Early neurodevelopment of HIV-exposed uninfected children in the era of antiretroviral therapy: a systematic review and meta-analysis

Abstract

Background: There are 15·4 million children who are HIV-exposed and uninfected worldwide. Early child development crucially influences later academic and socioeconomic factors. However, the neurodevelopmental outcomes of HIV-exposed uninfected (HEU) children in the era of maternal antiretroviral therapy (ART) remain unclear. We aimed to examine the effects of in-utero exposure to HIV and ART on child neurodevelopment.

Methods: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, Africa-Wide Information, PsycInfo, and Global Health databases from inception to May 27, 2020, for studies from the past two decades reporting neurodevelopment of HEU children aged 0-5 years compared with HIV-unexposed (HU) children (aim 1), and effects of different maternal ART regimens on neurodevelopment of HEU children (aim 2). We did narrative syntheses for both aims, and a random-effects meta-analysis of high-quality studies comparing HEU children and HU children, to obtain weighted pooled estimates of effect sizes. This study was registered with PROSPERO, CRD42018075910.

Findings: We screened 35 527 records and included 45 articles from 31 studies. Overall, 12 (57%) of 21 studies comparing HEU children and HU children found worse neurodevelopment in HEU children in at least one domain. Study design and methodological quality were variable, with heterogeneity across populations. Meta-analysis included eight high-quality studies comparing 1856 HEU children with 3067 HU children at ages 12-24 months; among HEU children with available data, 1709 (99%) of 1732 were exposed to ART. HEU children had poorer expressive language (effect size -0·17 [95% CI -0·27 to -0·07], p=0·0013) and gross motor function (-0·13 [-0·20 to -0·07], p<0·0001) than HU children, but similar cognitive development (-0·06 [-0·19 to 0·06], p=0·34), receptive language development (-0·10 [-0·23 to 0·03], p=0·14), and fine motor skills (-0·05 [-0·15 to 0·06], p=0·36). Results suggested little or no evidence of an effect of specific maternal ART regimens on neurodevelopment; study heterogeneity prevented meta-analysis.

Interpretation: HEU children are at risk of subtle impairments in expressive language and gross motor development by age 2 years. We found no consistent effect of maternal ART regimens analysed, although evidence was scarce. We highlight the need for large high-quality longitudinal studies to assess the neurodevelopmental trajectories of HEU children and to investigate underlying mechanisms to inform intervention strategies.

Funding: Wellcome Trust and Medical Research Council.

Figure 1

Study selection At the record screening stage, the main categories for excluding records were: (1) population: age range over 5 years; (2) exposure: not examining HIV-exposed uninfected children or only reporting on children living with HIV; and (3) outcome: no neurodevelopment outcomes. Of the total number of reports included (n=45), five contributed results for the primary and secondary outcomes of the first aim, one contributed results for the primary and secondary outcomes of the second aim, and four contributed results for the primary outcomes of both aims (appendix p 18). ART=antiretroviral therapy.

Figure 2

Neurodevelopment of HEU children compared with HU children CD=cognitive development. LD=language development. MD=motor development. AB=adaptive behaviour. SEB=social-emotional behaviour. HEU=HIV-exposed uninfected. HU=HIV-unexposed. ADBB=Alarm Distress Baby Scale. BINS=Bayley Infant Neurodevelopmental Screener. BSID-II=Bayley Scales of Infant and Toddler Development 2nd edition. BSID-III=Bayley Scales of Infant and Toddler Development 3rd edition. CDI=MacArthur-Bates Communicative Development Inventories. DDST-II=Denver Developmental Screening Test 2nd edition. DMC=Developmental Milestones Checklist. FSDQ=Full-Scale Developmental Quotient. GMDS=Griffiths Mental Development Scales. KABC-II=Kaufman Assessment Battery for Children 2nd edition. MDAT=Malawi Developmental Assessment Tool. MSEL=Mullen Scales of Early Learning. PDMS=Peabody Developmental Motor Scales. RITLS=Rossetti Infant-Toddler Language Scale. SDQ=Strengths and Difficulties Questionnaire. SONR=Snijders-Oomen Nonverbal Intelligence Test. VABS=Vineland Adaptive Behaviour Scales. Beery-VMI=Beery Buktenica Test of Visual Motor Integration. *Where the number differed across domains, the highest number is listed. †Where BSID-III composite scores are reported for language and motor development or BSID-II mental development index was used to reflect cognitive and language development; separately, where applicable, cognitive development was assessed using the MSEL cognitive composite score, MDAT total score, or GMDS general quotient. ‡Unadjusted analysis outcomes defined by statistical significance of p<0·05 or through 95% CIs in group comparisons of the mean or comparison of delay where applicable. §Age is given as 12 months if median age of assessment fell within 1 month of this time-point (appendix pp 19–20). ¶Delay reported here; on analysis of mean scores, Le Roux and colleagues reported no significant group differences in mean scores; Wedderburn and colleagues reported HEU children had lower receptive and expressive language scores than HU children in both unadjusted and adjusted analyses, and lower cognitive scores on unadjusted analysis. ||BSID-II differences at 6 and 18 months only, DDST differences at 6 months. **On analysis of adverse outcomes, HEU children had significantly more expressive language adverse outcomes than HU children on unadjusted and adjusted analyses. ††Studies included as median age within age range.

