Abstract
Background: Stillbirth rates in pregestational diabetes remain elevated despite advancements in fetal surveillance. Angiogenic biomarkers may be a useful adjunct to identify occult placental function and stratify fetal risk independent of fetal size.
Objective: To determine the gestational age-specific prevalence of angiogenic biomarker abnormalities, placental growth factor (PlGF) and soluble FMS-like tyrosine kinase 1 (sFlt-1)/PlGF ratio, and their association with perinatal outcomes in pregestational diabetes.
Study design: A masked prospective cohort study conducted in New Zealand from November 2022 to August 2024, including 40 people with type 1 and 58 with type 2 diabetes. Blood samples for sFlt-1 and PlGF were collected at four-week intervals from 20-36 weeks' gestation, immediately frozen, and analysed postpartum using Elecsys assays.
Results: Two temporal patterns of angiogenic biomarker abnormalities were identified: Early-onset, seen in 26% (95%CI 17-35%) of participants, characterised by a second-trimester PlGF <5th centile; and Late-onset, seen in 19% (95%CI 13-28%) of participants, characterised by a third-trimester sFlt-1/PlGF ratio >38 at a median (IQR) 35.9 (34.9-36.6) weeks' gestation. For a composite outcome of preterm birth, preeclampsia, or emergency caesarean section for intrapartum fetal compromise, abnormal angiogenic biomarkers collectively yielded a sensitivity of 86% (95%CI 71-94), specificity of 86% (95%CI 73-93), positive predictive value 82% (95% CI 67-91%), and negative predictive value 89% (95% CI 77-95%); in contrast Delphi fetal growth restriction criteria lacked sensitivity 7% (95%CI 2-20%), present in only 2.3% (1/44) of cases with abnormal angiogenic biomarkers and 5.6% (3/54) with normal biomarkers. Customised birthweight centiles were similar between the normal vs early-onset abnormality groups, [median (IQR) 73 (40-96) vs 84 (35-96); p=0.8] but higher in the late-onset abnormality vs normal group [92 (69-100); adjusted p=0.021].
Conclusions: In pregestational diabetes, angiogenic biomarker abnormalities predict adverse perinatal outcomes and signal occult placental dysfunction independent of apparent fetal growth restriction. Evaluation of routine angiogenic biomarker measurement as an adjunct to existing fetal surveillance protocols is warranted.