Enliven: Pediatrics and Neonatal Biology

Neonatal Cow Milk Sensitization in 143 Case-Reports Role of Early Exposure to Cow?s Milk Formula
General Information

Research Article

Arnaldo Cantani*

*Division of Pediatric Allergy and Immunology, Roma University "La Sapienza", Italy


Corresponding author


Arnaldo Cantani, Professor, Division of Pediatric Allergy and Immunology, Roma University “La Sapienza”, Italy, E-mail: acantani13@gmail.com

 

Received Date: 04thFebruary 2015

Accepted Date: 04th March 2015

Published Date: 12th March 2015


Citation


Cantani A (2015) Neonatal Cow Milk Sensitization in 143 Case-Reports Role of Early Exposure to Cow’s Milk Formula. Enliven: Pediatr Neonatol Biol 2(1): 002.

Copyright


@ 2015 Dr. Arnaldo Cantani. This is an Open Access article published and distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

Abstract

Objective:
Cow’s milk (CM) allergy (CMA) is a disease of infancy, usually appearing in the first months of life. Symptoms triggered by CM at first introduction are not completely defined. The evaluation of infants for possible CMA is one of the more common problems encountered by pediatricians. Purpose of this study was to investigate the prevalence of severe reaction to CM and clinical manifestation triggered by CM administration in the nurseries.

Materials and Methods:
The series includes 143 prospectively studied CM-allergic babies.

Results:
At the first introduction of CM, at the age of 1-8 months (median 4 months) all infants had immediate symptoms. The babies were probably sensitized during the first days of life. Particularly sensitizing appears to be the exposure to CM formulas in the neonatal nursery.

Discussion:
Little doses of allergens are more sensitizing than larger ones. We provide clear evidence of the immunological effects of oral antigen administration during the neonatal period, and discuss the possible critical allergen transmission to the nursing baby via breast milk (BM).

 

Introduction


A major cause of sensitization to CM in genetically predisposed neonates is the (in) advertent administration of CM in neonatal nurseries. Neonatal care should include 49-100% of such infants given supplements of CM or hydroly-sate formulas (HFs) during the first 3-4 days of life [1-5]. Among these babies CM allergy (CMA) was more fre-quent [6], until to 100% of infants, none of them had symptoms at the first CM administration [3]. Immediate re-actions at the subsequent CM feeding bring into focus a delayed effect of the “hidden bottle” [2]. Host et al [3] documented that the 40-860ml of CM received from 39 neonates during the first three days contained 0, 4-7, 4g of ß-lactoglobulin (ßLG). Feeding half of babies with a CM formula and half with HFs for 1-4 days and then with BM, if necessary supplemented with HFs until the third month, total IgE titers were at the 5th day significantly related to the dose and frequency of supplements received (200-500ml) [7], maintaining significances until 12 months [8] especially in at-risk babies.

In at-risk children, prospectively followed-up from birth during 18 months [9] and re-evaluated at age 4-6 [10], the cumulative prevalence of atopy was 18% in CM-fed or 33% in wholly BM-fed babies, in at-risk children the inci-dence was as high as 11 or 61%, respectively [9]. Newborns with 27-42 week gestational age and 2 SDs (standard deviation) below the mean normal weight at birth correspond to premature responding in a different manner to sen-sitization and onset of atopic manifestations. During the follow-up, the prevalence of atopy was nearly similar in both groups, yet skin prick tests (SPT) positive for CM significantly correlated with RAST only in CM-fed infants [10]. We have also studied four additional at risk infants who were exposed in the nursery to a first HF dose during their first days of life, and elicited acute allergic symptoms when fed again this HF at the end of an exclusive breastfeeding (data not shown).

Healthy newborns accidentally exposed to CM in a nursery develop a modest and transient antibody production (primary immune response). Such initial responses are self-limited and gradually resolve due to development of tol-erance despite unremitting allergen exposures. At the second encounter, CD4 clones from non-atopic infants have a Th1 profile, whereas in atopic infants provide help for IgE synthesis (secondary immune response) [11]. Remarkably, there appears to be a consensus that BM-feeding for at least 4-6 months will delay, if not prevent allergy [12-48], although a case of apparent sensitization via BM has been reported [48].