Figure 2

Neurodevelopment of HEU children compared with HU children CD=cognitive development. LD=language development. MD=motor development. AB=adaptive behaviour. SEB=social-emotional behaviour. HEU=HIV-exposed uninfected. HU=HIV-unexposed. ADBB=Alarm Distress Baby Scale. BINS=Bayley Infant Neurodevelopmental Screener. BSID-II=Bayley Scales of Infant and Toddler Development 2nd edition. BSID-III=Bayley Scales of Infant and Toddler Development 3rd edition. CDI=MacArthur-Bates Communicative Development Inventories. DDST-II=Denver Developmental Screening Test 2nd edition. DMC=Developmental Milestones Checklist. FSDQ=Full-Scale Developmental Quotient. GMDS=Griffiths Mental Development Scales. KABC-II=Kaufman Assessment Battery for Children 2nd edition. MDAT=Malawi Developmental Assessment Tool. MSEL=Mullen Scales of Early Learning. PDMS=Peabody Developmental Motor Scales. RITLS=Rossetti Infant-Toddler Language Scale. SDQ=Strengths and Difficulties Questionnaire. SONR=Snijders-Oomen Nonverbal Intelligence Test. VABS=Vineland Adaptive Behaviour Scales. Beery-VMI=Beery Buktenica Test of Visual Motor Integration. *Where the number differed across domains, the highest number is listed. †Where BSID-III composite scores are reported for language and motor development or BSID-II mental development index was used to reflect cognitive and language development; separately, where applicable, cognitive development was assessed using the MSEL cognitive composite score, MDAT total score, or GMDS general quotient. ‡Unadjusted analysis outcomes defined by statistical significance of p<0·05 or through 95% CIs in group comparisons of the mean or comparison of delay where applicable. §Age is given as 12 months if median age of assessment fell within 1 month of this time-point (appendix pp 19–20). ¶Delay reported here; on analysis of mean scores, Le Roux and colleagues reported no significant group differences in mean scores; Wedderburn and colleagues reported HEU children had lower receptive and expressive language scores than HU children in both unadjusted and adjusted analyses, and lower cognitive scores on unadjusted analysis. ||BSID-II differences at 6 and 18 months only, DDST differences at 6 months. **On analysis of adverse outcomes, HEU children had significantly more expressive language adverse outcomes than HU children on unadjusted and adjusted analyses. ††Studies included as median age within age range.

Figure 3

Forest plots of neurodevelopmental outcomes of HEU children compared with HU children included in the meta-analysis HEU=HIV-exposed uninfected. HU=HIV-unexposed.

