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Breast Milk: Revisited

      Human milk has been shown to be the ideal source of nutrition for most growing infants. Its composition continues to be an active area of investigation. In several studies in preferm and term infants, long-chain polyunsaturated fatty acids were found to improve the maturation of visual evoked potentials. The clinical significance of this finding, however, remains unclear. Nucleotides present in breast milk or added to infant formula seem to enhance the humoral immune response to vaccination. Whether breastfeeding protects susceptible infants from the risk of the development of diabetes mellitus type 1 is still controversial. Breastfeeding by mothers infected with the human immunodeficiency virus is not recommended. Other viruses and pollutants have also been found in breast milk. The importance of these in the long-term health of children remains to be established.

      Abbreviations:

      BSA (bovine serum albumin), DM-1 (diabetes mellitus type 1), H1V-1 (human immunodeficiency virus type 1), ICA69 (islet cell antigen 69), LC-PUFAs (long-chain polyunsaturated fatty acids)
      Breastfeeding is thought to be the optimal mode of nutrient delivery to term infants. Thus, manufacturers continue to develop infant formula by using breast milk as the standard. Several interesting and unresolved issues about breastfeeding and breast milk remain, however. In this review, we focus on (1) the association between diabetes mellitus type I (DM-1) and breastfeeding, (2) the benefits of long-chain polyunsaturated fatty acids (LC-PUFAs), (3) the importance of nucleotides, (4) the transmission of human immunodeficiency virus type 1 (HIV-1) in the breastfeeding process, and (5) the presence of pollutants in human milk.

      Breast Milk Composition

      Mature human milk differs from commercial infant formula (Table 1). To duplicate more closely some of the properties of human milk, commercial formulas now have added nucleotides and LC-PUFAs as well as decreased calcium and phosphorus concentrations. Breast milk, however, still has special properties. It seems to have a role in postnatal gut maturation, to have numerous immunologic benefits, and to contain several enzymes that facilitate digestion.
      • Hamosh M
      Digestion in the newborn.
      • Carver JD
      • Bamess LA
      Trophic factors for the gastrointestinal tract.
      • Orlando S
      The immunologic significance of breast milk.
      • Wagner CL
      • Anderson DM
      • Plttard III, WB
      Special properties of human milk.
      Table 1Comparisons Between Breast Milk and Infant Formula
      + = present; − = absent; ± = may or may not be present.
      Data from Heimburger and Weinsier.
      • Heimburger DC
      • Weinsier RL
      Infancy.
      FactorBreast milkInfant formula
      Protein (g/dL)1.11.5
      Calcium (mg/dL)3442-55
      Phosphorus (mg/dL)1428-39
      Iron (mg/L)0.512
      Long-chain polyunsaturated fatty acids+±
      Hormones (insulin-like growth factor I, insulin, growth factors)+
      Nucleotides++
      Pollutants, viruses+
      Enzymes+
      Other immune factors (IgA, lactoferrin, lysozyme, bifidus factor, macrophages, lymphocytes)+
      * + = present; − = absent; ± = may or may not be present.

