Coovadia HM, Rollins NC, Bland RM, Little K, Coutsoudis A, Bennish ML, Newell ML. Mother-to-Child Transmission of HIV-1 Infection during Exclusive Breastfeeding in the First 6 Months of Life: An Intervention Cohort Study. Lancet. 2007 Mar 31;369(9567):1107-16.
This study assessed maternal-to-child HIV transmission and infant survival associated with exclusive breastfeeding compared to other types of infant-feeding, among mothers and infants in KwaZulu Natal.
Prospective cohort study.
This study took place at nine antenatal clinics (seven rural, one semi-urban, and one urban) in KwaZulu Natal, South Africa.
Between October 2001 and April 2005, 2722 pregnant women were enrolled in antenatal care. Of these women, 1372 (50%) HIV-infected mothers gave birth. The analysis is based only on HIV-infected women and their children (first-born children in the case of twins). The median maternal age of HIV-infected women was 25.1 years (range 16.1-45.8); 44% were from rural clinic settings; 58% had seven or more years of primary education.
Single-dose nevirapine, to be taken at delivery, was provided at the first ANC visit. All women were given antenatal counseling about infant-feeding options and were recommended to choose either exclusive breastfeeding (EBF) or formula–feeding (replacement feeding, RF). Mothers were advised to stop all breastfeeding at six months. Breast-fed infants who received formula or water for 4 consecutive days or longer or who received any solid foods were classified as having received mixed breast feeding (MBF). A free six-month supply of commercial infant formula was provided for all women who wanted it for up to 12 months. All mother-infant pairs were visited regularly at home for six months by counselors for assistance in adhering to their infant-feeding plan; participants also attended a clinic every six weeks.
Study outcomes included feeding history, cumulative infant HIV transmission and mortality in the first six months. Information on feeding and mortality was collected by field monitors on a weekly basis. Blood for HIV testing was collected from infants at every clinic visit using a quantitative HIV RNA assay with a sensitivity of 80 copies/µL. Exclusive breastfeeding for infants was defined as receiving only breast milk and no other liquids or solids, except drops for vitamins or drugs.
Feeding choices: At birth, the vast majority of women chose EBF (83%); only 8% chose replacement-feeding, and 3% chose mixed breastfeeding. However, only 40% of mothers exclusively breastfed to six months; 82% exclusively breastfed for ≤6 weeks and 67% for ≤3 months. By six months 44% of mothers were practicing EBF, 20% RF and 46% MF. Women who chose, at birth, RF versus EBF were more likely to have CD4-cell counts less than 200 cells/µL (p=0.003).
HIV transmission: At 4–8 weeks of age, 15.0% (95% CI: 12.5–17.8) and at 20-26 weeks, 21.6% (95% CI: 19.1-24.4) infants were HIV-infected regardless of feeding status. Among EBF children 16.0% (95% CI: 13.0-19.6) were infected at 20-26 weeks. For those infants who were uninfected at six weeks, the subsequent HIV transmission rate was 0.032 per 100 child-days among EBF infants and 0.0436 per 100 child-days among MBF infants [relative hazard (RH) 1-56 (95% CI: 0.66-3.69)].
Factors associated with HIV transmission: In comparison to EBF infants, the following were strongly associated with HIV acquisition: breastfeeding plus solid food (HR 10.9, 95% CI: 1.5–78.0); breastfeeding plus formula (HR 1.8, 95% CI: 0.98–3.4, p=0.06); and early-mixed (before three months) (n=356) (HR 1.54, 95% CI: 1.10-2.15) and late-mixed feeding (after three months) (n=257) (HR 1.53, 95% CI: 1.07-2.20). HIV transmission risk at six months in the exclusive breastfeeding group was 34% for infants whose mothers had CD4 <200 cells/ µL and 17% in infants with mothers who had CD4 ≥200 cells/µL.
Mortality rates: Among 1034 EBF children regardless of HIV status, 94 (9.1%) died. Kaplan-Meier estimated 6-month mortality was 12.2% (95% CI: 10.1–14.9); 73 (78%) of the 94 infants who died were HIV-infected. Among RF children 8 (7.9%) of 101 died; Kaplan-Meier 3-month mortality estimate was 15.12% with no subsequent deaths. Among children with MBF from birth there were 5 (15.6%) deaths out of 32, all within the first 30 days of life. In a Cox model including EBF and RF infants, death was associated with RF (HR 2.06, 95% CI: 1.00-4.27). Among EBF infants the Kaplan-Meier estimate of HIV-free survival (absence of death or HIV infection) was 75.4% at 6 months.
The authors conclude that the substantial mortality associated with not breastfeeding emphasizes the importance of developing feeding policies appropriate to background infant-mortality rates, and breastfeeding remains a key intervention that can reduce mortality. Furthermore, authors emphasize the importance of promoting exclusive breastfeeding in HIV-uninfected mothers in high-prevalence settings; in addition to the proven survival benefits for the infant, if such mothers unknowingly become HIV-infected while breastfeeding, exclusive breastfeeding will carry a lower risk of transmission than will mixed breastfeeding.
Using the Newcastle-Ottawa assessment scale for cohort studies, this study received a good rating. The selection process allowed for a representative sample of women attending KwaZulu Natal antenatal clinics to be included in the study. Loss to follow-up was explained in detail, and mortality, HIV transmission, and feeding practices were obtained for children from birth to six months of age. Interpretation of study findings was complicated by lack of clarity in presentation of results and program objectives relative to the conclusions drawn by the authors.
