Neurodevelopment of breastfed HIV-exposed uninfected and HIV-unexposed children in South Africa

Abstract

Objectives: To assess neurodevelopment of breastfed HIV-exposed uninfected (HEU) and breastfed HIV-unexposed children in the context of universal maternal antiretroviral therapy (ART).

Design: Prospective study with antenatal enrolment and follow-up of breastfeeding HEU and HIV-unexposed mother-infant pairs through 12-18 months postpartum.

Setting: Peri-urban community, Cape Town, South Africa.

Participants: HEU (n = 215) and HIV-unexposed (n = 306) children.

Main outcome measures: Cognitive, motor and language development at median 13 (interquartile range 12-14) months of age: continuous and dichotomous Bayley Scales of Infant and Toddler Development Third Edition (delay defined as composite score <85).

Results: Incidence of preterm delivery (<37 weeks) was similar among HEU and HIV-unexposed children (11 vs. 9%, P = 0.31; median gestation 39 weeks); 48% were boys. Median breastfeeding duration was shorter among HEU vs. HIV-unexposed children (6 vs. 10 months). All HIV-infected mothers initiated lifelong ART (tenofovir-emtricitabine-efavirenz) antenatally. HEU (vs. HIV-unexposed) children had higher odds of cognitive delay [odds ratio (OR) 2.28 (95% confidence interval (CI) 1.13-4.60)] and motor delay [OR 2.10 (95% CI 1.03-4.28)], but not language delay, in crude and adjusted analysis. Preterm delivery modified this relationship for motor development: compared with term HIV-unexposed children, term HEU children had similar odds of delay, preterm HIV-unexposed children had five-fold increased odds of delay (adjusted OR 4.73, 95% CI 1.32; 16.91) and preterm HEU children, 16-fold increased odds of delay (adjusted OR 16.35, 95% CI 5.19; 51.54).

Conclusion: Young HEU children may be at increased risk for cognitive and motor delay despite universal maternal ART and breastfeeding; those born preterm may be particularly vulnerable.

FIGURE 1.. Study flow diagram

FIGURE 2.. Forest plots of adjusted odds ratios for developmental delay (BSID-III composite scores <85) by maternal HIV status and preterm delivery with term HIV-unexposed children as reference category across (a) cognitive, (b) motor and (c) language domains

(a) Adjusted OR (95% CI) for cognitive delay in term HIV-exposed uninfected children, 2.52 (1.09; 5.83); preterm HIV-unexposed children, 3.30 (0.85; 12.78); and preterm HIV-exposed uninfected children, 8.25 (2.69; 25.28) [Reference group, term HIV-unexposed children; model adjusted for maternal education, intimate partner violence, risky drinking, infant size (small-for-gestational-age) and duration of breastfeeding; p-value for interaction = 0.15] (b). Adjusted OR (95% CI) for motor delay in term HIV-exposed uninfected children, 1.17 (0.45; 3.07); preterm HIV-unexposed children, 4.73 (1.32; 16.91); and preterm HIV-exposed uninfected children, 16.35 (5.19; 51.54) [Reference group, term HIV-unexposed children; model adjusted for maternal education, housing, intimate partner violence, risky drinking, infant size (small-for-gestational-age) and duration of breastfeeding; p-value for interaction = 0.07] (c). Adjusted OR (95% CI) for language delay in term HIV-exposed uninfected children, 1.14 (0.65; 1.98); preterm HIV-unexposed children, 2.49 (1.00; 6.29); and preterm HIV-exposed uninfected children, 0.65 (0.18; 2.37). [Reference group, term HIV-unexposed children; model adjusted for maternal education, maternal age, intimate partner violence, risky drinking, infant size (small-for-gestational-age) and duration of breastfeeding; p-value for interaction = 0.04]

FIGURE 2.. Forest plots of adjusted odds ratios for developmental delay (BSID-III composite scores <85) by maternal HIV status and preterm delivery with term HIV-unexposed children as reference category across (a) cognitive, (b) motor and (c) language domains

(a) Adjusted OR (95% CI) for cognitive delay in term HIV-exposed uninfected children, 2.52 (1.09; 5.83); preterm HIV-unexposed children, 3.30 (0.85; 12.78); and preterm HIV-exposed uninfected children, 8.25 (2.69; 25.28) [Reference group, term HIV-unexposed children; model adjusted for maternal education, intimate partner violence, risky drinking, infant size (small-for-gestational-age) and duration of breastfeeding; p-value for interaction = 0.15] (b). Adjusted OR (95% CI) for motor delay in term HIV-exposed uninfected children, 1.17 (0.45; 3.07); preterm HIV-unexposed children, 4.73 (1.32; 16.91); and preterm HIV-exposed uninfected children, 16.35 (5.19; 51.54) [Reference group, term HIV-unexposed children; model adjusted for maternal education, housing, intimate partner violence, risky drinking, infant size (small-for-gestational-age) and duration of breastfeeding; p-value for interaction = 0.07] (c). Adjusted OR (95% CI) for language delay in term HIV-exposed uninfected children, 1.14 (0.65; 1.98); preterm HIV-unexposed children, 2.49 (1.00; 6.29); and preterm HIV-exposed uninfected children, 0.65 (0.18; 2.37). [Reference group, term HIV-unexposed children; model adjusted for maternal education, maternal age, intimate partner violence, risky drinking, infant size (small-for-gestational-age) and duration of breastfeeding; p-value for interaction = 0.04]

FIGURE 2.. Forest plots of adjusted odds ratios for developmental delay (BSID-III composite scores <85) by maternal HIV status and preterm delivery with term HIV-unexposed children as reference category across (a) cognitive, (b) motor and (c) language domains

(a) Adjusted OR (95% CI) for cognitive delay in term HIV-exposed uninfected children, 2.52 (1.09; 5.83); preterm HIV-unexposed children, 3.30 (0.85; 12.78); and preterm HIV-exposed uninfected children, 8.25 (2.69; 25.28) [Reference group, term HIV-unexposed children; model adjusted for maternal education, intimate partner violence, risky drinking, infant size (small-for-gestational-age) and duration of breastfeeding; p-value for interaction = 0.15] (b). Adjusted OR (95% CI) for motor delay in term HIV-exposed uninfected children, 1.17 (0.45; 3.07); preterm HIV-unexposed children, 4.73 (1.32; 16.91); and preterm HIV-exposed uninfected children, 16.35 (5.19; 51.54) [Reference group, term HIV-unexposed children; model adjusted for maternal education, housing, intimate partner violence, risky drinking, infant size (small-for-gestational-age) and duration of breastfeeding; p-value for interaction = 0.07] (c). Adjusted OR (95% CI) for language delay in term HIV-exposed uninfected children, 1.14 (0.65; 1.98); preterm HIV-unexposed children, 2.49 (1.00; 6.29); and preterm HIV-exposed uninfected children, 0.65 (0.18; 2.37). [Reference group, term HIV-unexposed children; model adjusted for maternal education, maternal age, intimate partner violence, risky drinking, infant size (small-for-gestational-age) and duration of breastfeeding; p-value for interaction = 0.04]