Palma Dos Reis Catarina R, O'Sullivan Joe, Ohuma Eric O, James Tim, Papageorghiou Aris T, Vatish Manu, Cerdeira Ana Sofia
Nuffield Department of Women's and Reproductive Health, University of Oxford, UK.
Merton College, University of Oxford, UK.
Am J Obstet Gynecol. 2025 Mar;232(3):317.e1-317.e17. doi: 10.1016/j.ajog.2024.06.010. Epub 2024 Jun 17.
The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor is a useful biomarker for preeclampsia. Since it is a measure of placental dysfunction, it could also be a predictor of clinical deterioration and fetal tolerance to intrapartum stress.
We tested the hypothesis that soluble fms-like tyrosine kinase 1 to placental growth factor ratio predicts time to delivery. Secondary objectives were to examine associations between the soluble fms-like tyrosine kinase 1 to placental growth factor ratio and mode of birth, fetal distress, need for labor induction, and birthweight z score.
Secondary analysis of the INSPIRE trial, a randomized interventional study on prediction of preeclampsia/eclampsia in which women with suspected preeclampsia were recruited and their blood soluble fms-like tyrosine kinase 1 to placental growth factor ratio was assessed. We stratified participants into 3 groups according to the ratio result: category 1 (soluble fms-like tyrosine kinase 1 to placental growth factor ≤38); category 2 (soluble fms-like tyrosine kinase 1 to placental growth factor >38 and <85); and category 3 (soluble fms-like tyrosine kinase 1 to placental growth factor ≥85). We modeled time from soluble fms-like tyrosine kinase 1 to placental growth factor determination to delivery using Kaplan-Meier curves and compared the 3 ratio categories adjusting for gestational age at soluble fms-like tyrosine kinase 1 to placental growth factor determination and trial arm with Cox regression. The association between ratio category and mode of delivery, induction of labor, and fetal distress was assessed using a multivariable logistic regression adjusting for gestational age at sampling and trial arm. The association between birthweight z score and soluble fms-like tyrosine kinase 1 to placental growth factor ratio was evaluated using multiple linear regression. Subgroup analysis was conducted in women with no preeclampsia and spontaneous onset of labor; women with preeclampsia; and participants in the nonreveal arm.
Higher ratio categories were associated with a shorter latency from soluble fms-like tyrosine kinase 1 to placental growth factor determination to delivery (37 vs 13 vs 10 days for ratios categories 1-3 respectively), hazards ratio for category 3 ratio of 5.64 (95% confidence interval 4.06-7.84, P<.001). A soluble fms-like tyrosine kinase 1 to placental growth factor ratio ≥85 had specificity of 92.7% (95% confidence interval 89.0%-95.1%) and sensitivity of 54.72% (95% confidence interval, 41.3-69.5) for prediction of preeclampsia indicated delivery within 2 weeks. A ratio category 3 was also associated with decreased odds of spontaneous vaginal delivery (Odds ratio [OR] 0.47, 95% confidence interval 0.25-0.89); an almost 6-fold increased risk of emergency cesarean section (OR 5.89, 95% confidence interval 3.05-11.21); and a 2-fold increased risk for intrapartum fetal distress requiring operative delivery or cesarean section (OR 3.04, 95% confidence interval 1.53-6.05) when compared to patients with ratios ≤38. Higher ratio categories were also associated with higher odds of induction of labor when compared to ratios category 1 (category 2, OR 2.20, 95% confidence interval 1.02-4.76; category 3, OR 6.0, 95% confidence interval 2.01-17.93); and lower median birthweight z score. Within subgroups of women a) without preeclampsia and with spontaneous onset of labor and b) women with preeclampsia, the log ratio was significantly higher in patients requiring intervention for fetal distress or failure to progress compared to those who delivered vaginaly without intervention. In the subset of women with no preeclampsia and spontaneous onset of labor, those who required intervention for fetal distress or failure to progress had a significantly higher log ratio than those who delivered vaginaly without needing intervention.