      Diabetes And Breastfeeding

      DM-1 is a common, chronic disorder of children, Epidemiologic data have implicated environmental factors as being important in the development of DM-1
      • Wadsworth EJ
      • Shield JP
      • Hunt LP
      • Baum JD
      A case-control study of environmental factors associated with diabetes in the under 5s.
      . The incidence of diabetes varies considerably worldwide, and persons from a country with a low incidence rate who immigrate to a country with a high rate acquire the higher incidence rate. Furthermore, the incidence of DM-1 shows evidence of epidemic influenza-like fluctuations, implicating local environmental factors.
      • Gersteln HC
      • VanderMeulen J
      The relationship between cow's milk exposure and type 1 diabetes.
      Our current understanding of the cause of DM-1 is that it is an immunologically mediated attack on pancreatic B cells in genetically susceptible persons. The role of environmental factors in this process has not been completely elucidated, but factors as diverse as exposure to foreign antigens to coffee consumption to infant feeding practices have been implicated.
      Three pieces of data form the basis of the hypothesis that early introduction of cow's milk may have a role in the cause of DM-1,
      • Gersteln HC
      • VanderMeulen J
      The relationship between cow's milk exposure and type 1 diabetes.
      • Schalt DA
      • Maclaren NK
      Cow's milk and insulin-dependent diabetes mellitus: innocent until proven guilty [editorial].
      • Scott FW
      • Morris JM
      • Kolb H
      Milk and type I diabetes.
      • Atkinson MA
      • Ellis TM
      Infants diets and insulin-dependent diabetes: evaluating the “cows' milk hypothesis” and a role for anti bovine serum albumin immunity.
      The first piece of evidence is a retrospective case-control study performed in Scandinavia in 1984 that showed that the incidence of DM-1 increased as the prevalence of breastfeeding decreased. The second is experimental data from diabetes-prone rats in which an amino acid-based formula was associated with a lower incidence of diabetes than was a formula made from 1% skim milk powder. The third is prospective, controlled data from patients with newly diagnosed DM-1 that showed that 100% of these patients had increased levels of IgG antibodies against bovine serum albumin (BSA), which could cross-react with a pancreatic B-cell protein, islet cell antigen 69 (ICA69). The theory is that, in susceptible persons, early exposure to the protein in cow's milk could cause such persons to become sensitized to BSA. At some later time, because of this early sensitization, the body mounts an immune response to the B cells of the pancreas, which have expressed autoantigen ICA69.
      Recent studies have not substantiated this hypothesis.
      • Gersteln HC
      • VanderMeulen J
      The relationship between cow's milk exposure and type 1 diabetes.
      • Schalt DA
      • Maclaren NK
      Cow's milk and insulin-dependent diabetes mellitus: innocent until proven guilty [editorial].
      • Scott FW
      • Morris JM
      • Kolb H
      Milk and type I diabetes.
      • Atkinson MA
      • Ellis TM
      Infants diets and insulin-dependent diabetes: evaluating the “cows' milk hypothesis” and a role for anti bovine serum albumin immunity.
      Meta-analysis of studies comparing breastfeeding and early consumption of cow's milk (by infants younger than 4 months of age) in the development of DM-1 do not show a strong association. The overall odds ratio unking DM-1 with less than 3 months’ duration of breastfeeding was approximately 1.5. A national British case-control study showed that infant feeding practices had no significant independent association with development of DM-1.
      • Heimburger DC
      • Weinsier RL
      Infancy.
      Furthermore, in animals that have development of DM-1, a wide variability has been noted in the diabetogenic potential of milk-containing diets. Other nutritional factors, including soybean and wheat proteins, seem to be more consistently associated with the development of diabetes. New data do not support an important role for either BSA or cow's milk whey protein as an etiologic dietary factor of DM-1 in mice. Finally, additional studies searching for the presence of antibodies to BSA in patients with newly diagnosed diabetes, as well as the cross-reactivity of these antibodies to autoantigen 1CA69, have not confirmed the earlier report.
      Whether breastfeeding protects susceptible infants from the risk of the development of DM-1 remains controversial. Most case-control studies are retrospective in design and are subject to recall bias. A large prospective, randomized study currently under way should help to clarify this issue. Infant feeding guidelines should not be changed until we have a better understanding of diabetogenic diets and exposure factors that may promote the development of DM-1. The American Academy of Pediatrics strongly encourages breastfeeding and the avoidance of commercially available cow's milk and products containing intact cow's milk protein during the first year of life in infants whose families have a strong history of DM-1, particularly those with a sibling who has diabetes.

