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Breast-feeding and maternal-infant transmission of human immunodeficiency virus type 1
CURRENT LITERATURE AND CLINICAL ISSUES
Breast-feeding and maternal-infant transmission of human immunodeficiency virus type I By 1993 more than 1 million children will have been infected with human immunodeficiency virus type 1, the vast majority acquiring infection from their mothers. 1'2 Most of the infected children reside in developing countries, where the prevalence of HIV-1 infection in women is highest. 1 Interruption of maternal-infant HIV-1 transmission has been hindered by lack of information regarding the timing and precise mechanisms of transmission. Available data suggest that postpartum transmission of HIV-I occurs. 3-13The purpose of this document is to review and consolidate existing information on postpartum transmission of HIV-1 through breast-feeding and to suggest additional studies to clarify the risks associated with breast-feeding. Apparent transmission of HIV-1 through breast-feeding was first described by Ziegler et al. 3 Since then, 22 infants who probably acquired HIV-1 through breast-feeding have been described. 3~3 In almost all instances, seroconversion in the mothers appears to have occurred after delivery, with subsequent infection of their children. In nine of the mothers, seroconversion occurred after postpartum blood transfusions, one mother was an intravenous drug user, and the remaining 12 women were assumed to have acquired HIV- 1 through heterosexual transmission. The presumptive mode of maternal-infant HIV-1 transmission in these cases was through breast-feeding, although the possibility that some of the women had been infected before delivery could not be ruled out. Van de Perre et al. ~2 provided the most convincing data in support of HIV-1 transmission through breast-feeding; they identified four women with seroconversion 4 or more months after delivery who apparently transmitted HIV-1 to their infants. It is unlikely that these women were infected at the time of delivery, so breastfeeding was the most likely means of HIV-I transmission. Persons with recent seroconversion and those with advanced
Supported in part by grants from the World Health Organization and grant No. 1RO1 A126521 from the National Institutes of Health. This document reflects the opinions of the authors and does not represent official policy of the World Health Organization or the U.S. Public Health Service. 9/34/37468
illness have high titers of HIV-1 in blood, and titers may be high in other body fluids, including milk. 14, 15 Thus women with high titers may be more likely to transmit HIV-1 through breast-feeding than women with asymptomatic infection who were infected before pregnancy. The HIV-1 has been demonstrated in human milk. Thiry et al. 16 isolated HIV-1 from milk supernatant collected from three symptom-free HIV-1 carriers, but the investigators were unable to isolate virus from milk lymphocytes; quantitative assays were not conducted. Although Vogt et a1.17 subsequently reported the isolation of HIV-1 from the cellular fraction of milk, the lack of details makes assessment difficult. Bucens et al.18 observed HIV- 1 virions within histiocytes and in the cell-free fraction of milk by electron microscopy. In addition, part of the HIV- 1 genome has been detected in mononuclear cells of colostrum collected from two symptom-free seropositive women. 19 More recently, we have detected HIV-1 viral DNA by polymerase chain reaction in 25 (73%) of 38 milk specimens from HIV-l-seropositive women and in none of 13 specimens from seronegative women. 2~ HIV-1
Human immunodeflciencyvirus type 1
Studies of cytomegalovirus and other viral agents known to be excreted in human milk have demonstrated that not all infected women excrete virus in their milk and that viruses may be shed intermittently.21 Therefore the failure to identify virus in a single specimen does not rule out virus excretion. Colostrum contains a higher concentration of lymphocytes and macrophages than later milk and may be more likely to harbor cell-associated viruses such as HIV- 1. Studies addressing the transmission ofHIV- 1 during breastfeeding should therefore evaluate sequentially collected specimens from seropositive women. The majority of breast:fed infants born to HIV-l-seropositive women remain uninfected. If HIV- 1 is present in the milk of a high percentage of seropositive women, factors present either in the milk or in the infant must diminish the risk of transmission through breast-feeding. Human milk contains a number of components that could reduce the infectivity of HIV-1, including immunoglobulins,leukocytes,
325
326
R u f f et al.
The Journal of Pediatrics August 1992
T a b l e . Comparison of maternal-infant HIV-1 transmission rates in breast-fed versus non-breast-fed infants born to
HIV- 1 seropositive women Rate of maternal-infant HIV-I transmission Bottle-fed infants
Breast-fed infants Country
Reference
No.
% Infected
No.
