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Infant formulas for primary allergy prevention
Correspondence 471
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
In another article, they state that ‘‘the harm of an asthma exacerbation may be short-lived and easily reversed (minor harm) or it may lead to hospitalization or even death (major harm).’’4 It would be a serious concern if patients in PCTs were suffering such ‘‘major harm’’ by being randomized to placebo. When one looks at the authors’ data regarding reported hospitalizations, however, one finds that the rate of hospitalization for patients enrolled in placebo arms of PCTs (5 of 4398; 0.1%) was almost identical to that of patients enrolled in active-treatment arms (9 of 8867; 0.1%).4 Of 1180 children who received placebos in asthma trials, there were no reported hospitalizations.4 Finally, of all patients enrolled in PCTs, there was a 0.1% rate of hospitalization, whereas there was a 0.9% rate of hospitalization in patients enrolled in active-control and add-on trials.4 This may indicate that patients were monitored more closely, or sicker patients excluded, in PCTs. I believe that these data support my conclusion that properly designed, reviewed, approved, and monitored PCTs of asthma may safely and ethically be conducted.3 The issues of ‘‘exacerbations’’ and ‘‘equipoise’’ both concern the question whether research subjects may be allowed to sacrifice anything to promote the purpose of the research. If the answer to this question is no, then the entire biomedical research enterprise is on dubious moral grounds. If a subject may not ethically bear the risk of being randomized for a short time to placebo, how does one ask the same subject to consent to phlebotomies, lung biopsies, bronchoprovocation challenges, or exposure to unknown risks of new immune modifying agents? If the current Declaration of Helsinki stands for barring researchers and subjects from participating in well designed, carefully monitored PCTs, then the World Medical Association should revisit this document. Robert F. Onder, MD, JD From the Washington University School of Medicine, Midwest Clinical Research, LLC, 711 Old Ballas Road, Suite 100, St Louis, MO 63141.
REFERENCES 1. Coffey MJ, Ross LF. Ethics of placebos in clinical asthma trials. J Allergy Clin Immunol 2006;117:470. 2. Emanuel EJ, Miller FG. The ethics of placebo-controlled trials: a middle ground. N Engl J Med 2001;345:915-9. 3. Onder RF. The ethics of placebo-controlled trials: the case of asthma. J Allergy Clin Immunol 2005;115:1228-34. 4. Coffey MJ, Wilfond B, Ross LF. Ethical assessment of clinical asthma trials including children subjects. Pediatrics 2004;133:87-94. Available online November 8, 2005. doi:10.1016/j.jaci.2005.09.015
Breast-feeding remains the gold standard; however, it is not an appropriate control for assessing the efficacy of reducing allergy risk. Intact cow milk formulas are associated with increased allergy risk, not breast-feeding. Therefore, neither breast-feeding nor other hydrolysates should be used as controls in assessing formulas for primary allergy prevention. Trials like that of Halken et al2 are cited, which compare hydrolysates with breast-feeding and not cow milk formula. Regarding extensive hydrolysates (EHs), the authors state, ‘‘Numerous studies have demonstrated the effectiveness’’ of EHs for allergy prevention. In support, they cite the recent Cochrane meta-analysis,3 which showed a preventive effect of hydrolysates compared with cow milk formulas (relative risk, 0.63; CI, 0.47-0.85). In fact, the risk reduction cited is based exclusively on trials comparing partial hydrolysates (PHs) with cow milk formula (p. 44 and 50).3 In comparing EHs with PHs, the authors state, ‘‘Several recent European studies.. All have shown superiority of extensively hydrolyzed formula over partial hydrolysates,’’ citing Halken et al2 and von Berg et al.4 As mentioned, Halken et al2 compared hydrolysates with breast-feeding (not the target for primary prevention), and von Berg et al4 found that some EHs are not effective, while Porch et al5 found no difference between EHs and PHs. The Cochrane meta-analysis3 concluded, ‘‘There is insufficient evidence to determine whether feeding with an extensively hydrolyzed formula has any advantage over a partially hydrolyzed formula for primary prevention.’’ Despite pointing out that not all EH formulas have shown efficacy, Friedman and Zeiger1 recommend, ‘‘Extensively hydrolyzed formulas should be encouraged as supplements to breast milk in high-risk infants..’’ The discussion neglects a critical issue: not all hydrolysates are created equal. The protein sources and hydrolysis methods used vary significantly and can affect efficacy; therefore, it is inappropriate to group hydrolysate formulas generically into partial and extensive. Of those formulas currently available, only 2 specific products have been adequately studied and have consistently demonstrated efficacy when compared with standard cow milk formulas: an EH casein (Nutramigen; Mead Johnson Nutritionals, Evansville, Ind) and a PH whey formula (Good Start or NAN HA or Beba HA; Nestle´, Glendale, Calif).3 My recent review6 authored with Robert Wood, MD, reviews the clinical trials in detail, although the formula manufacturers are not mentioned. Efficacy demonstrated in clinical trials, not degree of hydrolysis, should be the basis for recommendations. The authors’ recommendations could be misinterpreted; therefore, I propose the following recommendations:
Infant formulas for primary allergy prevention d
To the Editor: Friedman and Zeiger1 authored an excellent review on the merits of breast-feeding relative to allergy prevention. In it, the authors draw conclusions from the literature regarding the use of hydrolysate formulas for allergy prevention that deserve comment.
