Children of a syndemic: co-occurring and mutually reinforcing adverse child health exposures in a prospective cohort of HIV-affected mother-infant dyads in Cape Town, South Africa.

INTRODUCTION: Several HIV-related syndemics have been described among adults. We investigated syndemic vulnerability to hazardous drinking (HD), intimate partner violence (IPV) and household food insecurity (HFIS) in breastfed children born without HIV in urban South Africa. We compared those who were perinatally HIV exposed (CHEU) to those who were not (CHU), under conditions of universal maternal antiretroviral therapy (ART) and breastfeeding. METHODS: A prospective cohort of pregnant women living with HIV (WLHIV), and without HIV, were enrolled and followed with their infants for 12 months postpartum (2013-2017). All WLHIV initiated antenatal efavirenz-based ART. Measurements of growth (∼3 monthly), infectious cause hospitalisation, ambulatory childhood illness (2-week recall) and neurodevelopment (BSID-III, measured at ∼12 months' age) were compared across bio-social strata using generalised linear regression models, with interaction terms; maternal data included interview-based measures for HD (AUDIT-C), IPV (WHO VAW) and HFIS. RESULTS: Among 872 breastfeeding mother-infant pairs (n = 461 CHEU, n = 411 CHU), WLHIV (vs. HIV negative) reported more unemployment (279/461, 60% vs. 217/411, 53%; p = 0.02), incomplete secondary education (347/461, 75% vs. 227/411, 55%; p < 0.0001), HD (25%, 117/459 vs. 7%, 30/411; p < 0.0001) and IPV (22%, 101/457 vs. 8%, 32/411; p < 0.0001) at enrolment; and HFIS at 12 months (45%, 172/386 vs. 30%, 105/352; p > 0.0001). There were positive interactions between maternal HIV and other characteristics. Compared to food secure CHU, the mean difference (95% CI) in weight-for-age Z-score (WAZ) was 0.06 (-0.14; 0.25) for food insecure CHU; -0.26 (-0.42; -0.10) for food secure CHEU; and -0.43 (-0.61; -0.25), for food insecure CHEU. Results were similar for underweight (WAZ < -2), infectious-cause hospitalisation, cognitive and motor delay. HIV-IPV interactions were evident for ambulatory diarrhoea and motor delay. There were HIV-HD interactions for odds of underweight, stunting, cognitive and motor delay. Compared to HD-unexposed CHU, the odds ratios (95% CI) of underweight were 2.31 (1.11; 4.82) for HD-exposed CHU; 3.57 (0.84; 15.13) for HD-unexposed CHEU and 6.01 (2.22; 16.22) for HD-exposed CHEU. CONCLUSIONS: These data suggest that maternal HIV-related syndemics may partly drive excess CHEU health risks, highlighting an urgent need for holistic maternal and family care and support alongside ART to optimise the health of CHEU.

Cost-effectiveness of point-of-care versus centralised, laboratory-based nucleic acid testing for diagnosis of HIV in infants: a systematic review of modelling studies.

BACKGROUND: Point-of-care (POC) nucleic acid testing for diagnosis of HIV in infants facilitates earlier initiation of antiretroviral therapy (ART) than with centralised (standard-of-care, SOC) testing, but can be more expensive. We evaluated cost-effectiveness data from mathematical models comparing POC with SOC to provide global policy guidance. METHODS: In this systematic review of modelling studies, we searched PubMed, MEDLINE, Embase, the National Health Service Economic Evaluation Database, Econlit, and conference abstracts, combining terms for "HIV" + "infant"/"early infant diagnosis" + "point-of-care" + "cost-effectiveness" + "mathematical models", without restrictions from database inception to July 15, 2022. We selected reports of mathematical cost-effectiveness models comparing POC with SOC for HIV diagnosis in infants younger than 18 months. Titles and abstracts were independently reviewed, with full-text review for qualifying articles. We extracted data on health and economic outcomes and incremental cost-effectiveness ratios (ICERs) for narrative synthesis. The primary outcomes of interest were ICERs (comparing POC with SOC) for ART initiation and survival of children living with HIV. FINDINGS: Our search identified 75 records through database search. 13 duplicates were excluded, leaving 62 non-duplicate articles. 57 records were excluded and five were reviewed in full text. One article was excluded as it was not a modelling study, and four qualifying studies were included in the review. These four reports were from two mathematical models from two independent modelling groups. Two reports used the Johns Hopkins model to compare POC with SOC for repeat early infant diagnosis testing in the first 6 months in sub-Saharan Africa (first report, simulation of 25 000 children) and Zambia (second report, simulation of 7500 children). In the base scenario, POC versus SOC increased probability of ART initiation within 60 days of testing from 19% to 82% (ICER per additional ART initiation range US$430-1097; 9-month cost horizon) in the first report; and from 28% to 81% in the second ($23-1609, 5-year cost horizon). Two reports compared POC with SOC for testing at 6 weeks in Zimbabwe using the Cost-Effectiveness of Preventing AIDS Complications-Paediatric model (simulation of 30 million children; lifetime horizon). POC increased life expectancy and was considered cost-effective compared with SOC (ICER $711-850 per year of life saved in HIV-exposed children). Results were robust throughout sensitivity and scenario analyses. In most scenarios, platform cost-sharing (co-use with other programmes) resulted in POC being cost-saving compared with SOC. INTERPRETATION: Four reports from two different models suggest that POC is a cost-effective and potentially cost-saving strategy for upscaling of early infant testing compared with SOC. FUNDING: Bill & Melinda Gates Foundation, Unitaid, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, WHO, and Massachusetts General Hospital Research Scholars.

