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

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 and placental growth factor, and subsequent spontaneous abortion.

STUDY DESIGN: In the prospective observational Odense Child Cohort, 1676 pregnant women donated serum in early pregnancy, 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 <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, 0.996 (95% confidence interval, 0.995-0.997), and placental growth factor, 0.89 (95% confidence interval, 0.86-0.93). When analyzed by receiver operating characteristic cut-offs, women with soluble Fms-like kinase 1 <742 pg/mL had an odds ratio for spontaneous abortion of 12.1 (95% confidence interval, 6.64-22.2), positive predictive value of 11.70%, negative predictive value of 98.90%, positive likelihood ratio of 3.64 (3.07-4.32), and negative likelihood ratio of 0.30 (0.19-0.48). For placental growth factor <19.7 pg/mL, odds ratio was 13.2 (7.09-24.4), positive predictive value was 11.80%, negative predictive value was 99.0%, positive likelihood ratio was 3.68 (3.12-4.34), and negative likelihood ratio was 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 was 94.6%, positive likelihood ratio was 4.04 (2.57-6.35), and negative likelihood ratio was 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 vs low risk of spontaneous abortion. The cause and effect of angiogenic factor alterations in spontaneous abortions remain to be elucidated.