- Email: [email protected]
Maternal milk IgA and mother-to-child transmission of human immunodeficiency virus: Not a silver spoon
conjugate vaccines as a fourth dose in 15-20-month-old toddlers. Vaccine 2006;24:4017-23. 19. Scheifele DW, Halperin SA, Ochnio JJ, Ferguson AC, Skowronski DM. A modified vaccine reduces the rate of large injection site reactions to the preschool booster dose of diphtheria-tetanus-acellular pertussis vaccine: results of a randomized, controlled trial. Pediatr Infect Dis J. 2005;24:105966. Erratum in: Pediatr Infect Dis J 2006;25:229. 20. Zepp F, Knuf M, Habermehl P, Mannhardt-Laakmann W, Howe B, Friedland LR. Safety of reduced antigen content tetanus-diphtheria-acellular pertussis vaccine in adolescents as a 6th consecutive dose of acellular-pertussis containing vaccine. J Pediatr 2006;149:603-10. 21. Rennels MB, Deloria MA, Pichichero ME, Losonsky GA, Englund JA, Meade BD, et al. Extensive swelling after booster doses of acellular pertussis-tetanus-diphtheria vaccines. Pediatrics 2000;105:e12. 22. Woo EJ, Burwen DR, Gatumu SN, Ball R. Extensive limb swelling
after immunization: reports to the Vaccine Adverse Event Reporting System. Clin Infect Dis 2003;37:351-8. 23. Ward JI, Cherry JD, Chang SJ, Partridge S, Lee H, Treanor J, et al. Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med 2005;353:1555-63. 24. Disease Control and Epidemiology, Newfoundland and Labrador Department of Health and Community Services. Pertussis in Newfoundland and Labrador: 1991-2004. Can Commun Dis Rep 2005;31: 235-7. 25. Kandola K, Lea A, Santos M. Pertussis rates in Northwest Territories after introducing adult formulation acellular vaccine [abstract]. Can J Infect Dis Med Microbiol 2004;15:351. 26. CDC. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54(RR-7):1-21.
MATERNAL MILK IGA AND MOTHER-TO-CHILD TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS: NOT A SILVER SPOON
reast-feeding in the context of maternal human immunodeficiency virus (HIV)-1 infection is the subject of considerable controversy. Observational data have shown a consistent association between breast-feeding and postpartum HIV transmission to the newborn infant,1,2 and the risk of transmission has been quantified by a randomized, clinical trial as 16%, accounting for almost half of the HIV transmission in breast-feeding mothers.3 Indeed, the risk of consuming 1 L of breast milk from an infected mother may be similar to that of HIV transmission during an episode of unprotected heterosexual sex.4 However, breast milk also is a vital source of both nutrition and immune protection for a newborn child. As a result, in settings where infant mortality exceeds 40 per 1000, the survival benefit of breast-feeding may exceed the mortality attributable to breast milk–associated HIV transmission.5 It also has been hypothesized that HIV transmission may be reduced by the practice of exclusive breast-feeding, rather than mixing breast milk with water or formula feeding.6 It is within a trial examining the utility of exclusive breast-feeding that the study by Kuhn et al7 in this issue of The Journal explores the immune correlates of breast milk transmission of HIV. Why most infants can breast-feed from an HIV-infected mother for prolonged periods without acquiring HIV infection is poorly understood. Breast milk contains both cell-free and cellassociated HIV, both of which have been associated with an increased risk of transmission.8 Viral transmission is thought to occur across the infant’s gastrointestinal mucosa, aided by low gastric acidity, although the process is poorly understood.9 Breast milk, particularly colostrum, is rich in both innate and acquired immune factors, many of which have been shown to influence HIV infectivity and transmission in vitro and in vivo.9 Potential
B
HIV
Editorials
Human immunodeficiency virus