d
Health professionals should base formula recommendations for primary allergy prevention in nonexclusively breast-fed infants on demonstrated efficacy compared with standard intact cow milk protein formulas. The protein source, degree and method of hydrolysis, and manufacturer should be included as part of the recommendation.
472 Correspondence
d
J ALLERGY CLIN IMMUNOL FEBRUARY 2006
Health professionals should consider acceptability, palatability, and cost of these products when making recommendations. Tiffani Hays, MS, RD, LDN, CDE
From the Johns Hopkins Childrens Nutrition Center, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins Hospital, 600 North Wolfe Street, Brady 302, Baltimore, MD 21287. Disclosure of potential conflict of interest: T. Hays has a consultant arrangement with Nestle´, USA.
REFERENCES 1. Friedman N, Zeiger R. The role of breast-feeding in the development of allergies and asthma. J Allergy Clin Immunol 2005;115:1238-48. 2. Halken S, Hansen KS, Jacobsen HP, Estmann A, Faelling AE, Hansen LG, et al. Comparison of a partially hydrolyzed infant formula with two extensively hydrolyzed formulas for allergy prevention: a prospective, randomized study. Pediatr Allergy Immunol 2000;11:149-61. 3. Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants (Cochrane Review). In: The Cochrane Library, Issue 4. Chichester, UK: John Wiley & Sons, Ltd; 2003. 4. Von Berg A, Koletzko S, Gru¨bl A, Filipiak-Pittroff B, Wichmann H, Bauer CP, et al. German Infant Nutritional-Intervention Study Group. The effect of hydrolyzed cow’s milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol 2003;111:533-40. 5. Porch MC, Shahane AD, Leiva LE, Elston RC, Sorensen RU. Influence of breast milk, soy or two hydrolyzed formulas on the development or allergic manifestations in infants at risk. Nutr Res 1998;18:1413-24. 6. Hays TL, Wood RA. A systematic review of the role of hydrolysate infant formulas in allergy prevention. Arch Pediatr Adolesc Med 2005;159: 810-6. Available online November 14, 2005. doi:10.1016/j.jaci.2005.09.012
Reply To the Editor: We would like to thank Ms Hays1 for her interesting comments. Our review2 of the role of breast-feeding in the development of allergies and asthma was primarily designed to discuss what one would lose in this respect if one decided to not recommend breast-feeding in atopic families. Our discussion of supplemental formulas in this context was included to illustrate that for those who cannot breast-feed or who need supplementation to breastfeeding, using an extensively hydrolyzed formula was an alternative recommended by the American Academy of Pediatrics (AAP)3 and supported by the literature. However, we do appreciate the opportunity to clarify this recommendation. We agree that when fully evaluating the role of hydrolysate formulas in the development of atopy, it is particularly important to compare these formulas with cow’s milk formula. The Cochrane meta-analysis by Osborn and Sinn4 to which we referred found evidence that feeding with hydrolyzed formulas reduces infant allergies compared with feeding with cow’s milk formula. The conclusions also stated that there was insufficient
evidence to determine whether feeding with an extensively hydrolyzed formula had any advantage over a partially hydrolyzed formula. We therefore turned to the largest controlled study of hydrolyzed formulas with regard to the prevention of atopy, the German Infant Nutritional Intervention (GINI) Study.5 With respect to the reduction in the development of any allergic manifestation by age 1 year, the GINI study demonstrated the superiority of an extensively hydrolyzed casein formula compared with cow’s milk formula but not of a partially hydrolyzed whey formula compared with cow’s milk formula. With regard to the development of atopic dermatitis alone by 1 year, both an extensive casein hydrolysate (P 5 .007) and a partial whey hydrolysate (P 5 .048) appeared protective compared with cow’s milk formula. However, as the authors state, in the presence of atopic dermatitis in the family, the partial whey hydrolysate lost its protective