Preterm Delivery as a Unique Pathophysiologic State Characterized by Maternal Soluble FMS-Like Tyrosine Kinase 1 and Uterine Artery Resistance During Pregnancy: A Longitudinal Cohort Study

Abstract

Background: Preterm delivery (PTD) may be characterized by altered interrelationships among angiogenic factors and measures of placental function. We analyzed the longitudinal relationship between maternal serum concentrations of soluble fms-like tyrosine kinase 1 (sFlt1), an important antiangiogenic factor, and uterine artery resistance in pregnancies resulting in preterm and term deliveries.

Methods: Data were collected in a longitudinal cohort study involving 278 women monitored at 6 to 10, 10 to 14, 16 to 20, 22 to 26, and 32 to 36 weeks of gestation. Concentrations of maternal serum sFlt1 were determined using solid-phase enzyme-linked immunosorbent assay, and uterine artery resistance indices (RI) were measured by Doppler velocimetry at each interval. Preterm delivery was defined as birth before 37-weeks completed gestation. Data analyses used multivariable repeated measures regression models.

Results: Uterine artery RI decreased across gestation. As pregnancy progressed, RI trajectories diverged for term and preterm deliveries; the mean RI was significantly higher in third trimester for pregnancies resulting in PTD ( P = .08). sFlt1 was stable through 21 3/7 weeks of gestation and then increased rapidly; women who delivered preterm had significantly higher sFlt1 levels in the third trimester ( P = .04). The relationship between uterine artery RI and sFlt1 from the prior visit was significantly different between the groups ( P < .0001). For term deliveries, higher sFlt1 concentrations were associated with a smaller RI at the subsequent visit (β = -.08, 95% confidence interval [CI]: -0.14 to -0.02). For PTD, higher sFlt1 concentrations were associated with a larger uterine artery RI (β = .14, 95% CI: 0.06 to 0.22).

Conclusion: PTD is characterized by altered relationships between angiogenic factors and placental vascular blood flow starting in early pregnancy.

Keywords: Doppler ultrasound; Flt1 protein; angiogenic factors; longitudinal analysis; placental development; pregnancy; preterm birth.

Figure 1.

The gestational age dependence of the uterine artery resistance index (RI). Regression lines calculated using a quadratic model are shown for term (solid line) and preterm (dashed line) deliveries.

Figure 2.

The gestational age dependence of the maternal serum soluble fms-like tyrosine kinase 1 (sFlt1) concentration (ng/mL). Regression lines for term (solid line) and preterm (dashed line) deliveries were calculated using a simple piecewise model, in which values were allowed to change linearly over time until 21 3/7 weeks of gestation, at which point a quadratic term was allowed.

Figure 3.

The relationship between maternal serum soluble fms-like tyrosine kinase 1 (sFlt1) concentration (ng/mL) and uterine artery resistance index (RI) plotted at median gestational age (GA) of 19 2/7 weeks for term (solid line) and preterm (dashed line) deliveries. The relationship between sFlt1 and uterine artery RI does not vary with GA, although the predicted values of uterine artery RI do change with GA.