protective innate factors include ␣ defensins,10 Lewis X component,11 natural antibodies to CCR512 and lactoferrin;13 acquired immune factors present in breast milk include maternal HIVspecific IgA, IgG, and cytotoxic T lymphocytes.9 Kuhn et al7 examined the potential protective role of HIV-specific IgA in human milk from HIV-infected mothers. Although HIV-specific IgG antibodies predominate over IgA in human milk, secretory IgA is found in the human milk of roughly 50% of infected women, has been shown to prevent epithelial HIV transcytosis, and is felt to be more mucosally active than IgG.9 Mucosal HIV-specific IgA has been found in the genital tract of exposed uninfected individuals, implying a potential role in protective mucosal immunity,14 although there are no data linking IgA to improved outcome in HIV-infected individuals. In effect, the authors hoped that the provision of maternal IgA in the milk of infected mothers might act as a form of passive infant immunization to protect against HIV acquisition. The investigators collected milk from mothers soon after delivery and measured blood CD4 count, HIV RNA viral load in blood and breast milk, and HIV-specific IgA levels in breast milk. Mothers who See related article, p 611 transmitted HIV to their infants during the Reprint requests: Rupert Kaul, Clinical Scipostpartum period (casence Division, Medical Sciences Building es; n ⫽ 26) were com#6356, University of Toronto, Toronto, pared with a random Ontario, Canada, M5S1A8. E-mail: [email protected]. sample of mothers who J Pediatr 2006;149:591-3 did not (controls; n ⫽ 0022-3476/$ - see front matter 64). All of the mothers Copyright © 2006 Mosby Inc. All rights practiced breast-feeding reserved. exclusively. As expected, 10.1016/j.jpeds.2006.08.024 591
transmission was associated with a higher HIV RNA viral load in milk, which in turn correlated with increased blood HIV viral load and decreased blood CD4 T-lymphocyte count. There was no association between breast milk IgA and any of these parameters, but, unexpectedly, IgA was more common in the milk of transmitting mothers compared with nontransmitting controls. Although a previous smaller case-control study showed no association between IgA and protection,15 there has been no previous suggestion that IgA might enhance transmission. What are the practical implications of these finding? Within the limitations of the case-control format, this was a well-done study, and the demonstration that maternal IgA does not protect against milk transmission of HIV is definitive. There are a few potential confounding factors, although these do not change the overall conclusion. It is notoriously difficult to measure mucosal IgA, with poor interlaboratory agreement,16 and the overall rates of IgA detection were high compared with previous studies (50/64; 78%). However, this is an experienced laboratory, with personnel appropriately blinded to case-control status. Without measurement of the secretory component, whether the IgA represented true secretory (ie, locally produced) IgA or may have been derived from blood is unclear. This may have some significance, because the secretory component may be important, particularly in immune exclusion at mucosal surfaces.17 None of these concerns should detract from the conclusion that maternal IgA was not protective—although this conclusion is not completely unexpected. In general, both virus-specific IgA and IgG from an HIV-infected individual poorly neutralize autologous virus. In the case of blood IgG, this is known to be the result of rapid virus mutation to escape from host antibody responses.18 Certainly, the lack of protection offered by autologous antibodies (IgA or IgG) in an HIV-infected person should not be taken to mean that HIV-specific antibodies could not be protective if induced before exposure in an uninfected person, such as in the context of active or passive vaccination. Why does IgA appear to enhance HIV transmission? Kuhn et al note that IgA levels in breast milk could reflect higher local HIV replication or diversity. It is also possible that higher IgA levels in transmitting mothers could represent a host’s attempt to control virus that has undergone more extensive immune escape. IgA levels in maternal milk are higher after premature delivery, as