effect to reduce the development of atopic dermatitis. The GINI study also showed that an extensively hydrolyzed whey formula, one not currently available in the United States, was not protective for the development of allergic manifestations or atopic dermatitis for reasons unknown at this time. Although we agree that more studies need to be performed to determine better the role of hydrolysate formulas in the prevention of atopy, based on the data currently available, we did not feel that there was enough evidence to alter the conclusions of the AAP published in 20003: ‘‘Infants at high risk for developing allergy, identified by a strong (biparental; parent, and sibling) family history of allergy may benefit from exclusive breastfeeding or a hypoallergenic formula or possibly a partial hydrolysate formula. Conclusive studies are not yet available to permit definitive recommendations.’’ At this time, of the commercially available hydrolysate formulas in the United States, only extensive casein hydrolysates have been shown to be hypoallergenic. Ms Hays1 is correct to point out that not all extensive hydrolysates provide allergy preventive benefits as noted with the extensive whey hydrolysate in the GINI study. As such, we do agree that for allergy prevention, one should recommend only those hydrolysate formulas with proven preventive properties. Further studies may suggest revision of these recommendations in the future with a greater role given to partially hydrolyzed formulas, particularly if the cost and palatability are taken into consideration. However, it should be remembered, as we noted in detail2 and as recommended by the AAP,3 that breastfeeding, given its nutritional, immunological, physiological, and psychological benefits, is the feeding of first choice for newborns, including infants at high risk for allergic disease. Noah J. Friedman, MD Robert S. Zeiger, MD, PhD From the Southern California Permanente Medical Group, 7060 Clairemont Mesa Blvd, San Diego, CA 92111.
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
In another article, they state that ‘‘the harm of an asthma exacerbation may be short-lived and easily reversed (minor harm) or it may lead to hospitalization or even death (major harm).’’4 It would be a serious concern if patients in PCTs were suffering such ‘‘major harm’’ by being randomized to placebo. When one looks at the authors’ data regarding reported hospitalizations, however, one finds that the rate of hospitalization for patients enrolled in placebo arms of PCTs (5 of 4398; 0.1%) was almost identical to that of patients enrolled in active-treatment arms (9 of 8867; 0.1%).4 Of 1180 children who received placebos in asthma trials, there were no reported hospitalizations.4 Finally, of all patients enrolled in PCTs, there was a 0.1% rate of hospitalization, whereas there was a 0.9% rate of hospitalization in patients enrolled in active-control and add-on trials.4 This may indicate that patients were monitored more closely, or sicker patients excluded, in PCTs. I believe that these data support my conclusion that properly designed, reviewed, approved, and monitored PCTs of asthma may safely and ethically be conducted.3 The issues of ‘‘exacerbations’’ and ‘‘equipoise’’ both concern the question whether research subjects may be allowed to sacrifice anything to promote the purpose of the research. If the answer to this question is no, then the entire biomedical research enterprise is on dubious moral grounds. If a subject may not ethically bear the risk of being randomized for a short time to placebo, how does one ask the same subject to consent to phlebotomies, lung biopsies, bronchoprovocation challenges, or exposure to unknown risks of new immune modifying agents? If the current Declaration of Helsinki stands for barring researchers and subjects from participating in well designed, carefully monitored PCTs, then the World Medical Association should revisit this document. Robert F. Onder, MD, JD From the Washington University School of Medicine, Midwest Clinical Research, LLC, 711 Old Ballas Road, Suite 100, St Louis, MO 63141.