Health Service Utilization by Young Children with Autism Spectrum Disorder Versus Global Developmental Delay at a Tertiary Center in a Resource-Limited Setting.

OBJECTIVE: We investigated patterns and predictors of health service utilization (HSU) among children with autism spectrum disorder (ASD) and global developmental delays (GDD, non-ASD) attending tertiary services in a resource-constrained setting. METHOD: Caregivers and children (diagnosed with either ASD or GDD) attending the developmental service were enrolled into a retrospective cohort study. Sociodemographic factors, clinical factors, and service use over the preceding year were collected using structured questionnaires and medical record reviews. RESULTS: We enrolled 240 households (116 ASD, 124 GDD; ages 3-8 years; male:female ratio 2:1). The majority (84%) had moderate-to-severe symptoms, and 42% were nonverbal. Children with GDD had higher levels of underlying syndromic diagnoses than those with ASD (46, 37.1%; 14, 9.5%); (p < 0.01) and more co-occurring comorbidities (51, 41.0%; 14, 12.1%; p = 0.0001). Those with GDD had higher mean total HSU visits (13.3; 11.5; p = 0.02), higher mean specialist visits (4.0:2.0; p = 0.001), and more hospitalizations than those with ASD (38, 31%; 16, 14%; p = 0.02). Other services were similarly attended by both groups: therapy 6.0 (2.0-10.0), emergency visits 1.0 (1.0-2.0), auxiliary services 0 (0-1.0), and primary care visits 0 (0-1.0). Having an employed parent was the strongest predictor of increased HSU (p = 0.05). CONCLUSION: Despite high functional impairment in this cohort, many households underutilized therapy services. There was skewed attendance of emergency and specialist services over primary care services. Children with GDD had greater HSU compared with those with ASD, primarily because of more specialist visits. HSU could be improved by caregiver education, household economic empowerment, and strengthening of primary care services.

Alcohol use and intimate partner violence in HIV-uninfected pregnant women in Cape Town, South Africa.

In settings with a high burden of HIV, pregnant women often experience a cluster of risk factors, including alcohol use and intimate partner violence (IPV). These interrelated risks are poorly understood among pregnant women at risk of HIV in sub-Saharan Africa. We aim to determine cross-sectional associations between pregnant women's alcohol use and victimization due to IPV in the HIV-Unexposed-Uninfected Mother-Infant Cohort Study in Cape Town, South Africa. Women who tested HIV-negative at first antenatal care (ANC) visit were followed to delivery. Trained interviewers collected demographic and psychosocial information, including recent alcohol use and experiences of IPV victimization. We assess the prevalence of alcohol use and associations with IPV using multivariable logistic regression. In 406 HIV-uninfected pregnant women (mean age = 28 years; mean gestational age = 21 weeks), 41 (10%) reported alcohol consumption in the past 12 months; 30/41 (73%) of these at hazardous levels. Any and hazardous alcohol use were associated with greater odds of reporting past year IPV (adjusted odds ratio [aOR] for hazardous use: 3.24, 95% CI = 1.11, 7.56; aOR for any alcohol use: 2.97, 95% CI = 1.19, 7.45). These data suggest the occurrence of overlapping HIV risk factors among pregnant women and may help design improved health interventions in this population.

