8 to 15.8) were term and not low birth weight (≥2500 g), 10.7 million (7.6 to 15.0) were term and low birth weight (<2500 g) and 1.5 million (0.9 to 2.6) were preterm. In low and middle income countries, an estimated 606 500 (495 000 to 773 000) neonatal deaths were attributable to infants born small for gestational age, 21.9% of all neonatal deaths. The largest burden was in South Asia, where the prevalence was the highest (34%); about 26% of neonatal deaths were attributable to infants born small for gestational age. Reduction of the prevalence of small for gestational age from 19.3% to 10.0% in these countries could reduce neonatal deaths by 9.2% (254 600 neonatal deaths; 164 800 to 449 700). Conclusions In low and middle income countries, about one in five infants are born small for gestational age, and one in four neonatal deaths are among such infants. Increased efforts are required to improve the quality of care for and survival of these high risk infants in low and middle income countries