Pregnancy and perinatal outcomes stratified by soluble fms-like tyrosine kinase-1 and placental growth factor gestation-specific thresholds in women with suspected preeclampsia.

Abstract

To evaluate gestational age appropriate soluble fms-like tyrosine kinase-1 and placental growth factor concentrations in determining abnormal outcomes in women with suspected preeclampsia. Retrospective single-center study of 457 singleton pregnancies from a tertiary referral center in the United Kingdom. Four subgroups were defined using gestational age-adjusted thresholds for soluble fms-like tyrosine kinase-1 (>95th centile) and placental growth factor (<fifth centile). Continuous variables were assessed for normality; non-normally distributed data were analyzed using the Kruskal-Wallis test with Bonferroni-adjusted pairwise comparisons. Log-transformed biochemical, angiogenic, and ultrasound variables were analyzed using one-way analysis of variance (df=3) with Dunnett post hoc comparisons versus controls (df=1). Categorical variables were compared using chi-square or Fisher's exact tests with post hoc comparisons where appropriate. A two-tailed P value <0.05 was considered statistically significant. Amongst singleton pregnancies with available soluble fms-like tyrosine kinase-1/placental growth factor ratios, angiogenic profiling classified women into 4 groups. Group 1 (soluble fms-like tyrosine kinase-1>95th, PlGF <fifth; n=100), Group 2 (soluble fms-like tyrosine kinase-1>95th, placental growth factor >fifth; n=58), Group 3 (soluble fms-like tyrosine kinase-1<95th, placental growth factor <fifth; n=31), and controls (Group 4) (soluble fms-like tyrosine kinase-1<95th, placental growth factor >fifth; n=268). Distinct angiogenic and ultrasonographic profiles were observed between groups (one-way analysis of variance, F (3,453), P<0.001). On post hoc Dunnett's, when compared to controls, Groups 1 and 3 with low placental growth factor (<fifth centile) had a significantly lower mean first trimester pregnancy associated plasma protein-A (0.6, [95% CI 0.6-0.7] and 0.5, [0.4-7.0] vs 0.9 [0.8-1.0]; df=1, P<0.001) and higher second trimester combined uterine artery Doppler pulsatility index (1.47 [1.35-1.59] and 1.31 [1.13-1.51] vs 0.98 [0.93-1.02]; df=1, P<0.001). Markers of maternal end-organ involvement also demonstrated strong group-level differences (one-way analysis of variance, F(3,453), P<0.001). On post hoc Dunnett's, when compared to controls, Groups 1 and 2 (sFlt-1>95th centile) had a significantly lower mean platelet count (182.8 [168-198.8] and 176.7 [160.4-194.6] vs 212.5 [204.9-220.4]; df=1, P<0.01), higher mean creatinine levels (70.1 [65.2-75.4] and 70.1 [63.3-78.3] vs 59.4 [57.7-61.2]; df=1, P<0.01) and higher mean urine protein: creatinine ratios (93 [68.7-126.1] and 58.9 [38.9-89.0] vs 25.8 [22.2-29.9]; df=1, P<0.01). The incidence of preeclampsia occurring before 37 weeks was higher in Groups 1 to 3 when compared to the controls, occurring in 78.0%, 39.7%, 31.3%, and 6.7% of pregnancies, respectively (P<0.001). Adverse neonatal outcomes were clustered particularly in Group 1 which had the lowest median gestational age at birth (median 33.4 [29.2-35.7] and lowest birthweight centile (0.26 [0.00-2.71]. The incidence of small for gestational age infants and need for neonatal intensive care unit admission was significantly higher across Groups 1 to 3 when each of the groups was individually compared to the controls (P<0.001 for all). Stillbirths occurred only in Groups 1 (5.3%, n=5) and 3 (6.9%, n=2) which had low placental growth factor levels <fifth centile. Stratification of women with suspected preeclampsia using gestational age-specific thresholds for soluble fms-like tyrosine kinase-1 and placental growth factor can identify distinct maternal and fetal phenotypes with significantly different clinical outcomes. Elevated soluble fms-like tyrosine kinase-1 concentrations appear to be strongly associated with severe maternal disease, whilst low placental growth factor appears to correlate with adverse fetal and neonatal outcomes including growth restriction, stillbirth, and prolonged neonatal intensive care stay.