Results from this study are similar to others that have shown that exclusive breastfeeding carries a significantly lower risk of HIV transmission than does mixed breastfeeding.(1,2) However, EBF, MBF and RF were not randomly assigned, and therefore residual confounding may have influenced the results. Moreover, there were only small numbers of women who elected RF and large numbers who crossed over from EBF to MBF during the study, both of which have the possibility of introducing error. Even though the primary objective of the study was to evaluate HIV transmission among women who breastfed, the authors also examined whether EBF was associated with lower HIV transmission and lower mortality compared to other feeding options. They found that EBF had a lower mortality than RF and that, while risk of postnatal HIV transmission was slightly higher among MBF children, introduction of solid foods resulted in a dramatic increase in risk of transmission. The findings regarding MBF, including introduction of formula, early MBF and late MBF are marginally significant, which may be a function of small numbers.
It is unlikely that a true randomized controlled trial with high adherence to EBF, MBF and RF to measure risks of HIV transmission and mortality among both HIV infected and uninfected infants will ever be conducted. As such, cohort data such as these, will likely be the only data available to guide feeding policies. An earlier trial (3) found that RF significantly reduced risk of HIV transmission compared to EBF, but more recent programmatic data have found significantly higher mortality in infants who received RF compared to EBF.(4-7) Other results regarding HIV transmission and risk factors were similar to other studies, including postnatal transmission risk from breastfeeding alone.v This is evaluated among those infants who were HIV-negative at six weeks. Participants in this study showed higher adherence to EBF, compared to two other studies in which only 8% and 26% of mother-infant pairs were doing so at three months.(2,8) The relationship between increased HIV transmission and mortality in breastfed infants with mothers with CD4 counts <200 cells/ µL has been shown in others studies from Africa.(2,9,10,11)
The key findings of this study demonstrate that early introduction of semi-solid foods especially and formula and animal milk, to a lesser extent, increase the risk of postnatal mother-to-child HIV transmission if infants are also breastfeeding. It also documents mortality risk among children receiving RF. Its consistency with other studies that have found a higher risk of postnatal transmission among children receiving MBF compared to EBF suggests that MBF should be discouraged. Postnatal HIV transmission could potentially be low with RF, but problems with increased mortality due to other causes remain, particularly those associated with contaminated water and lack of sterilization of bottles. If women are unable to exclusively breastfeed after a certain point in time, they should transition to exclusive formula-feeding, rather than a mixed regimen. Because postnatal HIV transmission is significantly higher among mothers with CD4 <200, providing eligible women with ART is an important means to improve the survival of not only the mother, but also her infant.
- 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: a prospective cohort study. South African Vitamin A Study Group. Lancet 1999 Aug 7;354(9177):471-6.
- Iliff PJ, Piwoz EG, Tavengwa NV, Zunguza CD, Marinda ET, Nathoo KJ, et al. Early exclusive breastfeeding reduces the risk of postnatal HIV-1 transmission and increases HIV-free survival. AIDS 2005 Apr 29;19(7):699-708.
- Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha A, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000 Mar 1;283(9):1167-74.
- Sinkala M 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. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 74, 2007.
- Onyango C, M.F., Bagenda D, Mubiru M , Musoke P , Fowler M , Jackson J, and L Guay, Early Breastfeeding Cessation among HIV-exposed Negative Infants and Risk of Serious Gastroenteritis: Findings from a Perinatal Prevention Trial in Kampala, Uganda, in Fourteenth Conference on Retroviruses and Opportunistic Infections (CROI). 2007: Los Angeles.
- Kourtis A, D.F., L Hyde, H C Tien, C Chavula, N Mumba, M Magawa, R Knight, C Chasela, C van der Horst, and the BAN Study Team Diarrhea in Uninfected Infants of HIV-infected Mothers Who Stop Breastfeeding at 6 Months: The BAN Study Experience, in Fourteenth Conference on Retroviruses and Opportunistic Infections (CROI). 2007: Los Angeles.
- Kafulafula G, T.M., Hoover D, Li Q, Kumwenda N, MipandoL, Taha T, Mofenson L, and Fowler M, Post-weaning Gastroenteritis and Mortality in HIV-uninfected African Infants Receiving Antiretroviral Prophylaxis to Prevent MTCT of HIV-1, in Fourteenth Conference on Retroviruses and Opportunistic Infections (CROI). 2007: Los Angeles.
- Coutsoudis A, Pillay K, Kuhn L, Spooner E, Tsai WY, Coovadia HM, et al. 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 Feb 16;15(3):379-87.
- Leroy V, Karon JM, Alioum A, Ekpini ER, van de Perre P, Greenberg AE, et al. Postnatal transmission of HIV-1 after a maternal short-course zidovudine peripartum regimen in West Africa. AIDS 2003 Jul 4;17(10):1493-501.
- Coutsoudis A, Dabis F, Fawzi W, Gaillard P, Haverkamp G, Harris DR, et al. Late postnatal transmission of HIV-1 in breast-fed children: an individual patient data meta-analysis. J Infect Dis 2004 Jun 15;189(12):2154-66. Epub 2004 May 26.
- Fawzi W, Msamanga G, Spiegelman D, Renjifo B, Bang H, Kapiga S, et al. Transmission of HIV-1 through breastfeeding among women in Dar es Salaam, Tanzania. J Acquir Immune Defic Syndr 2002 Nov 1;31(3):331-8.