REFERENCES 1. Coffey MJ, Ross LF. Ethics of placebos in clinical asthma trials. J Allergy Clin Immunol 2006;117:470. 2. Emanuel EJ, Miller FG. The ethics of placebo-controlled trials: a middle ground. N Engl J Med 2001;345:915-9. 3. Onder RF. The ethics of placebo-controlled trials: the case of asthma. J Allergy Clin Immunol 2005;115:1228-34. 4. Coffey MJ, Wilfond B, Ross LF. Ethical assessment of clinical asthma trials including children subjects. Pediatrics 2004;133:87-94. Available online November 8, 2005. doi:10.1016/j.jaci.2005.09.015
Breast-feeding remains the gold standard; however, it is not an appropriate control for assessing the efficacy of reducing allergy risk. Intact cow milk formulas are associated with increased allergy risk, not breast-feeding. Therefore, neither breast-feeding nor other hydrolysates should be used as controls in assessing formulas for primary allergy prevention. Trials like that of Halken et al2 are cited, which compare hydrolysates with breast-feeding and not cow milk formula. Regarding extensive hydrolysates (EHs), the authors state, ‘‘Numerous studies have demonstrated the effectiveness’’ of EHs for allergy prevention. In support, they cite the recent Cochrane meta-analysis,3 which showed a preventive effect of hydrolysates compared with cow milk formulas (relative risk, 0.63; CI, 0.47-0.85). In fact, the risk reduction cited is based exclusively on trials comparing partial hydrolysates (PHs) with cow milk formula (p. 44 and 50).3 In comparing EHs with PHs, the authors state, ‘‘Several recent European studies.. All have shown superiority of extensively hydrolyzed formula over partial hydrolysates,’’ citing Halken et al2 and von Berg et al.4 As mentioned, Halken et al2 compared hydrolysates with breast-feeding (not the target for primary prevention), and von Berg et al4 found that some EHs are not effective, while Porch et al5 found no difference between EHs and PHs. The Cochrane meta-analysis3 concluded, ‘‘There is insufficient evidence to determine whether feeding with an extensively hydrolyzed formula has any advantage over a partially hydrolyzed formula for primary prevention.’’ Despite pointing out that not all EH formulas have shown efficacy, Friedman and Zeiger1 recommend, ‘‘Extensively hydrolyzed formulas should be encouraged as supplements to breast milk in high-risk infants..’’ The discussion neglects a critical issue: not all hydrolysates are created equal. The protein sources and hydrolysis methods used vary significantly and can affect efficacy; therefore, it is inappropriate to group hydrolysate formulas generically into partial and extensive. Of those formulas currently available, only 2 specific products have been adequately studied and have consistently demonstrated efficacy when compared with standard cow milk formulas: an EH casein (Nutramigen; Mead Johnson Nutritionals, Evansville, Ind) and a PH whey formula (Good Start or NAN HA or Beba HA; Nestle´, Glendale, Calif).3 My recent review6 authored with Robert Wood, MD, reviews the clinical trials in detail, although the formula manufacturers are not mentioned. Efficacy demonstrated in clinical trials, not degree of hydrolysis, should be the basis for recommendations. The authors’ recommendations could be misinterpreted; therefore, I propose the following recommendations:
Infant formulas for primary allergy prevention d
To the Editor: Friedman and Zeiger1 authored an excellent review on the merits of breast-feeding relative to allergy prevention. In it, the authors draw conclusions from the literature regarding the use of hydrolysate formulas for allergy prevention that deserve comment.
d
Health professionals should base formula recommendations for primary allergy prevention in nonexclusively breast-fed infants on demonstrated efficacy compared with standard intact cow milk protein formulas. The protein source, degree and method of hydrolysis, and manufacturer should be included as part of the recommendation.
472 Correspondence
d
J ALLERGY CLIN IMMUNOL FEBRUARY 2006
Health professionals should consider acceptability, palatability, and cost of these products when making recommendations. Tiffani Hays, MS, RD, LDN, CDE
From the Johns Hopkins Childrens Nutrition Center, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins Hospital, 600 North Wolfe Street, Brady 302, Baltimore, MD 21287. Disclosure of potential conflict of interest: T. Hays has a consultant arrangement with Nestle´, USA.
