Poor growth has been reported in HIV-infected children and is associated with decreased survival [1–6]. In untreated children, HIV impact on growth is considerable, but HAART may ameliorate this effect . Furthermore, compared with infants of HIV-uninfected mothers, all infants of HIV-infected mothers have significantly lower mean birth weights, especially when maternal HIV is advanced [2,7–12].
Far less is known about the effect of maternal HIV infection on subsequent growth of HIV-exposed, but uninfected, children, particularly from Africa. European cohorts have described normal growth in HIV-exposed children compared with children born to HIV-uninfected mothers [1,5] as has a very small study from Rwanda in the late 1980s . However, small studies from Durban, South Africa  and Zambia  have suggested lower weights in HIV-uninfected infants born to HIV-infected mothers compared with population standards or infants of HIV-uninfected mothers. Further, results from another recently published trial from Zambia show marked declines in weight-for-age z-scores in HIV-uninfected children of HIV-infected mothers between 4.5 and 15 months, though the decline was less marked in infants who were breastfed . In large African cohorts, growth has not been compared with that of children born to HIV-uninfected mothers from the same population, nor have growth patterns over age been based on appropriate population-based reference standards [16,17].
Infant feeding also significantly affects growth. The new WHO growth standards, launched in 2006 and designed to show how children should grow with optimal nutrition, acknowledge early differences in growth patterns between breastfed and nonbreastfed infants, with the mean weight of breastfed infants being above the median of the American standards (with most children formula fed), during the first half of infancy . Early life growth patterns of uninfected children of HIV-infected mothers, by feeding patterns over age, have not been described in detail .
Recommendations on infant feeding for HIV-infected mothers have largely been based on risks of HIV transmission and early morbidity . Information on infant growth associated with early feeding practices is important for policy makers and provides further information to balance the risks and benefits associated with breastfeeding – that is, acquisition of HIV through breast milk vs. the morbidity associated with avoidance or early cessation of breastfeeding.
Extensive breastfeeding support was provided to women in the Vertical Transmission study (VTS) [20,21], which thus provides a unique opportunity to explore the effect of exclusive breastfeeding (EBF) in the first 6 months of life and the impact of maternal HIV infection, on growth, in terms of weight, in the first 24 months of life. Weight is examined as it is a useful medium and long-term indicator of outcome; feasible to measure in resource-limited settings; and interpretable in global terms. We assessed factors affecting weights of children of HIV-infected mothers with respect to standards from a directly comparable reference group of children born to HIV-uninfected mothers from the same area.
Population and methods
HIV-infected and HIV-uninfected pregnant women were enrolled into the VTS, a nonrandomized intervention cohort study, from seven rural, one semi-urban and one urban primary healthcare clinics in KwaZulu-Natal (2001–2004). Women were counseled on infant feeding choices antenatally and supported postnatally by lay counselors during home visits . An independent group of field workers conducted home visits weekly from birth to 9 months and documented all feeds and morbidity episodes for each day of the preceding week. HIV prevalence rate among pregnant women in the study area was approximately 40% . High rates of EBF were achieved, with a median duration of approximately 175 days, irrespective of maternal HIV status .
After delivery, mothers and infants attended study clinics, monthly from 6 weeks to 9 months and then quarterly to 2 years. At each visit, the child was assessed by a study nurse who recorded a medical history and performed a physical examination. In addition, HIV status was determined by quantitative HIV RNA assay. For this analysis, infants were categorized as uninfected, infected perinatally (positive PCR at 4–8 weeks after delivery) or infected postnatally (positive PCR after 8 weeks of age) [21,23,24]. Gestational age was based on both the date of the last menstrual period and palpation by the midwife. Prematurity and severe prematurity were defined as deliveries 37 or less and 34 or less weeks gestation, respectively.
Anthropometric measurements were carried out at each visit by trained study clinic assistants, who had completed secondary school and received standardized anthropometry training. Strict adherence to the techniques taught was emphasized during regular in-service training and quality assurance checks were conducted by the clinic manager throughout the study period.
All clinics used the same measuring equipment: a scale with precision within 10 g for newborns; and for older children, portable electronic weighing scales with taring capability and a precision to 100 g (UNICEF Electronic Scale 890), as recommended by WHO . The clinic manager checked calibration using standard metal weights at approximately weekly intervals.
