Maternal serum levels of soluble fms-like tyrosine kinase-1 and placental growth factor at 20 and 28 weeks of gestational age and the risk of spontaneous preterm birth

• Published in: American journal of obstetrics and gynecology 2023-08, Vol.229 (2), p.164.e1-164.e18
• Main Authors: Sovio, Ulla, Gaccioli, Francesca, Cook, Emma, Charnock-Jones, D. Stephen, Smith, Gordon C.S.
• Format: Article
• Language: English
• Subjects: Biomarkers; Female; fetal growth; fetal stress; Gestational Age; Humans; Infant, Newborn; Placenta; Placenta Growth Factor; placental insufficiency; Pre-Eclampsia; Pregnancy; Premature Birth - epidemiology; Prospective Studies; protein biomarkers; spontaneous preterm birth; Vascular Endothelial Growth Factor Receptor-1
• ISSN: 0002-9378; 1097-6868
• DOI: 10.1016/j.ajog.2023.02.001

Spontaneous preterm birth is the endpoint of multiple different pathophysiological pathways. Fetal growth restriction, assessed by serial ultrasonic fetal biometry, has been shown to predict both preterm and early-term spontaneous labor. The soluble fms-like tyrosine kinase-1 to placental growth factor ratio is predictive of early-term spontaneous labor, but its association with spontaneous preterm birth is unclear. This study aimed to determine whether maternal serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and the soluble fms-like tyrosine kinase-1: placental growth factor ratio at 20 and 28 weeks’ gestation, and the rate of change in these biomarkers between 20 and 28 weeks were predictive of risk of spontaneous preterm birth. The biomarkers were measured in maternal serum at 20- and 28-weeks’ gestation in women recruited to a prospective cohort of unselected nulliparous women as part of the Pregnancy Outcome Prediction study in Cambridge, United Kingdom. The risk of spontaneous preterm birth was assessed using Cox regression and competing-risks regression. Associations from Cox regression were quantified by the adjusted hazard ratio for a 1 standard deviation higher level of a given biomarker or a 1 standard deviation increase in the marker between 20 and 28 weeks’ gestation. A previously identified risk factor, slow femur length growth, was used as an additional predictor of spontaneous preterm birth for the purpose of risk stratification. Of the 3763 participants in the analysis, 95 (2.5%) had spontaneous preterm birth and 54 (1.4%) had medically indicated preterm birth. At 20 weeks’ gestation, higher levels of soluble fms-like tyrosine kinase-1 and the soluble fms-like tyrosine kinase-1:placental growth factor ratio were associated with reduced risk of spontaneous preterm birth (adjusted hazard ratio [95% confidence interval], 0.75 [0.61–0.92]; P=.006 and 0.71 [0.59–0.87]; P=.0009, respectively). At 28 weeks’ gestation, there was no association between either soluble fms-like tyrosine kinase-1 or placental growth factor and the risk of spontaneous preterm birth, but there was a U-shaped relation with the soluble fms-like tyrosine kinase-1:placental growth factor ratio. However, when the biomarkers were quantified as the rate of increase between 20 and 28 weeks’ gestation, there were strong positive associations between spontaneous preterm birth and rate of increase in soluble fms-like tyrosine kinase-1 (1.36 [1.13–1.63]