% Infected
United States (New York City) United States (Haitian) Haiti Zaire Congo
40 38 41 37 42
0 25 230 33 65
NA 28 25 18 52
38 54 0 16 0
29 33 NA 25 NA
NA, Not applicable.
lactoferrin, and lysozymes. 22, 23 Human milk also contains nonspecific lipid-dependent activity directed primarily against enveloped viruses, and enzymes in the infant's stomach may induce the release of additional lipids that contribute to antiviral activity.24 Last, human milk contains additional factors that inhibit the binding of HIV-1 envelope glycoproteins to CD4. 25 The risk of HIV-1 transmission associated with oral exposure to virus appears to be very low. 26, 27 Several investigators have reported inhibition of HIV-1 by saliva, probably by a combination of factors including salivary glycoproteins and virus-specific IgG and IgA. 28, 29 The presence of such salivary factors in children born to HIV-1-seropositive women has not been assessed. The virus is acid labile, and therefore the pH of the stomach might also affect survival of maternal HIV-l-infected cells transmitted to the child during breast-feeding. Achlorhydria, as in very young and premature infants, might enhance survival of ingested HIV- 1. Whether free virus infects intact intestinal mucous membranes or HIV-l-infected cells from milk enter the infant's circulation has not been well established. Milk macrophages may survive under conditions simulating the intestine,3~ and there is some evidence suggesting transfer of cell-mediated immunity from mothers to their breast-fed infants.3~-33Adachi et al. 34 and Moyer et al. 35demonstrated that HIV can infect gastrointestinal cell lines, and p24 antigen has been detected in intestinal biopsy specimens from HIV-infected patients. 36 Disruption of vaginal mucous membranes by infection or trauma has been associated with an increased risk of sexually transmitted HIV-1 infections. Common childhood infections such as oral candidiasis, gingivostomatitis, pharyngitis, and gastroent~gritis could affect oral and intestinal mucosal integrity, possibly facilitating transmission of HIV-1 infection. Although the potential for HIV-1 transmission through breast-feeding exists, the fraction of maternal-infant trans-
mission attributable to breast-feeding has not been established. The limited data comparing the rate of maternal-infant transmission in breast-fed and bottle-fed populations are somewhat contradictory. Manzila et al. 37 found no differences in HIV-1 infection rates among infants born to seropositive women who received only breast-feeding, only artificial milk, or a combination of both. Hutto et al. 3s also failed to detect any significant difference in the rate of HIV-1 transmission between breast-fed and bottle-fed infants. In contrast, Blanche et al., 39 and more recently the European Collaborative Study (C. Peckham: personal communication, Feb. 15, 1992), noted a higher rate of HIV-1 transmission to breast-fed infants than bottle-fed infants. Cohort studies in different populations have shown similar maternal-infant transmission rates among breastfed and bottle-fed infants4~ (Table). However, these studies may not be directly comparable because of differing methods, and the data are insufficient to adjust statistically for potentially confounding factors. In developing countries with high infant mortality rates, many children die during their first year of life without a definitive determination of H I V - 1 infection status. Thus maternal-infant transmission rates may be underestimated in developing countries, precluding the detection of slight differences in transmission rates among different populations. Even a small increase in the risk of transmission through breast-feeding could affect large numbers of infants in developing countries. If the maternal-infant transmission rates in breast- and bottle-fed infants are 30% and 25%, respectively, and if 1 million children are breast fed by HIV-l-seropositive women each year, then 50,000 additional children could be infected through breast-feeding. However, any theoretical risks associated with breastfeeding must be balanced against the other, beneficial effects of breast-feeding. The course of HIV-1 infection in children varies greatly and may be affected by several factors, including the adequacy of nutritional intake and the
Volume 121 Number 2
Breast-feeding and maternal-infant HIV-1 transmission
