Luke C. Mullany

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.

Topical applications of chlorhexidine to the umbilical cord for prevention of omphalitis and neonatal mortality in southern Nepal: a community-based, cluster-randomised trial

BACKGROUND Omphalitis contributes to neonatal morbidity and mortality in developing countries. Umbilical cord cleansing with antiseptics might reduce infection and mortality risk, but has not been rigorously investigated. METHODS In our community-based, cluster-randomised trial, 413 communities in Sarlahi, Nepal, were randomly assigned to one of three cord-care regimens. 4934 infants were assigned to 4.0% chlorhexidine, 5107 to cleansing with soap and water, and 5082 to dry cord care. In intervention clusters, the newborn cord was cleansed in the home on days 1-4, 6, 8, and 10. In all clusters, the cord was examined for signs of infection (pus, redness, or swelling) on these visits and in follow-up visits on days 12, 14, 21, and 28. Incidence of omphalitis was defined under three sign-based algorithms, with increasing severity. Infant vital status was recorded for 28 completed days. The primary outcomes were incidence of neonatal omphalitis and neonatal mortality. Analysis was by intention-to-treat. This trial is registered with , number NCT00109616. FINDINGS Frequency of omphalitis by all three definitions was reduced significantly in the chlorhexidine group. Severe omphalitis in chlorhexidine clusters was reduced by 75% (incidence rate ratio 0.25, 95% CI 0.12-0.53; 13 infections/4839 neonatal periods) compared with dry cord-care clusters (52/4930). Neonatal mortality was 24% lower in the chlorhexidine group (relative risk 0.76 [95% CI 0.55-1.04]) than in the dry cord care group. In infants enrolled within the first 24 h, mortality was significantly reduced by 34% in the chlorhexidine group (0.66 [0.46-0.95]). Soap and water did not reduce infection or mortality risk. INTERPRETATION Recommendations for dry cord care should be reconsidered on the basis of these findings that early antisepsis with chlorhexidine of the umbilical cord reduces local cord infections and overall neonatal mortality.

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).

Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial

INTRODUCTION Iron deficiency is widespread in the developing world and is especially common in young children who live on the Indian subcontinent. Supplementation with iron and folic acid alleviates severe anaemia and enhances neurodevelopment in deficient populations, but little is known about the risks of mortality and morbidity associated with supplementation. METHODS We did a community-based, cluster-randomised, double-masked, placebo-controlled, 2x2 factorial trial in children aged 1-36 months and residing in southern Nepal. We randomly assigned children daily oral supplementation to age 36 months with: iron (12.5 mg) and folic acid (50 microg; n=8337), zinc alone (10 mg), iron, folic acid, and zinc (n=9230), or placebo (n=8683); children aged 1-11 months received half the dose. Our primary outcome measure was all-cause mortality, and our secondary outcome measures included cause-specific mortality and incidence and severity of diarrhoea, dysentery, and acute respiratory illness. Analyses were by intention to treat. This study is registered at , number NCT00109551. FINDINGS The iron and folic acid-containing groups of the study were stopped early in November, 2003, on the recommendation of the data and safety monitoring board; mortality in these groups did not differ from placebo and there was low power to detect positive or negative effects by the time enrollment was completed. We continued to enroll children to the placebo and zinc alone groups. 25,490 children participated and analyses are based on 29,097.3 person-years of follow-up. There was no difference in mortality between the groups who took iron and folic acid without or with zinc when compared with placebo (HR 1.03, 95% CI 0.78-1.37, and 1.00, 0.74-1.34, respectively). There were no significant differences in the attack rates for diarrhoea, dysentery, or respiratory infections between groups, although all the relative risks except one indicated modest, non-significant protective effects. INTERPRETATION Daily supplementation of young children in southern Nepal with iron and folic acid with or without zinc has no effect on their risk of death, but might protect against diarrhoea, dysentery, and acute respiratory illness.

Obstetric care in low-resource settings: what who and how to overcome challenges to scale up?

Each year, approximately 2 million babies die because of complications of childbirth, primarily in settings where effective care at birth, particularly prompt cesarean delivery, is unavailable.

Time to initiation of breastfeeding and neonatal mortality and morbidity: a systematic review