      Lc-Pufas And Breast Milk

      One of the major differences between breast milk and commercial formulas has been that breast milk contains many LC-PUFAs. LC-PUFAs are important components of all cellular membranes, especially in the developing retina and the gray matter of the brain. They seem to be essential for neurodevelopment because their incorporation in central nervous system tissues continues during the first 2 years of life.
      • Bendich A
      • Brack PE
      Rationale for the introduction of long chain polyunsaturated fatty acids and for concomitant increase in the level of vitamin Ein infants formulas.
      Studies comparing formula-fed and breast-fed infants have shown that infants who are fed commercial formula have less docosahexaenoic acid (22;6n-3) in their brain cortex than do breast-fed infants.
      • Gibson RA
      • Neumann MA
      • Makrides M
      Effect of dietary docohexaenoic acid on brain composition and neural function in term infants.
      Some prospective studies have shown that improved neurologic function, specifically better visual evoked potentials, can be associated with breastfeeding rather than with formula feeding. Some investigators have suggested that the maturation pattern of visual evoked potentials is slower in preterm infants who did not receive LC-PUFAs.
      • Bendich A
      • Brack PE
      Rationale for the introduction of long chain polyunsaturated fatty acids and for concomitant increase in the level of vitamin Ein infants formulas.
      These findings, however, have not been substantiated by all investigators.
      • Bendich A
      • Brack PE
      Rationale for the introduction of long chain polyunsaturated fatty acids and for concomitant increase in the level of vitamin Ein infants formulas.
      In addition, the clinical significance of the improved visually evoked potentials is unclear.
      Despite the unclear nature of these findings, LC-PUFAs have been added to some commercial formulas. When LC-PUFAs are included, the antioxidant requirements are higher. Vitamin E may need to be increased in these formulas.
      • Bendich A
      • Brack PE
      Rationale for the introduction of long chain polyunsaturated fatty acids and for concomitant increase in the level of vitamin Ein infants formulas.
      LC-PUFAs contain a large number of unsaturated double bonds. Therefore, there is an increased potential for oxidation that results in the increased requirement for antioxidant protection. The American Academy of Pediatrics has no current recommendation regarding the addition of LC-PUFAs.
      • Bendich A
      • Brack PE
      Rationale for the introduction of long chain polyunsaturated fatty acids and for concomitant increase in the level of vitamin Ein infants formulas.

      Breast Milk And Nucleotides

      Nucleotides (naturally present in breast milk) seem to be essential nutrients for rapidly dividing tissues such as the intestinal epithelium and lymphoid cells. In rats, data support the importance of nucleotides for normal development, maturation, and repair of the gastrointestinal tract.
      • Uauy R
      • Quan R
      • Gil A
      Role of nucleotides in intestinal development and repair; implications for infant nutrition.
      In normally growing infants, however, nucleotide supplementation does not seem to have a significantly beneficial effect on the gastrointestinal tract.
      • Cosgrove M
      • Davies DP
      • Jenkins HR
      Nucleotide supplementation and the growth of term small for gestational age infants.
      Clinical studies that have shown a benefit are limited to one that reported improved growth in a group of infants who were small for gestational age
      • Cosgrove M
      • Davies DP
      • Jenkins HR
      Nucleotide supplementation and the growth of term small for gestational age infants.
      and one that reported a lower incidence of diarrhea-related disease.
      • Brunser O
      • Espinoia J
      • Araya M
      • Crochet S
      • Gil A
      Effect of dietary nucleotide supplementation on diarrhoeal disease in infants.
      In addition to their effect on the gastrointestinal tract, nucleotides have also been implicated to be important for the immune system. Studies in mice have shown that restriction of dietary nucleotides decreases cell-mediated immunity. Human studies suggest that the humoral immune response of preterm and term newborns is increased when nucleotides arc added to their formulas.
      • Martinez-Augustin O
      • Boza JJ
      • Del Pino Jl
      • Lucena I
      • Martlnez-Valverde A
      • Gil A
      Dietary nucleotides might influence the humoral immune response against cow's milk proteins in preterm neonates.
      • Pickering LK
      • Granoff DM
      • Erickson JR
      • Masor ML
      • Cordle CT
      • Schaller JP
      • et al.
      Modulation of the immune system by human milk and infant formula containing nucleotides.
      Breast milk is the best source of nucleotides for infants, In the absence of breastfeeding, the addition of nucleotides to infant formula within the range of concentrations found in mature human milk seems to be safe. Strong evidence for the clinical efficacy of nucleotide supplementation is still lacking, but numerous studies are currently under way.