Relationship between pre-pregnancy maternal body mass index and infant weight trajectories in HIV-exposed and HIV-unexposed infants.

BACKGROUND: Maternal HIV and antiretroviral therapy (ART) exposure in utero may influence infant weight, but the contribution of maternal y body mass index (BMI) to early life overweight and obesity is not clear. OBJECTIVE: To estimate associations between maternal BMI at entry to antenatal care (ANC) and infant weight through approximately 1 year of age and to evaluate whether associations were modified by maternal HIV status, maternal HIV and viral load, breastfeeding intensity through 6 months or timing of entry into ANC. METHODS: We followed HIV-uninfected and -infected pregnant women initiating efavirenz-based ART from first antenatal visit through 12 months postpartum. Infant weight was assessed via World Health Organization BMI and weight-for-length z-scores (WLZ) at 6 weeks, 3, 6, 9 and 12 months. We used multivariable linear mixed-effects models to estimate associations between maternal BMI and infant z-scores over time. RESULTS: In 861 HIV-uninfected infants (454 HIV-exposed; 407 HIV-unexposed), nearly 20% of infants were overweight or obese by 12 months of age, regardless of HIV exposure status. In multivariable analyses, increasing maternal BMI category was positively associated with higher infant BMIZ and WLZ scores between 6 weeks and 12 months of age and did not differ by HIV exposure status. However, HIV-exposed infants had slightly lower BMIZ and WLZ trajectories through 12 months of age, compared with HIV-unexposed infants across all maternal BMI categories. Differences in BMIZ and WLZ scores by HIV exposure were not explained by timing of entry into ANC or maternal viral load pre-ART initiation, but z-scores were slightly higher for HIV-exposed infants who were predominantly or exclusively versus partially breastfed. CONCLUSIONS: These findings suggest maternal BMI influences early infant weight gain, regardless of infant HIV exposure status. Intervention to reduce maternal BMI may help to address growing concerns about obesity among HIV-uninfected children.

High blood pressure at entry into antenatal care and birth outcomes among a cohort of HIV-uninfected women and women living with HIV initiating antiretroviral therapy in South Africa.

OBJECTIVE: To examine associations between high blood pressure (BP) when entering antenatal care (ANC) and birth outcomes in a cohort of pregnant HIV- and women living with HIV (WLHIV) initiating antiretroviral treatment (ART). STUDY DESIGN: Prospective cohort study. MAIN OUTCOME MEASURES: Cesarean delivery, preterm birth (<37 weeks' gestation), low birthweight (LBW, <2500 g), small-for-gestational age (SGA, <10th percentile), and large-for-gestational age (LGA, >10th percentile for GA). RESULTS: Of 1116 women (median GA 20 weeks; WLHIV 53%), 48% (53% WLHIV; 43% HIV-) entered ANC with high BP, defined as elevated (120-129 or < 80 mmHg), stage 1 (>130-139 or 80-89) or stage 2 hypertension (≥140 / or ≥ 90). WLHIV were more likely to have high BP (RR 1.32; 95%CI 1.12-1.57), controlling for pre-pregnancy body mass index and additional confounders. In multivariable analysis, there was no evidence that high BP increased the risk of cesarean delivery (RR 1.10, 95% CI 0.92-1.30), preterm birth (RR 1.15, 95% CI 0.81-1.62), LBW (RR 1.16, 95% CI 0.84-1.60) or SGA (RR 1.02, 0.72-1.44), overall or when stratified by HIV-status. High BP was associated with an increased risk of LGA (RR 1.43; 95% CI 1.00-2.03). CONCLUSION: In this setting, half of women had high BP at entry into ANC, with WLHIV at increased risk of high BP. There was no strong evidence that high BP increased the risk of adverse birth outcomes overall, or by HIV-status, with the exception of LGA. WLHIV may be at high risk of high BP during pregnancy and should be monitored closely.

Does HIV infection modify the relationship between pre-pregnancy body mass index and adverse birth outcomes?

