Kuhn L, Sinkala M, Kankasa C, Semrau K, Kasonde P, Scott N, et al. High uptake of exclusive breastfeeding and reduced early post-natal HIV transmission. PLoS ONE. 2007 Dec 6;2(12):e1363.
To test the hypothesis that exclusive breastfeeding (EBF) compared with non-EBF is associated with a lower risk of early postnatal HIV transmission.
A prospective observational study, nested within a randomized trial which evaluated whether stopping all breastfeeding at 4 months improves HIV-free survival of infants born to HIV-infected mothers.(1)
HIV-infected women were recruited between May 2001 and September 2004 from prevention of mother-to-child transmission (PMTCT) programs established at two antenatal clinics in Lusaka, Zambia. These programs initially offered nevirapine prophylaxis. In 2004, treatment programs were established at these centers where, after consenting, eligible women at any stage of follow-up started on first-line treatment regimens. Cotrimoxazole was given to all women with CD4 counts <200 cells/mL after November 2003 and to all infants from 6 weeks to 12 months of age. At the time the study began, PMTCT programs using single-dose nevirapine prophylaxis were only beginning to be established, and infant formula was not provided as part of these programs. Replacement feeding was not deemed a safe alternative to breastfeeding due to disadvantaged economic circumstances and high rates of infectious diseases.
HIV-seropositive women were eligible for enrollment if they intended to breastfeed, accepted nevirapine, had no severe pregnancy complications and agreed to the requirements of the study.
All women included in the study were encouraged to breastfeed exclusively for 4 months. Counseling to support EBF began at antenatal visits and included education about reduction of HIV transmission. Study counselors were trained using a modification of the WHO breastfeeding training program. Educational messages about EBF were included in community education and outreach activities, including community drama presentations and talks. Nurse midwives who attended deliveries, even if they were not study staff, were trained to support initiation of breastfeeding as soon as possible after delivery. A home visit scheduled 4 days after delivery focused on preventing early problems with initiating breast-feeding. Study counselors conducted clinic-based counseling sessions every month post-partum. Clinic visits were interspersed with home visits so that contact with the participant occurred every 2 weeks, up to 6 months after delivery. In addition, participants organized themselves into "mothers' support groups" which engaged in various income-generating and self-help activities. Infant formula was not provided before 4 months, barring exceptional circumstances (e.g., maternal death or severe illness or desertion of the infant).
There were two possible random assignments: 1. Participants randomized to the intervention group were encouraged to breastfeed exclusively to 4 months and then to stop breastfeeding abruptly, or as rapidly as possible. Infant formula and weaning cereal were provided to the women in this group at 4 months if they elected to adhere to their random assignment; 2. participants randomized to the control group were encouraged to exclusively breastfeed to 6 months and then to introduce complementary foods (not provided by the study) gradually while continuing to breastfeed. The duration of breastfeeding in this group was based on the women's informed choice. Women were told their random assignment usually around 2 months post-partum.
The primary outcome was to analyze associations between actual feeding practices and early postnatal HIV transmission. Postnatal HIV transmission was measured by regular heel-stick blood samples collected from infants to 24 months of age (on the day of birth, at 1 week, and at 1, 2, 3, 4, 4.5, 5, 6, 9, 12, 15, 18, 21, and 24 months of age) and tested by polymerase chain reaction (PCR). Clinic visits scheduled at these time-points included a structured questionnaire about feeding practices. Questions included 24-hour, 1-week, and since-last-visit recall about infant consumption of any non-breast milk substances. Questions were asked about the frequency of feeding all non-breast milk items and reasons for any non-EBF. Non-EBF was treated as a time-dependent covariate, which changed from EBF to non-EBF irreversibly the first time anything other than breast milk (or prescribed medicines) was reported as fed on the structured questionnaire. As a separate assessment, counselors recorded their opinion following the counseling session as to whether breastfeeding was exclusive or not. A secondary outcome was to collect data necessary to make statistical adjustments for possible confounding by major risk factors for HIV transmission, namely, maternal CD4 count and viral load. For this analysis, blood samples were drawn from women at enrollment during pregnancy. In the case of multiple surviving infants per woman, the first-born was selected for participation.