      Breast Milk And The Acquired Immunodeficiency Syndrome

      In 1985, the Centers for Disease Control and Prevention first advised against breastfeeding by women with HIV after a confirmed case of HIV transmission to an infant whose mother had received a postpartum transfusion from an HIV-infected donor. This contrasts a 1992 recommendation from the World Health Organization and the United Nations International Children's Emergency Fund that suggested that breastfeeding should be promoted in all populations, irrespective of the HIV status of the mother.
      • Stiehm ER
      Newborn factors in maternal-infant transmission Df pédiatrie HIV infection.
      This apparent contradiction seems to be related to the risk of transmission of HIV through breast milk, which is thought to be lower than the risk of the infant dying of other infectious diseases and malnutrition in developing countries. As of 1996, 24 case reports had confirmed vertical transmission of HIV-1 by breastfeeding from mothers who had seroconvcrsion after delivery. In studies estimating the rate of transmission of HIV-1 from mothers infected before delivery, the vertical transmission rate for breastfeeding has ranged from 14 to 68%. Results from a meta-analysis show a breast milk transmission rate of 14% from mothers who were scropositive at the time of delivery and 29% from those who had primary infection during the postpartum period.
      • Stiehm ER
      Newborn factors in maternal-infant transmission Df pédiatrie HIV infection.
      Thus, primary HIV infection and prolonged breastfeeding (more than 6 months) are associated with increased transmissibility. Some evidence exists that banking of human milk (a process in which the cellular fraction has been lysed and the milk has undergone storage with lipolysis of milk fats) before giving it to an infant decreases the risk of the transmission of HIV. Banking of human milk, however, also causes a progressive decrease in the amount of IgA. Other possible intervention strategies to decrease transmissibility include early weaning, use of antiretrovirals, and administration of vitamin A supplements to the mother.
      • Black RF
      Transmission of HIV-1 in the breast-feeding process.
      • Atkinson MA
      • Ellis TM
      Infants diets and insulin-dependent diabetes: evaluating the “cows' milk hypothesis” and a role for anti bovine serum albumin immunity.
      The high cost of antiretrovirals prohibits their use in large areas of the developing world. A possibility exists that breastfeeding of infants who are known to be infected with HIV may be beneficial in preventing other infections. Breastfeeding by HIV-infected mothers is not recommended, however, except in this setting. A large, prospective randomized trial currently under way comparing breastfeeding to bottle feeding of infants of HIV-positive African mothers should help to clarify the risks of breastfeeding in this population in developing countries.

      Is Breast Milk Polluted?

      Although substantial attention has been given to the risks of breastfeeding when the mother is taking prescription drugs, less consideration has been given to the presence of chemical pollutants in human milk. During the past 4 decades, some members of the DDT (2,2[4-chlorophenyl]-1,1,1-trichloroethane) family have been detected in all samples of human milk worldwide. Additional compounds often found in human milk have included hexachloro-benzene, cyclodiene pesticides, and polychlorinated biphenyls.(tm) These compounds are not well excreted through urine and stool, and they occur in higher concentrations in human milk than in the serum of the mother. Such compounds do not seem to be in such high concentrations in cow's milk, either because of less exposure or because the increased milk production in cows dilutes the concentrations.
      Currently, data confirming morbidity in infants exposed to these chemicals through breastfeeding have been minimal, although mass poisonings have been reported in infants affected through breast milk. Laboratory research, however, has confirmed that the developing neurologic system is particularly sensitive to some of these chemicals. Whether exposure to such chemicals predisposes the infant or mother (or both) to an increased risk of the development of cancer remains to be established.
      • Rogan WJ
      Pollutants in breast milk.
      The presence of these compounds in breast milk is an additional reason for decontamination of the environment. Despite the presence of these chemical residues, breastfeeding continues to be recommended because its benefits seem to outweigh its risks.

      Conclusion

      Questions about the clinical importance of LC-PUFAs in neurodcvclopment and of nucleotides in maintaining the integrity of both the gastrointestinal tract and the immune system remain to be answered. The clinical significance of the improved visual evoked potentials in infants receiving LC-PUFAs remains unclear. Recent studies in humans suggest an improved humoral immune response in newborns fed with formula to which nucleotides were added. Whether breast milk protects susceptible infants from the risk of the development of DM-1 is still controversial, Breastfeeding by HIV-infected mothers is not recommended unless the infant is infected with HIV. Large, prospective randomized trials should facilitate a better understanding of these unresolved issues.

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