BACKGROUND: South Africa faces dual epidemics of HIV and obesity; however, little research has explored whether HIV status influences associations between pre-pregnancy body mass index (BMI) and adverse birth outcomes. OBJECTIVES: To examine associations between pre-pregnancy body mass index (BMI) and adverse birth outcomes, and if they differ by HIV status. METHODS: We followed HIV-uninfected and -infected pregnant women initiating antiretroviral therapy (ART) from first antenatal visit through delivery. HIV-infected women initiated ART (tenofovir-emtricitabine/lamivudine-efavirenz) in pregnancy. Estimated pre-pregnancy BMI (kg/m2 ) was categorised as underweight (<18.5), normal (18.5-24.9), overweight (25.0-29.9), and obese (≥30.0). We used modified Poisson regression to estimate risk ratios (RR) for associations between pre-pregnancy BMI and adverse birth outcomes and explored modification by HIV status. RESULTS: Among 1116 women (53% HIV-infected), 44% of HIV-uninfected women and 36% of HIV-infected women were classified as obese; 4% of women were underweight. Overall, 12% of infants were delivered preterm (<37 weeks), 10% small for gestational age (SGA, <10th percentile), and 9% large for gestational age (LGA, >90th percentile). Compared to HIV-uninfected women, HIV-infected women on ART had less LGA (5% vs 13%) but more SGA (12% vs 8%), and a similar proportion of preterm (13% vs 11%) infants. Pre-pregnancy BMI was not associated with preterm birth. Among HIV-uninfected women, obesity modestly increased the risk of LGA (RR 1.34, 95% confidence interval [CI] 0.82, 2.19), and underweight modestly elevated the risk of SGA (RR 1.66, 95% CI 0.79, 3.46). These associations were attenuated among HIV-infected women (RR 1.07, 95% CI 0.44, 2.64 for LGA, and RR 1.34, 95% CI 0.49, 3.64 for SGA). CONCLUSIONS: In this urban African setting of high HIV prevalence, pre-pregnancy obesity was common and did not vary by HIV status. In HIV-uninfected women, obesity increased the risk of LGA and being underweight the risk of SGA, compared with among HIV-uninfected women.

Postpartum obesity and weight gain among human immunodeficiency virus-infected and human immunodeficiency virus-uninfected women in South Africa.

In South Africa, up to 40% of pregnant women are living with human immunodeficiency virus (HIV), and 30-45% are obese. However, little is known about the dual burden of HIV and obesity in the postpartum period. In a cohort of HIV-uninfected and HIV-infected pregnant women initiating antiretroviral therapy in Cape Town, South Africa, we examined maternal anthropometry (weight and body mass index [BMI]) from 6 weeks through 12 months postpartum. Using multinomial logistic regression, we estimated associations between baseline sociodemographic, clinical, behavioural, and HIV factors and being overweight-obese I (BMI 25 to <35), or obese II-III (BMI >35), compared with being underweight or normal weight (BMI <25), at 12 months postpartum. Among 877 women, we estimated that 43% of HIV-infected women and 51% of HIV-uninfected women were obese I-III at enrollment into antenatal care, and 51% of women were obese I-III by 12 months postpartum. On average, both HIV-infected and HIV-uninfected women gained, rather than lost, weight between 6 weeks and 12 months postpartum, but HIV-uninfected women gained more weight (3.3 kg vs. 1.7 kg). Women who were obese I-III pre-pregnancy were more likely to gain weight postpartum. In multivariable analyses, HIV-infection status, being married/cohabitating, higher gravidity, and high blood pressure were independently associated with being obese II-III at 12 months postpartum. Obesity during pregnancy is a growing public health concern in low- and middle-income countries, including South Africa. Additional research to understand how obesity and HIV infection affect maternal and child health outcomes is urgently needed.

Infectious morbidity of breastfed, HIV-exposed uninfected infants under conditions of universal antiretroviral therapy in South Africa: a prospective cohort study.

