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Patterns of postnatal growth in HIV-infected and Hiv-exposed children

Sheila Isanaka, Christopher Duggan, Wafaie W Fawzi
DOI: http://dx.doi.org/10.1111/j.1753-4887.2009.00207.x 343-359 First published online: 1 June 2009

Abstract

HIV infection can contribute to disturbances in both linear growth and weight gain in early childhood, with disturbances often apparent as early as 3 months of age. There is little evidence for a difference in the early growth of HIV-exposed but uninfected children compared to healthy controls. Owing to the close association of growth with immune function and clinical progression, an understanding of growth patterns may be an important tool to ensure the provision of appropriate care to HIV-infected and exposed children. Timely growth monitoring may be used to improve the clinical course and quality of life of these children.

  • child
  • HIV
  • postnatal growth

INTRODUCTION

The HIV/AIDS pandemic is one of the most important challenges in global health today. In 2007, 33 million people worldwide were estimated to be living with HIV.1 The epidemic in much of the world has been concentrated among populations most at risk, such as men who have sex with men, injection drug users, sex workers and their sexual partners. In sub-Saharan Africa, home to more than two of every three infected people, the HIV/AIDS epidemic has been sustained in the general population and resulted in increased burdens of disease for both women and children. The majority of people living with HIV in sub-Saharan Africa are women, and nearly 90% of children infected with HIV live in this region.1

HIV infection in children is generally due to vertical transmission either during the antenatal and perinatal periods or through breastfeeding. Most studies suggest no difference in the birth size of HIV-positive and -negative children born to HIV-infected women, as HIV transmission appears to occur late in gestation.2 Infection can, however, contribute to disturbances in both linear growth and weight gain in early childhood. Growth failure is now recognized as one of the most common manifestations of HIV infection in children, with failure to thrive reported in 20–70% of infected children.3 Contributing to the onset of immune deficiency and opportunistic infection, impaired growth is a sensitive indicator of morbidity and mortality in HIV-infected children.4,5

A number of longitudinal studies have now explored the association between HIV and postnatal growth over time and described a variety of disturbed growth patterns. Differences in observed growth patterns may result from underlying differences in the populations studied, including differences in prenatal growth patterns, the availability of antiretroviral (ARV) therapy, food supplementation or socioeconomic conditions, or from differences in disease manifestation due to virus subtypes, prevalence of sexually transmitted diseases (STD) or nutritional deficiencies.

This review focuses on studies that have examined the association of HIV infection or HIV exposure with postnatal growth over time. It includes all longitudinal studies conducted to date, summarizes the evidence relating HIV infection and HIV exposure to growth in children, and suggests clinical and research implications and priorities.

LITERATURE SEARCH METHODS

The patterns of postnatal growth are described in three groups of children defined as follows: 1) HIV-infected children, the majority of which are infected perinatally during late pregnancy and delivery or postnatally during breastfeeding. A small proportion of HIV-infected children acquire HIV through other routes, including transfusion with blood or blood products; 2) children exposed to but not infected with HIV; these children, referred to as seroreverters, are born to HIV-infected mothers but are not HIV-positive themselves; and 3) healthy controls, including children without HIV exposure or infection born to HIV-negative mothers. The impact of HIV infection is evaluated by summarizing differences in postnatal growth in HIV-infected children versus seroreverters, and the impact of HIV exposure is evaluated by summarizing differences in seroreverters versus healthy controls.

Studies included in this review were identified through a PubMed search of the literature. All papers published from January 1, 1985 to January 1, 2009 were identified by use of the term “HIV” together with the term “child growth.” Inclusion criteria were as follows: 1) outcomes included anthropometric indices/velocity (e.g., height, weight, head circumference, height-for-age, weight-for-age, weight-for-height, body mass index [BMI]) or body composition measures (e.g., triceps skinfold thickness, arm muscle circumference, fat free mass, or body cell mass); 2) “exposure” groups included HIV-infected children, seroreverters and/or HIV-uninfected children born to HIV-negative mothers; 3) longitudinal design; and 4) publication in the English language. The focus of this review was limited to longitudinal studies in order to describe postnatal growth dynamics associated with HIV infection and HIV exposure over time. Case reports and studies on the effects of antiretroviral treatment were not included.

