Supplementary Material for: The Association between Serum Bilirubin and Kernicterus Spectrum Disorder: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> Total serum bilirubin (TSB) is used in managing neonates with jaundice, but clear evidence on its association with major outcomes is lacking. <b><i>Objectives:</i></b> We evaluated the association between TSB and kernicterus spectrum disorder (KSD). <b><i>Methods:</i></b> We searched PubMed, EMBASE, and CENTRAL till July 2021. Two authors independently selected relevant cohort studies, extracted data (CHARMS checklist), assessed risk of bias (RoB) (QUIPS tool), and rated certainty-of-evidence (Grades of Recommendation, Assessment, Development, and Evaluation). We pooled adjusted odds ratio (aOR) (random-effect) via generic inverse variance methods. <b><i>Results:</i></b> From 2,826 records retrieved, we included 37 studies (<i>n</i> = 648,979). Fifteen studies had low, 16 moderate, and 6 high RoB, with majority having concerns on confounder adjustment and statistical analysis. Twenty-two studies contributed meta-analysis data, and 15 were summarized narratively. TSB appears associated with KSD in infants with certain risk factors (aOR 1.10, 95% CI: 1.07–1.13; 5 studies [<i>n</i> = 4,484]). However, TSB (aOR 1.10, 95% CI: 0.98–1.23; 1 study [<i>n</i> = 34,533]) or hyperbilirubinemia (aOR 1.00, 95% CI: 0.51–1.95; 2 studies [<i>n</i> = 56,578]) have no clear association with kernicterus or neurological diagnosis in overall neonatal population (moderate-certainty-evidence). One study shows that infants with hyperbilirubinemia appear likelier to develop attention-deficit disorder (aOR 1.90, 95% CI: 1.10–3.28) and autistic spectrum disorder (aOR 1.60, 95% CI: 1.03–2.49, <i>n</i> = 56,019) (low-certainty-evidence). Certain clinical factors appear associated with KSD, although very few studies contributed to the analyses. <b><i>Conclusions:</i></b> Despite the importance of this question, there is insufficient high-quality evidence on the independent prognostic value of TSB for adverse neurodevelopmental outcomes in most neonatal populations. Future studies should incorporate all known risk factors alongside TSB in a multivariable analysis to improve certainty-of-evidence.

<b><i>背景：</i></b> 血清总胆红素（total serum bilirubin, TSB）常用于黄疸新生儿的临床管理，但目前仍缺乏其与主要不良结局关联的明确证据。<b><i>目标：</i></b> 本研究旨在评估血清总胆红素与胆红素脑病谱系疾病（kernicterus spectrum disorder, KSD）之间的关联。<b><i>方法：</i></b> 我们检索了截至2021年7月PubMed、EMBASE及CENTRAL数据库的相关文献。由两名研究者独立筛选符合纳入标准的队列研究，提取研究数据（采用CHARMS核查表）、评估偏倚风险（risk of bias, RoB，使用QUIPS工具），并对证据确定性进行分级（Grades of Recommendation, Assessment, Development, and Evaluation）。我们通过通用逆方差法采用随机效应模型合并调整后的比值比（adjusted odds ratio, aOR）。<b><i>结果：</i></b> 从检索获得的2826条记录中，最终纳入37项研究（总样本量n=648979）。其中15项研究偏倚风险较低，16项为中等，6项为较高，多数研究在混杂因素调整与统计分析环节存在相关顾虑。22项研究提供了可用于荟萃分析的数据，其余15项仅进行了叙述性总结。在携带特定危险因素的婴儿中，血清总胆红素与KSD存在显著关联（调整后比值比aOR=1.10，95%置信区间CI：1.07~1.13；共5项研究，n=4484）。然而，在整体新生儿人群中，血清总胆红素（aOR=1.10，95%CI：0.98~1.23；1项研究，n=34533）或高胆红素血症（aOR=1.00，95%CI：0.51~1.95；2项研究，n=56578）与胆红素脑病或神经系统诊断并无明确关联（证据确定性为中等）。另有一项研究显示，高胆红素血症婴儿罹患注意缺陷障碍（aOR=1.90，95%CI：1.10~3.28）及孤独症谱系障碍（aOR=1.60，95%CI：1.03~2.49；n=56019）的风险更高（证据确定性为低）。尽管部分临床因素与KSD存在关联，但相关分析仅依托极少数研究完成。<b><i>结论：</i></b> 尽管该研究问题具有重要临床价值，但目前尚无足够高质量证据证实血清总胆红素对大多数新生儿人群不良神经发育结局的独立预后价值。未来研究应在多变量分析中纳入所有已知危险因素与血清总胆红素，以提升证据确定性。