Chatterjee A, Bosch RJ, Hunter DJ, Fataki MR, Msamanga GI, Fawzi WW. Maternal disease stage and child undenutrition in relation to mortality among children born to HIV-infected women in Tanzania. JAIDS 2007 Dec 15;46(5):599-606.
To examine whether the mother's HIV disease stage during pregnancy and malnutrition in the child are associated with child mortality.
A prospective cohort study based on a randomized, double-blind, placebo-controlled trial to study the effects on maternal and child health of vitamin supplements in HIV-infected women during pregnancy and lactation.
Four antenatal clinics in Dar es Salaam, Tanzania.
939 HIV-infected women between 12 and 27 weeks of gestation and residents of Dar es Salaam who were enrolled in the clinical trial and the singleton-birth children born to them.
There was no intervention in this cohort analysis, but women in the original clinical trial were randomized into four arms of different combinations of vitamins or placebo. Twin-birth children were excluded. Beginning with a first postnatal clinic visit 6 weeks after birth, children born to women in the trial were followed with monthly visits to the study clinic. Home visits were made if a clinic visit was missed, and neighbors and relatives were contacted for the survival status of the mother and child. Children had a complete physical examination by a study physician, and age, height, weight data were taken by trained nurses. At each visit, mothers provided a detailed history of their child's illness and breast-feeding status since the last clinic visit.
At baseline, 6 weeks postpartum, and every 6 months thereafter, mothers provided blood samples for absolute counts of CD4 T cells and complete blood cell counts, including hemoglobin concentration and erythrocyte sedimentation rate (ESR). Assessment of viral load was done in a randomly selected subset of 387 women at baseline and during delivery. Children provided a blood sample at birth, at 6 weeks, and every 3 months thereafter for assessment of HIV infection and at birth and every 6 months thereafter for absolute CD4 T-cell counts. HIV-1 infection was diagnosed if the children had a peripheral mononuclear cell (PBMC) specimen confirmed by polymerase chain reaction (PCR) before 18 months of age or an ELISA confirmed by a Western blot test at or after 18 months of age.
The primary outcome was child mortality during 24 months of follow-up.
Among the 939 children included in the study, 228 died during 17,568 child-months of follow-up, and 257 children were known to be infected with HIV during follow-up. The median maternal CD4 count at baseline was 402 cells/mm3 (interquartile range [IQR]: 278 to 529 cells/mm3). At baseline, 38% of women had a CD4 count of <350 cells/mm3, and 20% were in WHO HIV disease stage 2 or greater. Viral load measurement was available for 177 women at delivery. In a random subset of 387 women at baseline; 49% had a viral load of ≥ 50,000 copies/mL. Mothers of 38 children died during follow-up.
Mother's immunological status measured by CD4 count and mother's HIV disease measured by HIV viral load were both significantly associated with child mortality and more strongly among HIV-uninfected than HIV-infected children. Children whose mothers' baseline CD4 count was at <350 cells/mm3 had a 1.74 times (95% confidence interval [CI]: 1.32 to 2.30) greater risk of mortality through 24 months of follow-up than did children whose mothers' baseline CD4 count was ≥350 cells/mm3. The relative risk (RR) was greater in HIV-uninfected (hazard ratio [HR] = 2.00, 95% CI: 1.36 to 2.94) than in HIV-infected (HR = 1.38, 95% CI: 0.94 to 2.03) children.
Greater maternal viral load also was associated with increased risk of child mortality, especially among infants not known to be infected with HIV. An advanced HIV stage in the mother at baseline was associated with an increased risk of mortality in HIV-uninfected children that was borderline statistically significant (HR = 1.51, 95% CI: 0.98 to 2.32; P = 0.06). Other proxy indicators of poor maternal health and nutritional status also were associated with risk of child death, namely, low maternal hemoglobin concentration at delivery (HR = 1.53, 95% CI: 1.04 to 2.24) and increased ESR at delivery (HR = 1.44, 95% CI: 0.97 to 2.14; P = 0.07). Among HIV-infected children, but not HIV-uninfected children, increased ESR in the mothers at baseline was associated with an increased risk of child death that was borderline statistically significant.