Materials and Methods


We have prospectively studied 143 CM-allergic babies, 79 males and 64 females aged 4-8 months (median 5 months) with IgE-mediated CMA, who attended between June 1997 and December 1999 the Allergy and Clinical Immunology Division of Rome University “La Sapienza”. The diagnosis was based on SPTs, all positive to CM, and oral food challenges (OFCs) done in a hospital setting which were positive to CM in 74 babies, to egg in one baby, and to a HF in 50. In total, 125 out of 143 babies (87.4%) were positive to OFCs.

Parents of each child gave details of their allergic disease (if any) and their informed consent. The babies were defined at risk of atopy when at least one parent had or had had diagnosed and treated atopic disease.

Data were statistically analyzed using the Student t and the X2 tests.


Results


At the first introduction of CM, at the age of 1-8 months (median 4 months) all infants had immediate symptoms, as follows: anaphylactic shock (9 cases), urticaria-angioedema (37 cases = 25.9%), skin rash (13 cases = 9.1%), di-arrhea (25 cases = 17.5%), vomiting (19 cases = 13.3%), respiratory manifestations (wheezing or rhinitis) (18 cases = 12.6%), and worsening of atopic dermatitis (AD) (59 cases = 41.2%). Several children had more than one allergic manifestation.

All children but twelve (82.8%) had positive family history for atopy (p = 0.0001).

Only 10/143 infants (14.3%) were fed CM since birth; the other 133 were BM-fed for 3-8 months (median 4.5 months). Two children breastfed from birth were probably sensitized to CM proteins present in BM since their conditions improved when the nursing mothers followed dietetic restrictions.

Analyzing the clinical charts of the infants and interviewing the parents, we learned that 133 (93%) of the CM-allergic babies were fed a CM formula in the neonatal nursery in the first days of life. (p = 0.0001)


Discussion


In this prospective study we learned that as many as 133 newborns were fed CM in the newborn nurseries, and this data tallies well with previously alluded to studies. As a result of OFCs, a larger proportion of babies (41.2%) had a worsening of AD symptoms, however it is remarkable that 12.6% presented with respiratory manifestations.

As previously reported, there is a large consensus that BM-feeding for at least 4-6 months will delay, if not prevent allergy [12-48]. A note of caution is their unmatched results owing to methodological differences. Given that CM and egg allergens are present in BM, it was also thought that a maternal diet excluding the above allergens may be important in atopy prevention [13,34,42]. A typical case was reported by Lifschitz et al, an anaphylactic shock due to CM protein hypersensitivity in a newborn who was mistakenly fed BM that had been expressed before CM products were eliminated from his mother’s diet, as it is correctly shown in the title [48]. More than 70 years ago Talbot documented that AD in a fully breast-fed infant could be related to chocolate ingested by the mother, and that AD cleared up when the nursing mother avoided the offending food [49], a phenomenon recently confirmed [3].

However, IgE-mediated sensitization through BM is rather rare: 0.042% [50] or 0,28% [3]. Therefore, inadvertent exposure to CM appears to be far more important than the very low CM amounts transmitted via BM [51]. A note regarding a study based on HFs for allergy prevention: the frequency of BM-feeding was high (98%), and in 232 not randomized such babies the incidence of CMA was 1.3%. The study is far more important because newborns who received a CM formula in the nursery were not included into the program [17]. We have stressed the negative effects of the maternity wards. To avoid the possible risks it should be clearly stated that giving any formula in the first few days of life is strictly forbidden unless prescribed by a pediatrician or demanded by a mother who is unwill-ing or incapable to breastfeed her baby [41].

A new front was unexpectedly opened up by the significant report that a 22- week-old fetus responds to a great variety of oral and inhalant allergens including CM ßLG, and egg ovalbumin [52]. That is why reducing intake of highly allergenic foods in the last trimester has not been found to be worthwhile in atopy prevention in at-risk babies [51,53-55].

