Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Boston Medical Center, Boston, MA.
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX.
Am J Obstet Gynecol MFM. 2020 Aug;2(3):100140. doi: 10.1016/j.ajogmf.2020.100140. Epub 2020 May 17.
Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin.
To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed.
This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 17 to 21 weeks' gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 19 and 20 weeks' gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0-3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality.
A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <32 weeks' gestation and 838 noncases at ≥32 weeks' gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <32 weeks' gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <32 weeks' gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55-0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (22<body mass index≤37 kg/m), resulted in an area under the receiver operating characteristic curve of 0.76 (95% confidence interval, 0.59-0.93; P=.023). The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio predicted neonatal outcomes with respective area under the receiver operating characteristic curve of 0.67 (95% confidence interval, 0.57-0.77; P=.005) and 0.78 (95% confidence interval, 0.63-0.93; P=.026) for neonatal composite morbidity and mortality scores of ≥3 or 4. In addition, the ratio of insulin-like growth factor-binding protein 4 to sex hormone binding globulin significantly stratified neonates with increased length of hospital stay (log rank P=.023).
We confirmed in an independent cohort the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio as a predictor of very preterm birth, with additional prediction of increased length of neonatal hospital stay and increased severity of adverse neonatal outcomes. Potential uses of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin predictor may be to risk stratify patients for implementation of preterm birth preventive strategies and direct patients to appropriate levels of care.
早产仍然是妊娠的常见且严重的并发症。目前仍需要有效的、准确的早产筛查方法。我们之前使用蛋白质组学方法发现并验证了（早产风险的蛋白质组评估研究，NCT01371019）一种早产预测因子，由胰岛素样生长因子结合蛋白 4 与性激素结合球蛋白的比值组成。
在一个与之前开发的队列不同的独立队列中，确定胰岛素样生长因子结合蛋白 4 与性激素结合球蛋白的比值预测自发性和医学上需要的极早产的性能。
这是在美国 18 个地点进行的前瞻性观察性研究（自发性早产风险预测因子的多中心评估，NCT02787213）。女性在 17 至 21 周妊娠时采血。为了确认，我们计划分析随机选择的在 19 至 20 周妊娠时采血的亚组女性，研究参与者的其余结果将被隐瞒，以便未来的验证研究使用。通过质谱法分析参与者的血清。使用 PREGNANT 试验（NCT00615550，Hassan 等人）的方法分析新生儿发病率和死亡率的复合评分。0-3 分数反映了发病率或新生儿重症监护病房住院时间的增加，4 代表围产期死亡率。
共有 5011 名女性入组，其中 847 名女性纳入本计划的亚组分析。有 9 例 <32 周妊娠的早产病例和 838 例≥32 周妊娠的非病例；847 名婴儿中有 21 名新生儿复合发病率和死亡率指数评分≥3，其中 4 名评分≥4。<32 周妊娠的早产和更严重的新生儿结局中，胰岛素样生长因子结合蛋白 4 与性激素结合球蛋白的比值明显更高。胰岛素样生长因子结合蛋白 4 与性激素结合球蛋白的比值显著预测了 <32 周的妊娠（接受者操作特征曲线下面积，0.71；95%置信区间，0.55-0.87；P=.016）。在前一次验证研究中进行了体重指数分层（22<体重指数≤37kg/m），结果显示接受者操作特征曲线下面积为 0.76（95%置信区间，0.59-0.93；P=.023）。胰岛素样生长因子结合蛋白 4 与性激素结合球蛋白的比值预测新生儿结局的接受者操作特征曲线下面积分别为 0.67（95%置信区间，0.57-0.77；P=.005）和 0.78（95%置信区间，0.63-0.93；P=.026），用于新生儿复合发病率和死亡率评分≥3 或 4。此外，胰岛素样生长因子结合蛋白 4 与性激素结合球蛋白的比值显著分层了住院时间延长的新生儿（对数秩检验，P=.023）。
我们在一个独立的队列中证实了胰岛素样生长因子结合蛋白 4 与性激素结合球蛋白的比值作为极早产的预测因子，并且还能预测新生儿住院时间延长和不良新生儿结局严重程度增加。胰岛素样生长因子结合蛋白 4 与性激素结合球蛋白预测因子的潜在用途可能是为患者实施早产预防策略进行风险分层，并指导患者接受适当级别的护理。