Other than at birth, when infants were placed in a weighing tray, children were held by their mothers for weighing. First, a mother's weight was recorded and then the scale tared and the baby given to her to hold. Each child had two weights recorded; the mean value was later calculated during analysis. If the two recorded weights had a difference greater than 100 g, a third measurement was taken and the two weights within 100 g were recorded . Weights were measured at scheduled clinic visits at birth, 6, 10, 14, 18, 22 and 26 weeks and then 7, 8, 9, 12, 15, 18, 21 and 24 months. Children's lengths and head circumferences were also measured at scheduled visits, but this analysis examines weights only, for the reasons given above.
Anthropometric measurements were also taken on mothers. The mid-upper arm circumference (MUAC), taken at 6 weeks postdelivery, using a 5-mm blank lead-in millimeter graded tape measure, has been used in these analyses .
At the time of the study, HAART was not available for treatment to delay HIV disease progression for either women or children, but single-dose nevirapine was provided to all HIV-infected women and their infants to reduce peripartum mother-to-child transmission . The Biomedical Research Ethics Committee, University of KwaZulu-Natal, approved the study; all participating women gave written informed consent.
Data, recorded on individual study forms, were scanned using optical imaging recognition software (Teleform, San Diego, California, USA), thus minimizing data entry errors.
To be eligible for this analysis, maternal HIV status had to be known and the child had to have a gestational age at birth between 18 and 45 weeks and at least one growth measurement after birth. Gestational age was assessed by the study nurse at the antenatal booking visit using a combination of date of last menstrual period and abdominal palpation; ultrasounds were not routinely conducted. This resulted in a small proportion of liveborn children with extreme gestational ages at delivery who were excluded from analysis.
Only growth measurements on HIV-uninfected children born to HIV-uninfected mothers contributed data to the reference population. Children weighing less than 2500 g at birth were excluded if they were born preterm, but included if born at term. To avoid the influence of measurement outliers in the construction of the weight-for-age standards, seven (<0.1%) observations falling outside ±4 SDs of the sample median were also excluded.
z-scores for weight were calculated to examine levels and patterns of growth among children born to HIV-infected mothers. z-scores, indicating how many SDs an observation is above or below the mean, were constructed to allow comparison between children born to infected mothers and the reference population (HIV-uninfected children born to uninfected mothers). Weight-for-age standards for male and female children were constructed separately by fitting the Box-Cox normal distribution (LMS method) using the GAMLSS (Generalized Additive Models for Location, Scale and Shape) method . The resulting growth standards for weight-for-age were then used to obtain z-scores for each weight measurement for children born to HIV-infected women by age and sex.
Examining deviations in growth from the reference population
After adjusting for infant's birth weight and maternal MUAC measured at 6 weeks postpartum, z-scores over age were examined by HIV-infection status, infant feeding practice and maternal CD4 cell count using linear mixed effects (LME) models. A mixed effects model assumes that each parameter is the sum of both a fixed and random component, wherein the fixed components are the same for all individuals in the population and the random components differ between individuals . The use of a LME model, therefore, accounts for individual variability through the random effects, but allows for a population average to be estimated via the fixed effects. The model selection was based on the Akaike Information Criterion (AIC) . The following variables were considered in the LME regression model and retained if inclusion resulted in an improved AIC: mother's MUAC, as a proxy for maternal nutrition status, maternal CD4 cell count closest to delivery, type of water source and latrine facility and rural/urban residence. The child's sex was not significant and its inclusion did not result in an improvement in fit of the model.
Calculations were done in R version 2.6.0  using the function GAMLSS and LME.
A total of 1498 children were born to HIV-infected mothers. Thirty-six pairs of twins and 43 children with reported extreme gestational ages were excluded (<18 weeks or >45 weeks), leaving 1383 children of HIV-infected mothers. Of these, 1261 with at least one weight measurement after birth are included.
A total of 1432 children were born to HIV-uninfected mothers, 1250 had information on the child's HIV status and 1231 were HIV-negative (19 were HIV-infected, born to mothers with primary HIV infection). Twenty-one pairs of twins and 61 children with extreme gestational ages were excluded (<18 weeks or >45 weeks). A further 48 (4.1%) preterm children with a birth weight less than 2500 g and 19 (1.8%) preterm children with missing birth weights were also excluded leaving 1061 children for analysis.
Compared with HIV-uninfected women, HIV-infected women were older, more likely to deliver premature and low birth weight infants and to have fewer clinic visits (Table 1). Deaths among HIV-infected women and their infants were more likely than those in HIV-uninfected women. Sociodemographic characteristics of HIV-infected and HIV-uninfected women were similar.
Growth of children born to HIV-infected women
Figure 1 shows the weight z-scores for infected and uninfected children of HIV-infected mothers. z-scores for HIV-infected children are below the reference standard; at 6 weeks, the difference was 240 g for male children and 200 g for female children and at 52 weeks, 420 g for male children and 405 g for female children.
