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.


METHODS
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).


CONCLUSIONS
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.
Institute for Clinical Research, University of Southern Denmark, Odense, Denmark; Hans Christian Andersen Research, Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark. Electronic address: louise.bjoerkholt.andersen@rsyd.dk.
Louise B
LB
Andersen
Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark; Experimental and Clinical Research Center, Max-Delbrueck Center and Charité, Berlin, Germany; Helios-Klinikum Berlin, Berlin, Germany.
Ralf
R
Dechend
Departments of Medicine and of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
S Ananth
SA
Karumanchi
Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark.
Jan
J
Nielsen
Institute for Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Obstetrics and Gynecology, Odense University Hospital, Odense, Denmark.
Jan S
JS
Joergensen
Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark; Odense Child Cohort, Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark; Odense Patient Data Explorative Network, Odense University Hospital, Odense, Denmark.
Tina K
TK
Jensen
Institute for Clinical Research, University of Southern Denmark, Odense, Denmark; Hans Christian Andersen Research, Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.
Henrik T
HT
Christesen
D000022:Abortion, Spontaneous / Q000097:blood* / Q000453:epidemiology; D000328:Adult; D005260:Female; D006801:Humans; D000072483:Placenta Growth Factor / Q000097:blood*; D011237:Predictive Value of Tests; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
C000608036:PGF protein, human; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
biomarkers; blighted ovum; first-trimester pregnancy failure; missed abortion; placental growth factor; prediction; prenatal screening; soluble Fms-like kinase 1; spontaneous abortion