The soluble fms-like tyrosine kinase 1 to placental growth factor ratio might be helpful in risk stratification of patients who present with suspected preeclampsia regarding clinical deterioration, intrapartum fetal distress, and mode of birth (including the need for intervention in labor).
可溶性fms样酪氨酸激酶1与胎盘生长因子的比值是子痫前期的一项有用生物标志物。由于它是胎盘功能障碍的一种衡量指标，它也可能是临床病情恶化及胎儿对产时应激耐受性的预测指标。
我们检验了可溶性fms样酪氨酸激酶1与胎盘生长因子比值可预测分娩时间的假设。次要目的是研究可溶性fms样酪氨酸激酶1与胎盘生长因子比值与分娩方式、胎儿窘迫、引产需求及出生体重Z评分之间的关联。
对INSPIRE试验进行二次分析，该试验是一项关于子痫前期/子痫预测的随机干预研究，招募疑似子痫前期的女性并评估其血液中可溶性fms样酪氨酸激酶1与胎盘生长因子的比值。我们根据比值结果将参与者分为3组：1类（可溶性fms样酪氨酸激酶1与胎盘生长因子≤38）；2类（可溶性fms样酪氨酸激酶1与胎盘生长因子>38且<85）；3类（可溶性fms样酪氨酸激酶1与胎盘生长因子≥85）。我们使用Kaplan-Meier曲线对从可溶性fms样酪氨酸激酶1与胎盘生长因子测定到分娩的时间进行建模，并通过Cox回归比较3个比值类别，同时校正可溶性fms样酪氨酸激酶1与胎盘生长因子测定时的孕周及试验分组。使用多变量逻辑回归校正采样时的孕周及试验分组，评估比值类别与分娩方式、引产及胎儿窘迫之间的关联。使用多元线性回归评估出生体重Z评分与可溶性fms样酪氨酸激酶1与胎盘生长因子比值之间的关联。在未患子痫前期且自然发动分娩的女性、患子痫前期的女性以及未接受揭示性干预组的参与者中进行亚组分析。
较高的比值类别与从可溶性fms样酪氨酸激酶1与胎盘生长因子测定到分娩的潜伏期较短相关（1-3类比值对应的时间分别为37天、13天和10天），3类比值的风险比为5.64（95%置信区间4.06-7.84，P<.001）。可溶性fms样酪氨酸激酶1与胎盘生长因子比值≥85对于预测子痫前期提示在2周内分娩的特异性为92.7%（95%置信区间89.0%-95.1%），敏感性为54.72%（95%置信区间41.3-69.5）。与比值≤38的患者相比，3类比值还与自然阴道分娩几率降低相关（比值比[OR]0.47，95%置信区间0.25-0.89）；急诊剖宫产风险增加近6倍（OR 5.89，95%置信区间3.05-11.21）；产时因胎儿窘迫需要手术分娩或剖宫产的风险增加2倍（OR 3.04，95%置信区间1.53-6.05）。与1类比值相比，较高的比值类别也与引产几率增加相关（2类，OR 2.20，95%置信区间1.02-4.76；3类，OR 6.0，95%置信区间2.01-17.93）；且出生体重Z评分中位数较低。在a）未患子痫前期且自然发动分娩的女性和b）患子痫前期的女性亚组中，与未干预自然阴道分娩的患者相比，因胎儿窘迫或产程无进展需要干预的患者的对数比值显著更高。在未患子痫前期且自然发动分娩的女性子集中，因胎儿窘迫或产程无进展需要干预的患者的对数比值显著高于未干预自然阴道分娩的患者。
可溶性fms样酪氨酸激酶1与胎盘生长因子比值可能有助于对疑似子痫前期患者在临床病情恶化、产时胎儿窘迫及分娩方式（包括产程中干预需求）方面进行风险分层。
