Growth and neurodevelopmental outcomes of children with in utero growth restriction due to placental insufficiency and modification by maternal HIV status

Abstract

Background: South Africa is burdened with a high prevalence of HIV infection in pregnant women (30.0%). Nevertheless, access to antiretroviral therapy (ART) has greatly increased, leading to an expanding population of HIV-exposed-uninfected children (CHEU). Adverse birth outcomes, including intrauterine growth restriction (IUGR), have been documented in women living with HIV, even when on ART. Child HIV exposure, anaemia and IUGR due to placental insufficiency carry significant risks to early child growth and neurodevelopment. This study determined and compared growth and neurodevelopmental outcomes, micronutrient intakes, and anaemia in CHEU compared to a control group of HIV-unexposed-uninfected children (CHUU) stratified by history of placental insufficiency. Methods: An abnormal umbilical artery resistance index (UmA-RI) on pregnancy Doppler ultrasound was used to detect placental insufficiency as a proxy for IUGR. The cross-sectional study investigated 271 mother-child pairs at 18-months postnatal, grouped into four subgroups: CHUU with normal UmA-RI (CHUU/N-RI; control group), CHEU with normal UmA-RI (CHEU/N-RI; single exposure), CHUU with abnormal UmA-RI (CHUU/AbN-RI; single exposure) and CHEU with abnormal UmA-RI (CHEU/AbN-RI; double exposure). Pregnancy and birth information was available. World Health Organisation standard procedures were followed to collect anthropometric data and compute z-scores. International Guide for Monitoring Child Development (GMCD) was used for developmental screening, and Bayley Scale of Infant and Toddler Development III (Bayley-III) was used to test for cognitive, language and motor development. Premature births were corrected for gestational age. Previously used questionnaires and quantified 24-hour dietary recall were used to collect sociodemographic variables and dietary intake. FoodFinder™ 3.0 was used for meal analysis, quantifying dietary intake of iron, zinc, and iodine. Both maternal and children's haemoglobin concentrations were tested using HemoCue® Hb 201+. Comparisons were performed using independent t-test and Mann-Whitney U test. Spearman’s correlation and regression models were used to determine associations. Results: Lower length-for-age z-scores (LAZ) were observed in CHEU than CHUU ( 0.71±1.23 vs 0.05±1.32; p=0.004), and children who had abnormal UmA-RI than normal counterparts ( 0.68±1.53 vs 0.14±1.29; p<0.001). CHEU/AbN-RI had the lowest LAZ compared to CHUU/N-RI ( 1.3±1.3 vs 0.03±1.30; p<0.001). The prevalence of stunting (LAZ < 2) was higher in CHEU/AbN-RI (40.0%) and CHEU/N-RI (16.0%) than in CHUU/N-RI (4.8%); p<0.001 and p=0.016, respectively. GMCD screening indicated a concern for delay in gross motor development among 21.4% of CHEU/AbN-RI. Bayley-III test demonstrated lower mean cognitive scores in CHEU/AbN-RI compared to CHUU/N-RI: 93.9±12.9 vs 100.0±10.6; p=0.045, with 21.4% of CHEU/AbN-RI having mild delay in cognitive development. Further, zinc intake and weight-for-age z-scores were positively associated with language (r=0.10; p=0.042) and motor (r=0.10; p=0.028) development, respectively. Above one-third of children were mildly anaemic: CHUU/N-RI: 44.4%, CHEU/N-RI: 44.7%, CHUU/AbN-RI: 40.0% and CHEU/AbN-RI: 33.3%. In the CHEU group, maternal haemoglobin concentrations were associated with child haemoglobin concentrations: β=0.19, 95% confidence interval (CI) (0.02,0.36); p=0.028. There was no evidence to suggest an association between maternal or child haemoglobin concentration and child neurodevelopment. On further analysis cognitive development was positively associated with LAZ: β=3.34, 95%CI (1.13,5.54), P=0.004 in the CHEU group. Conclusion: Maternal HIV exposure and placental insufficiency are risk factors for stunting and cognitive deficits, both independently and compounded. CHEU and children who had IUGR are a high-risk population in need of identification and appropriate interventions within child health and nutrition-sensitive programmes. Childhood anaemia remains a paramount public health concern.