presence of other infections. By providing optimal nutrition for infants in developing countries and protection against respiratory and gastrointestinal infections, breast-feeding may slow the course of HIV- 1 disease in perinatally infected infants. In one small study, breast-fed HIV-l-infected children progressed to acquired immunodeficiency syndrome at a slower rate than did bottle-fed infants.43 Whether the quantity and composition of milk from HIV1-seropositive women differ from those of seronegative women is also unknown and warrants further study. Studies of larger numbers of breast-fed and non-breast-fed HIV-l-infected infants are indicated to evaluate both the potential benefits and the possible risks associated with breast-feeding. The use of anti-HIV-1 chemotherapeutic agents in lactating women may affect transmission or progression of HIV-1 infection among breast-fed infants. The excretion and antiretroviral effects of these drugs in milk need to be evaluated. If the drugs are excreted in milk, infants may receive specific anti-HIV-1 therapy while maintaining the recognized benefits of breast-feeding. However, the potential risks to infants associated with use of these medications require careful evaluation, especially for the majority of infants who remain uninfected. Determining the role of breast-feeding in the transmission of HIV-1 from mother to infant is important for the establishment of public health policy. The protective effects of breast-feeding on infant survival and nutritional status vary depending on socioeconomic status and the availability of other preventive and therapeutic measures. In developing countries the use of alternatives to breast-feeding is associated with increased rates of malnutrition and death. 44"46 The recommendations of advisory bodies reflect the differing perceived risks and benefits of breast-feeding by HIV-l-seropositive women. In several industrialized countries, including the United States, Canada, Great Britain, France, Australia, and the former Soviet Union, HIV- 1-seropositive women have been advised not to breastfeed. 47 However, in developing countries where safe and effective alternatives are not available, the World Health Organization recommends that women breast-feed regardless of their HIV-1 serologic status. 48 The majority of infants born to HIV-1-seropositive women do not become infected, so failure to breast-feed would likely result in an increased rate of adverse outcomes for these infants. Heymann49 and Kennedy et al. 5~ modeled the potential impact of HIV-1 transmission by breast-feeding and the negative impact on childhood survival rates associated with withholding of breast-feeding in developing countries. In settings where the infant mortality rate is high, the benefits from breast-feeding exceed the potential added risk of HIV-1 transmission
327
by breast-feeding. Thus, for most women in developing countries who were infected with HIV-1 before or during pregnancy, the World Health Organization's recommendation to breast-feed regardless of HIV-1 status appears appropriate. However, additional data are needed to guide decision making in this complex and often emotional area of public health policy. The available epidemiologic and virologic data regarding transmission of HIV-1 through breast-feeding are incomplete. The prevalence rate and viability of HIV-1 and anti-HIV-1 activity in human milk should be further defined. Studies should be conducted in several communities with differing socioeconomic and sanitary conditions to determine whether the presence of HIV-1 in human milk is associated with transmission of infection to infants. The impact of breast-feeding on the infant mortality rate and on the nutritional status and rate of HIV-1 infection of infants born to H IV-1-seropositive women should also be evaluated. Although randomized clinical trials would ideally provide answers to these questions, practical and ethical problems limit the ability to implement such studies. Until additional data become available, it will be difficult to assess accurately the risk of HIV-1 transmission through breast-feeding, and we must continue to base our recommendations for seropositive mothers on limited information.
Andrea J. Ruff, MD Neal A. Halsey, MD Jacqueline Coberly, PhD Department of International Health Johns Hopkins University School of Hygiene and Public Health Baltimore, MD 21205 Reginald Boulos, MD, MPH Centers for Development and Health Port-au-Prince, Haiti REFERENCES
