The effect of brief neonatal exposure to cows' milk on atopic symptoms up to age 5

Aims: To determine the effect of brief early exposure to cows'' milk on the expression of atopy during the first five years of life. Methods: Follow up analysis of a double blind, placebo controlled, randomised feeding intervention trial (BOKAAL study). Subjects were 1108 children from 1533 initially randomised breast fed neonates in the Netherlands. Atopic disease and prevalence of allergic symptoms at age 1, 2, and 5, and specific IgE at age 1 and 5 were determined. Results: Atopic disease in the first year was found in 10.0% (cows'' milk) versus 9.3% (placebo) of the children, with a relative risk (RR) of 1.07. No differences were found in the second year either. At age 5, atopic disease was found in 26.3% (cows'' milk) versus 25.0% (placebo), RR 1.05. There was no difference in the prevalence of allergic symptoms. Specific IgE to cows'' milk (RAST positive 2+ or more) was 5.8% (cows'' milk) versus 4.1% (placebo) at age 1 (RR 1.43), and 5.3% versus 3.0% at age 5 (RR 1.77). There was no difference in sensitisation to other common allergens between the two groups. Conclusion: Early, brief exposure to cows'' milk in breast fed children is not associated with atopic disease or allergic symptoms up to age 5.     

Milk antigen absorption in the preterm and term neonate.

The concentrations of beta-lactoglobulin was measured in the sera of 47 preterm an term neonates during the first few days of life under standardised conditions after feeding with a cows'' milk''based formula. Preterm neonates, particularly those of less than 33 weeks'' gestation, had higher serum concentrations of beta-lactoglobulin than term neonates given an equivalent mild feed. Prior feeding with breast milk did not diminish the amount of beta-lactoglobulin absorbed. Our results suggest tha te ability of the gastrointestinal tract to exclude antigenically intact food proteins increases with gestational age and that gut closure occurs normally before birth in man.     

Randomised controlled trial of brief neonatal exposure to cows' milk on the development of atopy

OBJECTIVE—To determine the effect of brief early exposure to cows'' milk on atopy in the first 2 years of life.DESIGN—Double blind, placebo controlled, randomised feeding intervention trial (Bokaal study).SETTING—Dutch midwifery practices.PARTICIPANTS—1533 breast fed neonates.INTERVENTION—Exposure to cows'' milk protein (n = 758) or a protein free placebo (n = 775) during the first 3 days of life.MAIN OUTCOME MEASURES—Clinical atopic disease and any positive radioallergosorbent (RAST) tests at 1 year of age.RESULTS—Atopic disease in the first year was found in 10.0% (cows'' milk) v 9.3% (placebo) of the children, with a relative risk of 1.07; in the second year, atopic disease was found in 9.6% v 10.2%, respectively, with a relative risk of 0.94. Per protocol analysis showed similar results. Any RAST positive test was found in 9.4% (cows'' milk) v 7.9% (placebo) of children, with a relative risk of 1.19. Stratified analysis for high family risk of allergy showed a doubled incidence of atopic disease but no effect from the intervention.CONCLUSION—Early and brief exposure to cows'' milk in breast fed children does not increase the risk of atopic disease in the first 2years.     

Infant feeding and subsequent risk of atopic eczema.

An attempted controlled trial of exclusively breast fed neonates with atopic parents, to assess the effectiveness of breast feeding in preventing atopic allergy, was not successfully achieved. Analysis of the data as an observational study, however, provided evidence that breast feeding offers some protection against eczema in genetically vulnerable infants. Feeds of soya preparations were associated with eczema as often as cows'' milk based feeds.     