In conclusion, as early as in 1935 Ratner [56] recommended that isolated CM feedings to BM-fed infants should be avoided during the newborn period.


References


  1. Bergmann RL, Bergmann KE, Lau-Schadensdorf S, Luck W, Dannemann A, et al. (1994) Atopic disease in infancy. The German multicenter atopy study (MAS-90). Pediatr Allergy Im­munol 5: 19-25.

  2. Cantani A, Gagliesi D (1996) Severe reactions to cow’s milk in very young in­fants at risk of atopy. Allergy Asthma Proc 17: 205-208.

  3. Høst A, Husby S, Østerballe O (1988) A prospective study of cow’s milk allergy in ex­clusively breast-fed infants. Incidence, pathogenetic role of early inadvertent exposure to cow's milk formula, and characterization of bovine milk protein in human milk. Acta Paediatr Scand 77: 663-670.

  4. Schwartz RH (1991) IgE-mediated allergic reactions to cow’s milk. Immunol Al­lergy Clin North Am 11: 717-741.

  5. Stintzing G, Zetterström R (1979) Cow’s milk allergy, incidence and pathoge­netic role of early exposure to cow’s milk formula. Acta Paediatr Scand  68: 383-387.

  6. Halken S, Jacobsen HP, Høst A, Holmenlund D (1995) The effect of hypo-aller­genic formulas in infants at risk of allergic disease. Eur J Clin Nutr 49: S77-S83.

  7. Schmitz J, Digeon B, Chastang C, Dupouy D, Leroux B, et al. (1992) Effects of brief early exposure to par­tial­ly hydro­l­yzed and whole cow milk proteins. J Pediatr 121: S85-S89.

  8. Strobel S, Einfluß (1996) des Stillens und der Flaschenernährung auf der En­twick­lung der Immunität im Kindesalter. Monatsschr Kinderheilkd 144: S161-S168.

  9. Lindfors A, Enocksson E (1988) Development of atopic disease after early ad­min­i­stration of cow milk formula. Allergy 43: 11-16.

  10. Lindfors ATB, Danielsson L, Enocksson E, Johansson SGO, Westin S (1992) Al­le­rgic symptoms up to 4-6 years of age in children given cow milk neona­tally. A prospective study. Allergy 47: 207-211.

  11. Kay AB (2001) Advances in Immunology: Allergy and allergic diseases (First of two parts) N Engl J Med  344: 30-37.

  12. Matthew DJ, Taylor B, Norman PA, Turner MW (1977) Prevention of eczema. Lancet 1: 321-324.

  13. Businco L, Marchetti F, Pellegrini G, Cantani A, Perlini R (1983) Prevention of atopic dis­ease in “at risk newborns” by prolonged breast-feeding. Ann Al­lergy 51: 296-299.

  14. Arshad SH, Hide DW (1992) Effect of environmental factors on the deve­lopment of allergic disorders in infancy. J Allergy Clin Immunol 90: 235-241.

  15. Chandra RK (1979) Prospective studies of the effect of breast feeding on inci­dence of in­fection and allergy. Acta Paediatr Scand 68: 691-694.

  16. Saarinen UM, Backman A, Kajosaari M, Simes M (1979) Prolonged breast-feeding as pro­phylaxis for atopic disease. Lancet 2: 163-166.

  17. Halken S, Hansen KS, Jakobsen HP, Estmann A, Faelling AE, et al. (2000) Comparison of a partially hydrol­yzed infant formula with two extensively hydrolyzed formulas for allergy prevention: A prospective, randomized study. Pediatr Allergy Immunol 11: 149-161.

  18. Kaufman HS, Frick OL (1981) Prevention of asthma. Clin Allergy 11: 549-553.

  19. Hide DW, Guyer BM (1981) Clinical manifestations of allergy related to breast and cows’ milk-feeding. Arch Dis Child 56: 172-175.

  20. Gruskay FL (1982) Comparison of breast, cow, and soy feedings in the prev­en­tion of onset of allergic disease: A 15-year prospective study. Clin Pediatr 21: 486-491.