I. Chin J. Current and future dimensions of the HIV/AIDS pandemic in women and children. Lancet 1990;336:221-4. 2. OxtobyM. Perinatally acquired human immunodeficiencyvirus infection. Pediatr Infect Dis 1990;9:609-19. 3. Ziegler J, Cooper D, Johnson R, Gold J. Postnatal transmission of AIDS-associated retrovirus from mother to infant. Lancet 1985;1:896-8. 4. Lcpage P, Van de Perre P, Carael M, et al. Postnatal transmissionfrom mother to child [Letter]. Lancet 1987;2:400. 5. Weinbreck P, Loustaud V, Denis F, Vidal B, Mounier M, de Lumley L [Letter]. Postnatal transmission of HIV infection. Lancet 1988;1:482. 6. Ziegler J, Stewart G, Penny R, Stuckey M, Good S. Breast feeding and transmission of HIV from mother to infant lab-
328
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stract]. Fourth International Conference on AIDS, Stockholm, June 1988. 7. Colebunders R, Kapita B, Nekwei W, et al. Breastfeeding and transmission of HIV [Letter]. Lancet 1988;2:1487. 8. Oxtoby M. Human immunodeficiency virus and other viruses in human milk: placing the issues in broader perspective. Pediatr Infect Dis J 1988;7:825-35. 9. Hira S, Mangrola U, Mwale C, et al. Apparent vertical transmission of human immunodeficiency virus type 1 by breastfeeding in Zambia. J PEDIATR 1990;117:421-4. 10. Osoba A, Fairclough D, Waller D, et al. Maternal transmission of human immunodeficiency virus (HIV). Saudi Med J 1990;11:125-9. 11. Stiehm E, Vink P. Transmission of human immunodeficiency virus infection by breast-feeding. J PEDIATR 199l;118:410-2. 12. Van de Perre P, Siminon A, MseUati P, et al. Postnatal transmission of the human irnmunodeficiency virus type 1 from mother to infant: a prospective cohort study in Kigali, Rwanda. N Engl J Med 1991;325:593-8. 13. Malaviya A, Pande I, Adya C, Kumar A, Kakkar R, Khan M. Circumstantial evidence of HIV transmission via breast milk. J Acquir Immune Defic Syndr 1992;5:102. 14. Clark S, Saag M, Decker W, et al. High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-I infection. N Engl J Med 1991;324:954-60. 15. Daar E, Moudgil T, Meyer R, Ho D. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med 1991;324:961-4. 16. Thiry L, Sprecher-Goldberger S, Jonckheer T, et al. Isolation of AIDS virus from cell-free breast milk of three healthy virus carriers [Letter]. Lancet 1985;2:891-2. 17. Vogt M, Witt D, Craven D, et al. Isolation of HTLV-III/LAV from cervical secretions of women at risk for AIDS [Letter]. Lancet 1986;1:525. 18. Bucens M, Armstrong J, Stuckey M. Virologic and electron microscopic evidence for postnatal HIV transmission via breast milk [Abstract]. Fourth International Conference on AIDS, Stockholm, June 1988. 19. Pezzella M, Caprilli F, Cordiali F, Crescimbeni E, La Rosa F, Castiglione H. The presence of HIV-1 genome in human colostrum from asymptomatic seropositive mothers [Abstract]. Sixth International Conference on AIDS, San Francisco, 1990. 20. Ruff A, Coberly J, Farzadegan H, et al. Detection of HIV-1 by PCR in breast milk [Abstract]. Seventh International Conference on AIDS, Florence, Italy, 1991. 21. Pass R. Epidemiology and transmission of cytomegalovirus. J Infect Dis 1985;152:243-8. 22. Ogra S, Ogra P. Human breast milk. In: Remington J, Klein J, eds. Infectious diseases of the fetus and newborn infant. Philadelphia: WB Saunders, 1990:68-88. 23. Welsh J, May J. Anti-infective properties of breast milk. J PEDIATR 1979;94:1-9. 24. Issacs C, Thormar H, Pessolano T. Membrane-disruptive effect of human milk: inactivation of enveloped viruses. J Infect Dis 1986;154:966-71. 25. Newburg D, Viscidi R, RuffA, Yolken~:~A human milk factor inhibits binding of human immunodeficiency virus to the CD4 receptor. Pediatr Res 1992;31:22-8. 26. Lifson A, O'Malley P, Hessol N, Buchbinder S, Cannon L, Rutherford G. HIV seroconversion in two homosexual men
The Journal of Pediatrics August 1992
27. 28.
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30.
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32.
33.
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35.
36.
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38.
39.
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41.
42.
43.
after receptive oral intercourse with ejaculation: Implications for counseling concerning safe sexual practices. Am J Public Health 1991;81:1509-11. Rozenbaum W, Gharakhanian S, Cardon B, Duval E, Coulaud J. HIV transmission by oral sex [Letter]. Lancet 1988;1:1395. Archibald D, Cole G. In vitro inhibition of HIV-1 infectivity by human salivas. AIDS Res Hum Retroviruses 1990;6:142532. Sun D, Archibald D, Furth P. Variation of secretory antibodies in parotid saliva to human immunodeficiency virus type l with HIV-1 disease stage. AIDS Res Hum Retroviruses 1990;6:933-41. Blau H, Passwell H, Levanon M, Davidson J, Kohen F, Ramot B. Studies on human macrophages: effect of activation on phagocytosis and secretion of prostaglandin E2 