Study population. The study randomized 958 live-born infants of HIV-infected mothers. For this analysis, 56 (5.8%) infants were excluded because they had a positive HIV test result at ≤3 days (presumed intrauterine infections); 61 (6.4%) were excluded because they had a positive results by 6 weeks (presumed intrapartum infections); 11 (1.1%) died by 6 weeks of age without positive HIV results and 6 died with positive results; and 55 (5.7%) were lost to follow-up or had been withdrawn by 6 weeks. Forty-one (5.3%) of the children were excluded once they were known to have stopped breastfeeding before 4 months. The final analysis included 734 infants surviving HIV-free to 6 weeks and still breastfeeding at 4 months.
Uptake of EBF. Viewed cross-sectionally, >94% of women reported EBF at each clinic visit. Viewed longitudinally, 613 (83.5%) reported EBF up to 4 months. The most common reasons for non-EBF was that the infant was either crying or sick (n=41) and that the infant was cared for by others (n=24). Non-human milk was the most commonly given non-EBF item, followed by other non-milk liquids. Semi-solids were rarely given. The counselors' opinions were poor predictors of whether non-EBF would be reported in the questionnaires (i.e., sensitivity=0.44, specificity=0.98 at 4 months). Women who reported non-EBF before 4 months were significantly more likely to be primiparous, report going out of the home without the child, be single, have a full-time job, have a water source inside their home or on their property, have a refrigerator, and have delivered at the tertiary hospital. There were no significant differences in markers of severity of HIV disease between EBF and non-EBF women.
Reduced HIV transmission with EBF. Using Kaplan-Meier methods, the risk of post-natal HIV transmission before 4 months was significantly lower among 613 women who reported EBF (cumulative probability of a positive PCR by 4 months=0.040 [n=24]; 95% CI: 0.024-0.055) compared with risk among 121 women who reported non-EBF (probability=0.102 [n=12]; 95% CI: 0.047-0.157; p=0.004). In unadjusted analysis, non-EBF was associated with a >3-fold increased risk of early postnatal HIV transmission (relative hazard [RH] =3.48; 95% CI: 1.71-7.08). The association remained significant (RH=2.68; 95% CI: 1.28-5.62) after adjusting for maternal CD4 count, plasma viral load, syphilis screening results and low birth weight. None of the socioeconomic or other characteristics that differed between women reporting EBF and non-EBF were associated with postnatal transmission. If non-EBF was defined as giving non-human milk, semi-solids, or non-milk liquids only (i.e., allowing water or "other" items to be given) in the last 24 hours or at least once per week, the association with transmission was slightly stronger (RH=5.56; 95% CI: 2.43-12.74). Giving water or "other" substances was not associated with a significant increase in transmission (RH=1.87; 95% CI: 0.73-4.81). If non-EBF was defined as giving the child any non-breast milk items five or more times per week or within the past 24 hours, the association with transmission was weaker (RH=2.04; 95% CI: 0.72-5.78) than if non-EBF was defined as giving any non-breast milk items less regularly (i.e., one to four times per week and not in the last 24 hours) (RH=4.12; 95% CI: 1.93-8.79). Maternal CD4 count was a strong predictor of early post-natal transmission, with 86.1% of early postnatal infections occurring among women with CD4 counts <350 cells/mL. Among women with CD4 counts <350 cells/mL, the cumulative probability of postnatal HIV transmission by 4 months was 0.191 (95% CI: 0.095-0.288) for non-EBF (n=65) and 0.063 (95% CI: 0.036-0.091) for EBF (n=306) (RH=3.40; 95% CI: 1.58-7.33) after adjusting for viral load, syphilis status and low birth weight. Among women with CD4 counts >350 cells/mL, there were no infections by 4 months for non-EBF (n=56), and the cumulative probability of postnatal transmission was 0.017 (95% CI: 0.002-0.031) for EBF (n=307). Exclusion of the 6 women who received antiretroviral therapy (ART) during pregnancy and person-time censoring for the 3 women who started ART after delivery did not change the adjusted association between non-EBF and transmission.