Papers meeting the inclusion criteria were reviewed to extract information on study design, exposure and outcome measurement methods, statistical techniques, confounding factors, and results. The literature cited in papers recovered through the initial PubMed search was also reviewed to supplement the originally identified publications. All relevant studies are summarized by study setting (i.e., economically “developed” countries including the United States, Europe, and Australia versus economically “less developed” countries including those of Latin America, sub-Saharan Africa, and Asia) to facilitate the identification of possibly different patterns of postnatal growth and to separate the confounding effects of differing levels of treatment and care from the exposure of interest. Results are presented separately for the impact of HIV infection (HIV-infected children versus seroreverters) and for the impact of HIV exposure (seroreverters versus healthy controls) on postnatal growth. Results from studies that include all three groups of children are included in both two-group comparisons. Results from studies describing the postnatal growth of HIV-infected versus HIV-uninfected children (without determination of the uninfected child's HIV exposure status) are presented with results on the impact of HIV infection.

EPIDEMIOLOGICAL EVIDENCE

The initial PubMed search identified 845 publications, among which 37 were ultimately identified as longitudinal studies that examined the association of HIV infection or exposure with postnatal growth. From the identification of the first pediatric case of HIV in the early 1980s to 1990, only one study was identified through this review that considered the association between HIV status of children and postnatal growth.6 The 1990s saw an increase in evidence for an association between HIV status and growth in children, with 24 new research papers published on this issue between 1990 and 2000.429 Many of these early reports were from populations in the United States and Europe. Data on the anthropometric characteristics of HIV-infected and HIV-exposed children in other settings, including sub-Saharan Africa, largely became available only in the latter half of the 1990s.418

DEVELOPED COUNTRIES

HIV infection and postnatal growth

Seventeen studies compared the postnatal growth of HIV-infected and HIV-exposed but uninfected children in developed countries (Table 1). All studies were from the United States or Western Europe and the mean duration of follow-up ranged from 4 months to 10 years.

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Table 1

Longitudinal studies from developed countries comparing postnatal growth of HIV-infected children versus children exposed but not infected with HIV.

graphic

Linear growth

Of the 13 studies that examined the association of infection status with height, 11 provided supportive evidence of lower height-for-age among HIV-infected children compared to seroreverters.931 In studies in which an association was found and results were reported, the difference in height-for-age Z-scores between HIV-infected children and seroreverters ranged from −0.73 to −0.90 Z at 12 months and −0.31 to −0.91 Z at 18 months after birth. In studies that presented differences in height (cm), the differences were small and ranged between 1 and 3 cm through 4 years of age.1230 At 10 years of age, the European Collaborative Study observed a difference of −7.6 cm in the heights of HIV-infected children versus seroreverters.31 Impairment in height-for-age was most often noted within 3–4 months following birth,931 but it was also seen at 15 months.13 Early differences in height-for-age were found to persist 1930 or increase through follow-up.931 HIV-infected children, compared to seroreverters, were also found to have increased risks of linear growth failure (defined as HAZ < −2, growth < 4 cm/y or height deceleration of >10%; 27% versus 12.8%),32 stunting (7/18 versus 1/29),29 and failure to thrive (IRR = 3.9).23 One multisite study from the United States did not support an association between HIV infection and lower height-for-age 19–21 months after birth.15 Similarly, no difference was found in mean height before versus after HIV seroconversion in a small group of hemophiliac boys.25

Weight gain

The same 13 studies evaluated the association of HIV infection with weight-for-age, and 10 of them reported significantly lower weight-for-age in HIV-infected children than in seroreverters.931 In the studies in which an association was found and results were reported, the difference in weight-for-age Z score between HIV-infected children and seroreverters ranged from −0.81 to −0.92 Z at 6 months, −0.55 to −0.91 Z at 12 months, −0.77 to −0.98 Z at 18 months, and −0.57 Z at 24 months after birth. Differences in weight (kg) were less than −1.5 kg through 4 years of follow-up.1230 Compared to seroreverters, HIV-infected children were lighter by 0.61 to 0.65 kg at 6 months, 0.75 kg at 12 months, 0.63 kg at 24 months, and 0.71 to 0.90 kg at 48 months after birth. After 10 years of follow-up, HIV-infected children in the European Collaborative Study were 6.95 kg lighter than seroreverters.31 Two smaller studies by Pollack et al.19,29 did not support a link between HIV infection and weight, either as median weight, weight-for-age Z or number underweight with 18 months of follow-up, and the ratio of weight to 50th centile for age25 and weight velocity24 did not differ by HIV infection status in two other small studies. Of the eight studies in which both lower height-for-age and weight-for-age among HIV-infected children were detected and the timing reported, it was common for differences in height and weight to become apparent at the same time.1431 The change in weight, however, was also observed before9 and after1330 differences in height.