BACKGROUND: Without breastfeeding and maternal antiretroviral therapy (ART), HIV-exposed uninfected (HEU) infants have greater infectious morbidity than HIV-unexposed (HU) infants. We hypothesised that with the introduction of universal maternal ART, breastfed HEU and HU infants would have similar morbidity. METHODS: We prospectively studied a cohort of HIV-infected pregnant women initiating ART, and a parallel group of HIV-uninfected pregnant women, starting from their first antenatal care visit at the Gugulethu Midwife Obstetrics Unit in Cape Town, South Africa. All pregnant women attending their first antenatal care visit were eligible for enrolment if aged 18 years or older and planning to deliver in Cape Town, without gestational age restrictions. HIV-infected women were participants of the Maternal Child Health ART (MCH-ART) study, and HIV-uninfected women were participants of the HIV-Unexposed Uninfected (HU2) study. All enrolled women were followed up during pregnancy and through delivery. At the early neonatal visit (scheduled for the first week after birth), mother-infant pairs who practiced any breastfeeding in the first 7 days of life were eligible for further postnatal follow-up for at least 12 months post partum. HIV infection was excluded among HEU infants at ages 6 weeks and 12 months by PCR. We evaluated the effect of HIV exposure on two primary outcomes: hospitalisation (all-cause and infection-related admission to hospital) and longitudinal prevalence of child infectious illness (diarrhoea and presumed lower respiratory tract infection [LRTI]). Hospitalisation data were abstracted from routine health records. Crude and adjusted incidence rate ratios (aIRRs; with adjustment for maternal HIV disease severity, timing of ART initiation, breastfeeding, timely vaccination, and birth outcomes [gestational size and age]) for infection-related hospitalisations were calculated from Poisson regression models (with variance corrected for clustering). Prevalence of infant infectious illness was based on maternal self-report for the preceding 2 weeks of each visit, with questions based on Demographic and Health Survey (DHS) questionnaires. Infants who acquired HIV infection during follow-up were excluded from this analysis. MCH-ART is registered on ClinicalTrials.gov, NCT01933477. FINDINGS: Pregnant women were recruited between March 20, 2013, and Aug 19, 2015. Mother-infant pairs (HEU, n=459; HU, n=410) were followed up for a median of 12 months until March 24, 2017. Compared with HU infants, HEU infants had more infection-related hospitalisations between the age of 8 days and 3 months (HEU, 34·2 admissions per 100 child-years [24·4-47·9] vs 9·8 per 100 child-years [95% CI 5·1-18·8]; IRR 3·50 [95% CI 1·68-7·30]), but rates were similar at other ages. In infants aged 8 days to 3 months, infection-related hospitalisations for HEU infants with healthier mothers (n=84; ART initiation at <24 weeks' gestation, CD4 count >350 cells per µL, HIV viral load <4·0 log10 copies per mL: 15·88 admissions per 100 child-years [5·12-49·23]) approximated those of HU infants (9·77 per 100 child-years [5·08-18·78]; aIRR 1·28 [0·27-6·05]). HEU infants of mothers with late ART initiation (at ≥24 weeks' gestation) and advanced disease (CD4 count ≤350 cells per µL and HIV viral load ≥4·0 log10 copies per mL; n=44) had the highest admission rate (40·44 per 100 child-years [15·18-107·74]; aIRR 5·01 [1·50-16·71]). In this age group, reduced admissions were seen in HEU infants with optimal breastfeeding (initiated within 1 h of birth and exclusive through age 3 months) and timely vaccination (required doses received within 2 weeks of indicated age; n=90; 9·63 admissions per 100 child-years [2·41-38·49]). Between birth and age 6 months, HEU infants had an almost five times greater prevalence of LRTIs than HU infants (aPR 4·69 [2·40-9·17]), and a three-times greater prevalence of diarrhoeal illness (aPR 2·93 [1·70-5·07]). After age 6 months, these associations were ameliorated. INTERPRETATION: Despite ART in pregnancy, breastfed HEU infants versus breastfed HU infants had transiently increased infectious morbidity risks in early infancy. However, differences were driven by factors potentially amenable to intervention, including delayed diagnosis and ART initiation in HIV-positive mothers, and suboptimal breastfeeding and vaccination of their infants. FUNDING: US National Institute of Child Health and Human Development, Elizabeth Glaser Pediatric AIDS Foundation, South African Medical Research Council, Fogarty Foundation and the Office of AIDS Research.

Short-term outcomes of HIV-exposed and HIV-unexposed preterm, very low birthweight neonates: a longitudinal, hospital-based study.