the authors discuss, and prematurity enhances HIV transmission. HIV-specific IgA levels were associated with lower birth weight, and although the association with transmission remained after controlling for birth weight, data on gestational age at delivery were not presented. Total immunoglobin levels, including IgA, increase in blood with progression of HIV disease, and so increased HIV-specific IgA may reflect a generalized increase in total IgA in both the plasma and milk of women with more advanced disease. Finally, the frequency of other protective innate immune factors in breast milk was not examined. Overall, the data on potential enhancement of transmission by maternal HIV-specific IgA are less robust, and more 592
Editorials
detailed studies of the virology and immunology of human milk are needed to confirm this. In summary, this well-performed study shows that IgA antibodies in the milk of an HIV-infected mother will not protect her child from acquiring HIV if she continues to breastfeed. Where local circumstances allow the infant to receive nutrition safely by alternate means, this should be encouraged. Whether exclusive breast-feeding is safer than intermittent breast-feeding in settings where there is no safer alternative remains to be seen; the results of the larger trial in which this substudy was nested may provide some guidance on this issue. The findings do not provide evidence one way or the other as to the potential protective efficacy of HIV-specific IgA induced by active or passive vaccination. Rupert Kaul, MD, PhD Clinical Science Division University of Toronto Toronto, Ontario, Canada, M5S1A8
REFERENCES 1. Embree JE, Njenga S, Datta P, Nagelkerke NJ, Ndinya-Achola JO, Mohammed Z, et al. Risk factors for postnatal mother-child transmission of HIV-1. Aids 2000;14:2535-41. 2. John GC, Nduati RW, Mbori-Ngacha DA, Richardson BA, Panteleeff D, Mwatha A, et al. Correlates of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission: association with maternal plasma HIV-1 RNA load, genital HIV-1 DNA shedding, and breast infections. J Infect Dis 2001;183:206-12. 3. Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha A, et al. Effect of breast-feeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000;283: 1167-74. 4. Richardson BA, John-Stewart GC, Hughes JP, Nduati R, MboriNgacha D, Overbaugh J, et al. Breast-milk infectivity in human immunodeficiency virus type 1–infected mothers. J Infect Dis 2003;187:736-40. 5. Kuhn L, Stein Z, Susser M. Preventing mother-to-child HIV transmission in the new millennium: the challenge of breast-feeding. Paediatr Perinat Epidemiol 2004;18:10-6. 6. Rollins N, Meda N, Becquet R, Coutsoudis A, Humphrey J, Jeffrey B, et al. Preventing postnatal transmission of HIV-1 through breast-feeding: modifying infant feeding practices. J Acquir Immune Defic Syndr 2004;35:188-95. 7. Kuhn L, Trabattoni D, Kankasa C, Sinkala M, Lissoni F, Ghosh M, et al. HIV-specific secretory IgA in breast milk of HIV-positive mothers is not associated with protection against HIV transmission among breast-fed infants. J Pediatr 2006;149:611-6. 8. John-Stewart G, Mbori-Ngacha D, Ekpini R, Janoff EN, Nkengasong J, Read JS, et al. Breast-feeding and transmission of HIV-1. J Acquir Immune Defic Syndr 2004;35:196-202. 9. Kourtis AP, Butera S, Ibegbu C, Belec L, Duerr A. Breast milk and HIV-1: vector of transmission or vehicle of protection? Lancet Infect Dis 2003;3:786-93. 10. Kuhn L, Trabattoni D, Kankasa C, Semrau K, Kasonde P, Lissoni F, et al. Alpha-defensins in the prevention of HIV transmission among breastfed infants. J Acquir Immune Defic Syndr 2005;39:138-42. 11. Naarding MA, Ludwig IS, Groot F, Berkhout B, Geijtenbeek TB, Pollakis G, et al. Lewis X component in human milk binds DC-SIGN and inhibits HIV-1 transfer to CD4⫹ T lymphocytes. J Clin Invest 2005;115:3256-64. 12. Bouhlal H, Latry V, Requena M, Aubry S, Kaveri SV, Kazatchkine MD, et al. Natural antibodies to CCR5 from breast milk block infection of macrophages and dendritic cells with primary R5-tropic HIV-1. J Immunol 2005;174:7202-9.
