Background: The relationship between in-utero antiretroviral (ARV) drug exposure and child growth needs further study as current data provide mixed messages. We compared postnatal growth in the first 18-months of life between children who are HIV-exposed uninfected (CHEU) with fetal exposure to ARV drugs (prophylaxis or triple-drug therapy (ART)) and CHEU not exposed to ARVs. We also examined other independent predictors of postnatal growth. Methods: We analysed data from a national prospective cohort study of 2526 CHEU enrolled at 6-weeks and followed up 3-monthly till 18-months postpartum, between October 2012 and September 2014. Infant anthropometry was measured, and weight-for-age (WAZ) and length-for-age (LAZ) Z-scores calculated. Generalized estimation equation models were used to compare Z-scores between groups. Results: Among 2526 CHEU, 617 (24.4%) were exposed to ART since -pregnancy (pre-conception ART), 782 (31.0%) to ART commencing post-conception, 879 (34.8%) to maternal ARV prophylaxis (Azidothymidine (AZT)), and 248 (9.8%) had no ARV exposure. In unadjusted analyses, preterm birth rates were higher among CHEU with no ARV exposure than in other groups. Adjusting for infant age, the mean WAZ profile was lower among CHEU exposed to pre-conception ART [-0.13 (95% confidence interval − 0.26; − 0.01)] than the referent AZT prophylaxis group; no differences in mean WAZ profiles were observed for the post-conception ART (− 0.05 (− 0.16; 0.07)), None (− 0.05 (− 0.26; 0.16)) and newly-infected (− 0.18 (− 0.48; 0.13)) groups. Mean LAZ profiles were similar across all groups. In multivariable analyses, mean WAZ and LAZ profiles for the ARV exposure groups were completely aligned. Several non-ARV factors including child, maternal, and socio-demographic factors independently predicted mean WAZ. These include child male (0.45 (0.35; 0.56)) versus female, higher maternal education grade 7–12 (0.28 (0.14; 0.42) and 12 + (0.36 (0.06; 0.66)) versus ≤ grade7, employment (0.16 (0.04; 0.28) versus unemployment, and household food security (0.17 (0.03; 0.31). Similar predictors were observed for mean LAZ. Conclusion: Findings provide evidence for initiating all pregnant women living with HIV on ART as fetal exposure had no demonstrable adverse effects on postnatal growth. Several non-HIV-related maternal, child and socio-demographic factors were independently associated with growth, highlighting the need for multi-sectoral interventions. Longer-term monitoring of CHEU children is recommended.
The 2012 South African Prevention of Mother to Child Transmission of HIV Evaluation (SA-PMTCT-E) was a nationally-representative health facility-based cross-sectional study that enrolled 6-week (range 4–8 weeks) old infants attending immunization clinics in 9 South African provinces, with the primary aim to measure national PMTCT programme’s early effectiveness [20, 21]. In brief, nurse data collectors sampled mother-infant pairs systematically in large facilities (where participants were recruited at selected fixed intervals based on the target sample) or consecutively in small facilities (where all eligible participants were recruited until target sample obtained) during 6-week immunization visits. Sick infants needing emergency care or hospitalization were excluded. Infant HIV exposure was used as a marker of maternal HIV status. This was established through antibody testing [Genscreen HIV1/2 Ab EIA (enzyme immunoassay) Bio-Rad and confirmatory Vironostika HIV Uni-form II plus O, bioMérieux, France] on infant dried blood spots. Infant HIV infection status was assessed using polymerase chain reaction (PCR) testing [COBAS AmpliPrep/COBAS TaqMan assay, Roche, New Jersey] on the same dried blood spots [2]. Infants whose mothers reported living with HIV or infants with a positive 6-week HIV antibody test regardless of maternal self-reported HIV status, were eligible for recruitment into a prospective cohort study, nested within a national cross-sectional survey, to measure vertical transmission risk until 18-months postpartum. Recruitment was from 29 October 2012 to 31 May 2013, with follow-up until September 2014. Detailed cohort methods are described elsewhere [2]. In brief, consenting mother-infant pairs were followed at 3, 6, 9, 12, 15 and 18-months during scheduled facility visits coinciding with routine childcare appointments. Infant blood specimens collected between 6-weeks and 15-months underwent afore-mentioned diagnostic tests. At the 18-month visit, study nurses documented results from routinely-administered HIV-1 rapid test (SD Bioline HIV 1/2 3.0 Titma Health, Pty) on the child. Our primary exposure of interest was fetal exposure to maternal ARV, based on self-reported maternal ARV drug use data obtained using a structured questionnaire. During the study period, the national PMTCT programme was implementing CD4 count criteria-based life-long maternal ART initiation (CD4 cell counts ≤ 350 cells/mm3) and infant prophylaxis (World Health Organization (WHO) PMTCT policy Option