Neurodevelopmental effects of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children versus HIV-unexposed and uninfected children in Uganda and Malawi: a prospective cohort study

Boivin, Michael J.; Maliwichi, Limbika; Ogwang, Lillian Wambuzi; Kawalazira, Rachel; Sikorskii, Alla; Familiar‐Lopez, Itziar; Kuteesa, Agatha; Nyakato, Mary; Mutebe, Alex; Namukooli, Jackie L; Mallewa, Macpherson; Ruiseñor-Escudero, Horacio; Aizire, Jim; Taha, Taha E.; Fowler, Mary Glenn

doi:10.1016/s2352-3018(19)30083-9

Cited by 47 publications

(67 citation statements)

References 23 publications

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“…Furthermore, mothers were not randomized to ART use or regimen, so it would be difficult to ascertain whether any associations were due to ART or confounding. A recent sub‐analysis from the PROMISE trial, in which mothers were randomized to ART regimens, found that triple antiretroviral use during pregnancy and breastfeeding did not influence neurodevelopmental outcomes through five years of age among CHEU .…”

Section: Discussionmentioning

confidence: 99%

“…At two years of age, a study from Botswana showed expressive language delay and a study from South Africa found receptive and expressive language delay . In contrast, a study from Uganda and Malawi did not find difference in neurodevelopmental outcomes in CHEU compared to CHU aged one to five years . Since the vast majority of CHEU reside in sub‐Saharan Africa, where HIV exposure, undernutrition and poverty overlap and interact, further explorations of neurodevelopment among CHEU are required.…”

Section: Introductionmentioning

confidence: 98%

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Early child development in children who are HIV‐exposed uninfected compared to children who are HIV‐unexposed: observational sub‐study of a cluster‐randomized trial in rural Zimbabwe

et al. 2020

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Introduction Exposure to maternal HIV may affect early child development (ECD), although previous studies have reported heterogeneous findings. We evaluated ECD among children who were HIV‐exposed uninfected (CHEU) and children who were HIV‐unexposed (CHU) recruited to the SHINE trial in rural Zimbabwe. Methods SHINE was a community‐based cluster‐randomized trial of improved infant feeding and/or improved water, sanitation and hygiene. Pregnant women were enrolled between 2012 and 2015. We assessed ECD in a sub‐study at 24 months of age, between 2016 and 2017, using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social development); MacArthur‐Bates Communicative Development Inventory (CDI) (assessing vocabulary and grammar); A‐not‐B test (assessing object permanence); and a self‐control task. Mothers and infants were tested longitudinally for HIV. We used generalized estimating equations to compare ECD scores between CHEU and CHU, accounting for the cluster‐randomized design. Primary results were adjusted for trial‐related factors that could affect measurement reliability of ECD: study nurse, age of child, calendar month of birth, sex and randomized arm. Results A total of 205 CHEU and 1175 CHU were evaluated. Mean total MDAT score was 90.6 (SD 8.7) in CHEU compared to 92.4 (9.1) in CHU (adjusted mean difference −1.3, 95% CI: −2.3, −0.3), driven mostly by differences in gross motor (−0.5, 95% CI: −0.9, −0.2) and language scores (−0.6, 95% CI: −1.1, −0.1). There was evidence that fine motor scores were lower in CHEU (adjusted mean difference −0.4, 95% CI: −0.8, 0.0) but no evidence of a difference in social scores (0.1, 95% CI: −0.2, 0.4). Mean MacArthur‐Bates CDI vocabulary score was 57.9 (SD 19.2) in CHEU compared to 61.3 (18.8) in CHU (adjusted mean difference −2.9 words, 95% CI: −5.7, −0.1). Object permanence and self‐control scores were similar between groups. Conclusions CHEU in rural Zimbabwe had total child development and vocabulary scores that were approximately 0.15 standard deviations lower than CHU at two years of age. More detailed and specific studies are now needed to unravel the reasons for developmental delay in CHEU and the likelihood that these delays persist in the longer term.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Early child development in children who are HIV‐exposed uninfected compared to children who are HIV‐unexposed: observational sub‐study of a cluster‐randomized trial in rural Zimbabwe

et al. 2020

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“…This result was unexpected given that studies elsewhere have reported similar neurodevelopment progression in HEU children as seen in their unexposed counterparts [16,18,45]. However, cases of poor neurodevelopment in HEU children have also been reported, with ART exposure implicated as the likely contributing factor [15,[46][47][48]. These inconsistent findings may be attributed to the heterogeneity of regimens and ART treatment guidelines used in different studies, and over time.…”