REFERENCES 1. Friedman N, Zeiger R. The role of breast-feeding in the development of allergies and asthma. J Allergy Clin Immunol 2005;115:1238-48. 2. Halken S, Hansen KS, Jacobsen HP, Estmann A, Faelling AE, Hansen LG, et al. Comparison of a partially hydrolyzed infant formula with two extensively hydrolyzed formulas for allergy prevention: a prospective, randomized study. Pediatr Allergy Immunol 2000;11:149-61. 3. Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants (Cochrane Review). In: The Cochrane Library, Issue 4. Chichester, UK: John Wiley & Sons, Ltd; 2003. 4. Von Berg A, Koletzko S, Gru¨bl A, Filipiak-Pittroff B, Wichmann H, Bauer CP, et al. German Infant Nutritional-Intervention Study Group. The effect of hydrolyzed cow’s milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol 2003;111:533-40. 5. Porch MC, Shahane AD, Leiva LE, Elston RC, Sorensen RU. Influence of breast milk, soy or two hydrolyzed formulas on the development or allergic manifestations in infants at risk. Nutr Res 1998;18:1413-24. 6. Hays TL, Wood RA. A systematic review of the role of hydrolysate infant formulas in allergy prevention. Arch Pediatr Adolesc Med 2005;159: 810-6. Available online November 14, 2005. doi:10.1016/j.jaci.2005.09.012
Reply To the Editor: We would like to thank Ms Hays1 for her interesting comments. Our review2 of the role of breast-feeding in the development of allergies and asthma was primarily designed to discuss what one would lose in this respect if one decided to not recommend breast-feeding in atopic families. Our discussion of supplemental formulas in this context was included to illustrate that for those who cannot breast-feed or who need supplementation to breastfeeding, using an extensively hydrolyzed formula was an alternative recommended by the American Academy of Pediatrics (AAP)3 and supported by the literature. However, we do appreciate the opportunity to clarify this recommendation. We agree that when fully evaluating the role of hydrolysate formulas in the development of atopy, it is particularly important to compare these formulas with cow’s milk formula. The Cochrane meta-analysis by Osborn and Sinn4 to which we referred found evidence that feeding with hydrolyzed formulas reduces infant allergies compared with feeding with cow’s milk formula. The conclusions also stated that there was insufficient
evidence to determine whether feeding with an extensively hydrolyzed formula had any advantage over a partially hydrolyzed formula. We therefore turned to the largest controlled study of hydrolyzed formulas with regard to the prevention of atopy, the German Infant Nutritional Intervention (GINI) Study.5 With respect to the reduction in the development of any allergic manifestation by age 1 year, the GINI study demonstrated the superiority of an extensively hydrolyzed casein formula compared with cow’s milk formula but not of a partially hydrolyzed whey formula compared with cow’s milk formula. With regard to the development of atopic dermatitis alone by 1 year, both an extensive casein hydrolysate (P 5 .007) and a partial whey hydrolysate (P 5 .048) appeared protective compared with cow’s milk formula. However, as the authors state, in the presence of atopic dermatitis in the family, the partial whey hydrolysate lost its protective effect to reduce the development of atopic dermatitis. The GINI study also showed that an extensively hydrolyzed whey formula, one not currently available in the United States, was not protective for the development of allergic manifestations or atopic dermatitis for reasons unknown at this time. Although we agree that more studies need to be performed to determine better the role of hydrolysate formulas in the prevention of atopy, based on the data currently available, we did not feel that there was enough evidence to alter the conclusions of the AAP published in 20003: ‘‘Infants at high risk for developing allergy, identified by a strong (biparental; parent, and sibling) family history of allergy may benefit from exclusive breastfeeding or a hypoallergenic formula or possibly a partial hydrolysate formula. Conclusive studies are not yet available to permit definitive recommendations.’’ At this time, of the commercially available hydrolysate formulas in the United States, only extensive casein hydrolysates have been shown to be hypoallergenic. Ms Hays1 is correct to point out that not all extensive hydrolysates provide allergy preventive benefits as noted with the extensive whey hydrolysate in the GINI study. As such, we do agree that for allergy prevention, one should recommend only those hydrolysate formulas with proven preventive properties. Further studies may suggest revision of these recommendations in the future with a greater role given to partially hydrolyzed formulas, particularly if the cost and palatability are taken into consideration. However, it should be remembered, as we noted in detail2 and as recommended by the AAP,3 that breastfeeding, given its nutritional, immunological, physiological, and psychological benefits, is the feeding of first choice for newborns, including infants at high risk for allergic disease. Noah J. Friedman, MD Robert S. Zeiger, MD, PhD From the Southern California Permanente Medical Group, 7060 Clairemont Mesa Blvd, San Diego, CA 92111.