and lysozyme. Pediatr Res 1983;17:241-5. Ogra S, Wientraub D, Ogra P. Immunologic aspects of human colostrum and milk. III. Fate and absorption of cellular and soluble components in the gastrointestinal tract of the newborn. J Immunol 1977;119:245-8. Mohr J. The possible induction and/or acquisition of cellular hypersensitivity associated with ingestion of colostrum. J PEmATR 1973;82:1062-4. Schlesinger J, Covelli H. Evidence for transmission of lymphocyte responses to tuberculin by breast feeding. Lancet 1977;2:529-32. Adachi A, Loenig S, Gendelman H, et al. Productive, persistent infection of human colorectal cell lines with human immunodeficiency virus. J Virol 1987;61:209-13. Moyer M, Huot R, Ramirez A, Joe S, Meltzer M, Gendelman H. Infection of human gastrointestinal cells by HIV-1. AIDS Res Hum Retroviruses 1990;6:1409-15. Ullrich R, Zeitz M, Heise W, L'age M, Hoffken G, Riecken E. Small intestinal structure and function in patients infected with human immunodeficiency virus (HIV): evidence of HIV-induced enteropathy. Ann Intern Med 1989;11 l(l):1521. Manzila T, Baende E, Kabagabo U, Nsa W, Zola B, Ryder R. Perinatally acquired HIV infection: absence of additional risk due to breast feeding in a cohort of 108 infants born to HIV(+) mothers [Abstract]. The implications of AIDS for mothers and infants. Paris, November 1989. Hutto C, Parks W, Lai S, et al. A hospital-based prospective study of perinatal infection with human immunodeficiency virus type 1. J PEOf~ATR199l;118:347-53. Blanche S, Rouzioux C, Moscato ML, et at. A prospective study of infants born to women seropositive for human immunodeficiency virus type 1. N Engl J Med 1989;320:1643-8. Thomas PA, NYC Perinatal HIV Transmission Collaborative Study Group. Early predictors and rate of perinatal HIV disease [Abstract]. Fifth International Conference on AIDS, Montreal, June 1989. Halsey, NA, Boulos R, Holt E, et al. Transmission of HIV-I infections from mothers to infants in Haiti: impact on childhood mortality and malnutrition. JAMA 1990;264:2088-92. Lallemont M, Lallemont-LeCoeur S, Cheynier D, et al. Mother-child transmission of HIV-I and infant survival in Brazzaville, Congo. AIDS 1989;3:643-6. Tozzi A, Pezzotti P, Greco D. Does breast-feeding delay progression to AIDS in HIV-infected children? AIDS 1990; 4:1293-4.
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Breast-feeding and maternal-infant HIV-1 transmission
44. Clements J, Sack D, Harris J, et al. Breastfeeding and the risk of severecholera in rural Bangladeshchildren. Am J Epidemiol 1990;131:400-11. 45. Wright A, Holberg C, Martinez F, et al. Breastfeeding and lower respiratory tract illness in the first year of life. BMJ 1989;299:946-9. 46. Howie P, Forsyth J, Ogston S, et al. Protective effect of breastfeeding against infection. BMJ 1990;300:11-6. 47. Centers for Disease Control. Recommendationsfor assisting in the prevention of perinatal transmission of human T-lymphotrophic virus type III/lymphadenopathy-associated virus and acquired immunodeficiency syndrome. MMWR 1985; 34:721-26, 731.
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48. World Health Organization. Breast-feeding/breast milk and human immunodeficiencyvirus (HIV). Wkly Epidemiol Ree 1987;62:245-6. 49. Heymann S. Modelingthe impact of breastfeedingby HIV infected women on child survival. Am J Public Health 1990; 80:1305-9. 50. Kennedy K, Fortney J, Bonhomme H, Potts M, Lamptey P, Carswell W. Do the benefits of breastfeeding outweigh the risks of postnatal transmission of HIV via breast milk? Trop Doct 1990;20:25-9.
CORRECTIONS In the article "Visual and Brain Function Measurements in Studies of n-3 Fatty Acid Requirements of Infants," (Uauy et al.), which appeared in the supplement to the APril 1992 issue of THE JOURNAL, the last sentence of the abstract (page S168), printed as "Studies of term infants suggest that visual acuity is more mature in formula-fed relative to breast-fed infants at 4 months and 3 years of age," should read "Studies of term infants suggest that visual acuity is more mature in breast-fed than in formula-fed infants at 4 months and 3 years of age." In the article "Pancreatitis in Young Children With Cystic Fibrosis" (Atlas et al.), which appeared in the May 1992 issue of THE JOURNAL, the first sentence of paragraph 2 in the Discussion section (page 758) reads "None o f our patients is homozygous for the AF508 mutation; this is consistent with the pancreatic sufficiency." However, additional molecular study of patient 5 found her to be homozygous for AF508. This finding does not change the conclusion of the article.