Section: Discussionmentioning

confidence: 81%

Neurodevelopment of HIV-exposed uninfected children in Cape Town, South Africa

et al. 2020

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Background Evidence shows that antiretroviral (ART) exposure is associated with neurodevelopmental delays in human immunodeficiency virus (HIV)-exposed uninfected (HEU) children. However, there are few insights into modifiable maternal and child factors that may play a role in improving neurodevelopment in HEU children. We used a parent-centric neurodevelopment tool, Ages & Stages Questionnaire (ASQ) to examined neurodevelopment in HEU children at 12–24 months of age, and associations with maternal and child factors. Methods 505 HIV-infected women (initiated ART pre- or during pregnancy) with live singleton births attending primary health care were enrolled; 355 of their HEU children were assessed for neurodevelopment (gross motor, fine motor, communication, problem solving and personal-social domains) at 12–24 months using age-specific ASQ administered by a trained fieldworker. Associations with maternal and child factors were examined using logistic regression models. Results Among mothers (median age 30 years, IQR, 26–34), 52% initiated ART during pregnancy; the median CD4 count was 436 cells/μl (IQR, 305–604). Most delayed neurodevelopment in HEU children was in gross (9%) and fine motor (5%) functions. In adjusted models, maternal socio-economic status (aOR 0.42, 95% CI 0.24–0.76) was associated with reduced odds of delayed gross-fine motor neurodevelopment. Maternal age ≥35 years (aOR 0.22, 95% CI 0.05–0.89) and maternal body mass index (BMI) <18.5 (aOR 6.76, 95% CI 1.06–43.13) were associated with delayed communication-problem-solving-personal-social neurodevelopment. There were no differences in odds for either domain by maternal ART initiation timing. Conclusions Delayed neurodevelopment was detected in both gross and fine motor functions in this cohort of HEU children, with strong maternal predictors that may be explored as potentially modifiable factors associated with neurodevelopment at one to two years of age.

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“…Thus, varying rates of ART usage and specific drug agents in different populations are another potential explanation for mixed findings in the literature. In fact, a recently published study of RCT data from Malawi and Uganda by Boivin et al (2019) even suggests that mothers being maintained on triple ART pre-and post-partum may be protective for CHEU development, while less intensive treatment regimens result in poorer outcomes. However, in our study, in which only early therapies (primarily Neviripine alone) were available to participants, we still observed no differences in development between the CHEU and CHUU groups.…”

Section: Discussionmentioning

confidence: 99%

“…The KABC-II is designed for children ages 3-18. It was chosen for its demonstrated reliability and crosscultural functionality, including use in other African countries and pilot testing results of the isiZulu language version in South Africa (Kaufman & Kaufman, 2004;Ajayi et al 2017a;Debeaudrap et al, 2018;Boivin et al, 2018Boivin et al, , 2019.…”

Section: Methodsmentioning

confidence: 99%

Cognitive and Language Development at Age 4–6 Years in Children HIV‐Exposed But Uninfected Compared to Those HIV‐Unexposed and to Children Living With HIV

Gruver

Kvalsvig

Knox

et al. 2020

New Directions for Child and Adolescent Development

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Perinatal HIV infection is associated with delayed neurocognitive development, but less is known about children perinatally HIV‐exposed but uninfected (CHEU). We compared cognitive and language outcomes in 4–6‐year old CHEU versus children HIV‐unexposed and uninfected (CHUU) and children living with HIV (CLHIV). We enrolled 1,581 children (77% of the child population) in five communities in KwaZulu‐Natal, South Africa. Children completed: Grover‐Counter Scale of cognitive development, sub‐scales of the Kaufman Assessment Battery for Children, Reynell Developmental Language Scales. HIV status of children and primary caregivers was determined by repeated rapid tests or report of prior testing. We conducted a cross‐sectional multivariable linear regression on 922 dyads with complete data (257 CHEU, 627 CHUU, 38 CLHIV). On all outcome measures, CHEU and CHUU groups had comparable scores; CLHIV scored significantly lower. Emerging global progress toward the elimination of vertical HIV transmission may not only reduce mortality, but also positively impact child development.

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Neurodevelopmental effects of ante-partum and post-partum antiretroviral exposure in HIV-exposed and uninfected children versus HIV-unexposed and uninfected children in Uganda and Malawi: a prospective cohort study

Cited by 47 publications

References 23 publications

Early child development in children who are HIV‐exposed uninfected compared to children who are HIV‐unexposed: observational sub‐study of a cluster‐randomized trial in rural Zimbabwe

Early child development in children who are HIV‐exposed uninfected compared to children who are HIV‐unexposed: observational sub‐study of a cluster‐randomized trial in rural Zimbabwe

Neurodevelopment of HIV-exposed uninfected children in Cape Town, South Africa

Cognitive and Language Development at Age 4–6 Years in Children HIV‐Exposed But Uninfected Compared to Those HIV‐Unexposed and to Children Living With HIV

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