Elsevier

The Lancet

Volume 364, Issue 9441, 2–8 October 2004, Pages 1236-1243
The Lancet

Articles
Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis

https://doi.org/10.1016/S0140-6736(04)17140-7Get rights and content

Summary

Background

HIV contributes substantially to child mortality, but factors underlying these deaths are inadequately described. With individual data from seven randomised mother-to-child transmission (MTCT) intervention trials, we estimate mortality in African children born to HIV-infected mothers and analyse selected risk factors.

Methods

Early HIV infection was defined as a positive HIV-PCR test before 4 weeks of age; and late infection by a negative PCR test at or after 4 weeks of age, followed by a positive test. Mortality rate was expressed per 1000 child-years. We investigated the effect of maternal health, infant HIV infection, feeding practices, and age at acquisition of infection on mortality assessed with Cox proportional hazards models, and allowed for random effects for trials grouped geographically.

Findings

378 (11%) of 3468 children died. By age 1 year, an estimated 35·2% infected and 4·9% uninfected children will have died; by 2 years of age, 52·5% and 7·6% will have died, respectively. Mortality varied by geographical region, and was associated with maternal death (adjusted odds ratio 2·27, 95% CI 1·62–3·19), CD4+ cell counts <200 per μL (1·91, 1·39–2·62), and infant HIV infection (8·16, 6·43–10·33). Mortality was not associated with either ever breastfeeding and never breastfeeding in either infected or uninfected children. In infected children, mortality was significantly lower for those with late infection than those with early infection (0·52, 0·39–0·70). This effect was also seen in analyses of survival from the age at infection (0·74, 0·55–0·99).

Interpretation

These findings highlight the necessity for timely antiretroviral care, for support for HIV-infected women and children in developing countries, and for assessment of prophylactic programmes to prevent MTCT, including child mortality and infection averted.

Introduction

Every year, between 570 000 and 740 000 children are estimated to be newly infected with HIV-1.1 Many of these infections are through mother-to-child transmission (MTCT), which can take place before, during, or after delivery.2, 3, 4 An estimated 420 000–580 000 of these children die every year.1 Almost all paediatric infections occur in sub-Saharan Africa, where frequency of HIV infection in women of childbearing age can reach 35% or more.

Without antiretroviral treatment, most HIV-infected children die before their fifth birthday and HIV is a considerable component of increased childhood mortality rates,5, 6 and about 20% of children vertically infected with HIV progress to AIDS or death in the first year of life.7, 8 Infants who acquire HIV infection in utero or intrapartum will probably progress to serious disease or death more rapidly than those who become infected in the breastfeeding period,9 but there is little evidence to confirm this suggestion. Disease progression is probably associated with maternal HIV-RNA viral load8, 10 and quickens in settings with a high background rate of other infections and nutritional problems.11, 12

Antiretroviral prophylaxis reduces the risk of MTCT late in pregnancy and during delivery, and (together with elective caesarean section and replacement feeding) has resulted in substantially reduced rates of MTCT.4 However, elective caesarean section is not feasible as an intervention in most resource-poor settings, and postnatal transmission from mother-to-child through breastfeeding remains important where avoidance of breastfeeding is not a realistic option.13, 14, 15 To assess programmes to prevent MTCT and improve clinical management of infected women and their children, mortality data of HIV-infected and HIV-uninfected children of infected mothers are urgently required.

Several trials have been undertaken in sub-Saharan countries to investigate the effect of peripartum and infant feeding interventions in risk reduction of HIV infection via MTCT,4, 16 with paediatric follow-up for 18–24 months and information about infant feeding. Pooling of the data from such trials provides an opportunity to assess mortality rates in children of HIV-infected women, and to establish whether a mortality differential exists between those with evidence of early infection and those with late infection.

Section snippets

Methods

Principal investigators of all nine clinical trials undertaken in sub-Saharan Africa16 were asked to participate in this study; seven agreed to a combined analysis of their mortality data in children of HIV-infected mothers.16, 17, 18, 19, 20, 21, 22, 23 Investigators of two trials declined the invitation because the timing of the request was inconvenient.14, 24 Only the breastfeeding arm of the Nairobi trial was included.21 Eligibility criteria for inclusion of the randomised,

Statistical analysis

We calculated overall mortality as a rate per 1000 child-years of follow-up, and used the Kaplan-Meier method to estimate survival curves for every variable. To account for heterogeneity in the trials grouped by geographical location, we fitted penalised Cox proportional hazards regression models using restricted maximum likelihood with frailty terms corresponding to random effects from a Gaussian distribution. We used this analysis to obtain adjusted odds ratios,25 both overall and for

Role of the funding source

The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

3468 singleton children were included in this analysis, with 23 519 visits (median seven visits per child [range one to 48]). Median age at last follow-up was 15·5 months (range 1 day to 58·4 months); total number of child-months' follow-up was 45 805.

Table 1 summarises characteristics of the children and their mothers. Overall cumulative mortality in mothers during follow-up was 31 per 1000, and was higher in east and west Africa than in South Africa. Median maternal CD4+ cell count around the

Discussion

We present estimates of risk of mortality in children born to HIV-infected mothers in Africa, on the basis of a large dataset. Our results accord with previous findings of high mortality in vertically-infected children, more than half of whom will have died by age 2 years. Although our estimates are high, they should be regarded as minimum estimates, since they refer to children who were included in research studies in which health-care support might have been better than that outside research

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