Breastfeeding stimulates total and cow's milk-specific salivary IgA in infants

Breastfeeding may increase the rate of mucosal maturation and IgA production. We sought to determine the effect of breastfeeding vs. formula-feeding on the maturation of oral mucosa by measuring the salivary total antibodies and cow's milk protein-specific IgA. Fifty-eight saliva samples were collected from 39 healthy, full term infants. At the age of 3 months (n = 25) eight infants received only breast milk and seventeen formula (cow's milk based n = 10, hydrolysed n = 7) and breast milk; and at the age of 6 months (n = 33) eleven received breast milk, seventeen formula and breast milk and five were not breastfed any more (cow's milk based n = 14, hydrolysed n = 8). Total IgA, IgG, IgM and protein, and β-lactoglobulin specific IgA were measured from saliva with enzyme-linked immunoassay (ELISA). The antibody results were proportioned to total protein. No differences in antibody levels between the feeding groups were found at 3 months of age. At 6 months, total IgA, total IgM and β-lactoglobulin-specific IgA were higher among the breastfed infants compared to those receiving formula as supplement to breast milk or not breastfed any more (breast milk vs. any formula p = 0.029, p = 0.015, p = 0.058; breast milk vs. cow's milk formula p = 0.025, p = 0.044, p = 0.038). To conclude, breastfeeding stimulated the mucosal immune system to produce IgA to saliva, which is a marker for immunological maturation and likely provides protection against environmental antigens.     

Reactivity of secretory IgA antibodies in breast milk from 107 Japanese mothers to 20 environmental antigens

The secretory IgA (sIgA) antibody response to 20 environmental antigens, including microorganisms, toxins, food, and inhaled allergens, was evaluated in the breast milk from 107 Japanese mothers 1-10 days after delivery. Specific sIgA antibody responses were detected in most milk samples against almost all of the antigens tested, although there was a wide variation in the specific sIgA antibody profiles of each individual's milk. With regard to twelve bacterial antigens, highly specific sIgA antibody responses were detected against Escherichia coli, Yersinia enterocolitica, and Pseudomonas aeruginosa. With regard to eight nonbacterial antigens, highly specific sIgA antibody responses were detected against rotavirus, cholera, and pertussis toxins. Similar sIgA antibody profiles were obtained when the 107 milk specimens were divided into colostrum (milk 1-5 days after delivery, n = 36) and transitional milk (milk 6-10 days after delivery, n = 71). This study provides information on the possible protective role of human milk sIgA antibodies and will serve as a baseline for future studies.     

Clinical and pH-metric characteristics of gastro-oesophageal reflux secondary to cows' milk protein allergy.

AIMS: The primary aim was to assess whether there were differences in symptoms, laboratory data, and oesophageal pH-metry between infants with primary gastro-oesophageal reflux and those with reflux secondary to cows'' milk protein allergy (CMPA). PATIENTS AND METHODS: 96 infants (mean(SD) age 7.8(2.0) months) with either primary gastro-oesophageal reflux, reflux with CMPA, CMPA only, or none of these (controls) were studied. Symptoms, immunochemical data, and oesophageal pH were compared between the four groups and the effect of a cows'' milk protein-free diet on the severity of symptoms was also assessed. RESULTS: 14 out of 47(30%) infants with gastro-oesophageal reflux had CMPA. These infants had similar symptoms to those with primary gastro-oesophageal reflux but higher concentrations of total IgE and circulating eosinophils (p < 0.005) and IgG anti-beta lactoglobulin (p < 0.003). A progressive constant reduction in oesophageal pH at the end of a feed, which continued up to the next feed, was seen in 12 out of 14 patients with gastro-oesophageal reflux secondary to CMPA and in 24 of 25 infants with CMPA only. No infants with primary gastro-oesophageal reflux and none of the controls had this pattern. A cows'' milk protein-free diet was associated with a significant improvement in symptoms only in infants with gastro-oesophageal reflux with CMPA. CONCLUSION: A characteristic oesophageal pH pattern is useful in distinguishing infants with gastro-oesophageal reflux associated with CMPA.     

Cows' milk-sensitive enteropathy.

Serial small intestinal biopsies related to withdrawal and challenge with cows'' milk are described in 5 infants with cows'' milk protein intolerenace. On the basis of these serial observations the existence of a cows'' milk-sensitive enteropathy in infancy is clearly established. The cows'' milk-sensitive mucosal lesion varied in its severity ranging from a partly flat mucosa to a mild degree of partial villous atrophy. Intraepithelial lymphocyte counts rose after a positive milk challenge, but on only one occasion to a level outside the normal range. The technique of serial biopsies related to dietary milk enables a firm diagnosis of cows'' milk intolerance to be made upon the basis of a single milk challenge. Clinically this appears to be a temporary condition which disappears by the age of 2 years.     

