Risk Factors for Severe Neonatal Hyperbilirubinemia in Low and Middle-Income Countries: A Systematic Review and Meta-Analysis

Background
Available evidence suggests that low- and middle-income countries (LMICs) bear the greatest burden of severe neonatal hyperbilirubinemia characterized by disproportionately high rates of morbidity, mortality and neurodevelopmental disorders compared to high-income countries. We set out to identify the risk factors that contribute to the burden of severe hyperbilirubinemia in the most developmentally disadvantaged LMICs to highlight areas for action and further research.
Methods
We systematically searched PubMed, Scopus, Ovid EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), WHO Library Database (WHOLIS), African Index Medicus (AIM), African Journals Online (AJOL), LILACS, and IndMed for reports published between January 1990 and June 2014. We included only studies that controlled for the effects of confounding variables in determining maternal and infant risk factors for severe hyperbilirubinemia. We conducted meta-analysis of the eligible studies and computed the summary risk estimates with random effects models.
Results
A total of 13 studies with 1,951 subjects and 32,208 controls from India, Nigeria, Pakistan, Nepal and Egypt were identified and analyzed. The pooled data showed that primiparity (OR, 1.59; 95% CI:1.26-2.00), delivery outside public hospitals (OR, 6.42; 95% CI:1.76-23.36), ABO incompatibility (OR, 4.01; 95% CI:2.44-6.61), Rhesus hemolytic disease (OR, 20.63; 95% CI:3.95-107.65), G6PD deficiency (OR, 8.01; 95% CI:2.09-30.69), UGT1A1 polymorphisms (OR, 4.92; 95% CI:1.30-18.62), low gestational age (OR, 1.71; 95% CI:1.40-2.11), underweight/weight loss (OR, 6.26; 95% CI:1.23-31.86), sepsis (OR, 9.15; 95% CI:2.78-30.10) and high transcutaneous/total serum bilirubin levels (OR, 1.46; 95% CI:1.10-1.92) placed infants at increased risk of severe hyperbilirubinemia or bilirubin induced neurologic dysfunctions. Low social class was not associated with an increased risk of severe hyperbilirubinemia.
Conclusions
Infants at risk of severe hyperbilirubinemia in LMICs are associated with maternal and neonatal factors that can be effectively addressed by available interventions to curtail the disease burden prevailing in the affected countries.

研究背景
现有证据表明，低收入和中等收入国家（low- and middle-income countries, LMICs）承担着重度新生儿高胆红素血症的最沉重疾病负担，与高收入国家相比，其发病率、死亡率及神经发育障碍的比例显著偏高。本研究旨在明确在社会经济发展最为滞后的低收入和中等收入国家中，导致重度高胆红素血症疾病负担的危险因素，以期明确可采取行动及开展进一步研究的方向。

研究方法
本研究系统检索了PubMed、Scopus、Ovid EMBASE、《护理及相关健康文献累积索引》（Cumulative Index to Nursing and Allied Health Literature, CINAHL）、世界卫生组织图书馆数据库（WHOLIS）、非洲医学索引（African Index Medicus, AIM）、非洲在线期刊（African Journals Online, AJOL）、LILACS以及IndMed，检索时限为1990年1月至2014年6月发表的相关报告。本研究仅纳入那些在明确重度高胆红素血症的母婴危险因素时，对混杂变量的影响进行了控制的研究。我们对符合纳入标准的研究进行了Meta分析，并采用随机效应模型计算了合并风险估计值。

研究结果
最终共纳入来自印度、尼日利亚、巴基斯坦、尼泊尔及埃及的13项研究，包含1951例病例及32208例对照。合并数据分析显示，初产（比值比[OR]=1.59，95%置信区间[CI]：1.26~2.00）、非公立医疗机构分娩（OR=6.42，95%CI：1.76~23.36）、ABO血型不合（OR=4.01，95%CI：2.44~6.61）、Rh溶血病（OR=20.63，95%CI：3.95~107.65）、葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症（OR=8.01，95%CI：2.09~30.69）、UGT1A1基因多态性（OR=4.92，95%CI：1.30~18.62）、低胎龄（OR=1.71，95%CI：1.40~2.11）、低出生体重/体重下降（OR=6.26，95%CI：1.23~31.86）、败血症（OR=9.15，95%CI：2.78~30.10）以及高经皮胆红素/血清总胆红素水平（OR=1.46，95%CI：1.10~1.92）均会增加婴儿罹患重度高胆红素血症或胆红素诱导神经功能障碍的风险。社会阶层低下与重度高胆红素血症的发病风险升高无显著关联。

研究结论
低收入和中等收入国家中存在重度高胆红素血症风险的婴儿，其发病与母婴双方的危险因素相关；针对这些危险因素采取现有干预措施，可有效减轻受影响国家当前的疾病负担。