A total of 910 (75%) children, with 9411 measurements, born to HIV-infected mothers were included in a multivariable model; 300 (25%), with 2154 measurements, were excluded because of missing data on birth weight, maternal CD4 cell count and MUAC. There were no significant differences between those excluded from this analysis and those included with respect to the mean z-score at birth (mean −0.22 vs. −0.24; P = 0.77) or gestational age at delivery (36.9 vs. 37.7 weeks; P = 0.44), though those excluded had significantly fewer study visits [median 2 (interquartile range; IQR 1–9) vs. 11 (IQR 7–15); P < 0.0001].
Of the variables considered for inclusion in the model, a linear term in age, birth weight, maternal MUAC, maternal CD4 cell count closest to delivery, infant feeding type and infant HIV infection status were required in the final model, with the presence of an interaction effect between age and birth weight also improving the model fit significantly. The adjusted coefficients of change in z-score for weight are presented in Table 2. Again, the reference group is composed of HIV-uninfected children of HIV-uninfected mothers. HIV-exposed children, whose mothers were at a less advanced stage of disease, were more consistently of a more appropriate weight for their age than those whose mothers had lower CD4 cell counts (Table 2). Children born to mothers with a MUAC at least 28.35 cm were estimated to have a weight z-score 0.38 higher than that of a child born to a mother with a MUAC less than 25.7 cm, which at birth equates to being on the 58th weight percentile, as opposed to the 42nd. Overall, children given breast milk had an average z-score 0.048 higher compared with children receiving no breast milk.
To explore further the differences between HIV-uninfected and HIV-infected children, Fig. 2a shows the unadjusted z-scores for weight for HIV-uninfected children of HIV-infected mothers to oscillate around zero and this indicates that these children's growth is close to that of the reference population, irrespective of feeding mode. On the other hand, in HIV-infected infants, breastfeeding was associated with consistently higher z-scores than other feeding modes, more pronounced in the first 4 months, and particularly in the first 6 weeks, where the difference was 130 g for male children and 110 g for female children (Fig. 2b). This difference was more marked for infants infected perinatally; breastfed infants demonstrated substantially better growth in the first 6 weeks compared with those receiving no breast milk (data not shown).
Sociodemographic characteristics were examined to allow for differences in environmental and economic conditions (e.g. water or fuel), which may impact on complementary feeding preparation and subsequent child growth; these were not statistically different between HIV-infected and HIV-uninfected mothers (see Table 1). Most women had access to piped water, but few had piped water in their own homestead. Figure 3 shows the unadjusted z-scores of HIV-exposed children by water supply; the most marked differences were between 1 and 2 years of age when children with piped water in their homes had higher z-scores compared with those with other water supplies, irrespective of feeding modality.
Growth of children born to HIV-infected and HIV-uninfected women
Between 3 and 12 months of age, weights of children born to infected mothers differed significantly from those born to uninfected mothers (data not shown). On average, the weight of a child of an HIV-infected mother was 0.19 lower z-score than that of an HIV-uninfected child of an HIV-uninfected mother; this equates to the 42nd weight percentile based on reference curves created from the weight data on HIV-uninfected children born to uninfected women.
Growth of HIV-negative children of HIV-infected and uninfected mothers
This large African cohort of children, with repeated growth measurements over 2 years and rigorous collection of infant feeding data, allows detailed examination of weight gain in children of HIV-infected women compared with the reference population of infants born to HIV-uninfected women from the same setting. These novel analyses allow for maternal circumstances and environmental factors. The objective of this paper was not to describe the growth of children in rural KwaZulu-Natal and to compare this to international standards or the growth of children elsewhere, but to evaluate whether maternal HIV infection status and the mode of feeding made a difference to the longitudinal weights of children. For these reasons, we chose to develop our own reference standard. An alternative approach would have been to calculate weight-for-age z-scores using the new WHO growth standards , a methodology recently used in a cohort of HIV-exposed children from Zambia .
One of the key findings of this study is that the growth of HIV-exposed but HIV-uninfected children was as good as that of the reference population. This is a significant and new [3,14] result for two reasons: first, up to 40% of infants are born to HIV-infected mothers in southern Africa, of whom the majority will be exposed but uninfected. The growth and development of these children is important, but often overlooked. Second, previous studies have shown that uninfected-exposed children may be at greater risk of morbidity and mortality compared with infants of HIV-uninfected mothers, particularly in poor, rural settings like ours . Undernutrition is a significant predictor of child mortality in developing countries [32–35], in areas of low  and high HIV prevalence [37,38] and is associated with poor early development . We postulate that EBF for 6 months may compensate for vulnerabilities experienced by HIV-exposed-uninfected children [37,40], which may include maternal morbidity, decreased caring ability for infants and increased exposure to opportunistic infections [41,42].