HIV infection in the child was significantly associated with increased risk of death, and the magnitude of risk varied depending on time of diagnosis. Children diagnosed within 49 days of birth had a greater risk of mortality (HR = 6.23, 95% CI: 4.43 to 8.76) compared with those who had diagnosis after 49 days of birth (HR = 2.83, 95% CI: 1.95 to 4.11). The association between child undernutrition as a time-varying predictor and mortality over the next month was examined using anthropometric indices at each clinic visit and also was assessed by lagging the measurements 3 months. The lag was used to separate the effect of malnutrition from that of any acute, pre-death illness. Being underweight (weight-for-age z-score of ≤2) at a previous clinic visit was associated with an HR for death of 3.88 (95% CI: 2.66 to 5.66), and a somewhat attenuated HR of 2.23 (95% CI: 1.30 to 3.85) when weight-for-age was lagged by 3 months. Wasting (weight-for-height z-score of ≤2) was associated with an even greater risk of mortality (HR = 5.35, 95% CI: 3.38 to 8.48), and only slightly greater risk (HR = 2.45, 95% CI: 1.13 to 5.31) when the weight-for-height z-score lagged by 3 months. Children who were stunted (height-for age z-score ≤2) also were at a significantly higher risk of mortality, and the strength of association was attenuated slightly when the assessment was lagged by 3 months.
The authors conclude that mothers' low CD4 cell count during pregnancy is related to increased risk of mortality in their children. Child undernutrition, as measured by wasting, stunting, or underweight, also is strongly associated with greater mortality. The effect of mothers' low CD4 cell count and high HIV viral load may be stronger on HIV-uninfected children.
This cohort study is of good quality because it is a double-blind randomized trial with a clearly ascertained endpoint of mortality. One limitation is that it lacks description of losses to follow-up, although the frequent (monthly) visits and follow-up of mortality with neighbors should have minimized this potential weakness.
Results from this study in Tanzania are similar to those found in studies done in other countries. A small study from Thailand found more than a 4-fold increased risk of death through 1 year of follow-up among HIV-infected children if the maternal CD4 count at delivery was <400 cells/mL.(1) Two studies from the United States reported an association between maternal CD4 cell count at delivery and mortality in HIV-infected children, although the association was not significant in one of the studies after adjusting for HIV RNA level and HIV disease category.(2,3) In this study, the association between maternal CD4 cell count and mortality among HIV-uninfected children is similar to that reported from a study in Zambia that had 4 months of follow-up for child mortality.(4)
To have maximum effect on child survival in regions with high prevalence of HIV, there is a need to integrate other health interventions with programs for treatment and care of HIV-infected women and children. These interventions include comprehensive care and treatment for opportunistic infections and anemia during pregnancy and prevention and treatment of childhood malnutrition.
- Chearskul S, Chotpitayasunondh T, Simonds RJ, et al. Survival, disease manifestation and early predictors of disease progression among children with perinatal human immunodeficiency virus infection in Thailand. Pediatrics. 2002;110:25-30.
- Lambert G, Thea DM, Pliner V, et al. Effect of maternal CD4+ cell count, acquired immunodeficiency syndrome, and viral load on disease progression in infants with perinatally acquired human immunodeficiency virus type 1 infection. J Pediatr. 1997;130:890-897.
- Abrams EJ, Wiener J, Carter R, et al. Maternal health factors and early pediatric antiretroviral therapy influence the rate of perinatal HIV-1 disease progression in children. AIDS. 2003;17:867-877.
- Kuhn L, Kasonde P, Sinkala M, et al. Does severity of HIV disease in HIV-infected mothers affect mortality and morbidity among their uninfected infants? Clin Infect Dis. 2005;41:1654-1661.