Stunting Mediates the Association between Small-for-Gestational-Age and Postneonatal Mortality123

Background: In sub-Saharan Africa, one-third of all births are small for gestational age (SGA), and 4.4 million children are stunted; both conditions increase the risk of child mortality. SGA has also been shown to increase the risk of stunting. Objective: We tested whether the association between SGA and postneonatal mortality is mediated by stunting. Methods: We used longitudinal data from children aged 6 wk to 24 mo (n = 12,155) enrolled in the ZVITAMBO (Zimbabwe Vitamin A for Mothers and Babies) trial. HIV exposure was defined based on maternal HIV status at baseline. SGA was defined as birthweight <10th percentile of the INTERGROWTH-21st (International Fetal and Newborn Growth Consortium for the 21st Century) standards. We used a standard mediation approach by comparing the attenuation of the risk when the mediator was added to the model. We used Cox proportional hazards models first to regress SGA on postneonatal mortality, controlling for age. Stunting (length-for-age z score <−2) was then included in the model to test mediation. Results: Approximately 20% of children were term SGA, and 23% were stunted before their last follow-up visit. In this cohort, 31% of children were exposed to HIV; the HIV-exposed group represented a pooled group of HIV-infected and HIV-exposed but uninfected children. Postneonatal mortality was significantly higher among children born SGA (HR: 1.5; 95% CI: 1.3, 1.7). This association was attenuated and not statistically significant when stunting was included in the model, suggesting a mediation effect (HR: 1.1; 95% CI: 0.91, 1.3). When stratified by HIV exposure status, we observed a significant attenuation of the risk, suggesting mediation, only among HIV-exposed children (model 1, HR: 1.3; 95% CI: 1.1, 1.6; model 2, HR: 1.1; 95% CI: 0.88, 1.3). Conclusions: This analysis aids in investigating pathways that underlie an observed SGA-mortality relation and may inform survival interventions in undernourished settings.

[1]  W. Fawzi,et al.  Linear Growth Faltering Among HIV-Exposed Uninfected Children , 2016, Journal of acquired immune deficiency syndromes.

[2]  C. Evans,et al.  HIV-Exposed Uninfected Infants in Zimbabwe: Insights into Health Outcomes in the Pre-Antiretroviral Therapy Era , 2016, Front. Immunol..

[3]  T. Fenton,et al.  INTERGROWTH-21st very preterm size at birth reference charts , 2016, The Lancet.

[4]  José Villar,et al.  International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project , 2014, The Lancet.

[5]  M. Tchuente,et al.  Low Birth Weight in Perinatally HIV-Exposed Uninfected Infants: Observations in Urban Settings in Cameroon , 2014, PloS one.

[6]  Jean H Humphrey,et al.  The stunting syndrome in developing countries , 2014, Paediatrics and international child health.

[7]  L. Moulton,et al.  Stunting Is Characterized by Chronic Inflammation in Zimbabwean Infants , 2014, PloS one.

[8]  W. Fawzi,et al.  Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries. , 2013, International journal of epidemiology.

[9]  R. Martorell,et al.  Maternal and child undernutrition and overweight in low-income and middle-income countries , 2013, The Lancet.

[10]  W. Fawzi,et al.  Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis , 2013, The Lancet.

[11]  Ayesha Sania,et al.  National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010 , 2013, The Lancet. Global health.

[12]  W. Fawzi,et al.  Associations of Suboptimal Growth with All-Cause and Cause-Specific Mortality in Children under Five Years: A Pooled Analysis of Ten Prospective Studies , 2013, PloS one.

[13]  A. Elliott,et al.  Maternal HIV infection and other factors associated with growth outcomes of HIV-uninfected infants in Entebbe, Uganda , 2013, Public Health Nutrition.

[14]  Linda Valeri,et al.  Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. , 2013, Psychological methods.

[15]  C. Victora,et al.  Worldwide Timing of Growth Faltering: Revisiting Implications for Interventions , 2010, Pediatrics.

[16]  K. Dewey,et al.  Systematic review of the efficacy and effectiveness of complementary feeding interventions in developing countries. , 2008, Maternal & child nutrition.

[17]  Robert E Black,et al.  What works? Interventions for maternal and child undernutrition and survival , 2008, The Lancet.

[18]  L. Moulton,et al.  Child Mortality According to Maternal and Infant HIV Status in Zimbabwe , 2007, The Pediatric infectious disease journal.

[19]  J. Hargrove,et al.  HIV incidence among post-partum women in Zimbabwe: risk factors and the effect of vitamin A supplementation , 2006, AIDS.

[20]  Mercedes Onis,et al.  WHO Child Growth Standards based on length/height, weight and age , 2006, Acta paediatrica (Oslo, Norway : 1992). Supplement.

[21]  L. Moulton,et al.  Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. , 2006, The Journal of infectious diseases.

[22]  A. Brotherton,et al.  Principles of nutritional assessment , 2006 .

[23]  L. Moulton,et al.  Effect of postpartum maternal or neonatal vitamin A supplementation on infant mortality among infants born to HIV-negative mothers in Zimbabwe. , 2005, The American journal of clinical nutrition.

[24]  R. Bailey,et al.  Growth of children according to maternal and child HIV, immunological and disease characteristics: a prospective cohort study in Kinshasa, Democratic Republic of Congo. , 1999, International journal of epidemiology.

[25]  L. Adair,et al.  Age-specific determinants of stunting in Filipino children. , 1997, The Journal of nutrition.

[26]  R. Yolken,et al.  Longitudinal growth during the first 2 years of life in children born to HIV-infected mothers in Malawi, Africa. , 1996, Pediatric AIDS and HIV infection.

[27]  D. A. Kenny,et al.  Process Analysis , 1981, Plastics Process Analysis, Instrumentation, and Control.