Division of Obstetrics and Gynaecology, Oslo University Hospital Ullevål, Oslo, Norway.
Faculty of Medicine, University of Oslo, Oslo, Norway.
PLoS One. 2020 Oct 20;15(10):e0240473. doi: 10.1371/journal.pone.0240473. eCollection 2020.
Post-term pregnancies have increased risks for adverse fetal and maternal outcomes. Maternal concentrations of the placenta-associated proteins placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) have been identified as predictors for preeclampsia and fetal growth restriction, both syndromes of placental dysfunction. We have proposed that low maternal circulating PlGF and increased sFlt-1 are general markers for syncytiotrophoblast stress, which increases at and beyond term, even in apparently uncomplicated pregnancies. Our aim was to establish circulating PlGF, sFlt-1, and sFlt-1/PlGF reference ranges in healthy post-term pregnancies (gestational week ≥40+2), comparing with healthy term pregnancies and evaluating associations between time to delivery and biomarker percentiles.
Of 501 healthy, singleton post-term pregnancies prospectively recruited between September 2016 and December 2017 at our tertiary obstetric department, 426 with an uncomplicated delivery outcome contributed PlGF and sFlt-1 serum concentrations for reference range construction. A retrospective, cross-sectional, term group with an uncomplicated delivery outcome (n = 146) served as comparison. Differences in percentile values between groups and confidence intervals were calculated by quantile regression.
In post-term pregnancies the 5th, 50th, and 95th percentiles for PlGF were: 70, 172, and 496 pg/mL; for sFlt-1: 2074, 4268, and 9141 pg/mL; and for sFlt-1/PlGF 5.3, 25.5, and 85.2. Quantile regression analyses comparing the post-term to the term group showed for PlGF a trend towards higher 10th through 30th percentiles, for sFlt-1 significantly higher 10th through 80th percentiles, and for sFlt-1/PlGF ratio significantly higher 30th percentile and significantly lower 95th percentile. PlGF below the 5th percentile and sFlt-1/PlGF ratio above the 95th percentile was associated with shorter time to delivery (p = 0.031 and p = 0.025, respectively).
Our findings support the concept of increasing syncytiotrophoblast stress post-term in clinically healthy pregnancies. Whether post-term dysregulated angiogenic markers reflect a biological placental clock merits further investigation.
过期妊娠会增加胎儿和母体不良结局的风险。胎盘相关蛋白胎盘生长因子（PlGF）和可溶性 fms 样酪氨酸激酶-1（sFlt-1）的母体浓度已被确定为先兆子痫和胎儿生长受限的预测因子，这两种综合征均为胎盘功能障碍。我们提出，低母体循环 PlGF 和增加的 sFlt-1 是合体滋养层应激的一般标志物，这种应激在足月时甚至在看似正常的妊娠中都会增加。我们的目的是建立健康过期妊娠（妊娠周≥40+2）的循环 PlGF、sFlt-1 和 sFlt-1/PlGF 参考范围，与健康足月妊娠进行比较，并评估到达分娩时间与生物标志物百分位数之间的关系。
在我们的三级产科部门于 2016 年 9 月至 2017 年 12 月期间前瞻性招募的 501 例健康、单胎过期妊娠中，426 例分娩结局无并发症的产妇提供了 PlGF 和 sFlt-1 血清浓度以构建参考范围。一个具有无并发症分娩结局的回顾性、横截面、足月组（n=146）作为比较。通过分位数回归计算组间百分位数值的差异和置信区间。
在过期妊娠中，PlGF 的第 5、50 和 95 百分位数分别为：70、172 和 496 pg/mL；sFlt-1：2074、4268 和 9141 pg/mL；sFlt-1/PlGF 为 5.3、25.5 和 85.2。将过期妊娠组与足月组进行比较的分位数回归分析显示，PlGF 的第 10 至 30 百分位有升高趋势，sFlt-1 的第 10 至 80 百分位明显升高，sFlt-1/PlGF 比值的第 30 百分位明显升高，第 95 百分位明显降低。PlGF 低于第 5 百分位数和 sFlt-1/PlGF 比值高于第 95 百分位数与分娩时间缩短有关（p=0.031 和 p=0.025）。
我们的发现支持在临床健康妊娠中，足月后合体滋养层应激增加的概念。过期妊娠时失调的血管生成标志物是否反映了胎盘的生物时钟，值得进一步研究。