Breast-feeding and maternal-infant transmission of human immunodeficiency virus type I By 1993 more than 1 million children will have been infected with human immunodeficiency virus type 1, the vast majority acquiring infection from their mothers. 1'2 Most of the infected children reside in developing countries, where the prevalence of HIV-1 infection in women is highest. 1 Interruption of maternal-infant HIV-1 transmission has been hindered by lack of information regarding the timing and precise mechanisms of transmission. Available data suggest that postpartum transmission of HIV-I occurs. 3-13The purpose of this document is to review and consolidate existing information on postpartum transmission of HIV-1 through breast-feeding and to suggest additional studies to clarify the risks associated with breast-feeding. Apparent transmission of HIV-1 through breast-feeding was first described by Ziegler et al. 3 Since then, 22 infants who probably acquired HIV-1 through breast-feeding have been described. 3~3 In almost all instances, seroconversion in the mothers appears to have occurred after delivery, with subsequent infection of their children. In nine of the mothers, seroconversion occurred after postpartum blood transfusions, one mother was an intravenous drug user, and the remaining 12 women were assumed to have acquired HIV- 1 through heterosexual transmission. The presumptive mode of maternal-infant HIV-1 transmission in these cases was through breast-feeding, although the possibility that some of the women had been infected before delivery could not be ruled out. Van de Perre et al. ~2 provided the most convincing data in support of HIV-1 transmission through breast-feeding; they identified four women with seroconversion 4 or more months after delivery who apparently transmitted HIV-1 to their infants. It is unlikely that these women were infected at the time of delivery, so breastfeeding was the most likely means of HIV-I transmission. Persons with recent seroconversion and those with advanced
Supported in part by grants from the World Health Organization and grant No. 1RO1 A126521 from the National Institutes of Health. This document reflects the opinions of the authors and does not represent official policy of the World Health Organization or the U.S. Public Health Service. 9/34/37468
illness have high titers of HIV-1 in blood, and titers may be high in other body fluids, including milk. 14, 15 Thus women with high titers may be more likely to transmit HIV-1 through breast-feeding than women with asymptomatic infection who were infected before pregnancy. The HIV-1 has been demonstrated in human milk. Thiry et al. 16 isolated HIV-1 from milk supernatant collected from three symptom-free HIV-1 carriers, but the investigators were unable to isolate virus from milk lymphocytes; quantitative assays were not conducted. Although Vogt et a1.17 subsequently reported the isolation of HIV-1 from the cellular fraction of milk, the lack of details makes assessment difficult. Bucens et al.18 observed HIV- 1 virions within histiocytes and in the cell-free fraction of milk by electron microscopy. In addition, part of the HIV- 1 genome has been detected in mononuclear cells of colostrum collected from two symptom-free seropositive women. 19 More recently, we have detected HIV-1 viral DNA by polymerase chain reaction in 25 (73%) of 38 milk specimens from HIV-l-seropositive women and in none of 13 specimens from seronegative women. 2~ HIV-1
Human immunodeflciencyvirus type 1
Studies of cytomegalovirus and other viral agents known to be excreted in human milk have demonstrated that not all infected women excrete virus in their milk and that viruses may be shed intermittently.21 Therefore the failure to identify virus in a single specimen does not rule out virus excretion. Colostrum contains a higher concentration of lymphocytes and macrophages than later milk and may be more likely to harbor cell-associated viruses such as HIV- 1. Studies addressing the transmission ofHIV- 1 during breastfeeding should therefore evaluate sequentially collected specimens from seropositive women. The majority of breast:fed infants born to HIV-l-seropositive women remain uninfected. If HIV- 1 is present in the milk of a high percentage of seropositive women, factors present either in the milk or in the infant must diminish the risk of transmission through breast-feeding. Human milk contains a number of components that could reduce the infectivity of HIV-1, including immunoglobulins,leukocytes,
325
326
R u f f et al.
The Journal of Pediatrics August 1992
T a b l e . Comparison of maternal-infant HIV-1 transmission rates in breast-fed versus non-breast-fed infants born to
HIV- 1 seropositive women Rate of maternal-infant HIV-I transmission Bottle-fed infants
Breast-fed infants Country
Reference
No.
% Infected
No.
