研究目的  

早产作为全球公共卫生议题中的关键挑战，是五岁以下儿童死亡的主要原因。研究表明，母亲慢性肾脏病（Chronic Kidney Disease，CKD）与子代早产风险增加相关。高估算肾小球滤过率（Estimated Glomerular Filtration Rate，eGFR）可能是CKD的早期阶段，但探究母亲备孕期高eGFR与子代早产发生风险关联的证据相对有限。此外，目前仅有一项研究探究父亲备孕期肾功能对早产的影响，研究结论仍不确定。本研究基于国家免费备孕期健康检查项目（National Free Preconception Health Examination Project，NFPHEP）数据库，旨在评估母亲、父亲及双方备孕期eGFR对子代早产发生风险的影响，以期为我国围产期保健和临床决策提供理论依据。

研究方法

研究对象为2010-2019年间参与NFPHEP且于2020年12月31日前完成妊娠结局随访的育龄夫妇。根据父/母备孕期血清肌酐水平，采用慢性肾脏病流行病学协作（Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI）公式计算eGFR。基于eGFR年龄特异性百分位数（Percentile，P）进行分组，分别为对照组（P_5- P₉₅）、低eGFR组（5）和高eGFR组（>P₉₅）。结局包括子代早产和早产亚组（超早产、极早产、中期早产和晚期早产）。多因素Logistic回归模型用于评估母亲、父亲及双方备孕期eGFR异常对子代早产和早产亚组的影响。采用限制性立方样条（Restricted Cubic Spline，RCS）探究母亲、父亲备孕期eGFR异常与子代早产和早产亚组的非线性关联。采用归因病例数和人群归因分数（Population Attributable Fraction，PAF）评价暴露于母亲、父亲及双方备孕期eGFR异常的子代早产归因风险。进行亚组分析评估不同亚组中母亲、父亲备孕期eGFR异常对子代早产的影响，并进一步评估交互作用。

研究结果

1. 本研究共纳入6,784,956对夫妇，共有395,837例早产儿（5.83%）。早产各亚组发病率如下：超早产为0.19%，极早产为0.70%，中期早产为0.83%，晚期早产为4.11%。与对照组相比，母亲备孕期低eGFR和高eGFR与子代早产发生风险升高相关，比值比（odds ratio，OR）及其95%置信区间（confidence interval，CI）分别为1.08（95%CI：1.07-1.10）和1.13（95%CI：1.11-1.14）。早产亚组的结果表明，母亲备孕期低eGFR和高eGFR对子代超早产风险影响最强，OR值分别为1.16（95%CI：1.08-1.24）和1.43（95%CI：1.33-1.53）。RCS结果显示，母亲备孕期年龄特异性eGFR水平百分位数与子代早产和早产亚组发生风险大致呈U形关联。亚组分析结果显示，在未患高血压的亚组中母亲备孕期eGFR水平异常与子代早产发生风险的关联更高。

2. 与对照组相比，父亲备孕期低eGFR和高eGFR与子代早产发生风险升高相关，OR值分别为1.16（95%CI：1.14-1.17）和1.06（95%CI：1.05-1.08）。早产亚组的结果表明，父亲备孕期低eGFR和高eGFR对子代超早产风险影响最强，OR值分别为1.19（95%CI：1.11-1.29）和1.14（95%CI：1.06-1.23）。父亲备孕期年龄特异性eGFR水平百分位数与子代早产和早产亚组发生风险大致呈U形关联。亚组分析结果显示，在父亲未患高血压和母亲备孕期eGFR异常的亚组中，父亲备孕期eGFR水平异常与子代早产发生风险的关联更高。

3. 与对照组相比，父母双方备孕期低eGFR或高eGFR子代早产风险最高，OR值分别为1.24（95%CI：1.21-1.27）和1.24（95%CI：1.20-1.28）。早产亚组的结果表明，父母双方备孕期低eGFR或高eGFR对超早产风险影响更强，OR值分别为1.31 （95%CI：1.15-1.50）和1.49（95%CI：1.28-1.73）。

研究结论

父母备孕期eGFR水平与子代早产的发生风险呈U型关联，高eGFR或低eGFR均可显著增加子代早产的发生风险，其中对子代超早产风险影响最强。非高血压人群更容易受到备孕期eGFR水平异常的影响。与eGFR水平均正常的父母相比，低eGFR水平或高eGFR水平的父母子代早产的风险显著增加。除关注低eGFR水平的女性外，还需要加强对备孕期高eGFR的女性和eGFR水平异常的男性的个体化管理和治疗。

关键词：肾功能；肾小球滤过率；早产；相关性研究

Objectives  

Preterm birth is a significant global burden and one of the leading causes of neonatal mortality. Accumulating evidence indicates that maternal chronic kidney disease (CKD) before or during pregnancy is associated with the risk of preterm birth in offspring. Glomerular hyperfiltration is proposed as an indicator of early-stage of chronic kidney disease, but evidence regarding the association of maternal preconception hyperfiltration with the risk of preterm birth in offspring remains limited. Additionally, to date, only one study has investigated the impact of paternal preconception renal function on preterm birth, the findings remain inconclusive. This study, based on the National Free Preconception Health Examination Project (NFPHEP) database, conducts a cohort design investigating the association of maternal, paternal, and parental preconception estimated glomerular filtration rate (eGFR) with preterm birth risk in offspring. The findings will provide critical evidence to inform perinatal healthcare strategies and clinical decision-making.