  21. Juto P, Möller C, Enberg S, Björkstén B (1982) Influence of type of feeding on lymphocyte function and development of infantile allergy. Clin Allergy 12: 409-416.

  22. Fergusson DM, Horwood LJ, Shannon FT (1983) Asthma and infant diet. Arch Dis Child 58: 48-51.

  23. Kajosaari M, Saarinen UM (1983) Prophylaxis of atopic disease by six months total solid food elimination. Evaluation of 135 exclusively breast-fed infants of atopic families. Acta Paediatr Scand 72: 411-414.

  24. Hide DW, Guyer BM (1985) Clinical manifestations of allergy related to breast- and cow’s milk-feeding. Pediatrics 76: 973-975.  

  25. Moore WJ, Midwinter RE, Morris AF, Colley JR, Soothill JF (1985) Infant feeding and subse­quent risk of atopic eczema. Arch Dis Child 60: 722-726.

  26. Chandra RK, Puri S, Suraiya C, Cheema PS (1986) Influence of maternal food antigen avoidance during pregnancy and lactation on incidence of atopic ec­zema in infants. Clin Allergy 16: 563-569.

  27. Vandenplas Y, Sacre L (1986) Influences of neonatal serum IgE concentration, fam­ily history and diet on the incidence of cow’s milk allergy. Eur J Pediatr 145: 493-495.

  28. Miskelly FG, Burr ML, Vaughan-Williams E, Fehily AM, Butland BK, et al. (1988) In­fant feeding and al­lergy. Arch Dis Child 63: 388-393.

  29. Hattevig G, Kjellman N, Sigurs N, Björkstén B, Kjellman NI (1989) Effect of mater­nal avoidance of eggs, cow’s milk and fish during lactation upon al­ler­gic manifesta­tions in infants. Clin Exp Allergy 19: 27-32.

  30. Chandra RK, Puri S, Hamed A (1989) Influence of maternal diet during lactation and use of formula feeds on development of atopic eczema in high risk in­fants. BMJ 299: 228-230.

  31. Chandra RK, Singh G, Shridhara B (1989) Effect of feeding whey hydrolysate, soy and conventional cow milk formulas on incidence of atopic diseases in high risk infants. Ann Allergy 63: 102-106.

  32. Lucas A, Brooke OG, Morley R, Cole TJ, Bamford MF (1990) Early diet of preterm in­fants and development of allergic or atopic disease: ran­domised prospec­tive study. BMJ 300: 837-840.

  33. Chandra RK, Hamed A (1991) Cumulative incidence of atopic disorders in high risk in­fants feed whey hydrolysate, soy and conventional cow milk formu­las. Ann Allergy 67: 129-132.

  34. Sigurs N, Hattevig G, Kjellman B (1992) Maternal avoidance of eggs, cow’s milk, and fish during lactation: effect on allergic manifestations, skin prick-tests, and specific IgE antibodies in children at age 4 years. Pediatrics 89: 735-739.

  35. Burr ML, Limb ES, Maguire MJ, Amarah L, Eldridge BA, et al. (1993) Infant feeding, wheezing, and al­ler­gy: a prospective study. Arch Dis Child 68: 724-728.

  36. Halken S, Høst A, Hansen LG, Østerballe O (1993) Pre­ventive effect of feeding high-risk infants a ca­sein hydrolysate formula or an ultrafiltrated whey hy­drolysate formula. A prospective, randomized, com­parative clinical study. Pe­diatr Allergy Immu­nol 4: 173-181.

  37. Kajosaari M (1994) Atopy prevention in childhood: the role of diet. Prospec­tive 5-year follow-up of high-risk infants with six months exclusive breastfeed­ing and solid food elimination. Pediatr Allergy Immunol 5: 26-28.

  38. Host A, Husby S, Osterballe O (1988) A prospective study of cow’s milk allergy in ex­clusi­ve­ly breast-fed infants. Incidence, pathogenetic role of early inadvertent exposure to cow's milk formula, and characterization of bovine milk protein in human milk. Acta Paediatr Scand 77: 663-670.