% Infected
United States (New York City) United States (Haitian) Haiti Zaire Congo
40 38 41 37 42
0 25 230 33 65
NA 28 25 18 52
38 54 0 16 0
29 33 NA 25 NA
NA, Not applicable.
lactoferrin, and lysozymes. 22, 23 Human milk also contains nonspecific lipid-dependent activity directed primarily against enveloped viruses, and enzymes in the infant's stomach may induce the release of additional lipids that contribute to antiviral activity.24 Last, human milk contains additional factors that inhibit the binding of HIV-1 envelope glycoproteins to CD4. 25 The risk of HIV-1 transmission associated with oral exposure to virus appears to be very low. 26, 27 Several investigators have reported inhibition of HIV-1 by saliva, probably by a combination of factors including salivary glycoproteins and virus-specific IgG and IgA. 28, 29 The presence of such salivary factors in children born to HIV-1-seropositive women has not been assessed. The virus is acid labile, and therefore the pH of the stomach might also affect survival of maternal HIV-l-infected cells transmitted to the child during breast-feeding. Achlorhydria, as in very young and premature infants, might enhance survival of ingested HIV- 1. Whether free virus infects intact intestinal mucous membranes or HIV-l-infected cells from milk enter the infant's circulation has not been well established. Milk macrophages may survive under conditions simulating the intestine,3~ and there is some evidence suggesting transfer of cell-mediated immunity from mothers to their breast-fed infants.3~-33Adachi et al. 34 and Moyer et al. 35demonstrated that HIV can infect gastrointestinal cell lines, and p24 antigen has been detected in intestinal biopsy specimens from HIV-infected patients. 36 Disruption of vaginal mucous membranes by infection or trauma has been associated with an increased risk of sexually transmitted HIV-1 infections. Common childhood infections such as oral candidiasis, gingivostomatitis, pharyngitis, and gastroent~gritis could affect oral and intestinal mucosal integrity, possibly facilitating transmission of HIV-1 infection. Although the potential for HIV-1 transmission through breast-feeding exists, the fraction of maternal-infant trans-
mission attributable to breast-feeding has not been established. The limited data comparing the rate of maternal-infant transmission in breast-fed and bottle-fed populations are somewhat contradictory. Manzila et al. 37 found no differences in HIV-1 infection rates among infants born to seropositive women who received only breast-feeding, only artificial milk, or a combination of both. Hutto et al. 3s also failed to detect any significant difference in the rate of HIV-1 transmission between breast-fed and bottle-fed infants. In contrast, Blanche et al., 39 and more recently the European Collaborative Study (C. Peckham: personal communication, Feb. 15, 1992), noted a higher rate of HIV-1 transmission to breast-fed infants than bottle-fed infants. Cohort studies in different populations have shown similar maternal-infant transmission rates among breastfed and bottle-fed infants4~ (Table). However, these studies may not be directly comparable because of differing methods, and the data are insufficient to adjust statistically for potentially confounding factors. In developing countries with high infant mortality rates, many children die during their first year of life without a definitive determination of H I V - 1 infection status. Thus maternal-infant transmission rates may be underestimated in developing countries, precluding the detection of slight differences in transmission rates among different populations. Even a small increase in the risk of transmission through breast-feeding could affect large numbers of infants in developing countries. If the maternal-infant transmission rates in breast- and bottle-fed infants are 30% and 25%, respectively, and if 1 million children are breast fed by HIV-l-seropositive women each year, then 50,000 additional children could be infected through breast-feeding. However, any theoretical risks associated with breastfeeding must be balanced against the other, beneficial effects of breast-feeding. The course of HIV-1 infection in children varies greatly and may be affected by several factors, including the adequacy of nutritional intake and the
Volume 121 Number 2
Breast-feeding and maternal-infant HIV-1 transmission
presence of other infections. By providing optimal nutrition for infants in developing countries and protection against respiratory and gastrointestinal infections, breast-feeding may slow the course of HIV- 1 disease in perinatally infected infants. In one small study, breast-fed HIV-l-infected children progressed to acquired immunodeficiency syndrome at a slower rate than did bottle-fed infants.43 Whether the quantity and composition of milk from HIV1-seropositive women differ from those of seronegative women is also unknown and warrants further study. Studies of larger numbers of breast-fed and non-breast-fed HIV-l-infected infants are indicated to evaluate both the potential benefits and the possible risks associated with breast-feeding. The use of anti-HIV-1 chemotherapeutic agents in lactating women may affect transmission or progression of HIV-1 infection among breast-fed infants. The excretion and antiretroviral effects of these drugs in milk need to be evaluated. If the drugs are excreted in milk, infants may receive specific anti-HIV-1 therapy while maintaining the recognized benefits of breast-feeding. However, the potential risks to infants associated with use of these medications require careful evaluation, especially for the majority of infants who remain uninfected. Determining the role of breast-feeding in the transmission of HIV-1 from mother to infant is important for the establishment of public health policy. The protective effects of breast-feeding on infant survival and nutritional status vary depending on socioeconomic status and the availability of other preventive and therapeutic measures. In developing countries the use of alternatives to breast-feeding is associated with increased rates of malnutrition and death. 