Diet and faecal flora in the newborn: breast milk and infant formula.

This study examined the faecal flora on days 4, 14, and 28 of 17 breast fed babies and 26 bottle fed babies receiving a modern infant formula based on demineralized whey. Generally among breast fed babies bifidobacteria and staphylococci were the predominant organisms, whereas in the formula fed babies the predominant organisms were enterococci, coliforms, and clostridia. Despite the extensive modification of cows'' milk to make an infant formula resemble human breast milk, the results are very similar to those previously reported with unmodified cows'' milk baby feeds. The exact dietary factor responsible for these microbiological differences is unclear and in succeeding papers we have looked at the effects of protein quality, in particular the content of whey proteins, casein, and lactoferrin.     

Effect of continued feeding of cows' milk on asymptomatic infants with milk protein sensitive enteropathy.

The clinical response and the histological changes in the mucosa of the small bowel in response to continued feeding with cows'' milk protein were assessed over a period of 2-6 weeks in 24 infants who had shown histological changes without immediate clinical symptoms after challenge with a diet containing cows'' milk protein. Twenty of the 24 infants (83%) thrived well on cows'' milk protein. Jejunal biopsy specimens taken six to eight weeks after the initial biopsy showed histological improvement in all 20 infants compared with biopsy specimens taken soon after the challenge, which had shown mucosal damage. The mucosa had returned to normal in 12, was mildly abnormal in seven, and moderately abnormal in one. Corresponding improvements in the activities of mucosal enzymes were seen. In four of the 24 infants (17%) symptoms developed between three and six weeks. Histological examination of the jejunal biopsy specimens showed that mucosal damage had progressed in two, and remained the same in two; moreover, the disaccharidase activities remained depressed. The present study shows that most infants with enteropathy caused by sensitivity to cows'' milk protein but without clinical symptoms develop tolerance to the protein and the mucosa returns to normal despite continued feeding with cows'' milk protein.     

Macromolecular absorption and cows' milk allergy.

The absorption of macromolecules was analysed by measuring serum concentrations of human alpha-lactalbumin after feeding human milk, using a competitive radioimmunoassay. The control group consisted of 78 children fed by cows'' milk formula; concentrations of alpha-lactalbumin in their serum were low. The median concentrations in the different age groups varied between 7-13 micrograms alpha-lactalbumin/1 serum/1 human milk/kg body weight. Twenty-eight children with cows'' milk allergy were studied before introduction of a diet free of cows'' milk. Nineteen had gastrointestinal and nine skin symptoms. High serum alpha-lactalbumin concentrations were found. Only two children had alpha-lactalbumin concentrations below 100 micrograms alpha-lactalbumin/1 serum/1 human milk/kg body weight. Altogether 76 children on a diet free of cows'' milk were studied directly after a cows'' milk challenge; 26 developed symptoms. They had significantly higher serum alpha-lactalbumin values than the 50 children with no symptoms upon challenge. Eighteen of the 26 children with symptoms had serum alpha-lactalbumin concentrations of more than 100 micrograms/1 serum/1 human milk/kg body weight in contrast with two of the 50 with no symptoms. Total serum IgE antibodies were analysed in 43 children. No correlation was found between concentrations of serum IgE and serum alpha-lactalbumin in the children with cows'' milk allergy.     

Differentiation of cows' milk intolerance and gastro-oesophageal reflux.

The aim of this study was to compare a non-invasive test of small bowel permeability with a more invasive approach involving endoscopy, mucosal biopsy, and oesophageal pH monitoring for rapidly differentiating gastro-oesophageal reflux (GOR) and cows'' milk intolerance in 25 infants with persistent vomiting. Each subject underwent a cellobiose/mannitol permeability study, upper gastrointestinal endoscopy with oesophageal and small bowel biopsies, and a 24 hour pH study. Reflux disease and/or cows'' milk intolerance was responsible for vomiting in 24 (96%) of the subjects. Sixteen (64%) of the infants had GOR alone, four (16%) had GOR and cows'' milk intolerance, and four (16%) had cows'' milk intolerance alone. Morphometric analysis of small bowel biopsies was abnormal in 19% of the patients with GOR alone and in 67% with cows'' milk intolerance with or without GOR. The permeability test was abnormal in only 6% of the patients with GOR but in 100% with GOR and cows'' milk intolerance and in 100% with cows'' milk intolerance alone. The non-invasive permeability study aimed at rapid determination of cows'' milk intolerance should pre-empt a more invasive approach in the evaluation of infants with persistent vomiting.     