The Journal of Pediatrics • November 2006
13. Groot F, Geijtenbeek TB, Sanders RW, Baldwin CE, Sanchez-Hernandez M, Floris R, et al. Lactoferrin prevents dendritic cell–mediated human immunodeficiency virus type 1 transmission by blocking the DC-SIGN– gp120 interaction. J Virol 2005;79:3009-15. 14. Broliden K, Hinkula J, Devito C, Kiama P, Kimani J, Trabbatoni D, et al. Functional HIV-1–specific IgA antibodies in HIV-1– exposed, persistently IgG-seronegative female sex workers. Immunol Lett 2001;79:29-36. 15. Becquart P, Hocini H, Levy M, Sepou A, Kazatchkine MD, Belec L. Secretory anti-human immunodeficiency virus (HIV) antibodies in colostrum
and breast milk are not a major determinant of the protection of early postnatal transmission of HIV. J Infect Dis 2000;181:532-9. 16. Wright PF, Kozlowski PA, Rybczyk GK, Goepfert P, Staats HF, VanCott TC, et al. Detection of mucosal antibodies in HIV type 1–infected individuals. AIDS Res Hum Retroviruses 2002;18:1291-300. 17. Phalipon A, Cardona A, Kraehenbuhl JP, Edelman L, Sansonetti PJ, Corthesy B. Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo. Immunity 2002;17:107-15. 18. Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, et al. Antibody neutralization and escape by HIV-1. Nature 2003;422:307-12.
VARIATION AND “ABNORMALITY”: RECOGNIZING THE DIFFERENCES
ne of the greatest challenges in evaluating children’s development, particularly in the early years, is the question of what constitutes “abnormality.” In our professional training, we are exposed primarily to so-called “prevalent cases”—the children who are known to “have it.” We are instructed in the history and physical signs that accompany that “diagnosis” or condition. What is less well taught to, or experienced by, new learners is how to recognize developmental disabilities when they are “incident” cases (not yet formally identified). What did these children look like before the diagnosis? In a child who does not yet have the diagnosis, can we make the correct assessment that these are truly the early features of what is (or is going to prove to be), for example, cerebral palsy, or a language disability, or a form of pervasive developmental disorder, as opposed to a benign variant of development or behavior? One common approach to assessing children’s development is to use norm-referenced tools that provide a context or perspective on the function of a particular child relative to others. The report by van Haastert et al1 in this issue of The Journal provides important evidence that, among other things, we need to be sure that we are using the right “norms.” In an excellent cross-sectional study of the trajectories of motor development of apparently well ex-premature infants, they demonstrate an apparent consistent “lag” in the acquisition of motor skills in this population of infants assessed with a reliable, valid, standardized norm-referenced measure of infant motor development (the Alberta Infant Motor Scale [AIMS]2). At every stage, from 1 to 18 months, the premature infants scored significantly lower than the norms on the AIMS, which are based on the patterns of development of well full-term infants. How do we make sense of these findings? Do they constitute evidence of “abnormality” in this population? Should these infants all be referred for “therapy”? These questions are among the most challenging for anyone concerned with the developmental elements of a child’s health status and in determining how best to support families.
O
AIMS
Editorials
Alberta Infant Motor Scale
It is my opinion that in our efforts not to miss problems, we may place too much emphasis on labeling and “early” diagnosis,3,4 especially when we use norms as the basis of judgment. The question might then be raised as to whether we do more harm by missing children who “have it” or overidentifying children who turn out to be fine. Do our early interventions to, for example, “treat” early motor “delay” actually do more good than harm? In the case of ex-premature children, it is likely that most parents are already generally worried about their children’s developmental prognosis. This is based, realistically, on the infants’ prematurity, their recognized biological vulnerability, lengthy hospitalizations, and the many things parents may have heard along the way about the outcomes of “these babies.” In addition, our systematic follow-up of these infants is probably associated, consciously or not, with a “diagnostic suspicion bias” on our part, whereby we expect many of these vulnerable infants to experience