A: 1 April 2010- 31 March 2013). Women with CD4 cell counts > 350 cells/mm3 were given Azidothymidine (AZT) prophylaxis from 14 weeks gestation. In April 2013, the PMTCT programme transitioned to lifelong ART for all pregnant and lactating WLHIV (WHO PMTCT Option B+) [22, 23]. ART regimens generally consisted of Nevirapine, Tenofovir, and Lamivudine or Emtricitabine [24]. We classified reported maternal ARV exposure as follows in analyses: (1) “pre-conception ART” when ART was started before pregnancy, (2) “post-conception ART” when ART was started during pregnancy, (3) “AZT only” when only AZT-based prophylaxis was given, (4) “None” when a known WLHIV took no ARV drugs during pregnancy, and (5) “Newly-infected” when women reported to have been HIV-negative during pregnancy but their children’s 6-week HIV antibody test result was positive. Study questionnaires also included questions on self-reported 24-h and 1-week child feeding practices, maternal (Tuberculosis (TB), HIV, CD4 count, syphilis) and child (coughing, diarrhea) morbidity and treatment, maternal obstetric history, socio-demographics characteristics, and peripartum community social support at each time point. Trained nurse data collectors collected anthropometric data using standardised procedures based on WHO guidelines [25]. Child weight was measured using calibrated A&D personal precision weight scales (UC-321) and length using SECA portable baby length boards (SCA417BLM). Measurements were recorded in kilograms or centimeters to two decimal places. Birthweight, birth length, and gestational age were extracted from participant-held health booklets. We defined low birthweight (LBW) as birthweight < 2.5 kg; preterm birth (PTB) as birth before 37 completed weeks gestation; and small for gestational age (SGA) as birthweight for gestational age Z-score below − 1.28 [26]. We estimated birthweight and length–for-gestational-age Z-scores using Intergrowth international standards for assessing newborn size for term and pre-term infants [27] and LMSgrowth [28], and excluded gestational ages outside of range for these standards (20 to 24 weeks). We estimated weight-for-age (WAZ), weight-for-length (WLZ), and length-for-age (LAZ) Z-scores at each postnatal timepoint using WHO growth standards [29]. We considered infants as underweight and stunted if their WAZ and LAZ were below -2 standard deviations respectively [25]. Anthropometric measurements and Z-scores were flagged based on criteria (Additional file 1: Box 1), and set to missing if no plausible explanation was established. We performed statistical analyses using STATA standard edition version 15. We calculated frequencies for categorical variables and means (standard deviations) or medians (inter quartile range) for continuous variables. Proportions were compared using Pearson chi-squared test while F-test was used for comparing means. Generalized estimation equations, with a gaussian distribution, were used for univariable and multivariable regression analyses to account for correlations between repeated anthropometric measurements within the same participant. Model covariates were selected based on literature (Additional file 1: Fig. S1) [30] and quasi-likelihood under an independence model criterion. These criteria were also used to inform the best fitting final multivariable models, and to select the independent correlation structure [31]. Mean WAZ and LAZ over the study period were modelled on exposure group, infant age (in months) and important covariates including maternal age, education, employment status, syphilis and TB status, mode and place of delivery, birth attendant, household food security, housing type (brick or non-brick), access to flush toilet and electricity, infant breastfeeding, sex and geographic location. These covariates were treated as potential confounders in the adjusted models assessing the association between foetal ARV exposure and postnatal growth. They were also included as predictors in the multivariable predictive models assessing factors independently associated with study outcomes. Presence of effect measure modification was also explored. We excluded variables that were affected by exposures of interest and shared common causes with outcomes (i.e., LBW, SGA and PTB) from models to minimize bias introduced by adjustment of potential mediators in the presence of unmeasured common causes [32, 33]. We did not include survey sampling weights in final analyses because this adjustment (1) did not change the findings and (2) generally increases standard errors. Instead, we added province in models to adjust for the survey structure. Point estimates were calculated with 95% confidence intervals. Analyses only included CHEU and children were censored if they tested HIV PCR positive at last HIV negative PCR result or died (censored at time point when death was reported). Although statistical testing was performed at the 5% statistical significance level, results were interpreted primarily based on the precision of the estimates.