OBJECTIVE: To compare short-term outcomes of very low birthweight (VBLW, <1500 g) neonates by maternal HIV status. DESIGN: Retrospective hospital-based cohort in Cape Town, South Africa. RESULTS: Of 1579 mothers, 316 (20%) were HIV-positive; 183/316 (58%) received ≥8 weeks of antenatal antiretrovirals. HIV-exposed neonates (HIVE, vs HIV-unexposed, HIVU) had increased risk of necrotising enterocolitis (NEC; OR 1.93, 95% CI 1.27-2.92) and invasive ventilation (OR 1.35, 95% CI 1.01-1.79). Extremely low birthweight (ELBW, <1000 g) modified the HIV-exposure-mortality relationship: among ELBW neonates, HIVE vs HIVU mortality OR 1.75 (95% CI 1.13-2.69); among non-ELBW, OR 0.89 (95% CI 0.54-1.49). Antiretrovirals (≥8 vs <8 weeks/none) reduced NEC (OR 0.46, 95% CI 0.22-0.97) and invasive ventilation risks (OR 0.57, 95% CI 0.32-0.99). HIV-PCR results were available for 228/316 (72%) HIVE neonates; 11/228 (5%) tested positive. CONCLUSIONS: Among VLBW neonates, HIV-exposure was associated with increased risk of adverse short-term outcomes; antenatal antiretrovirals were protective.

HIV incidence during breastfeeding and mother-to-child transmission in Cape Town, South Africa.

: Despite widespread concerns about HIV incidence in pregnant and postpartum women, there are few data from Africa on HIV acquisition in breastfeeding and subsequent mother-to-child transmission. We measured HIV incidence in a prospective cohort of 413 peripartum and breastfeeding women who tested HIV-negative during pregnancy. In 377 woman-years accrued postpartum (median duration of follow-up, 1 year), there were seven women infected after delivery (postpartum incidence, 1.86/100 person-years; 95% confidence interval 0.88-3.89) with transmission to 2/7 (28%) infants.

Growth trajectories of breastfed HIV-exposed uninfected and HIV-unexposed children under conditions of universal maternal antiretroviral therapy: a prospective study.

BACKGROUND: Over 1 million HIV-exposed uninfected (HEU) children are born in sub-Saharan Africa annually. Little data exist on the risk of impaired growth in this population under current policies of universal maternal antiretroviral therapy (ART) with breastfeeding. We aimed to study the growth of breastfed HEU children born to women who initiated ART during pregnancy and compare their growth with that of breastfed HIV-unexposed (HU) children drawn from the same community. METHODS: A prospective cohort of HIV-uninfected and HIV-infected pregnant women, who were initiating ART, were enrolled at their first antenatal care visit in a primary care centre in Gugulethu, Cape Town, South Africa. HIV infected women were participants of the Maternal Child Health Antiretroviral Therapy (MCH-ART) study, and HIV-uninfected pregnant women were participants in the HIV-Unexposed-Uninfected (HU2) study. All women were followed up during pregnancy, through delivery, to the early postnatal visit, which was scheduled for the first week after birth. At this visit, eligible breastfeeding mother-child pairs were recruited for continuation of postnatal follow-up until approximately age 12 months. Child anthropometry was measured at around 6 weeks, and every 3 months from month 3 to month 12. Weight-for-age (WAZ), length-for-age (LAZ), weight-for-length (WLZ), head circumference-for-age, and body-mass index-for-age Z scores were compared between HEU and HU children longitudinally using mixed effects linear regression. At 12 months, proportions of HEU and HU children with moderate or severe malnutrition were compared cross-sectionally using logistic regression. MCH-ART is registered with ClinicalTrials.gov, number NCT01933477. FINDINGS: Between June, 2013, and April, 2016, 884 breastfeeding mothers and their newborn babies (HEU, n=471; HU, n=413) were enrolled into postnatal follow-up. Excluding 12 children who tested HIV positive during follow-up, 461 HEU and 411 HU children attended 4511 study visits in total, with a median of 6 visits (IQR 5-6) per child. Birth characteristics were similar (overall, 94 [11%] of 872 preterm [<37 weeks] and 90 [10%] small-for-gestational age [birthweight <10th percentile]). Median duration of breastfeeding was shorter among HEU than HU children (3·9 months [IQR 1·4-12·0] vs 9·0 months [IQR 3·0-12·0]). Although WAZ scores increased over time in both groups, HEU children had consistently lower mean WAZ scores than HU children (overall ß -0·34, 95% CI -0·47 to -0·21). LAZ scores decreased in both groups after 9 months. At 12 months, HEU children had lower mean LAZ scores than HU children (ß -0·43, -0·61 to -0·25), with a higher proportion of children stunted (LAZ score <-2: 35 [10%] of 342 HEU vs 14 [4%] of 342 HU children; odds ratio [OR] 2·67, 95% CI 1·41 to 5·06). Simultaneously, overweight (WLZ score >2) was common in both groups of children at 12 months (54 [16%] of 342 HEU vs 60 [18%] of 340 HU children; OR 0·87, 95% CI 0·58 to 1·31). INTERPRETATION: Compared with HU children, HEU children have small deficits in early growth trajectories under policies of universal maternal ART and breastfeeding. Large proportions of both HEU and HU children were overweight by 12 months, indicating substantial risks for early onset obesity among South African children. Although the longer-term metabolic effects of ART exposure in the context of childhood obesity warrants further investigation, addressing childhood obesity should be an urgent public health priority in this setting. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development, Elizabeth Glaser Pediatric AIDS Foundation, South African Medical Research Council, and the Fogarty Foundation.