Of the six studies in which weight-for-height was evaluated, five detected lower weight-for-height among HIV-infected children compared to seroreverters. The difference in weight-for-height Z scores ranged from −0.22 to −0.36 Z at 6 months, −0.01 to −0.08 Z at 12 months, and −0.58 to −0.70 Z at 18 months after birth. McKinney et al.14 did not detect an association between HIV infection and weight-for-length Z score with over 2 years of follow-up. The timing of observed differences in weight-for-height were concurrent with differences in both weight and height in two studies 12,15 and occurred after such changes in two others.9,30 In the large European Collaborative Study, significant height-adjusted differences in weight detected at 3 months after birth did not persist beyond 12 months.21 Two studies evaluated the association of HIV infection and BMI and found BMI to be lower in HIV-infected children compared to seroreverters in the first 6 months of life.10,12

Other measures

No difference in head-circumference-for-age was observed in HIV-infected children versus seroreverters in three of five studies that evaluated this outcome.1227 An early study from the United States by Miller et al.15 was the only longitudinal analysis examining changes in body composition in HIV-infected children over time. The rates of change in muscle mass, measured by arm muscle circumference and tricep skinfold thickness, were found to be lower in HIV-infected children compared to seroreverters. The rates of change in arm muscle circumference and tricep skinfold thickness were 2 mm/month and 0.89 mm/month lower in HIV-infected children, respectively. A cross-sectional analysis of a follow-up study of hemophiliac boys found no difference in tricep skinfold thickness between HIV-infected and -uninfected boys.16

HIV exposure and postnatal growth

There is less evidence on the association between HIV exposure (as opposed to HIV infection) and postnatal growth, with only seven studies evaluating the growth of HIV-exposed but -uninfected children in developed country settings (Table 2).

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Table 2

Longitudinal studies from developed countries comparing postnatal growth of children exposed but not infected with HIV versus children unexposed to HIV.

graphic

Linear growth

Four studies examined differences in height-for-age by HIV exposure status. The European Collaborative Study detected no difference in height-for-age between seroreverters and the reference population,31 and Ross et al.26 and Pollack et al.19 found no difference in linear growth between seroreverters and healthy controls. A smaller Italian study observed lower height-for-age in seroreverters compared to healthy controls, with mean height-for-age Z scores being 0.06 Z, 0.26 Z, and 0.46 Z lower in seroreverters at 6, 12, and 24 months of age, respectively.11 Lipman et al.32 reported a greater risk of growth failure (defined as height-for-age Z < −2, growth < 4 cm/year or height deceleration of >10%) among seroreverters compared to the reference population.

Weight gain

No study observed a difference in weight gain between HIV-exposed children and healthy controls. The weight-for-height and BMI of seroreverters were examined by one and two studies, respectively.1026 In the Italian studies, both weight-for-height and BMI were found to be higher among the seroreverters in the first few months after birth, but these differences decreased with time. By 4 months of age, seroreverters had similar weight-for-height and BMI scores as healthy controls. Ross et al.26 found no difference in BMI or change in BMI over 36 months of follow-up.

Other measures

The association between HIV exposure and head-circumference-for-age Z scores was assessed in one study, where no significant difference between seroreverters and healthy controls was observed.19

LESS DEVELOPED COUNTRIES

HIV infection and postnatal growth

Fifteen studies evaluated the association of HIV infection and postnatal growth in less developed country settings (Table 3). The majority of these reports were from sub-Saharan Africa, with only three studies identified from outside of the region. The duration of follow-up ranged from 4 months to 8 years.

