The effect of maternal soluble FMS-like tyrosine kinase 1 during pregnancy on risk of preterm delivery

Abstract

Objective: Soluble fms-like tyrosine kinase 1 (sFlt1) is an antiangiogenic protein that is associated with a number of disorders of placental angiogenesis. It has been hypothesized that disruption of placental angiogenesis may contribute to the pathophysiology of preterm delivery (PTD). However, the relationship of PTD risk to variation in sFlt1 levels is not well known. We investigate the relationship between longitudinal variation in maternal serum concentrations of sFlt1 and risk of PTD. Methods: Data were collected in a longitudinal cohort study involving 278 pregnant women. Maternal serum sFlt1 concentrations were measured at 6–10, 10–14, 16–20, 22–26, and 32–36 weeks gestation. Data analyses used longitudinal regression models using repeated measures that allow robust inferences from our modest sample size. The outcome was birth prior to 37 weeks gestation. Results: sFlt1 concentrations were higher in first trimester for preterm compared to term deliveries. This relationship reversed in second trimester because sFlt1 concentrations increased more rapidly across gestation for term deliveries. In Cox proportional hazards analyses, a 2 ng higher sFlt1 concentration across gestation was associated with a hazard ratio of 1.3 (95% CI: 1.1, 1.5) for PTD suggesting the importance of levels in early pregnancy. Conclusion: Elevated maternal serum sFlt1 concentration during pregnancy is associated with increased risk of PTD.

Keywords::

• Angiogenic factors
• Cox regression
• Flt1 protein
• longitudinal analysis
• placental hormones
• pregnancy

Acknowledgements

We thank Dr. Greg Dyson and Mr. Ray Lowery for their assistance with data analyses. We thank Dr. Marjorie Treadwell for help with collection of ultrasound data and Dr. Dawn P. Misra for her critical review of the manuscript.

Declaration of Interest: VKM was supported by a Doris Duke Clinical Scientist Development Award (Grant 2007092); a NIH Mentored Scientist Award (K08-HD045609), and a NIH Pediatric Child Health Research Center (K12-HD028820). PK was supported by University of Michigan’s Head and Neck Cancer Specialized Programs of Research Excellence Grant (5-P50-CA097248). The General Clinical Research Center at the University of Michigan Health System funded by grant number M01-RR000042 from the National Institutes of Health; the Michigan Clinical Research Unit which is supported by a Clinical and Translational Science Award grant number UL1RR024986 from the National Institutes of Health. JKS was supported by a postdoctoral award from Wayne State University.