HIV Viremia During Pregnancy and Neurodevelopment of HIV-Exposed Uninfected Children in the Context of Universal Antiretroviral Therapy and Breastfeeding: A Prospective Study.

BACKGROUND: Elevated HIV viral load (VL) in pregnancy has been linked to increased risk of mortality, immunologic abnormalities, infectious morbidity and restricted growth among HIV-exposed uninfected (HEU) children, but little is known about effects on child development. METHODS: HIV-infected women initiating lifelong antiretroviral therapy (ART; tenofovir + emtricitabine + efavirenz) antenatally were followed from first antenatal visit through delivery and with their breastfed infants postpartum. Cognitive, motor and expressive language development (Bayley Scales of Infant and Toddler Development-Third Edition; delay defined as score <85) were assessed on a subset of HEU infants. HIV VL was measured at ART initiation, in third trimester and around delivery. Cumulative viremia in pregnancy was expressed as log10 VL copies × year/mL [viremia copy-years (VCY)]. Relationships between VCY and development were examined after adjusting for socioeconomic, behavioral and psychosocial confounders. RESULTS: Women (median pre-ART log10 VL 4.1, CD4 349 cells/mm) commonly reported adverse social circumstances (44% informal housing, 63% unemployed, 29% risky drinking). Among 214 infants (median age, 13 months; 53% male; 13% born <37 weeks' gestation), viremia predicted lower motor and expressive language, but not cognitive, scores in crude and adjusted analysis [per log10 VCY increase, αß (95% confidence interval [CI]): motor, -2.94 (-5.77 to -0.11); language, -3.71 (-6.73 to -0.69) and cognitive -2.19 (-5.02 to 0.65)]. Increasing VCY also predicted higher relative odds of motor delay [adjusted odds ratio (aOR): 3.32; 95% CI: 1.36-8.14) and expressive language delay (aOR: 2.79; 95% CI: 1.57-4.94), but not cognitive delay (aOR: 1.68; 95% CI: 0.84-3.34). CONCLUSIONS: Cumulative maternal HIV viremia in pregnancy may have adverse implications for HEU child development.

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

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.

Optimizing Antiretroviral Therapy (ART) for Maternal and Child Health (MCH): Rationale and Design of the MCH-ART Study.

BACKGROUND: Prevention of mother-to-child transmission of HIV implementation faces significant challenges globally, particularly in the context of universal lifelong antiretroviral therapy (ART) for all HIV-infected pregnant women. METHODS: We describe the rationale and methods of the Maternal and Child Health-Antiretroviral Therapy (MCH-ART) study, an implementation science project examining strategies for providing HIV care and treatment to HIV-infected women who initiate ART during pregnancy and their HIV-exposed infants. RESULTS: MCH-ART is composed of 3 interrelated study designs across the antenatal and postnatal periods. Phase 1 is a cross-sectional evaluation of consecutive HIV-infected pregnant women seeking antenatal care; phase 2 is an observational cohort of all women from phase 1 who are eligible for initiation of ART following local guidelines; and phase 3 is a randomized trial of strategies for delivering ART to breastfeeding women from phase 2 during the postpartum period. During each phase, a set of study measurement visits is carried out separately from antenatal care and ART services; a maximum of 9 visits takes place from the beginning of antenatal care through 12 months postpartum. In parallel, in-depth interviews are used to examine issues of ART adherence and retention qualitatively, and costs and cost-effectiveness of models of care are examined. Separate substudies examine health outcomes in HIV-uninfected women and their HIV-unexposed infants, and the role of the adherence club model for long-term adherence and retention. DISCUSSION: Combining observational and experimental components, the MCH-ART study presents a novel approach to understand and optimize ART delivery for MCH.