BackgroundEarly breastfeeding is defined as the initiation of breastfeeding within twenty four hours of birth. While the benefits of breastfeeding have been known for decades, only recently has the role of time to initiation of breastfeeding in neonatal mortality and morbidity been assessed.ObjectiveTo review the evidence for early breastfeeding initiation practices and to estimate the association between timing and neonatal outcomes.MethodsWe systematically reviewed multiple databases from 1963 to 2011. Standardized abstraction tables were used and quality was assessed for each study utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Three meta-analyses were conducted for mortality among babies surviving to 48 hours.ResultsWe identified 18 studies reporting a direct association between early breastfeeding initiation and neonatal mortality and morbidity outcomes. The results of random effects analyses of data from 3 studies (from 5 publications) demonstrated lower risks of all-cause neonatal mortality among all live births (RR = 0.56 [95% CI: 0.40 – 0.79]) and among low birth weight babies (RR=0.58 [95% CI: 0.43 – 0.78]), and infection-related neonatal mortality (RR = 0.55 [95% CI: 0.36 – 0.84]). Among exclusively breastfed infants, all-cause mortality risk did not differ between early and late initiators (RR = 0.69 [95% CI: 0.27 – 1.75]).ConclusionsThis review demonstrates that early breastfeeding initiation is a simple intervention that has the potential to significantly improve neonatal outcomes and should be universally recommended. Significant gaps in knowledge are highlighted, revealing a need to prioritize additional high quality studies that further clarify the specific cause of death, as well as providing improved understanding of the independent or combined effects of early initiation and breastfeeding patterns.

The effect of umbilical cord cleansing with chlorhexidine on omphalitis and neonatal mortality in community settings in developing countries: a meta-analysis

BackgroundThere is an increased risk of serious neonatal infection arising through exposure of the umbilical cord to invasive pathogen in home and facility births where hygienic practices are difficult to achieve. The World Health Organization currently recommends ‘dry cord care’ because of insufficient data in favor of or against topical application of an antiseptic. The primary objective of this meta-analysis is to evaluate the effects of application of chlorhexidine (CHX) to the umbilical cord to children born in low income countries on cord infection (omphalitis) and neonatal mortality. Standardized guidelines of Child Health Epidemiology Reference Group (CHERG) were followed to generate estimates of effectiveness of topical chlorhexidine application to umbilical cord for prevention of sepsis specific mortality, for inclusion in the Lives Saved Tool (LiST).MethodsSystematic review and meta-analysis. Data sources included Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, PubMed, CINHAL and WHO international clinical trials registry. Only randomized trials were included. Studies of children in hospital settings were excluded. The comparison group received no application to the umbilical cord (dry cord care), no intervention, or a non-CHX intervention. Primary outcomes were omphalitis and all-cause neonatal mortality.ResultsThere were three cluster-randomised community trials (total participants 54,624) conducted in Nepal, Bangladesh and Pakistan that assessed impact of CHX application to the newborn umbilical cord for prevention of cord infection and mortality. Application of any CHX to the umbilical cord of the newborn led to a 23% reduction in all-cause neonatal mortality in the intervention group compared to control [RR 0.77, 95 % CI 0.63, 0.94; random effects model, I2=50 %]. The reduction in omphalitis ranged from 27 % to 56 % compared to control group depending on severity of infection. Based on CHERG rules, effect size for all-cause mortality was used for inclusion to LiST model as a proxy for sepsis specific mortality.ConclusionsApplication of CHX to newborn umbilical cord can significantly reduce incidence of umbilical cord infection and all-cause mortality among home births in community settings. This inexpensive and simple intervention can save a significant number of newborn lives in developing countries.

The effect of cord cleansing with chlorhexidine on neonatal mortality in rural Bangladesh: a community-based, cluster-randomised trial.

BACKGROUND Up to half of neonatal deaths in high mortality settings are due to infections, many of which can originate through the freshly cut umbilical cord stump. We aimed to assess the effectiveness of two cord-cleansing regimens with the promotion of dry cord care in the prevention of neonatal mortality. DESIGN We did a community-based, parallel cluster-randomised trial in Sylhet, Bangladesh. We divided the study area into 133 clusters, which were randomly assigned to one of the two chlorhexidine cleansing regimens (single cleansing as soon as possible after birth; daily cleansing for 7 days after birth) or promotion of dry cord care. Randomisation was done by use of a computer-generated sequence, stratified by cluster-specific participation in a previous trial. All livebirths were eligible; those visited within 7 days by a local female village health worker trained to deliver the cord care intervention were enrolled. We did not mask study workers and participants to the study interventions. Our primary outcome was neonatal mortality (within 28 days of birth) per 1000 livebirths, which we analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00434408. RESULTS Between June, 2007, and September, 2009, we enrolled 29 760 newborn babies (10 329, 9423, and 10 008 in the multiple-cleansing, single-cleansing, and dry cord care groups, respectively). Neonatal mortality was lower in the single-cleansing group (22·5 per 1000 livebirths) than it was in the dry cord care group (28·3 per 1000 livebirths; relative risk [RR] 0·80 [95% CI] 0·65-0·98). Neonatal mortality in the multiple-cleansing group (26·6 per 1000 livebirths) was not statistically significantly lower than it was in the dry cord care group (RR 0·94 [0·78-1·14]). Compared with the dry cord care group, we recorded a statistically significant reduction in the occurrence of severe cord infection (redness with pus) in the multiple-cleansing group (risk per 1000 livebirths=4·2 vs risk per 1000 livebirths=1·2; RR 0·35 [0·15-0·81]) but not in the single-cleansing group (risk per 1000 livebirths=3·3; RR 0·77 [0·40-1·48]). INTERPRETATION Chlorhexidine cleansing of a neonates umbilical cord can save lives, but further studies are needed to establish the best frequency with which to deliver the intervention. FUNDING United States Agency for International Development and Save the Childrens Saving Newborn Lives program, through a grant from the Bill & Melinda Gates Foundation.

