Spontaneous preterm birth—Early recurrent pregnancy bleeding, a neglected phenotype

The Preterm Birth International Collaborative (PREBIC) held its annual Biomarker Group meeting in Prague, Czech Republic, from January 30 to February 1, 2026. This year's meeting focused on a frequently overlooked phenotype of spontaneous preterm birth: early recurrent pregnancy bleeding. The association between the presence of microorganisms in amniotic fluid and vaginal bleeding was first described approximately two decades ago 1. Subsequently, observations on the presence of intra-amniotic infection or inflammation and vaginal bleeding in women with placenta previa were reported 2. Recently, Musilova et al. showed the association between intra-amniotic infection or inflammation and bleeding in the second trimester, as well as its clinical consequences. This report has brought renewed attention to this phenotype 3. In this editorial, we emphasize the importance of this phenotype and advocate for further research to elucidate its role in spontaneous preterm birth. Preterm birth represents a syndrome of syndromes rather than a discrete disease entity 4. At the same time, clinical care and translational research approaches continue to rely on broad categories that conceal important biological heterogeneity. The current approach to subcategorizing preterm birth first distinguishes between singleton and multiple pregnancies, followed by classification according to whether birth occurred spontaneously or was medically initiated by a health care provider. Spontaneous preterm birth is then further subdivided into preterm labor with intact membranes and preterm prelabor rupture of membranes. We propose that early recurrent pregnancy bleeding represents a third phenotype of spontaneous preterm birth (Figure 1). This phenotypic classification is essential to provide focused attention to this condition, rather than lumping it with other classes of preterm birth. Recognizing early recurrent pregnancy bleeding as a distinct phenotype will enable the basic, translational researchers and clinical communities to systematically investigate its underlying mechanisms and develop targeted clinical management strategies. Bleeding is a relatively common clinical event in the first trimester. However, only in a very small proportion of women does bleeding continue into the second trimester or appear for the first time during the second trimester 6. Such a pregnancy complication often follows a typical recurrent pattern and can be described as early recurrent pregnancy bleeding. Nevertheless, in clinical practice, it is largely framed as a short-term problem centered on miscarriage risk or the need for reassurance, rather than as a potential early predictor of later spontaneous preterm birth. More than two decades ago, studies using amniocentesis demonstrated that bleeding in the second and third trimesters might be associated with the presence of microorganisms and/or inflammation in the amniotic cavity 1, 2. These findings suggest that bleeding may reflect an underlying infectious or inflammatory process rather than a benign, self-limited event. More recent studies have strengthened this concept by showing that women with early recurrent bleeding are overrepresented among cases of preterm labor or preterm prelabor rupture of membranes and subsequent preterm birth, supporting the existence of a shared biological pathway across gestation 3. Systematic investigation of this phenotype offers a unique opportunity for mechanistic discovery, enabling deeper insight into the biological pathways driving preterm prelabor rupture of membranes or spontaneous preterm birth with intact membranes and facilitating the identification of novel preventive interventions. In parallel, such knowledge may support the development of pathway-informed biomarkers that allow earlier risk stratification in women presenting with early recurrent pregnancy bleeding. Emerging evidence also suggests that timely antibiotic interventions may play a role in reducing the intensity of the intra-amniotic inflammatory response 3. Recognizing and systematically studying this phenotype could therefore lead to earlier risk stratification, improved mechanistic understanding, and the development of targeted preventive strategies. Biomarker discovery for this phenotype must be closely linked to both the biological mechanism and timing. Biological sampling (e.g., amniotic fluid or maternal blood) around bleeding episodes could offer a unique opportunity to capture active biological processes. Current approaches to biomarker testing after a substantial latency period between the incidence and development of labor, or the lack thereof, miss the window for discovery research in pathobiology and for timely intervention. Candidate biomarkers might include hemostatic and thrombin-related markers, inflammatory and immune mediators, markers of tissue injury, and angiogenic factors derived from the placenta and fetal membranes 7. Recognition of early recurrent bleeding as a distinct phenotype also has important implications for targeted interventions within a given defined biological sub-phenotypes, including inflammatory, thrombin-mediated, and vascular pathways. Such a framework creates opportunities for drug repurposing, as well as the discovery of novel therapies. Crucially, it also provides a plausible explanation for why many previous interventions for spontaneous preterm birth have demonstrated limited efficacy: they were tested in heterogeneous populations without enrichment for the relevant biological pathway. Clinical interventions emerging from this framework should therefore be both phenotype-enriched and biomarker-stratified, allowing the design of pathway-targeted clinical trials. Outcome measures should also move beyond simple binary gestational age cutoffs. Instead, they should include delivery timing as a continuous measure, the specific phenotype of spontaneous preterm birth, and changes in biological or clinical markers (e.g., cervical changes, fetal membranes integrity, or resolution of bleeding). Such trial designs would better reflect the syndromic nature of spontaneous preterm birth and increase the likelihood of detecting clinically meaningful interventions. Finally, making this research agenda feasible will require changes in both policy and infrastructure. Standardized definitions of early recurrent bleeding should be mandated in funded cohorts and clinical trials, accompanied by minimum datasets capturing timing, recurrence, and severity. Second-trimester risk assessment represents a critical but underused gateway for spontaneous preterm birth research and should be integrated into longitudinal study designs. Funding mechanisms should prioritize event-driven biospecimen collection and adaptive, phenotype-informed trials. At the same time, regulatory authorities and health system stakeholders should recognize the potential cost-effectiveness of preventing spontaneous preterm birth in high-risk, biologically defined subgroups. Coordinated leadership from PREBIC in harmonization, validation, and translation could transform early recurrent bleeding from an overlooked symptom into a clinically actionable phenotype of spontaneous preterm birth 7. This editorial has been edited with the assistance of an artificial intelligence (AI) tool for language clarity, grammar, and stylistic improvement. The authors take full responsibility for the content of the review. The authors report no conflicts of interest. The author received no specific funding for this work.