44"46 The recommendations of advisory bodies reflect the differing perceived risks and benefits of breast-feeding by HIV-l-seropositive women. In several industrialized countries, including the United States, Canada, Great Britain, France, Australia, and the former Soviet Union, HIV- 1-seropositive women have been advised not to breastfeed. 47 However, in developing countries where safe and effective alternatives are not available, the World Health Organization recommends that women breast-feed regardless of their HIV-1 serologic status. 48 The majority of infants born to HIV-1-seropositive women do not become infected, so failure to breast-feed would likely result in an increased rate of adverse outcomes for these infants. Heymann49 and Kennedy et al. 5~ modeled the potential impact of HIV-1 transmission by breast-feeding and the negative impact on childhood survival rates associated with withholding of breast-feeding in developing countries. In settings where the infant mortality rate is high, the benefits from breast-feeding exceed the potential added risk of HIV-1 transmission
327
by breast-feeding. Thus, for most women in developing countries who were infected with HIV-1 before or during pregnancy, the World Health Organization's recommendation to breast-feed regardless of HIV-1 status appears appropriate. However, additional data are needed to guide decision making in this complex and often emotional area of public health policy. The available epidemiologic and virologic data regarding transmission of HIV-1 through breast-feeding are incomplete. The prevalence rate and viability of HIV-1 and anti-HIV-1 activity in human milk should be further defined. Studies should be conducted in several communities with differing socioeconomic and sanitary conditions to determine whether the presence of HIV-1 in human milk is associated with transmission of infection to infants. The impact of breast-feeding on the infant mortality rate and on the nutritional status and rate of HIV-1 infection of infants born to H IV-1-seropositive women should also be evaluated. Although randomized clinical trials would ideally provide answers to these questions, practical and ethical problems limit the ability to implement such studies. Until additional data become available, it will be difficult to assess accurately the risk of HIV-1 transmission through breast-feeding, and we must continue to base our recommendations for seropositive mothers on limited information.
Andrea J. Ruff, MD Neal A. Halsey, MD Jacqueline Coberly, PhD Department of International Health Johns Hopkins University School of Hygiene and Public Health Baltimore, MD 21205 Reginald Boulos, MD, MPH Centers for Development and Health Port-au-Prince, Haiti REFERENCES
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44. Clements J, Sack D, Harris J, et al. Breastfeeding and the risk of severecholera in rural Bangladeshchildren. Am J Epidemiol 1990;131:400-11. 45. Wright A, Holberg C, Martinez F, et al. Breastfeeding and lower respiratory tract illness in the first year of life. BMJ 1989;299:946-9. 46. Howie P, Forsyth J, Ogston S, et al. Protective effect of breastfeeding against infection. BMJ 1990;300:11-6. 47. Centers for Disease Control. Recommendationsfor assisting in the prevention of perinatal transmission of human T-lymphotrophic virus type III/lymphadenopathy-associated virus and acquired immunodeficiency syndrome. MMWR 1985; 34:721-26, 731.
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48. World Health Organization. Breast-feeding/breast milk and human immunodeficiencyvirus (HIV). Wkly Epidemiol Ree 1987;62:245-6. 49. Heymann S. Modelingthe impact of breastfeedingby HIV infected women on child survival. Am J Public Health 1990; 80:1305-9. 50. Kennedy K, Fortney J, Bonhomme H, Potts M, Lamptey P, Carswell W. Do the benefits of breastfeeding outweigh the risks of postnatal transmission of HIV via breast milk? Trop Doct 1990;20:25-9.
CORRECTIONS In the article "Visual and Brain Function Measurements in Studies of n-3 Fatty Acid Requirements of Infants," (Uauy et al.), which appeared in the supplement to the APril 1992 issue of THE JOURNAL, the last sentence of the abstract (page S168), printed as "Studies of term infants suggest that visual acuity is more mature in formula-fed relative to breast-fed infants at 4 months and 3 years of age," should read "Studies of term infants suggest that visual acuity is more mature in breast-fed than in formula-fed infants at 4 months and 3 years of age." In the article "Pancreatitis in Young Children With Cystic Fibrosis" (Atlas et al.), which appeared in the May 1992 issue of THE JOURNAL, the first sentence of paragraph 2 in the Discussion section (page 758) reads "None o f our patients is homozygous for the AF508 mutation; this is consistent with the pancreatic sufficiency." However, additional molecular study of patient 5 found her to be homozygous for AF508. This finding does not change the conclusion of the article.