Clinical outcomes of HIV-exposed, HIV-uninfected children in sub-Saharan Africa.

OBJECTIVE: HIV-exposed but HIV-uninfected (HEU) children are widely considered at increased risk of mortality and morbidity. Recent advances in prevention of mother-to-child HIV transmission (PMTCT) strategies, incorporating life-long universal maternal antiretroviral therapy (ART, "Option B+") with extended breastfeeding, may improve HEU child health substantially. We critically reviewed reports of mortality/morbidity among HEU and HIV-unexposed (HU) children in sub-Saharan Africa. METHODS: We searched Medline, EMBASE, CINAHL, PsycINFO, Academic Search Premier, Global Health & Psychosocial Instruments databases, conference abstracts, and reference lists for longitudinal studies from sub-Saharan Africa reporting mortality and clinical morbidity among HIV-uninfected children aged ≤10 years, by maternal HIV status. Studies were appraised by Newcastle-Ottawa Scale and ACROBAT-NRSI. Due to substantial heterogeneity of study designs, populations and results (I(2) = 75%), data were not synthesised. RESULTS: We included 37 reports (28 studies, 11 164 HEU children); methodological and reporting quality were variable. Most reports came from settings without universal access to maternal ART (n = 35). Results were conflicting, with some studies indicating increased risk of mortality, hospitalisation and/or under-nutrition among HEU children, while others found no evidence of increased risk. In subanalyses, improved maternal health, ART use and breastfeeding were strongly protective for all outcomes. Only 39% (11/28) of studies adjusted for major confounders. Reports from settings using universal maternal ART with breastfeeding (n = 2) found no differences in growth or development but did not report mortality or infectious morbidity. CONCLUSIONS: The existing literature provides little insight into HEU child health under recently adopted PMTCT strategies. There is a need for robust comparative data on HEU and HIV-unexposed child health outcomes under Option B+; optimising breastfeeding practices and increasing maternal use of ART should be urgent public health priorities.

South African measles outbreak 2009 - 2010 as experienced by a paediatric hospital.

INTRODUCTION: Between 2009 and 2010, South Africa experienced a major measles outbreak, with more than 18 000 confirmed cases reported to the National Institute of Communicable Diseases. METHODS: We studied measles admissions during the outbreak to Red Cross War Memorial Children's Hospital, Cape Town, between 1 November 2009 and 31 July 2010. Factors associated with mortality were retrospectively identified from notification records and hospital admissions data. Multivariate logistic regression was used to investigate potential risk factors for death. RESULTS: In total, 1 861 children were diagnosed with measles; 552 (30%) were admitted to hospital. The most common reason for admission was pneumonia (379 (68%)) and/or diarrhoea (262 (48%)). The median age at admission was 7.36 months (interquartile range (IQR) 5.0 - 10.7). The median duration of admission was 4 days (IQR 2 - 6); total hospital admission time was 3 746 days (10.3 child-years). HIV status was known in 404 (73%) children: 39/400 (14%) were HIV-infected. Eighteen children died (3% of all admissions); 15 (83%) of them were less than 1 year old. In the regression model, HIV-infection (adjusted odds ratio (aOR) 7.55, 95% confidence interval (CI) 2.27 - 25.12) and female sex (aOR 3.86, 95% CI 1.26 - 11.84) were associated with higher odds of death. CONCLUSIONS: There was a large paediatric admission burden during the 2009 - 2010 measles outbreak in Cape Town; young children were predominantly affected. HIV-infected children had a significantly higher case fatality.

Bacteremia in human immunodeficiency virus-infected children in Cape Town, South Africa.

Bacteremia contributes to morbidity of HIV-infected children. In a randomized controlled trial evaluating trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis, 47 bacteremias were detected. The incidence rate of bacteremia increased in the first 3 months after starting combination antiretroviral therapy (cART), but decreased by 74% once children were established on cART for more than 3 months. Children should be prioritized for early cART.