delay or abnormality in their developmental course. Consequently, we many too easily label as abnormal what I believe is often variation (as illustrated in the study by van Haastert et al). What then should be our goals in neonatal intensive care follow-up? Can we achieve a balance between looking for problems (with whatever diagnostic suspicion biases we have) and reassuring parents See related article, p 617 who are already vulnerable and worried? What is our tolerance Reprint requests: Peter Rosenbaum, MD, FRCP(C), Professor of Paediatrics, McMasfor uncertainty, and for ter University, Canada Research Chair in variation in early deChildhood Disability, Co-Director, CanChild Centre for Childhood Disability Revelopment of the sort search, IAHS Building, Room 408, McMasthat our Dutch colter University, 1400 Main Street West, leagues have so clearly Hamilton ON L8S 1C7, Canada. E-mail: [email protected]. reported? Depending J Pediatr 2006;149:593-4 on the nature of the 0022-3476/$ - see front matter neonatal follow-up Copyright © 2006 Mosby Inc. All rights services, it is certainly reserved. reasonable to combine 10.1016/j.jpeds.2006.08.030 593
after immunization: reports to the Vaccine Adverse Event Reporting System. Clin Infect Dis 2003;37:351-8. 23. Ward JI, Cherry JD, Chang SJ, Partridge S, Lee H, Treanor J, et al. Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med 2005;353:1555-63. 24. Disease Control and Epidemiology, Newfoundland and Labrador Department of Health and Community Services. Pertussis in Newfoundland and Labrador: 1991-2004. Can Commun Dis Rep 2005;31: 235-7. 25. Kandola K, Lea A, Santos M. Pertussis rates in Northwest Territories after introducing adult formulation acellular vaccine [abstract]. Can J Infect Dis Med Microbiol 2004;15:351. 26. CDC. Prevention and control of meningococcal disease. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2005;54(RR-7):1-21.
MATERNAL MILK IGA AND MOTHER-TO-CHILD TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS: NOT A SILVER SPOON
reast-feeding in the context of maternal human immunodeficiency virus (HIV)-1 infection is the subject of considerable controversy. Observational data have shown a consistent association between breast-feeding and postpartum HIV transmission to the newborn infant,1,2 and the risk of transmission has been quantified by a randomized, clinical trial as 16%, accounting for almost half of the HIV transmission in breast-feeding mothers.3 Indeed, the risk of consuming 1 L of breast milk from an infected mother may be similar to that of HIV transmission during an episode of unprotected heterosexual sex.4 However, breast milk also is a vital source of both nutrition and immune protection for a newborn child. As a result, in settings where infant mortality exceeds 40 per 1000, the survival benefit of breast-feeding may exceed the mortality attributable to breast milk–associated HIV transmission.5 It also has been hypothesized that HIV transmission may be reduced by the practice of exclusive breast-feeding, rather than mixing breast milk with water or formula feeding.6 It is within a trial examining the utility of exclusive breast-feeding that the study by Kuhn et al7 in this issue of The Journal explores the immune correlates of breast milk transmission of HIV. Why most infants can breast-feed from an HIV-infected mother for prolonged periods without acquiring HIV infection is poorly understood. Breast milk contains both cell-free and cellassociated HIV, both of which have been associated with an increased risk of transmission.8 Viral transmission is thought to occur across the infant’s gastrointestinal mucosa, aided by low gastric acidity, although the process is poorly understood.9 Breast milk, particularly colostrum, is rich in both innate and acquired immune factors, many of which have been shown to influence HIV infectivity and transmission in vitro and in vivo.9 Potential
B
HIV
Editorials
Human immunodeficiency virus
