Supplementary Material for: Nutritional Management of Low Birth Weight and Preterm Infants in Low and Low Middle-Income Countries

Introduction
Preterm and LBW infants are at an increased risk of morbidity and mortality compared with their term counterparts, with more than 20 million LBW infants born each year, the majority in LMICs. Given the increased vulnerability and higher nutritional needs of these infants, optimizing feeding strategies may play a crucial role in improving their health outcomes.
Methods
We updated evidence of Every Newborn Series published in The Lancet 2014 by identifying relevant systematic reviews, extracting LIC and LMIC data, and conducting revised meta-analysis for these contexts.
Results
We found 15 reviews; the evidence showed that early initiation of enteral feeding reduced neonatal mortality overall, but not in LIC/LMIC settings. Breastfeeding promotion interventions increased the prevalence of early initiation of breastfeeding and exclusive breastfeeding at three and six months of age in LMIC settings. There was an increased risk of neonatal mortality with formula milk in LIC/LMIC settings. Despite contributing to greater weight gain, there was a higher risk of necrotizing enterocolitis with formula milk overall. Breastmilk fortification and nutrient-enriched formula improved growth outcomes. Iron and vitamin A supplementation reduced anemia and mortality rates (LMIC), respectively. The evidence also suggested that benefits of various different micronutrient supplementation interventions such as zinc, calcium/phosphorous and vitamin D, outweigh the risks since our review demonstrates little to no adverse effects deriving from their supplementation, particularly for a breastfed preterm and/or LBW infant.
Conclusion
Early adequate nutritional support of preterm or LBW infant is paramount to averse adverse health outcomes, contribute to normal growth, resistance to infection and optimal development. Breastmilk feeding and micronutrient supplementation are crucial to reduce diarrhea incidence and mortality respectively while feed fortification or nutrient-enriched formula, when breast milk is not available, to enhance better growth especially in LMICs where there is higher population of growth restriction and stunting. This review also highlights need for randomized trials in LMICs at large scale to further strengthen the evidence.

引言
早产（Preterm）与低出生体重（Low Birth Weight, LBW）婴儿相较于足月婴儿，罹患疾病与死亡的风险显著升高；全球每年有超2000万低出生体重婴儿降生，其中绝大多数诞生于中低收入国家（Low- and Middle-Income Countries, LMICs）。鉴于此类婴儿的易感性更强、营养需求更高，优化喂养策略或对改善其健康结局起到关键作用。

方法
本研究对2014年发表于《柳叶刀》（The Lancet）的《Every Newborn》系列研究证据进行更新：通过检索相关系统综述、提取低收入国家（Low-Income Countries, LIC）与中低收入国家数据，并针对此类场景开展修正版荟萃分析。

结果
本次研究共纳入15篇综述；证据显示，早期肠内喂养可整体降低新生儿死亡率，但在低收入国家/中低收入国家场景中未观察到该获益。母乳喂养促进干预可提升中低收入国家场景下，婴儿出生后3个月与6个月时的早期母乳喂养启动率与纯母乳喂养率。在低收入国家/中低收入国家场景中，使用配方奶粉喂养会升高新生儿死亡风险。尽管配方奶粉喂养可带来更显著的体重增长，但整体而言会提升坏死性小肠结肠炎（Necrotizing Enterocolitis, NEC）的发病风险。母乳强化与营养强化配方奶粉可改善生长结局。补铁与维生素A补充剂分别可降低中低收入国家场景下的贫血发生率与死亡率。研究证据还表明，锌、钙/磷、维生素D等多种微量营养素补充干预的获益大于风险：本次综述证实，此类补充剂几乎不会产生不良反应，尤其适用于接受母乳喂养的早产和/或低出生体重婴儿。

结论
为早产或低出生体重婴儿提供早期充足的营养支持，是规避不良健康结局、促进正常生长、提升感染抵抗力与实现最优发育的核心举措。母乳喂养与微量营养素补充可分别有效降低腹泻发生率与死亡率；若无法获取母乳，采用喂养强化剂或营养强化配方奶粉则有助于改善生长状况，尤其适用于生长受限与发育迟缓患儿占比更高的中低收入国家。本综述同时呼吁在中低收入国家开展大规模随机对照试验，以进一步夯实相关研究证据。