Infant feeding in the second 6 months of life related to iron status: an observational study

Objective

To investigate the relationship between iron status in infancy and type of milk and weaning solids consumed.

Design

An observational cohort study.

Setting

928 term infants from the Avon Longitudinal Study of Parents and Children in 1993–94.

Methods

Haemoglobin and ferritin concentrations at 8 and 12 months were assessed in relation to type and quantity of milk intake at 8 months.

Results

By WHO criteria, 22.7% of the infants were anaemic at 8 months and 18.1% at 12 months. More breast‐ than formula‐fed infants were anaemic at 8 and 12 months. Cows'' milk as the main drink was associated with increased anaemia at 12 months and low ferritin at 8 and 12 months. No association was found between any nutrients and haemoglobin concentrations. Protein and non‐haem iron intakes were positively associated with ferritin concentrations and calcium intake negatively. This effect was more marked in infants being fed cows'' milk. More than 25% of infants in the breast milk and cows'' milk groups and 41% of infants having >6 breast feeds per day had iron intakes below the lower reference nutrient intake. Feeding cows'' milk or formula above 600 ml or >6 breast feeds per day was associated with lower intakes of solids.

Conclusions

Both breast and cows'' milk feeding were associated with higher levels of anaemia. Satisfactory iron intake from solids in later infancy is more likely if formula intake is <600 ml per day and breast feeds are limited to <6 feeds per day. Cows'' milk should be strongly discouraged as a main drink before 12 months.     

Cows' milk protein-sensitive enteropathy: an important contributing cause of secondary sugar intolerance in young infants with acute infective enteritis.

The effect of cows'' milk protein (CMP) on the mucosal disaccharidases was investigated in 23 infants with acute infective enteritis. Jejunal biopsies performed before and after cows'' milk provocation were subjected to histological examination and to mucosal disaccharidase enzyme (lactase, sucrase, and maltase) analyses. After milk challenge, changes in mucosal histology were observed in 18 infants, in 17 of them the levels of all 3 mucosal disaccharidases were much reduced. 10 of these infants developed diarrhoea and, in 6, the stools were positive for reducing sugar. It is concluded that CMP has a deleterious effect on the jejunal mucosa of young infants recovering from infective enteritis, so that in the management of young infants with sugar intolerance secondary to infective enteritis, CMP and lactose should be excluded from the diet.     

SERUM IgA IN THE NEONATE

ABSTRACT. Yap, P. L., Pryde, A., Latham, P. J. and McClelland, D. B. L. (MRC Unit of Reproductive Biology, 2 Forrest Road, Edinburgh; Department of Therapeutics, Edinburgh University, Neonatal Unit, Simpson Memorial Maternity Pavilion and Blood Transfusion Service, Royal Infirmary, Edinburgh). Serum IgA in the neonate: Molecular size, concentration and effect of breast feeding. Acta Paediatr Scand, 68: 695, 1979.—IgA concentrations in the serum of 48 six-day-old neonates (23 exclusively artificially fed, 25 exclusively breast fed) were measured using a double antibody radioimmunoassay. In 24 of the neonates, umbilical cord blood was also studied. Gel filtration was used to estimate the molecular size of IgA present in cord and neonatal serum. The arithmetic mean concentration of IgA (±S.E.M.) found in the 48 neonates was 2.6± 1.45 mg/l. No significant difference was detected between the breast fed and artificially fed neonates. Only 7S IgA was detected in cord blood and in neonatal serum. Six days of exclusive breast feeding therefore has no influence on total serum IgA levels on the sixth day of neonatal life nor does it result in detectable circulating 11S IgA at that time.     