protective innate factors include ␣ defensins,10 Lewis X component,11 natural antibodies to CCR512 and lactoferrin;13 acquired immune factors present in breast milk include maternal HIVspecific IgA, IgG, and cytotoxic T lymphocytes.9 Kuhn et al7 examined the potential protective role of HIV-specific IgA in human milk from HIV-infected mothers. Although HIV-specific IgG antibodies predominate over IgA in human milk, secretory IgA is found in the human milk of roughly 50% of infected women, has been shown to prevent epithelial HIV transcytosis, and is felt to be more mucosally active than IgG.9 Mucosal HIV-specific IgA has been found in the genital tract of exposed uninfected individuals, implying a potential role in protective mucosal immunity,14 although there are no data linking IgA to improved outcome in HIV-infected individuals. In effect, the authors hoped that the provision of maternal IgA in the milk of infected mothers might act as a form of passive infant immunization to protect against HIV acquisition. The investigators collected milk from mothers soon after delivery and measured blood CD4 count, HIV RNA viral load in blood and breast milk, and HIV-specific IgA levels in breast milk. Mothers who See related article, p 611 transmitted HIV to their infants during the Reprint requests: Rupert Kaul, Clinical Scipostpartum period (casence Division, Medical Sciences Building es; n ⫽ 26) were com#6356, University of Toronto, Toronto, pared with a random Ontario, Canada, M5S1A8. E-mail: [email protected]. sample of mothers who J Pediatr 2006;149:591-3 did not (controls; n ⫽ 0022-3476/$ - see front matter 64). All of the mothers Copyright © 2006 Mosby Inc. All rights practiced breast-feeding reserved. exclusively. As expected, 10.1016/j.jpeds.2006.08.024 591
transmission was associated with a higher HIV RNA viral load in milk, which in turn correlated with increased blood HIV viral load and decreased blood CD4 T-lymphocyte count. There was no association between breast milk IgA and any of these parameters, but, unexpectedly, IgA was more common in the milk of transmitting mothers compared with nontransmitting controls. Although a previous smaller case-control study showed no association between IgA and protection,15 there has been no previous suggestion that IgA might enhance transmission. What are the practical implications of these finding? Within the limitations of the case-control format, this was a well-done study, and the demonstration that maternal IgA does not protect against milk transmission of HIV is definitive. There are a few potential confounding factors, although these do not change the overall conclusion. It is notoriously difficult to measure mucosal IgA, with poor interlaboratory agreement,16 and the overall rates of IgA detection were high compared with previous studies (50/64; 78%). However, this is an experienced laboratory, with personnel appropriately blinded to case-control status. Without measurement of the secretory component, whether the IgA represented true secretory (ie, locally produced) IgA or may have been derived from blood is unclear. This may have some significance, because the secretory component may be important, particularly in immune exclusion at mucosal surfaces.17 None of these concerns should detract from the conclusion that maternal IgA was not protective—although this conclusion is not completely unexpected. In general, both virus-specific IgA and IgG from an HIV-infected individual poorly neutralize autologous virus. In the case of blood IgG, this is known to be the result of rapid virus mutation to escape from host antibody responses.18 Certainly, the lack of protection offered by autologous antibodies (IgA or IgG) in an HIV-infected person should not be taken to mean that HIV-specific antibodies could not be protective if induced before exposure in an uninfected person, such as in the context of active or passive vaccination. Why does IgA appear to enhance HIV transmission? Kuhn et al note that IgA levels in breast milk could reflect higher local HIV replication or diversity. It is also possible that higher IgA levels in transmitting mothers could represent a host’s attempt to control virus that has undergone more extensive immune escape. IgA levels in maternal milk are higher after premature delivery, as the authors discuss, and prematurity enhances HIV transmission. HIV-specific IgA levels were associated with lower birth weight, and although the association with transmission remained after controlling for birth weight, data on gestational age at delivery were not presented. Total immunoglobin levels, including IgA, increase in blood with progression of HIV disease, and so increased HIV-specific IgA may reflect a generalized increase in total IgA in both the plasma and milk of women with more advanced disease. Finally, the frequency of other protective innate immune factors in breast milk was not examined. Overall, the data on potential enhancement of transmission by maternal HIV-specific IgA are less robust, and more 592
Editorials