Growth and infant feeding
Most infants in our study received breast milk . The few HIV-infected women who opted for formula feed were carefully counseled and had better socioeconomic circumstances than those choosing for breastfeed , so were more likely to provide replacement feeds in an hygienic way. EBF for 6 months is critical for child survival [44–48]; international guidelines now recommend 6 months of EBF for HIV-exposed infants, unless they can be provided with replacement feeds in an ‘acceptable, feasible, affordable, sustainable and safe’ manner . We suggest that the optimal feeding practices of our women, together with support and other appropriate health interventions, resulted in the good growth of the HIV-exposed-uninfected children, true for infants who were breastfed or formula-fed. Overall, children given breast milk had an average weight 0.048 higher z-score compared with children receiving no breast milk, after allowing for birth weight, maternal MUAC, HIV infection status and maternal CD4 cell count. (300 children were excluded from the multivariate model because of missing data, as detailed in the Results section; as there were no significant differences with respect to birth weight or gestational age, it is unlikely that the exclusion of these children will have substantially affected the overall results). These findings further strengthen the recommendation of EBF for HIV-infected women  – not only is transmission lower than in mothers who mixed breastfed [21,49], and mortality from infectious diseases lower (in some settings) than in those infants who were formula-fed [45,50], but their long-term health in terms of growth is improved.
Growth of children and maternal health and water supply
The birth weight of children born to HIV-infected mothers was lower than that of infants born to HIV-uninfected mothers, in line with previous studies [2,7,12]. Children of larger women, measured by MUAC, were consistently heavier for age from birth than children of smaller women; and infants born to HIV-infected mothers with advanced disease (CD4 cell count<200 cells/μl) were always lighter, in accord with at least one previous study . To improve survival and longer term health of children, HIV-infected pregnant women with low CD4 cell counts need to be identified and fast-tracked for HAART to improve their virological, immunological and nutritional status prior to delivery .
There was no evidence to suggest that a potentially hazardous water supply would be associated with poor growth in the first 6 months, most likely because most women EBF. Once complementary feeds were introduced at 6 months of age, children in homes with piped water had the best z-scores for weight. Piped water not only provides a hygienic water supply with less risk of diarrhea for the child, but it is also a proxy for other socioeconomic circumstances, and those with piped water were probably more able to afford better quality complementary foods. However, this was only a trend that was unadjusted and based on small numbers, and further studies are required to substantiate this finding.
Growth of HIV-infected children
Not surprisingly, HIV-infected children were consistently lighter from birth compared with uninfected-exposed children, irrespective of feeding practice. Although the birth weights of infected children were lower than those of exposed-uninfected children, their weights continued to diverge from the early weeks to around 6–9 months of age, when the differences plateau. Data from Europe show continued divergence of weights of HIV-infected children until they commence on HAART when their growth improves [52–54]. During the study period, HAART was not available for HIV-infected infants in this area, resulting in early mortality of approximately half the infected children. HAART is now available in South Africa; the major challenge is identifying infected infants as early as possible and initiating treatment.
These encouraging results show that with good counseling for appropriate feeding choices and support for optimal feeding practices, HIV-uninfected children of HIV-infected women grew as well as those of uninfected women. These findings further strengthen the recommendations of EBF for HIV-infected women in resource-poor settings, for long-term child health.
We are grateful to all women and children enrolled in the study; the field, clinic, laboratory and data management staff at the Africa Center, including the managers (Thembi Blose, Zanele Fakude, Cookie Govender, Nqobile Mkhwanazi, Londiwe Mthethwa, Samukelisiwe Mtshali and Ntombizodumo Mkwanazi); Colin Newell who assisted with data management; Dave Perlman and Kobus Herbst for their assistance in database design; the Community Liaison Office at the Africa Center and the Community Advisory Board for their guidance and feedback throughout the study.
D.P. contributed to the analysis of data and drafted manuscript. R.B. contributed to the design and implementation of study, analysis of data and drafted manuscript. H.C. and A.C. contributed to the design of study and reviewed manuscript. N.R. contributed to the design and implementation of study and reviewed manuscript. M.-L.N. contributed to the design of study, analysis of data and drafted manuscript.
Wellcome Trust (Grant #063009/Z/00/2) and Africa Center (Grant #050534) supported this study.
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