母乳喂养婴儿早期引入致敏食物（Allergenic Foods）可以预防1-3岁食物过敏？-一项大样本随机对照试验
2016/07/07
背景：母乳喂养的婴儿应该在哪个年龄段开始食用致敏食物，目前尚不确切。本研究评估是否在母乳喂养的婴儿饮食中早期加入致敏食物能够预防未来食物过敏的发生。
方法：我们从普通人群中招募了1303名3个月大的纯母乳喂养的婴儿，并将其随机分配到2组，早期引入组和标准进食组，早期引入组为3个月时引入6种可引起过敏的食物，包括花生、熟鸡蛋、牛奶、芝麻、白鲑鱼肉和小麦；标准进食组为按照英国实践指南推荐纯母乳喂养婴儿约6个月大时进食可致敏食物的一组。主要观察终点，是在1-3岁期间出现对6种食物中一种或者多种食物产生过敏反应。
结果：根据意向性治疗分析（ITT)，标准进食组中595名参与者中42名对6种给定食物中一种或者多种发生过敏，发生率为7.1%；在早期引入组中为5.6%（32/567名）（P=0.32）。
根据符合方案集分析，任何食物过敏的发生率，早期引入组都显著低于标准进食组（2.4%比7.3%，P=0.01），比如花生过敏的发生率（0%比2.5%，P=0.003）、鸡蛋过敏率（1.4%比5.5%，P=0.009）；而两组的牛奶、芝麻、鱼和小麦过敏发生率未见显著的差异。
与进食更少量的相比，每周进食2g花生或者蛋清蛋白具有更低的食物过敏发生率。早期开始进食这6种食物很不容易实现但却是安全的。
结论：在意向性治疗分析中，此实验没有发现早期引入致敏食物预防食物过敏的作用。本研究提出一个问题，是否早期引入多种过敏性食物来预防食物过敏是具有剂量依赖性的效果，这值得进一步研究。
方法介绍：本研究根据意向性治疗原则（Intention-TO-Treat, ITT）法和符合方案集分析结果具有明显的差别。ITT是一种认为处理策略以想要治疗受试者（即计划好的治疗进程），而不是基于实际给与的治疗措施为基础进行评价，可以对效果做最好的评定的原则。其结果是分到一个处理组的受试者即应作为该组的成员被随访评价和分析，而不管他们是否依从计划的处理过程。因此，做ITT分析的数据集是全分析集，尽可能接近意向性处理原则的理想的受试者集，由所有随机化的受试者中以最小的和合理的方法剔除受试者得出，未完成的数据观测值以最后一次观测值转接到最后的观测值。
PP是Per-protocol的英文缩写，也即符合方案集分析。PP分析是对符合方案集做出的分析总结，符合方案集的受试者均按照方案完成了试验全过程，且没有违反入组标准。
由于分析集的差异，ITT分析与PP分析总是结果不相同，从符合方案集中排除相当大比例的受试者，对试验结果总是会产生影响，因此，一个临床试验规定，依从性不能低于80%。如果一个试验的依从性低于80%，则意味着试验失败。在最后的统计报告中，所有的疗效指标和安全性指标均需要报告ITT分析结果与PP分析结果，如果二者一致，说明试验结论可靠，反之，说明试验结论尚须进一步验证。
EAT Study Team. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants.
Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, Brough H, Marrs T, Radulovic S, Craven J, Flohr C, Lack G;
N Engl J Med. 2016 May 5;374(18):1733-43.
BACKGROUND:The age at which allergenic foods should be introduced into the diet of breast-fed infants is uncertain. We evaluated whether the early introduction of allergenic foods in the diet of breast-fed infants would protect against the development of food allergy.
METHODS:We recruited, from the general population, 1303 exclusively breast-fed infants who were 3 months of age and randomly assigned them to the early introduction of six allergenic foods (peanut, cooked egg, cow's milk, sesame, whitefish, and wheat; early-introduction group) or to the current practice recommended in the United Kingdom of exclusive breast-feeding to approximately 6 months of age (standard-introduction group). The primary outcome was food allergy to one or more of the six foods between 1 year and 3 years of age.
RESULTS:In the intention-to-treat analysis, food allergy to one or more of the six intervention foods developed in 7.1% of the participants in the standard-introduction group (42 of 595 participants) and in 5.6% of those in the early-introduction group (32 of 567) (P=0.32). In the per-protocol analysis, the prevalence of any food allergy was significantly lower in the early-introduction group than in the standard-introduction group (2.4% vs. 7.3%, P=0.01), as was the prevalence of peanut allergy (0% vs. 2.5%, P=0.003) and egg allergy (1.4% vs. 5.5%, P=0.009); there were no significant effects with respect to milk, sesame, fish, or wheat. The consumption of 2 g per week of peanut or egg-white protein was associated with a significantly lower prevalence of these respective allergies than was less consumption. The early introduction of all six foods was not easily achieved but was safe.
CONCLUSIONS:The trial did not show the efficacy of early introduction of allergenic foods in an intention-to-treat analysis. Further analysis raised the question of whether the prevention of food allergy by means of early introduction of multiple allergenic foods was dose-dependent. (Funded by the Food Standards Agency and others; EAT Current Controlled Trials number, ISRCTN14254740.).