Development of IgE and IgG antibodies to food and inhalant allergens in children at risk of allergic disease.

In a prospective study of 92 children with at least one atopic parent, the development of the specific antibody responses to food and inhalant allergens during the first 5 years of life were assessed. By the radioallergosorbent test egg specific IgE antibody occurred in about 30% of the children with the mean peak concentration at 12 months. By the second year the prevalence of this antibody had increased whereas the mean concentration had decreased. Milk specific IgE antibody could not be shown in any subject, including four whose skin tests yielded positive results. Food specific IgG antibody was noted by antigen binding radioimmunoassays at 3 months in most children. These responses had peaked and began to fall by the fifth year. In contrast few children had detectable IgE or IgG antibody to inhalant allergens before the first 2 years of life. Both the concentration and prevalence of specific antibody, however, increased from the second to the fifth year and was greater in children whose skin tests yielded positive results. Breast feeding was associated with an increase in the prevalence of positive results from skin tests but was not associated with detectable IgE antibody to both food proteins, a lower concentration of IgG antibody to cows'' milk, and was not associated with protection against the development of disease. A high level of exposure to dust mite was associated with an increased prevalence of positive results from skin tests to dust mite and appreciably higher antibody concentration. This study indicates differences in the humoral responses to food and inhalant allergens. Environmental factors appear to influence the development of these responses.     

Serum IgA in the neonate. Molecular size, concentration and effect of breast feeding

IgA concentrations in the serum of 48 six-day-old neonates (23 exclusively artificially fed, 25 exclusively breast fed) were measured using a double antibody radioimmunoassay. In 24 of the neonates, umbilical cord blood was also studied. Gel filtration was used to estimate the molecular size of IgA present in cord and neonatal serum. The arithmetic mean concentration of IgA (+/- S.E.M.) found in the 48 neonates was 2.6 +/- 1.45 mg/l. No significant difference was detected between the breast fed and artificially fed neonates. Only 7S IgA was detected in cord blood and in neonatal serum. Six days of exclusive breast feeding therefore has no influence on total serum IgA levels on the sixth day of neonatal life nor does it result in detectable circulating 11S IgA at that time.     

Prevalence of infant colic

Colic affected 16% of 843 infants. It was not related to breast or cows'' milk feeding. Increased prevalence was noted if cereals or solids had been introduced during the first 3 months of life and in infants from professional or skilled social groupings.     

晚发型母乳性黄疸患儿停母乳前后表皮生长因子的变化研究

目的 观察晚发型母乳性黄疸患儿停母乳前后患儿血清及母乳中表皮生长因子（epidermal growth factor,EGF）的变化。方法 选取30例足月晚发型母乳性黄疸患儿为研究对象,收集停母乳72 h前后两次的患儿血清及母乳,分别检测患儿血清中的总胆红素值、EGF浓度及母乳中的EGF浓度。结果 停母乳72 h后患儿血清总胆红素值及EGF浓度较停母乳前显著下降（均P<0.05）;而母乳中EGF浓度在停母乳前后差异无统计学意义（P >0.05）。结论 晚发型母乳性黄疸患儿停母乳前后母乳中EGF浓度无明显变化,而患儿血清中EGF浓度显著下降,其在晚发型母乳性黄疸中的作用及机制有待进一步研究。     

Diet and faecal flora in the newborn: casein and whey proteins.

Despite the extensive modifications of cows'' milk to make an infant formula resemble human breast milk, we showed in a previous study that the faecal flora of breast fed babies still differs substantially from that of formula fed babies. This paper describes the effects that differences in the distribution of whey proteins and caseins exert on the faecal flora. Faecal flora was examined in 33 babies receiving a whey formula, 29 babies receiving a casein formula, and 38 breast fed babies. Subsequently fewer babies in each group were studied at weeks 7, 11, and 15. More whey fed babies were colonised with bifidobacteria at 14 days compared with the casein fed group, more casein fed babies were colonised with bacteroides (at 14 days), and more had a dominant growth of enterococci (at week 7). It seems therefore that during the first two months that the whey predominant formula induced a faecal flora generally closer to that of breast fed babies than did a casein formula.