American journal of obstetrics and gynecology · 2026
Abnormal serum soluble fms-like tyrosine kinase 1 and placental growth factor as markers of occult placental dysfunction and fetal risk in pregestational diabetes: a prospective masked cohort study.
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Hughes Ruth C E, Williman Jonathan A, Lee Gene, Mackay Daniel
Аннотация
BACKGROUND: Stillbirth rates in pregestational diabetes remain elevated despite advancements in fetal surveillance. Angiogenic biomarkers may be a useful adjunct to identify occult placental dysfunction and stratify fetal risk independently of fetal size.
OBJECTIVE: To determine the gestational age-specific prevalence of angiogenic biomarker abnormalities, placental growth factor and soluble fms-like tyrosine kinase 1/placental growth factor ratio, and their associations with perinatal outcomes in pregestational diabetes.
STUDY DESIGN: A masked prospective cohort study was conducted in New Zealand from November 2022 to August 2024, including 40 people with type 1 and 58 people with type 2 diabetes. Blood samples for soluble fms-like tyrosine kinase 1 and placental growth factor were collected at 4-week intervals from 20 to 36 weeks' gestation, immediately frozen, and analyzed postpartum using Elecsys assays.
RESULTS: Of note, 2 temporal patterns of angiogenic biomarker abnormalities were identified: early-onset, seen in 26% (95% confidence interval, 17-35) of participants, characterized by a second-trimester placental growth factor <5th percentile; and late-onset, seen in 19% (95% confidence interval, 13-28) of participants, characterized by a third-trimester soluble fms-like tyrosine kinase 1/placental growth factor ratio >38 at a median (interquartile range) of 35.9 (34.9-36.6) weeks' gestation. For a composite outcome of preterm birth, preeclampsia, or emergency cesarean section for intrapartum fetal compromise, abnormal angiogenic biomarkers collectively yielded a sensitivity of 86% (95% confidence interval, 71-94), specificity of 86% (95% confidence interval, 73-93), positive predictive value of 82% (95% confidence interval, 67-91), and negative predictive value of 89% (95% confidence interval, 77-95). In contrast, Delphi fetal growth restriction criteria lacked sensitivity (7% [95% confidence interval, 2-20]), being present in only 1/44 (2.3%) of cases with abnormal angiogenic biomarkers and 3/54 (5.6%) with normal biomarkers. Customized birthweight percentiles were similar between the normal and early-onset abnormality groups (median [interquartile range], 73 [40-96] vs 84 [35-96]) (P=.8) but were higher in the late-onset abnormality group than in the normal group (92 [69-100]) (adjusted P=.021).
CONCLUSION: In pregestational diabetes, angiogenic biomarker abnormalities predict adverse perinatal outcomes and signal occult placental dysfunction independently of apparent fetal growth restriction. Evaluation of routine angiogenic biomarker measurement as an adjunct to existing fetal surveillance protocols is warranted.
OBJECTIVE: To determine the gestational age-specific prevalence of angiogenic biomarker abnormalities, placental growth factor and soluble fms-like tyrosine kinase 1/placental growth factor ratio, and their associations with perinatal outcomes in pregestational diabetes.
STUDY DESIGN: A masked prospective cohort study was conducted in New Zealand from November 2022 to August 2024, including 40 people with type 1 and 58 people with type 2 diabetes. Blood samples for soluble fms-like tyrosine kinase 1 and placental growth factor were collected at 4-week intervals from 20 to 36 weeks' gestation, immediately frozen, and analyzed postpartum using Elecsys assays.
RESULTS: Of note, 2 temporal patterns of angiogenic biomarker abnormalities were identified: early-onset, seen in 26% (95% confidence interval, 17-35) of participants, characterized by a second-trimester placental growth factor <5th percentile; and late-onset, seen in 19% (95% confidence interval, 13-28) of participants, characterized by a third-trimester soluble fms-like tyrosine kinase 1/placental growth factor ratio >38 at a median (interquartile range) of 35.9 (34.9-36.6) weeks' gestation. For a composite outcome of preterm birth, preeclampsia, or emergency cesarean section for intrapartum fetal compromise, abnormal angiogenic biomarkers collectively yielded a sensitivity of 86% (95% confidence interval, 71-94), specificity of 86% (95% confidence interval, 73-93), positive predictive value of 82% (95% confidence interval, 67-91), and negative predictive value of 89% (95% confidence interval, 77-95). In contrast, Delphi fetal growth restriction criteria lacked sensitivity (7% [95% confidence interval, 2-20]), being present in only 1/44 (2.3%) of cases with abnormal angiogenic biomarkers and 3/54 (5.6%) with normal biomarkers. Customized birthweight percentiles were similar between the normal and early-onset abnormality groups (median [interquartile range], 73 [40-96] vs 84 [35-96]) (P=.8) but were higher in the late-onset abnormality group than in the normal group (92 [69-100]) (adjusted P=.021).
CONCLUSION: In pregestational diabetes, angiogenic biomarker abnormalities predict adverse perinatal outcomes and signal occult placental dysfunction independently of apparent fetal growth restriction. Evaluation of routine angiogenic biomarker measurement as an adjunct to existing fetal surveillance protocols is warranted.