Background
The precise physiological mechanisms that initiate labour at term remain an area of active investigation. While uterine contractility and cervical maturation have been extensively studied, the role of placental angiogenic factors in modulating the timing of parturition has received comparatively less attention. Angiogenic biomarkers, particularly soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), are well-established in the pathophysiology of preeclampsia and fetal growth restriction. However, their involvement in normal labour physiology at term and post-term gestations has not been thoroughly characterized.
Low-risk pregnancies extending beyond 40 weeks represent a significant clinical challenge. Post-term pregnancies (≥41 weeks) are associated with increased risks of stillbirth, macrosomia, and operative delivery. Identifying reliable biomarkers that predict labour timing could enhance surveillance strategies and guide clinical decision-making regarding induction of labour. The study by Morr and colleagues addresses this gap by examining whether serum angiogenic biomarkers measured at term are associated with the onset of spontaneous labour and the success of induced labour in low-risk populations.
Study Design
This prospective, non-interventional, observational cohort study was conducted at a single tertiary care centre in Switzerland. The study enrolled low-risk pregnant women at term (≥37 weeks) and post-term (≥41 weeks) who were planning either spontaneous labour or induction of labour. Women with comorbidities, multiple gestations, or evidence of placental dysfunction were excluded to isolate the relationship between angiogenic factors and labour timing in uncomplicated pregnancies.
The primary exposure was serum concentration of sFlt-1 and PlGF, measured at the time of enrollment. In the spontaneous labour cohort (n=136), investigators assessed time intervals from biomarker sampling to onset of labour and to delivery. In the induced labour cohort (n=48), induction-to-delivery intervals were recorded. A subset of women who remained pregnant beyond term provided longitudinal samples to assess biomarker trajectories from term to post-term.
Key Findings
Association Between Angiogenic Biomarkers and Spontaneous Labour Timing
The central finding of this study was that higher sFlt-1 levels at term were significantly associated with a shorter interval from sampling to delivery in spontaneous labour (p=0.03). Similarly, women with elevated sFlt-1/PlGF ratios demonstrated shorter time to spontaneous delivery (p=0.03). This inverse relationship between anti-angiogenic markers and labour-to-delivery interval persisted after multivariable adjustment for gestational age at sampling, maternal body mass index, and parity, confirming that the sFlt-1/PlGF ratio independently predicts faster labour onset.
This association suggests that a shift toward an anti-angiogenic state at term may facilitate the inflammatory and mechanical processes that drive parturition. From a clinical perspective, women with higher sFlt-1/PlGF ratios at 38-40 weeks might be expected to enter labour sooner than those with lower ratios.
PlGF and Induction-to-Delivery Intervals
Among women undergoing induction of labour (n=48), higher PlGF concentrations were associated with longer induction-to-delivery intervals (p=0.02). Unlike the findings in spontaneous labour, sFlt-1 and the sFlt-1/PlGF ratio did not independently predict induction outcomes. This suggests that the pathways governing response to cervical ripening and oxytocin augmentation differ mechanistically from those initiating spontaneous labour. Placental angiogenic state may reflect overall uterine receptivity, but labour induction operates through pharmacologically induced pathways that may override endogenous biomarker-driven timing.
Biomarker Trajectories from Term to Post-Term
Longitudinal analysis revealed significant changes in angiogenic biomarkers as pregnancies progressed from term to post-term. PlGF declined substantially (median 208 pg/mL at term versus 148 pg/mL post-term, p<0.0001), while sFlt-1 increased (median 3128 pg/mL to 3631 pg/mL, p<0.0001). Correspondingly, the sFlt-1/PlGF ratio rose from 14 to 24 over the same interval (p<0.0001).
These progressive changes are consistent with physiological placental maturation and aging. The increasing anti-angiogenic profile may reflect normal term and post-term placental changes that prepare the uterus for labour. However, in some cases, an exaggerated anti-angiogenic shift could potentially contribute to placental insufficiency, explaining the increased perinatal risks observed in post-term pregnancies.
Expert Commentary and Clinical Implications
The findings from Morr and colleagues provide novel insights into the biological underpinnings of labour timing. The identification of angiogenic biomarkers as predictors of spontaneous labour onset represents a potentially important advance in obstetric stratification. However, several considerations warrant attention.
First, the sample size, while adequate for the primary analyses, was relatively modest, particularly for the induced labour subgroup. Larger validation studies across diverse populations would strengthen the generalizability of these findings. Second, the study was conducted at a single tertiary centre in Switzerland, and practice patterns regarding induction indications and protocols may limit applicability to other settings.
From a mechanistic standpoint, the inverse relationship between anti-angiogenic markers and labour timing aligns with the broader understanding of inflammation at the maternal-fetal interface. sFlt-1 antagonizes vascular endothelial growth factor (VEGF) signaling, and VEGF is known to influence uterine vascular remodeling and decidual activation. The upregulation of sFlt-1 may thus represent a final step in the cascade of events that prepares the placenta and uterus for labour.
The differential findings between spontaneous and induced labour underscore that labour induction does not simply accelerate naturally occurring processes but involves distinct pharmacological and physiological pathways. This distinction is clinically relevant when counseling women regarding expected induction timelines.
Conclusion
This prospective cohort study demonstrates that angiogenic serum biomarkers are meaningfully associated with labour timing in low-risk term and post-term pregnancies. Higher sFlt-1 and sFlt-1/PlGF ratios predict shorter intervals to spontaneous delivery, while higher PlGF predicts longer induction-to-delivery intervals. The progressive increase in anti-angiogenic factors from term to post-term reflects normal placental maturation but may also contribute to late-term perinatal risks.
These findings open avenues for incorporating angiogenic biomarker profiling into late-term pregnancy risk assessment. Women identified with an anti-angiogenic profile at 38-40 weeks might benefit from closer surveillance or earlier consideration of labour induction. Conversely, those with a more pro-angiogenic profile might be candidates for expectant management with appropriate monitoring. Further research should evaluate whether biomarker-guided decision-making improves maternal and neonatal outcomes in post-term pregnancies.
Funding: The study was conducted at a tertiary care centre in Switzerland. Specific funding sources were not detailed in the available abstract.
Reference: Morr AK, Baumann M, Raio L, Surbek D, Radan AP. Angiogenic Serum Biomarker Levels Are Related to Onset of Labour in Low-Risk Term and Post-Term Pregnancies: A Prospective Observational Cohort Study. BJOG. 2026 Mar 27. PMID: 41895736.