  39. Saarinen UM, Kajosaari M (1995) Breastfeeding as prophylaxis against atopic dis­ease: prospective follow-up study until 17 years old. Lancet 346: 1065-1069.

  40. Chandra RK (1997) Five-year follow-up of high-risk infants with family history of aller­gy who were exclusively breast- fed or fed partial whey hydrolysate, soy and convent­ional cow milk formulas. J Pediatr Gastroenterol Nutr 24: 380-388.

  41. Businco L, Lucenti P, Arcese G, Ziruolo G, Cantani A (1994) Immunogenicity of a so-called hypoallergenic formula in at risk babies: two case reports. Clin Exp Al­lergy 24: 42-45.

  42. Businco L, Cantani A, Meglio P, Bruno G (1987) Prevention of atopy: results of long-term (7 months to 8 years) follow-up. Ann Allergy 59: 183-186.

  43. Savilahti E, Tainio VM, Salmenperä L, Siimes MA, Perheentupa J (1987) Prolonged exclusive breast feed­ing and heredity as determinants in infantile atopy. Arch Dis Child 62: 269-273.

  44. Zeiger RS, Heller S, Mellon M, Forsythe AB, O'Connor RD (1989) Effect of combined ma­ternal and in­fant food-allergen avoidance on development of atopy in early infancy: a ran­dom­ized study. J Allergy Clin Immunol 84: 72-89.

  45. Arshad SH, Matthews S, Gant C, Hide DW (1992) Effect of allergen avoidance on de­velop­ment of allergic disorders in infancy. Lancet 339: 1493-1497.

  46. Halken S, Host A, Hansen LG, Osterballe O (1992) Effect of an allergy preven­tion pro­gramme on incidence of atopic symptoms in infancy. A prospective study of 159 “high-risk” infants. Allergy 47: 545-553.

  47. Zeiger RS, Heller S, Mellon MH, Halsey JF, Hamburger RN, Sampson HA (1992) Genet­ic and environmental factors affecting the development of atopy through age 4 in children of atopic parents: a prospective randomized study of food aller­gen avoidance. Pediatr Allergy Immunol 3: 110-127.

  48. Lifschitz CH, Hawkins HK, Guerra C, Byrd N (1988) Anaphylactic shock due to cow’s milk pro­tein hypersensitivity in a breast fed infant. J Pediatr Gas­tr­o­­en­terol Nutr 7: 141-144.

  49. Talbot FB (1918) Eczema in childhood. Med Clin North Am 1: 985-996.

  50. Cantani A, Ragno V, Businco L (1991) Natural history of IgE-mediated food al­ler­gy in fully breast-fed babies. Report of twenty-one cases (Follow-up to 19 years). Pediatr Allergy Immunol 2: 131-134.

  51. Becker AB (2000) Is primary prevention of asthma possible? Pediatr Pulmonol 30: 63-72.

  52. Jones AC, Miles EA, Warner JO, Colwell BM, Bryant TN, et al. (1996) Fetal peripheral blood mononuclear cell proliferative responses to mitogenic and allergenic stimuli during gestation. Pediatr Allergy Immunol 7: 109-116.

  53. Zeiger RS, Heller S, Mellon M, O’Connor R, Hamburger RN (1986) Effective­ness of di­etary manipulation in the prevention of food allergy in infants. J Al­lergy Clin Im­munol 78: 224-238

  54. Fälth-Magnusson K, Oman H, Kjellman NI (1987) Maternal abstention from cow’s milk and egg in allergy-risk pregnancies. Effect on antibody produc­tion in the mother and the newborn. Allergy 42: 64-73.

  55. Fälth-Magnusson K, Kjellman NI (1992) Allergy prevention by maternal elimina­tion diet during late pregnancy - a 5-year follow-up of a ran­dom­ized study. J Al­lergy Clin Immunol 89: 709-713.

  56. Ratner B (1935) The treatment of milk allergy and its basic principles. JAMA 105: 934-939.