detailed studies of the virology and immunology of human milk are needed to confirm this. In summary, this well-performed study shows that IgA antibodies in the milk of an HIV-infected mother will not protect her child from acquiring HIV if she continues to breastfeed. Where local circumstances allow the infant to receive nutrition safely by alternate means, this should be encouraged. Whether exclusive breast-feeding is safer than intermittent breast-feeding in settings where there is no safer alternative remains to be seen; the results of the larger trial in which this substudy was nested may provide some guidance on this issue. The findings do not provide evidence one way or the other as to the potential protective efficacy of HIV-specific IgA induced by active or passive vaccination. Rupert Kaul, MD, PhD Clinical Science Division University of Toronto Toronto, Ontario, Canada, M5S1A8
REFERENCES 1. Embree JE, Njenga S, Datta P, Nagelkerke NJ, Ndinya-Achola JO, Mohammed Z, et al. Risk factors for postnatal mother-child transmission of HIV-1. Aids 2000;14:2535-41. 2. John GC, Nduati RW, Mbori-Ngacha DA, Richardson BA, Panteleeff D, Mwatha A, et al. Correlates of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission: association with maternal plasma HIV-1 RNA load, genital HIV-1 DNA shedding, and breast infections. J Infect Dis 2001;183:206-12. 3. Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha A, et al. Effect of breast-feeding and formula feeding on transmission of HIV-1: a randomized clinical trial. JAMA 2000;283: 1167-74. 4. Richardson BA, John-Stewart GC, Hughes JP, Nduati R, MboriNgacha D, Overbaugh J, et al. Breast-milk infectivity in human immunodeficiency virus type 1–infected mothers. J Infect Dis 2003;187:736-40. 5. Kuhn L, Stein Z, Susser M. Preventing mother-to-child HIV transmission in the new millennium: the challenge of breast-feeding. Paediatr Perinat Epidemiol 2004;18:10-6. 6. Rollins N, Meda N, Becquet R, Coutsoudis A, Humphrey J, Jeffrey B, et al. Preventing postnatal transmission of HIV-1 through breast-feeding: modifying infant feeding practices. J Acquir Immune Defic Syndr 2004;35:188-95. 7. Kuhn L, Trabattoni D, Kankasa C, Sinkala M, Lissoni F, Ghosh M, et al. HIV-specific secretory IgA in breast milk of HIV-positive mothers is not associated with protection against HIV transmission among breast-fed infants. J Pediatr 2006;149:611-6. 8. John-Stewart G, Mbori-Ngacha D, Ekpini R, Janoff EN, Nkengasong J, Read JS, et al. Breast-feeding and transmission of HIV-1. J Acquir Immune Defic Syndr 2004;35:196-202. 9. Kourtis AP, Butera S, Ibegbu C, Belec L, Duerr A. Breast milk and HIV-1: vector of transmission or vehicle of protection? Lancet Infect Dis 2003;3:786-93. 10. Kuhn L, Trabattoni D, Kankasa C, Semrau K, Kasonde P, Lissoni F, et al. Alpha-defensins in the prevention of HIV transmission among breastfed infants. J Acquir Immune Defic Syndr 2005;39:138-42. 11. Naarding MA, Ludwig IS, Groot F, Berkhout B, Geijtenbeek TB, Pollakis G, et al. Lewis X component in human milk binds DC-SIGN and inhibits HIV-1 transfer to CD4⫹ T lymphocytes. J Clin Invest 2005;115:3256-64. 12. Bouhlal H, Latry V, Requena M, Aubry S, Kaveri SV, Kazatchkine MD, et al. Natural antibodies to CCR5 from breast milk block infection of macrophages and dendritic cells with primary R5-tropic HIV-1. J Immunol 2005;174:7202-9.
The Journal of Pediatrics • November 2006
13. Groot F, Geijtenbeek TB, Sanders RW, Baldwin CE, Sanchez-Hernandez M, Floris R, et al. Lactoferrin prevents dendritic cell–mediated human immunodeficiency virus type 1 transmission by blocking the DC-SIGN– gp120 interaction. J Virol 2005;79:3009-15. 14. Broliden K, Hinkula J, Devito C, Kiama P, Kimani J, Trabbatoni D, et al. Functional HIV-1–specific IgA antibodies in HIV-1– exposed, persistently IgG-seronegative female sex workers. Immunol Lett 2001;79:29-36. 15. Becquart P, Hocini H, Levy M, Sepou A, Kazatchkine MD, Belec L. Secretory anti-human immunodeficiency virus (HIV) antibodies in colostrum
and breast milk are not a major determinant of the protection of early postnatal transmission of HIV. J Infect Dis 2000;181:532-9. 16. Wright PF, Kozlowski PA, Rybczyk GK, Goepfert P, Staats HF, VanCott TC, et al. Detection of mucosal antibodies in HIV type 1–infected individuals. AIDS Res Hum Retroviruses 2002;18:1291-300. 17. Phalipon A, Cardona A, Kraehenbuhl JP, Edelman L, Sansonetti PJ, Corthesy B. Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo. Immunity 2002;17:107-15. 18. Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, et al. Antibody neutralization and escape by HIV-1. Nature 2003;422:307-12.
