Objectives: Little is known about the independent long-term effect on growth of exposure to maternal human immunodeficiency virus (HIV) infection. Growth patterns in uninfected children who are born to infected mothers have not been described in detail previously beyond early childhood, and patterns over age for infected and uninfected children have not been based on appropriate general population standards. In vertically HIV-infected children, poor growth has been suggested to be an early marker of infection or progression of disease. However, whether growth faltering is an independent HIV-related symptom or caused indirectly by other HIV clinical symptoms requires clarification. This information is needed to inform the debate on a possible effect of antiretroviral combination therapy on the height of infected children and would provide evidence for the use of specific interventions to improve height. The objective of this study was to describe growth (height and weight) patterns in infected and uninfected children who are born to HIV-infected mothers with respect to standards from a general population and to assess age-related differences in height and weight by infection status, allowing for birth weight, gestational age, gender, HIV-related clinical status, and antiretroviral therapy (ART).
Methods: Since 1987, children who were born to HIV-infected mothers in 11 centers in 8 European countries were enrolled at birth in the European Collaborative Study and followed prospectively according to a standard protocol. Height and weight were measured at every visit, scheduled at birth; 3 and 6 weeks; 3, 6, 9, 12, 15, 18, and 24 months; and every 6 months thereafter. Serial measurements of height and weight from birth to 10 years of age of 1403 uninfected and 184 infected children were assessed. We fitted linear mixed effects models allowing for variance changes over age and within-subject correlation using fractional polynomials and natural cubic splines. Growth patterns were compared with British 1990 growth standards and by infection status.
Results: Of the 1587 children enrolled, 810 were male and 777 were female; 1403 were not infected (681 boys, 722 girls), and 184 were infected (88 boys, 96 girls). Neither height nor weight was associated significantly with the main effects of HIV infection status at birth, but differences between infected and uninfected children increased with age. Uninfected children had normal growth patterns from early ages. Infected children were estimated to be significantly shorter and lighter than uninfected children with growth differences increasing with age. Differences in growth velocities between the infected and uninfected children increased after 2 years of age for height and after 4 years of age for weight and were more marked in the latter. Between 6 and 12 months, uninfected children grew an estimated 1.6% faster in height and 6.2% in weight than infected children; between ages 8 and 10 years, these figures were 16% and 44%, respectively. By 10 years, uninfected children were on average an estimated 7 kg heavier and 7.5 cm taller than infected children. Growth in uninfected children who were born before 1994, before the widespread use of ART prophylaxis to reduce vertical transmission, did not substantially differ from that of children who were born after 1994. To investigate whether the growth differences between infected and uninfected children were associated with HIV disease progression, we analyzed growth of infected children using the Centers for Disease Control and Prevention (CDC) clinical classification, in 3 groups: no symptoms, mild or moderate symptoms (A and B), and severe symptoms (C or death). Infected children with mild or serious symptoms lagged behind asymptomatic children in both height and weight, and these differences increased with age. Infected children who were born before availability of ART, before 1988, were more likely to reach a weight below the third centile for age than children who were born after 1994 when effective HIV treatment was widely available. Of the 184 infected children, 67 had been weighed and/or measured at least once while on combination (> or = 2 drugs) ART. Reflecting the longitudinal nature of the European Collaborative Study and the changing availability of HIV treatment, most of these measurements took place after 7 years of age, and therefore analyzing the possible effect of combination therapy on growth is difficult. The z scores for height and weight gain improved substantially in several children who received combination therapy regardless of their CDC clinical classification. To increase available information, we pooled all measurements according to CDC clinical classification and presence of combination therapy at the time of the observation. Weight and height significantly improved for severely ill children after combination therapy.
Conclusion: Using data from this large prospective European study, we investigated in comparison with general British standards growth patterns in the first 10 years of life of HIV-infected and uninfected children who were born to HIV-infected mothers. The duration of follow-up of uninfected as well as infected children makes this a unique data set. We allowed for repeated measurements for each child and the increase of variability in height and weight with age. Growth faltering may be related to the social environment, and our finding that uninfected children have normal growth, which is unaffected by exposure to maternal HIV infection, is consistent with observations that in Europe the HIV-infected population is more like the general population and less socioeconomically disadvantaged than that in the United States. However, HIV-infected children grew considerably slower, and differences between infected and uninfected children increased with age. Growth patterns in asymptomatic infected children were similar to those with only mild or moderate symptoms. However, compared with these 2 groups combined, severely ill children had poorer growth at all ages. Although limited by the small number of children who received combination therapy, severely ill children may benefit from such therapy in terms of improvements in weight and, to a smaller extent, in height. Growth faltering, particularly stunting, may adversely affect a child's quality of life, especially once they reach adolescence, and this should be taken into account when making decisions about starting and changing ART. Additional research will help to elucidate the relationship between combination therapy and improved growth, in particular regarding different regimens and the best timing of initiation for optimizing growth of infected children.