Impact of Newborn Skin-Cleansing With Chlorhexidine on Neonatal Mortality in Southern Nepal: A Community-Based, Cluster-Randomized Trial

OBJECTIVE. Hospital-based data from Africa suggest that newborn skin-cleansing with chlorhexidine may reduce neonatal mortality. Evaluation of this intervention in the communities where most births occur in the home has not been done. Our objective was to assess the efficacy of a 1-time skin-cleansing of newborn infants with 0.25% chlorhexidine on neonatal mortality. METHODS. The design was a community-based, placebo-controlled, cluster-randomized trial in Sarlahi District in southern Nepal. Newborn infants were cleansed with infant wipes that contained 0.25% chlorhexidine or placebo solution as soon as possible after delivery in the home (median: 5.8 hours). The primary outcome was all-cause mortality by 28 days. After the completion of the randomized phase, all newborns in study clusters were converted to chlorhexidine treatment for the subsequent 9 months. RESULTS. A total of 17530 live births occurred in the enrolled sectors, 8650 and 8880 in the chlorhexidine and placebo groups, respectively. Baseline characteristics were similar in the treatment groups. Intention-to-treat analysis among all live births showed no impact of the intervention on neonatal mortality. Among live-born infants who actually received their assigned treatment (98.7%), there was a nonsignificant 11% lower neonatal mortality rate among those who were treated with chlorhexidine compared with placebo. Low birth weight infants had a statistically significant 28% reduction in neonatal mortality; there was no significant difference among infants who were born weighing ≥2500 g. After conversion to active treatment in the placebo clusters, there was a 37% reduction in mortality among low birth weight infants in the placebo clusters versus no change in the chlorhexidine clusters. CONCLUSIONS. Newborn skin-wiping with chlorhexidine solution once, soon after birth, reduced neonatal mortality only among low birth weight infants. Evidence from additional trials is needed to determine whether this inexpensive and simple intervention could improve survival significantly among low birth weight infants in settings where home delivery is common and hygiene practices are poor.

Clean birth and postnatal care practices to reduce neonatal deaths from sepsis and tetanus: a systematic review and Delphi estimation of mortality effect

BackgroundAnnually over 520,000 newborns die from neonatal sepsis, and 60,000 more from tetanus. Estimates of the effect of clean birth and postnatal care practices are required for evidence-based program planning.ObjectiveTo review the evidence for clean birth and postnatal care practices and estimate the effect on neonatal mortality from sepsis and tetanus for the Lives Saved Tool (LiST).MethodsWe conducted a systematic review of multiple databases. Data were abstracted into standard tables and assessed by GRADE criteria. Where appropriate, meta-analyses were undertaken. For interventions with low quality evidence but a strong GRADE recommendation, a Delphi process was conducted.ResultsLow quality evidence supports a reduction in all-cause neonatal mortality (19% (95% c.i. 1–34%)), cord infection (30% (95% c.i. 20–39%)) and neonatal tetanus (49% (95% c.i. 35–62%)) with birth attendant handwashing. Very low quality evidence supports a reduction in neonatal tetanus mortality with a clean birth surface (93% (95% c.i. 77-100%)) and no relationship between a clean perineum and tetanus. Low quality evidence supports a reduction of neonatal tetanus with facility birth (68% (95% c.i. 47-88%). No relationship was found between birth place and cord infections or sepsis mortality. For postnatal clean practices, all-cause mortality is reduced with chlorhexidine cord applications in the first 24 hours of life (34% (95% c.i. 5–54%, moderate quality evidence) and antimicrobial cord applications (63% (95% c.i. 41–86%, low quality evidence). One study of postnatal maternal handwashing reported reductions in all-cause mortality (44% (95% c.i. 18–62%)) and cord infection ((24% (95% c.i. 5-40%)).Given the low quality of evidence, a Delphi expert opinion process was undertaken. Thirty experts reached consensus regarding reduction of neonatal sepsis deaths by clean birth practices at home (15% (IQR 10–20)) or in a facility (27% IQR 24–36)), and by clean postnatal care practices (40% (IQR 25–50)). The panel estimated that neonatal tetanus mortality was reduced by clean birth practices at home (30% (IQR(20–30)), or in a facility (38% (IQR 34–40)), and by clean postnatal care practices (40% (IQR 30–50)).ConclusionAccording to expert opinion, clean birth and particularly postnatal care practices are effective in reducing neonatal mortality from sepsis and tetanus. Further research is required regarding optimal implementation strategies.