VARIATION AND “ABNORMALITY”: RECOGNIZING THE DIFFERENCES
ne of the greatest challenges in evaluating children’s development, particularly in the early years, is the question of what constitutes “abnormality.” In our professional training, we are exposed primarily to so-called “prevalent cases”—the children who are known to “have it.” We are instructed in the history and physical signs that accompany that “diagnosis” or condition. What is less well taught to, or experienced by, new learners is how to recognize developmental disabilities when they are “incident” cases (not yet formally identified). What did these children look like before the diagnosis? In a child who does not yet have the diagnosis, can we make the correct assessment that these are truly the early features of what is (or is going to prove to be), for example, cerebral palsy, or a language disability, or a form of pervasive developmental disorder, as opposed to a benign variant of development or behavior? One common approach to assessing children’s development is to use norm-referenced tools that provide a context or perspective on the function of a particular child relative to others. The report by van Haastert et al1 in this issue of The Journal provides important evidence that, among other things, we need to be sure that we are using the right “norms.” In an excellent cross-sectional study of the trajectories of motor development of apparently well ex-premature infants, they demonstrate an apparent consistent “lag” in the acquisition of motor skills in this population of infants assessed with a reliable, valid, standardized norm-referenced measure of infant motor development (the Alberta Infant Motor Scale [AIMS]2). At every stage, from 1 to 18 months, the premature infants scored significantly lower than the norms on the AIMS, which are based on the patterns of development of well full-term infants. How do we make sense of these findings? Do they constitute evidence of “abnormality” in this population? Should these infants all be referred for “therapy”? These questions are among the most challenging for anyone concerned with the developmental elements of a child’s health status and in determining how best to support families.
O
AIMS
Editorials
Alberta Infant Motor Scale
It is my opinion that in our efforts not to miss problems, we may place too much emphasis on labeling and “early” diagnosis,3,4 especially when we use norms as the basis of judgment. The question might then be raised as to whether we do more harm by missing children who “have it” or overidentifying children who turn out to be fine. Do our early interventions to, for example, “treat” early motor “delay” actually do more good than harm? In the case of ex-premature children, it is likely that most parents are already generally worried about their children’s developmental prognosis. This is based, realistically, on the infants’ prematurity, their recognized biological vulnerability, lengthy hospitalizations, and the many things parents may have heard along the way about the outcomes of “these babies.” In addition, our systematic follow-up of these infants is probably associated, consciously or not, with a “diagnostic suspicion bias” on our part, whereby we expect many of these vulnerable infants to experience delay or abnormality in their developmental course. Consequently, we many too easily label as abnormal what I believe is often variation (as illustrated in the study by van Haastert et al). What then should be our goals in neonatal intensive care follow-up? Can we achieve a balance between looking for problems (with whatever diagnostic suspicion biases we have) and reassuring parents See related article, p 617 who are already vulnerable and worried? What is our tolerance Reprint requests: Peter Rosenbaum, MD, FRCP(C), Professor of Paediatrics, McMasfor uncertainty, and for ter University, Canada Research Chair in variation in early deChildhood Disability, Co-Director, CanChild Centre for Childhood Disability Revelopment of the sort search, IAHS Building, Room 408, McMasthat our Dutch colter University, 1400 Main Street West, leagues have so clearly Hamilton ON L8S 1C7, Canada. E-mail: [email protected]. reported? Depending J Pediatr 2006;149:593-4 on the nature of the 0022-3476/$ - see front matter neonatal follow-up Copyright © 2006 Mosby Inc. All rights services, it is certainly reserved. reasonable to combine 10.1016/j.jpeds.2006.08.030 593