Reverse causality. (i.e., child HIV infection increasing the likelihood of non-EBF). No association was found between non-EBF before 4 months and intrauterine or intrapartum infection.
Postnatal transmission older than 4 months. In the control group of the parent study, all women had introduced complementary foods by 6 months. Based on this data, the authors used actuarial life-table methods to investigate age-specific hazard rates of postnatal transmission. They found that in the first 4 months the overall hazard rate was 0.0107 (~1.1% per month) (95% CI: 0.0052-0.0161). In the intervals of 5-8 months and 9-12 months, the hazard rate remained in the 1% per month range. After 12 months, it declined to ~0.5% per month over the 12-24 month period (hazard rate=0.0052; 95% CI: 0.0014-0.0091). Among the EBF group, the monthly hazard rate in the first 4 months was <1% (0.0085; 95% CI: 0.0048-0.0122) compared with 2.4% (0.0244; 95% CI: 0.0100-0.0389) among the non-EBF group. Thus, there was a significant decline in the hazard of postnatal, non-EBF HIV transmission after the first 4 months.
The authors conclude that non-EBF more than doubles the risk of early postnatal HIV transmission in the first 4 months of life, and programs to support EBF should be expanded universally in low resource settings.
Using the Newcastle-Ottawa grading system, this study received a good rating because of the multidimensional intervention and timely data collection efforts. The lack of a non-EBF control group, however, limits the ability to assess the role of the intervention. The authors did not pursue such a control group because they believed it would be unethical. They attempt to minimize the limitations of the study design by looking at potential confounders (i.e., maternal CD4 count and viral load), as well as reverse causality.
Uptake of EBF was greater than the norm in this study. Despite "baby friendly" policies in Zambia, a 2001-2002 demographic health survey estimated that 45% of 2-3 month old infants were exclusively breastfed, declining to 15% by 4-5 months. The findings in this study; however, are consistent with at least three other large African studies, with only a slightly decreased reported HIV reduction.(2,3,4,5) This difference may be due to the author's definition of EBF (no occurrence of any non-breast milk item) or because few women gave their infants semi-solids, which conveys the high risks of postnatal HIV transmission.(4)
EBF is an affordable, feasible, acceptable, safe, and sustainable practice that also reduces HIV transmission in low resource settings. It should be promoted when formula feeding, which essentially eliminates postnatal HIV transmission, is not practical or desirable. Special attention to improve uptake and sustain EBF may be needed for young, primiparous mothers and for women working in the formal sectors. Mothers also need education on how to continue EBF when caring for sick and crying children. The high uptake of EBF in this study was likely due to its intensive, multidimensional interventions; replication outside the study environment will require a considerable investment of time and resources. The decrease in HIV transmission after 4 months that was associated with non-EBF suggests that efforts could be targeted to this early time period. Qualitative and social science research may be useful in identifying other potential interventions to promote EBF. Finally, the finding that irregular, rather than the regular, use of non-breast milk items was associated with stronger risk of HIV transmission underscores the importance of avoiding mixed feeding, which is commonly practiced in many developing areas.
- Sinkala M, Kuhn L , Kankasa C et al. No benefit of early cessation of breastfeeding at 4 months on HIV-free survival of infants born to HIV-infected mothers in Zambia: The Zambia Exclusive Breastfeeding Study. 14th CROI, 25-28 February 2007, Los Angeles, CA. Oral abstract LB 74.
- Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM. Influence of infant feeding patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa. Lancet 1999;354:471-76).
- Coutsoudis A, Pillay K, Kuhn L, Spooner E, Tsai WY, Coovadia HM. Method of feeding and transmission of HIV-1 from mothers to children by 15 months of age: prospective cohort study from Durban, South Africa. AIDS 2001;15:379-87.
- Iliff P, Piwoz E, Tavengwa N, Zunguza C, Marinda E, Nathoo K, et al. Early exclusive breastfeeding reduces the risk of postnatal HIV-1 transmission and increases HIV-free survival. AIDS 2005;19:699-708.
- Coovadia HM, Rollins NC, Bland RM, Little K, Coutsoudis A, Bennish ML, et al. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet 2007;369:1107-16.