Higher mortality in HIV-positive and HIV-negative children born to mothers with lower CD4 cell counts

Derek Thaczuk
Published: 17 January 2008

Children in sub-Saharan Africa born to mothers with CD4 cell counts under 350 cells/mm3 are more likely to die, whether or not the children themselves are HIV-positive, according to a study published in the Journal of Acquired Immune Deficiency Syndromes in December 2007. Child malnutrition and low maternal haemoglobin were associated with higher child mortality rates.

In sub-Saharan Africa in 2005, 570,000 children under 15 years of age died from HIV/AIDS-related causes. Studies have produced significant evidence that the mother's health during pregnancy significantly affects mortality risk in children who are born HIV-infected. Lower CD4 cell counts, higher viral loads, and more advanced disease in the mothers have all been associated with increased disease progression and death in their HIV-positive children, and, previous studies have suggested, possibly in HIV-uninfected children as well.

In this new study, Tanzanian and Harvard researchers analysed data from a previously published cohort trial to examine the effect of maternal disease state during pregnancy and child nutritional status on child mortality. The original trial, published in The Lancet in 1998, was a prospective, randomised, double-blind, placebo-controlled study of the effects of vitamin supplementation in HIV-positive pregnant Tanzanian women (Fawzi 1998).

Enrollment occurred at four clinics in Dar es Salaam, Tanzania. Eligible women were HIV-positive as confirmed by ELISA and Western blot, and between twelve and 27 weeks of gestation. In the original study, women were randomised to receive supplemental vitamin A, multivitamins, both, or neither. Standard antenatal care, including daily iron and folic acid supplementation, was provided.

A total of 984 children were born to the 1078 women enrolled; the study population for the current analysis consisted of the 939 live single births and their mothers. (Twins were excluded due to their inherently higher mortality risk.) At the time of enrollment, these 939 women had a median CD4 count of 402 cells/mm3; 38% had a CD4 cell count < 350 cells/mm3, and 20% were in WHO disease stage 2 or higher. Viral load measurements were available for a random subset of 387 women at the time of enrollment; 49% had a viral load ≥ 50,000 copies/ml.

Follow-up of the children included blood samples at birth, six weeks of age, and every three months thereafter for assessment of HIV infection, and at birth and every six months thereafter for CD4 cell counts. Of the 984 single births, 257 were confirmed as HIV positive by PCR testing before 18 months of age, or by ELISA and Western blot after 18 months.

There were 228 child deaths during 17,568 child-months of follow-up. Through 24 months, child mortality risk was 1.62 times higher (95% confidence interval [CI], 1.18 to 2.22, p = 0.003) for mothers with less than 350 CD4 cells/mm3 at delivery, and 1.74 times higher (95% CI, 1.32 to 2.30, p < 0.0001) for mothers with less than 350 CD4 cells/mm3 at baseline. The hazard ratio (HR) due to low maternal CD4 cell counts at baseline was, in fact, higher and more significant for children who were not HIV-infected (HR=2.00; 95% CI, 1.36 to 2.94, p = 0.0004) than for those who were (HR=1.38; 95% CI, 0.94 to 2.03, p = 0.09, not statistically significant).

Higher maternal viral load (≥50,000 copies/ml) at delivery was also a significant risk factor overall (HR=2.47; 95% CI, 1.22 to 5.02, p = 0.01), and an especially significant risk for HIV-negative children (HR=7.49; 95% CI, 2.36 to 23.71, p = 0.0006).

Other maternal factors significantly associated with overall child mortality were low haemoglobin (<8.5 g/dL) at delivery (HR=1.53; 95% CI, 1.04 to 2.24, p = 0.03), and increased erythrocyte sedimentation rate (ESR ≥81 mm/h) at delivery (HR=1.44; 95% CI, 0.97 to 2.14, p= 0.07), although this measure did not reach statistical significance.

Indicators of child malnutrition were also linked to mortality. When a three-month lag was introduced "to separate out the effect of malnutrition from that of any acute illness that might have immediately preceded death", risks of mortality included being underweight (weight-for-age z-score < -2) (HR=2.33, 95% CI, 1.30 to 3.85, p = 0.004), having wasting (weight-for-height z-score < -2) (HR=2.45, 95% CI, 1.13 to 5.31, p = 0.02), or stunted growth (height-for-age z-score < -2) (HR=2.21, 95% CI, 1.29 to 3.77, p = 0.004).

The researchers write that they "present evidence of increased risk of mortality among HIV-infected and uninfected children born to HIV-infected women who are at an advanced stage of HIV disease during pregnancy", with a nearly twofold increase in deaths before two years of age if the mother's CD4 count was under 350 cells/mm3. They also conclude that higher maternal viral load, maternal anaemia, and child undernutrition contribute to the risk of child mortality. Their findings "underline the need for … treatment and care of HIV-infected women and children to have a maximum impact on child survival in regions with high HIV prevalence."

Reference

Chatterjee A et al. Maternal disease stage and child undernutrition in relation to mortality among children born to HIV-infected women in Tanzania. J Acquir Immune Defic Syndr 46: 599-606, 2007.