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Table 3

Longitudinal studies from less developed countries comparing postnatal growth of HIV-infected children versus children exposed but not infected with HIV.

graphic

Linear growth

Of the ten studies in which height-for-age was examined, a negative association was consistently detected in all436 but one study.37 In studies in which an association was found and results reported, height-for-age Z scores were lower in HIV-infected children versus seroreverters by 0.23 to 1.55 Z at 6 months, 0.25 to 0.72 Z at 12 months, 0.44 to 1.53 Z at 18 months, and 0.68 to 1.53 Z at 24 months after birth. Differences in height-for-age detected as early as 3 months of age734 and before 1 year435 persisted throughout follow-up. HIV infection was also associated with lower gains in length velocity (−2.8 cm/year, 95% CI: −5.0–−0.6) among children 6–11 months of age in Tanzania,38 and HIV-infected adolescents in Brazil experienced greater decreases in height-for-age Z scores between their first and last measurements under follow-up than expected in the general population.36

Weight gain

A negative association between HIV infection and weight gain was detected in all ten studies in which this relationship was evaluated. The difference in weight-for-age Z score ranged from −0.20 to −1.72 Z at 6 months, −0.17 to −0.87 Z at 12 months, −0.87 to −1.43 Z at 18 months and −0.69 to −1.07 Z at 24 months after birth. HIV infection was also associated with lower yearly gains in weight among children aged 6 to 11 months (−1.26 kg, 95% CI: −2.53–0.02) and 12 to 23 months (−0.59 kg, 95% CI: −1.05–−0.12) at baseline in Tanzania38 and with an increased risk of growth disturbance, defined as weight-for-age < 5th percentile or no weight gain in 3 months, in Kenya.22 The decrease in weight-for-age Z score from the first to the last measurement under follow-up was also larger among HIV-infected adolescents than expected in the general population (ΔWAZ: −0.31).36 Differences in weight-for-age between groups was detected most consistently at the same time as differences in height-for-age,434 though two studies observed the change in weight several months before differences in height were apparent.17,33

The link between weight-for-height by infection status was inconsistent in the six studies that evaluated this outcome. Two studies provide supportive evidence of a negative association between weight-for-height and HIV infection. In these studies, the difference in weight-for-height between HIV-infected children and seroreverters ranged from −0.22 to −0.92 Z at 6 months, −0.04 to −0.50 Z at 12 months, −0.61 to −0.91 Z at 18 months, and −0.27 Z at 24 months after birth. In both studies, these differences were detected 6 or more months after differences in height- or weight-for-age became apparent. Four studies found no difference in weight-for-height in HIV-infected children compared to seroreverters.737 In three of these studies, no difference in weight-for-height was detected, despite significant differences in height-for-age and/or weight-for-age.734

Other measures

One study examined head-circumference-for-age and observed smaller head circumferences among HIV-infected children versus seroreverters from 3 to 30 months of age.7 The relative risk of failure to thrive among HIV-infected children versus seroreverters was assessed in two studies, with observed relative risks of 2.25 at 1 year and 46.57 at 2 years in Zambia6 and 4.48 (95% CI: 2.57, 7.81) in South Africa.18

HIV exposure and postnatal growth

In the six studies to evaluate the association between HIV exposure and postnatal growth in less developed country settings, a lack of association was fairly consistent between HIV exposure and height-for-age,739 weight-for-age,739 weight-for-height,8 and head-circumference-for-age (Table 4).7 The only exception was one study from Kenya in which height-for-age Z scores were found to be significantly lower at 1.5 months after birth (−0.19 Z versus −0.48 Z) and weight-for-height Z scores were greater at 6 months (0.10 Z versus 0.45 Z) and 18 months after birth (−0.73 Z versus −0.16 Z) among seroreverters compared to children born to HIV-negative mothers.37

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Table 4

Longitudinal studies in less developed countries comparing postnatal growth of children exposed but not infected with HIV versus children unexposed to HIV.

graphic

Strengths and limitations of studies

A number of strengths and limitations characterize the existing studies on HIV and postnatal growth. These are discussed below.

