Early pregnancy angiogenic markers and spontaneous abortion: an Odense Child Cohort study


  • L.B. Andersen
  • R. Dechend
  • S.A. Karumanchi
  • J. Nielsen
  • J.S. Joergensen
  • T.K. Jensen
  • H.T. Christesen


  • American Journal of Obstetrics and Gynecology


  • Am J Obstet Gynecol 215 (5): 594.e1-594.e11


  • BACKGROUND: Spontaneous abortion is the most commonly observed adverse pregnancy outcome. The angiogenic factors soluble Fms-like kinase 1 and placental growth factor are critical for normal pregnancy and may be associated to spontaneous abortion. OBJECTIVE: We investigated the association between maternal serum concentrations of soluble Fms-like kinase 1, placental growth factor and subsequent spontaneous abortion. STUDY DESIGN: In the prospective observational Odense Child Cohort, 1,676 pregnant women donated serum in early pregnancy, before gestational week 22 (median 83 days of gestation, interquartile range 71-103). Concentrations of soluble Fms-like kinase 1 and placental growth factor were determined with novel automated assays. Spontaneous abortion was defined as complete or incomplete spontaneous abortion, missed abortion or blighted ovum before 22+0 gestational weeks, and the prevalence was 3.52% (59 cases). The time-dependent effect of maternal serum concentrations of soluble Fms-like kinase 1 and placental growth factor on subsequent late first trimester or second trimester spontaneous abortion (n=59) was evaluated using a Cox proportional hazards regression model, adjusting for body mass index, parity, season of blood sampling and age. Furthermore, receiver operating characteristics were employed to identify predictive values and optimal cut-off values. RESULTS: In the adjusted Cox regression analysis, increasing continuous concentrations of both soluble Fms-like kinase 1 and placental growth factor were significantly associated with a decreased hazard ratio for spontaneous abortion, soluble Fms-like kinase 1 (95% confidence interval), 0.996 (0.995-0.997); placental growth factor 0.89 (0.86-0.93). When analyzed by receiver operating characteristics cut-offs, women with soluble Fms-like kinase 1 below 742 pg/mL had an odds ratio for spontaneous abortion of 12.1 (95% confidence interval 6.64-22.2), a positive predictive value of 11.70% and a negative predictive value of 98.90%, likelihood ratio (+) 3.64 (3.07-4.32), likelihood ratio (-) 0.30 (0.19-0.48). For placental growth factor below 19.7 pg/mL, odds ratio was 13.2 (7.09-24.4), positive predictive value 11.80% and negative predictive value 99.0%, likelihood ratio (+) 3.68 (3.12-4.34), likelihood ratio (-) 0.28 (0.17-0.45). In the sensitivity analysis of 54 spontaneous abortions matched 1:4 to controls on gestational age at blood sampling, the highest area under the curve was seen for soluble Fms-like kinase 1 in prediction of first trimester spontaneous abortion, 0.898 (0.834-0.962), and at the optimum cut-off of 725 pg/mL, negative predictive value was 51.4%, positive predictive value 94.6%, likelihood ratio (+) 4.04 (2.57-6.35) likelihood ratio (-) 0.22 (0.09-0.54). CONCLUSION: A strong, novel prospective association was identified between lower concentrations of soluble Fms-like kinase 1 and placental growth factor measured in early pregnancy and spontaneous abortion. A soluble Fms-like kinase 1 cut-off <742 pg/mL in maternal serum was optimal to stratify women at high risk vs. low risk of suffering spontaneous abortion. The cause and effect of angiogenic factor alterations in spontaneous abortions remain to be elucidated.