方法：我们从普通人群中招募了1303名3个月大的纯母乳喂养的婴儿，并将其随机分配到2组，早期引入组和标准进食组，早期引入组为3个月时引入6种可引起过敏的食物，包括花生、熟鸡蛋、牛奶、芝麻、白鲑鱼肉和小麦；标准进食组为按照英国实践指南推荐纯母乳喂养婴儿约6个月大时进食可致敏食物的一组。主要观察终点，是在1-3岁期间出现对6种食物中一种或者多种食物产生过敏反应。
结果：根据意向性治疗分析（ITT)，标准进食组中595名参与者中42名对6种给定食物中一种或者多种发生过敏，发生率为7.1%；在早期引入组中为5.6%（32/567名）（P=0.32）。
根据符合方案集分析，任何食物过敏的发生率，早期引入组都显著低于标准进食组（2.4%比7.3%，P=0.01），比如花生过敏的发生率（0%比2.5%，P=0.003）、鸡蛋过敏率（1.4%比5.5%，P=0.009）；而两组的牛奶、芝麻、鱼和小麦过敏发生率未见显著的差异。
与进食更少量的相比，每周进食2g花生或者蛋清蛋白具有更低的食物过敏发生率。早期开始进食这6种食物很不容易实现但却是安全的。
结论：在意向性治疗分析中，此实验没有发现早期引入致敏食物预防食物过敏的作用。本研究提出一个问题，是否早期引入多种过敏性食物来预防食物过敏是具有剂量依赖性的效果，这值得进一步研究。
方法介绍：本研究根据意向性治疗原则（Intention-TO-Treat, ITT）法和符合方案集分析结果具有明显的差别。ITT是一种认为处理策略以想要治疗受试者（即计划好的治疗进程），而不是基于实际给与的治疗措施为基础进行评价，可以对效果做最好的评定的原则。其结果是分到一个处理组的受试者即应作为该组的成员被随访评价和分析，而不管他们是否依从计划的处理过程。因此，做ITT分析的数据集是全分析集，尽可能接近意向性处理原则的理想的受试者集，由所有随机化的受试者中以最小的和合理的方法剔除受试者得出，未完成的数据观测值以最后一次观测值转接到最后的观测值。
PP是Per-protocol的英文缩写，也即符合方案集分析。PP分析是对符合方案集做出的分析总结，符合方案集的受试者均按照方案完成了试验全过程，且没有违反入组标准。
由于分析集的差异，ITT分析与PP分析总是结果不相同，从符合方案集中排除相当大比例的受试者，对试验结果总是会产生影响，因此，一个临床试验规定，依从性不能低于80%。如果一个试验的依从性低于80%，则意味着试验失败。在最后的统计报告中，所有的疗效指标和安全性指标均需要报告ITT分析结果与PP分析结果，如果二者一致，说明试验结论可靠，反之，说明试验结论尚须进一步验证。
（南方医科大学南方医院 袁亚飞 赵海金）
N Engl J Med. 2016 May 5;374(18):1733-43.
N Engl J Med. 2016 May 5;374(18):1733-43.
EAT Study Team. Randomized Trial of Introduction of Allergenic Foods in Breast-Fed Infants.
Perkin MR, Logan K, Tseng A, Raji B, Ayis S, Peacock J, Brough H, Marrs T, Radulovic S, Craven J, Flohr C, Lack G;
N Engl J Med. 2016 May 5;374(18):1733-43.
BACKGROUND:The age at which allergenic foods should be introduced into the diet of breast-fed infants is uncertain. We evaluated whether the early introduction of allergenic foods in the diet of breast-fed infants would protect against the development of food allergy.
METHODS:We recruited, from the general population, 1303 exclusively breast-fed infants who were 3 months of age and randomly assigned them to the early introduction of six allergenic foods (peanut, cooked egg, cow's milk, sesame, whitefish, and wheat; early-introduction group) or to the current practice recommended in the United Kingdom of exclusive breast-feeding to approximately 6 months of age (standard-introduction group). The primary outcome was food allergy to one or more of the six foods between 1 year and 3 years of age.
RESULTS:In the intention-to-treat analysis, food allergy to one or more of the six intervention foods developed in 7.1% of the participants in the standard-introduction group (42 of 595 participants) and in 5.6% of those in the early-introduction group (32 of 567) (P=0.32). In the per-protocol analysis, the prevalence of any food allergy was significantly lower in the early-introduction group than in the standard-introduction group (2.4% vs. 7.3%, P=0.01), as was the prevalence of peanut allergy (0% vs. 2.5%, P=0.003) and egg allergy (1.4% vs. 5.5%, P=0.009); there were no significant effects with respect to milk, sesame, fish, or wheat. The consumption of 2 g per week of peanut or egg-white protein was associated with a significantly lower prevalence of these respective allergies than was less consumption. The early introduction of all six foods was not easily achieved but was safe.
CONCLUSIONS:The trial did not show the efficacy of early introduction of allergenic foods in an intention-to-treat analysis. Further analysis raised the question of whether the prevention of food allergy by means of early introduction of multiple allergenic foods was dose-dependent. (Funded by the Food Standards Agency and others; EAT Current Controlled Trials number, ISRCTN14254740.).
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