Exposure assessment

The method and frequency of assessing HIV infection status in children is particularly relevant in the context of less developed countries, where transmission can continue to occur after birth through breastfeeding. In these settings, it is important to use tests for the presence of HIV antibodies (ELISA and Western blot assays) at 15 or 18 months of age in conjunction with more specific tests for presence of the virus (polymerase chain reaction assays) at younger ages to account for the time-varying nature of infection status owing to such postnatal transmission. Approximately half of the studies conducted in less developed country settings did not describe such methods for exposure assessment, nor did they account for the timing of transmission in the analysis.634 Only one recent study by Webb et al.35 used information from repeated PCR measures to account for the timing of transmission in the statistical analysis of differences in growth.

Insufficient exposure assessment also limited the interpretation of findings from one study from Zambia. In Makasa et al.,39 infants' infection status was not determined through laboratory methods. Analyses to evaluate the impact of HIV infection were limited to comparisons of postnatal growth by maternal infection status among children who appeared uninfected at the later follow-up and did not allow for explicit differentiation between HIV-infected children and seroreverters in the analysis.

Length of follow-up

Most studies evaluated the short-term effects of HIV on postnatal growth. Data beyond 2 years of age are limited, and the follow-up periods of less than 6 months found in some studies939 may not be long enough to capture the complete pattern of change in growth outcomes. Only two studies from sub-Saharan Africa report growth beyond 2 years. In the one study with follow-up from birth, the later effects of HIV on growth were found to be less than those earlier in life,7 but this result may be due to the lower survival of those most affected. One European cohort found significant weight and height deficits at 10 years.31 The six studies that enrolled children at older ages may provide some indication of the patterns of growth among HIV-infected and HIV-exposed children later in childhood.1636

Sample size

Studies often included a small number of subjects and were affected by considerable drop-out, limiting the reliability of conclusions at later time points.27,37 Ten studies from developed country settings929 and eight from less developed countries638 included approximately 50 or fewer HIV-positive children.

Choice of comparison group

Poor growth in children needs to be interpreted in the context of the health, care, and social environment. In evaluating the impact of HIV infection, nearly all studies in this review include comparisons of growth patterns between HIV-infected and HIV-exposed but uninfected children. This choice of comparison group appropriately controls for many of the differences in socioeconomic status and social background that may exist between children of HIV-positive and HIV-negative mothers, although it is unable to separate the effects of HIV infection from social factors. The design of five studies additionally allowed for comparison groups to be selected with consideration for other factors that may affect postnatal growth, by matching according to maternal age or parity712 or selecting healthy controls to be formula-fed as were children born to HIV-infected mothers.10,11

Studies from developed settings were less likely than those from less developed settings to include appropriate, healthy, population-based controls; as a result, there are fewer studies that use HIV-uninfected children born to HIV-negative mothers to describe the impact of HIV exposure (not infection) from developed countries (Tables 2 and 4). Three studies were found that compared the growth of HIV-infected children with that of HIV-uninfected children in which seroreverters could not be distinguished from healthy controls among the latter.638

Limited evidence for body composition endpoints

Information on body composition, including the distribution of fat and lean body mass, of children is important to characterize how the nutritional status of children changes with HIV infection. This review identified only one study that evaluated changes in body composition in HIV-infected children over time.15 The cross-sectional evidence on the relationship between HIV infection and exposure and body composition appears similarly limited.1643

Statistical methods

The study design and repeated measures used in longitudinal studies generally require data analysis methods that account for the correlation in repeated measurements and the increase in variability in weight and height with age. These more advanced models were successfully applied in 12 studies,438 but more than half of the studies reviewed did not account for the longitudinal nature of the data.644 Control for factors that may influence growth was also inconsistent across studies. Potential confounding due to covariates associated with growth, such as birth weight, gestational age, gender, dietary intake and maternal factors, was not controlled for in the majority of studies644 but was considered in others.439

COMMENTS

Taken together, the available data can be used to highlight a number of implications for clinical practice, as well as suggest possible mechanisms of HIV-related growth failure. The data suggest that HIV infection is associated with profound and long-lasting defects in weight and height throughout infancy and childhood. The current evidence indicates that differences in growth patterns become apparent by 3–4 months of age, persist, and perhaps increase with time. Wasting associated with HIV infection was less common than stunting or underweight. It is possible that HIV-infected children experience nearly proportional declines in both height and weight such that normal weight-for-height is maintained7,34 or that wasting in HIV-infected children may become apparent only as children become more sick. The data available also reveal no significant differences in the early growth of seroreverters and healthy controls, suggesting that viral exposure without infection does not affect growth. These patterns of growth faltering were similar across developed and less developed country settings, despite differences in access to supplemental feeding and antiretroviral therapy and other factors including women's routes of transmission, virus subtypes, and prevalence of STDs, drug use and nutritional deficiencies.