Figure 4

Differences in neurodevelopment of HIV-exposed uninfected children by maternal ART CD=cognitive development. LD=language development. MD=motor development. AB=adaptive behaviour. SEB=social-emotional behaviour. HEU=HIV-exposed uninfected. HU=HIV-unexposed. ART=antiretroviral therapy. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor. PI=protease inhibitor. ASQ=Ages & Stages Questionnaire. BSID-III=Bayley Scales of Infant & Toddler Development 3rd edition. CDI=MacArthur-Bates Communicative Development Inventories. DASII=Development Assessment Scale for Indian Infants. DMC=Developmental Milestones Checklist. GFTA=Goldman-Fristoe Test of Articulation. KABC-II=Kaufman Assessment Battery for Children 2nd edition. MSEL=Mullen Scales of Early Learning. PPVT-3=Peabody Picture Vocabulary Test 3rd edition. PSED=Personal, Social and Emotional Development. TELD-3=Test of Early Language Development 3rd edition. VABS=Vineland Adaptive Behaviour Scales. VMI=Visual Motor Integration. WPPSI=Wechsler Preschool and Primary Scale of Intelligence. cART=combination ART defined in the SMARTT cohort as three or more drugs from two or more antiretroviral classes. *Number (n) given refers to the first visit in studies with multiple time-points, unless otherwise stated; group numbers differ across domains and ages and where multiple different drugs were assessed. †Unadjusted analysis outcomes defined by statistical significance of p<0·05 or through 95% CIs in group comparisons of the mean or comparison of delay where applicable. Where unadjusted analyses were not reported, adjusted analyses are presented instead. ‡These studies also had HU child groups; see figure 2. §Age is given as 12 months if median age of assessment fell within 1 month of this timepoint (appendix pp 23–24). ¶At age 4 years, MSEL cognitive composite scores were higher for children of mothers on antenatal and postnatal triple ART versus children of mothers not on triple ART consistently. ||Kacanek and colleagues regimen: abacavir/zidovudine/lamivudine versus lopinavir–ritonavir/zidovudine/lamivudine; Alcaide and colleagues and Cassidy and colleagues efavirenz regimens: efavirenz/tenofovir/emtricitabine. **Stratified results for the age-point over 5 years are not presented due to review inclusion criteria. ††Multiple individual drugs assessed. At age 12 months, atazanavir increased odds of late language emergence (especially started in 2nd and 3rd trimester). Saquinavir had a similar effect although significance was lost on sensitivity analyses. Other drugs did not have significant associations. ‡‡Conception and 1st trimester efavirenz exposure worse that 2nd and 3rd trimester. §§Language impairment assigned as receptive language; speech impairment assigned as expressive language.

Figure 4

Differences in neurodevelopment of HIV-exposed uninfected children by maternal ART CD=cognitive development. LD=language development. MD=motor development. AB=adaptive behaviour. SEB=social-emotional behaviour. HEU=HIV-exposed uninfected. HU=HIV-unexposed. ART=antiretroviral therapy. NNRTI=non-nucleoside reverse transcriptase inhibitor. NRTI=nucleoside reverse transcriptase inhibitor. PI=protease inhibitor. ASQ=Ages & Stages Questionnaire. BSID-III=Bayley Scales of Infant & Toddler Development 3rd edition. CDI=MacArthur-Bates Communicative Development Inventories. DASII=Development Assessment Scale for Indian Infants. DMC=Developmental Milestones Checklist. GFTA=Goldman-Fristoe Test of Articulation. KABC-II=Kaufman Assessment Battery for Children 2nd edition. MSEL=Mullen Scales of Early Learning. PPVT-3=Peabody Picture Vocabulary Test 3rd edition. PSED=Personal, Social and Emotional Development. TELD-3=Test of Early Language Development 3rd edition. VABS=Vineland Adaptive Behaviour Scales. VMI=Visual Motor Integration. WPPSI=Wechsler Preschool and Primary Scale of Intelligence. cART=combination ART defined in the SMARTT cohort as three or more drugs from two or more antiretroviral classes. *Number (n) given refers to the first visit in studies with multiple time-points, unless otherwise stated; group numbers differ across domains and ages and where multiple different drugs were assessed. †Unadjusted analysis outcomes defined by statistical significance of p<0·05 or through 95% CIs in group comparisons of the mean or comparison of delay where applicable. Where unadjusted analyses were not reported, adjusted analyses are presented instead. ‡These studies also had HU child groups; see figure 2. §Age is given as 12 months if median age of assessment fell within 1 month of this timepoint (appendix pp 23–24). ¶At age 4 years, MSEL cognitive composite scores were higher for children of mothers on antenatal and postnatal triple ART versus children of mothers not on triple ART consistently. ||Kacanek and colleagues regimen: abacavir/zidovudine/lamivudine versus lopinavir–ritonavir/zidovudine/lamivudine; Alcaide and colleagues and Cassidy and colleagues efavirenz regimens: efavirenz/tenofovir/emtricitabine. **Stratified results for the age-point over 5 years are not presented due to review inclusion criteria. ††Multiple individual drugs assessed. At age 12 months, atazanavir increased odds of late language emergence (especially started in 2nd and 3rd trimester). Saquinavir had a similar effect although significance was lost on sensitivity analyses. Other drugs did not have significant associations. ‡‡Conception and 1st trimester efavirenz exposure worse that 2nd and 3rd trimester. §§Language impairment assigned as receptive language; speech impairment assigned as expressive language.