Methods

The study included couples who enrolled in the NFPHEP from 2010 to 2019 and had finished pregnancy outcome monitoring by December 31, 2020. Parental preconception renal function status was defined based on age-specific percentile (P) categories of the estimated glomerular filtration rate (eGFR), calculated from serum creatinine, using the chronic kidney disease epidemiology collaboration (CKD-EPI) formula, as follows: normal group (P₅-P₉₅), low eGFR (5) and high eGFR (>P₉₅). The study outcomes included preterm birth and its subcategories. Adjusted multivariable logistic regression model was employed to access the association of maternal, paternal, and parental preconception eGFR with preterm birth in offspring. We examined non-linear associations between maternal or paternal preconception eGFR with preterm birth using restricted cubic spline (RCS). We assessed the attributable risk of preterm birth in offspring exposed to abnormal eGFR using attributable cases and population attributable fraction (PAF). We further conducted subgroup analyses to assess the effect of maternal/paternal preconception eGFR on preterm birth in offspring across various subgroups, and to access the effect modifications.

Results

1. This study included a total of 6,784,956 couples. Among 6,784,956 singleton live births, 395,837 cases of preterm birth (5.83%) were observed. The incidences of preterm birth subcategories were as follows: extremely preterm birth, 0.19%; very preterm birth, 0.70%; moderate preterm birth, 0.83%; and late preterm birth, 4.11%. Compared with the reference group, maternal preconception low eGFR and high eGFR were associated with elevated risk of preterm birth in offspring, with odds ratio (OR) of 1.08 (95% confidence interval [CI]: 1.07 to 1.10) for low eGFR and 1.13 (95%CI: 1.11 to 1.14) for high eGFR. Subgroup analysis of preterm birth revealed that maternal preconception low eGFR and high eGFR demonstrated the strongest association with the risk of extremely preterm birth, with OR of 1.16 (95%CI: 1.08 to 1.24) for low eGFR and 1.43 (95%CI: 1.33 to 1.53) for high eGFR. The RCS results demonstrated nonlinear U-shaped association of maternal preconception age-stratified percentiles of eGFR with preterm birth. The association of maternal eGFR with preterm birth in offspring appeared to be more pronounced when mothers without hypertension.

2. Compared with the reference group, paternal preconception low eGFR and high eGFR were associated with increased risk of preterm birth in offspring, with OR of 1.16 (95% CI: 1.14 to 1.17) for low eGFR and 1.06 (95%CI: 1.05 to 1.08) for high eGFR. The subgroup analysis of preterm birth revealed that paternal preconception low eGFR and high eGFR demonstrated the strongest association with the risk of extremely preterm birth, with OR of 1.19 (95% CI: 1.11 to 1.29) for low eGFR and 1.14 (95%CI: 1.06 to 1.23) for high eGFR. The RCS results showed U-type dose-response associations of paternal preconception age-stratified percentiles of eGFR with preterm birth. The association of paternal eGFR with preterm birth in offspring appeared to be more pronounced when fathers without hypertension, or mothers with abnormal eGFR.

3. Compared with the reference group (parents with normal eGFR), the highest risk of preterm birth in offspring was observed in parents with low eGFR (OR: 1.24, 95%CI: 1.21-1.27) and parents with high eGFR (OR: 1.24, 95%CI: 1.20-1.28). The subgroup analysis of preterm birth demonstrated that parents with low and high eGFR exhibited strongest associations with the risk of extremely preterm birth, with OR of 1.31 (95%CI: 1.15 to 1.50) for low eGFR and 1.49 (95% CI: 1.28 to 1.73) for high eGFR.

Conclusion

Parental preconception eGFR exhibited U-shaped associations with the risk of preterm birth in offspring, where both low and high eGFR significantly increased the risk of preterm birth. Notably, this association was most pronounced for extremely preterm birth in offspring. Normotensive individuals appeared more susceptible to the adverse effects of abnormal preconception eGFR. Compared to parents with normal eGFR, those with either low or high eGFR demonstrated significantly higher risks of preterm birth in offspring. To prevent preterm birth in offspring, except for providing guidance for females with low eGFR, health care providers should be more active in providing health care services and reproductive guidance to females with high eGFR and males with abnormal eGFR.

Keywords: Renal function; eGFR; Preterm birth; Association