It was common for differences in weight-for-age to become apparent at the same time as differences in height-for-age in both developed and less developed country settings. As weight is more likely to decrease before height in conditions of protein-energy malnutrition, this pattern of concurrent impairment of weight and height could indicate that other mechanisms may underlie HIV-related growth failure. Possible mechanisms include HIV-related disturbances to energy balance,4048 gastrointestinal disturbance and malabsorption,4952 and neuroendocrine changes.2858 Growth failure may also occur as a direct result of HIV infection, independent of the variety of secondary illnesses that accompany infection.3061

Understanding of the temporal course and mechanisms of growth impairment through future longitudinal study will continue to be important for the early intervention and care of HIV-infected children if impaired growth precedes and contributes to the onset of immune deficiency and opportunistic infection. Further research in a number of specific areas continues to be warranted to broaden and deepen our current understanding of the impact of HIV on postnatal growth. This includes development of evidence on the effect of HIV infection on body composition in children. As noted above, few studies have addressed the association between HIV infection and exposure and body composition in children. These limited studies suggest that HIV-infected children experience a preferential loss of lean body mass compared to fat, similar to that seen in adults.62 As changes in body composition may be an additional risk factor for disease progression, further study is needed to describe changes in body composition in HIV-infected children over time.

Evaluation of the effect of HIV infection on adolescent growth and development should also remain a research priority. Advances in the management of HIV means that many perinatally infected children reach adolescence. Only a small number of studies, however, have examined the effect of HIV on adolescent growth and pubertal development to date.4164 Given the increasing survival of this population and the limited information on the effect of HIV on growth and development after 4 years of age, more information on how HIV infection may interact with adolescent growth and maturation is needed. Evaluation of the effect of nutritional intervention / supplementation on growth, immune status and disease progression in children is similarly important. The well-known interaction between nutrition and immune function suggests that nutritional interventions may have the potential to limit morbidity and mortality in HIV-infected individuals.65 The role of micronutrient status on HIV infection has been examined in several trials in adults and children,66 though more information on the effectiveness of various macronutrient interventions is still required. Finally, evidence on the effect of ARV therapy on growth and body composition in HIV-infected children must continue to be developed and summarized. ARV therapy has improved the virological, immunological, and clinical outcomes of HIV-infected children, and studies on its effects on growth are now becoming available.6168 Additional efforts to develop and consolidate information on the effects of such treatment on growth and body composition in the long-term and in less developed country settings are required.

CONCLUSION

Poor growth is common among children infected with HIV and, as a contributor to immune dysfunction, it is associated with disease progression and decreased survival. In this review, we aimed to characterize and quantify the effect of HIV infection and exposure on growth in children. There appears to be little difference in the early growth of HIV-exposed but uninfected and healthy controls; however, abnormal growth patterns in HIV-infected children have been documented in both developed and less developed country settings. A variety of disturbed growth patterns have been described, with disturbances in both height and weight among HIV-infected children often apparent as early as 3 months of age and increasing with time. Owing to the close association of growth with immune function and clinical progression among HIV-infected children, an understanding of the growth patterns of HIV-infected children may represent an important tool in targeting children for further assessment. Timely growth monitoring may be used to identify those with suboptimal growth, ensure the provision of appropriate care and treatment to these children, and help improve their clinical course and quality of life.

Acknowledgments

Funding.  This study was supported in part by the National Institutes of Health (grants R01 HD048969 and R01 HD043688). Sheila Isanaka was supported by the Berkowitz Fellowship in Public Health Nutrition (Harvard School of Public Health) and the Caroline Cady Hewey Fund (Harvard University).

REFERENCES

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