Purpose Spontaneous preterm birth (sPTB), particularly early preterm birth and mid-trimester loss, remains poorly understood and difficult to predict. The INSIGHT cohort was established to create a deeply phenotyped, longitudinal pregnancy dataset integrating clinical data and biological sampling to investigate the mechanisms of cervical shortening and sPTB, with a focus on linking innate immune responses, the vaginal microbiome, and host biology to identify early biomarkers of risk.

Participants 2272 pregnant women (8+0 –28+0 weeks’ gestation) were enrolled as high or low risk of preterm birth based on obstetric history, cervical length, cervical procedures, multiple pregnancy, or Müllerian anomalies. Serial clinical data and biological samples, including cervicovaginal specimens and blood, were collected throughout pregnancy.

Findings to date The cohort has generated comprehensive multi-omic data, including transcriptomic, microbiome, metabolomic, proteomic, and immune profiling. Key findings demonstrate that maternal plasma cfRNA can predict early sPTB months before clinical presentation, and that integration of cervicovaginal microbiota, metabolites, and host immune markers improves risk prediction and provides mechanistic insight into inflammatory pathways leading to sPTB.

Future plans Recruitment concluded in 2023, with final visits occurring in 2024. Ongoing analyses focus on refining predictive models, defining biological subtypes of preterm birth, and translating integrated biomarker panels into clinically scalable risk stratification tools.

STRENGTHS AND LIMITATIONS OF THIS STUDY

Large, prospective longitudinal cohort (Strength): Ten years of recruitment with repeat sampling enabled detailed study of biological pathways leading to sPTB.

Broad risk spectrum with clear definitions (Strength): Inclusion of both high and low-risk women using pre-specified clinical criteria supported robust comparative analyses and biomarker discovery.

Multicentre NHS recruitment (Strength): Inclusion of several sites, particularly the diverse Lambeth population at St Thomas’, enhanced population diversity and external validity.

Hospital-based, high-risk enrichment (Limitation/Strength): Recruitment from specialist preterm birth clinics and secondary/tertiary care may limit generalisability to lower-risk or primary care populations. However, it did ensure many preterm birth events were captured prospectively in this study.

Incomplete follow-up and limited late sampling (Limitation): Attrition and sampling only up to a prespecified gestation (defined by standard clinical pathway) reduced full pregnancy coverage of longitudinal data.

RMT reports a funded collaboration and a consulting fee paid by Mirvie Inc. to Kings College London (KCL) for a collaborative project involving cfRNA measurement in a subset of INSIGHT samples. AHS reports a funded collaboration paid by Pregnolia AG to KCL for a study measuring cervical stiffness using the Pregnolia device in a subset of INSIGHT participants.

Funding for the INSIGHT cohort was provided from Tommys Charity (Reg charity no. 1060508), NIHR Biomedical Research Centre (BRC) based at Guys and St Thomas National Health Service Foundation Trust, the Rosetrees Trust (no. 298582, M303-CD1), Borne Foundation (no. 1167073), and MRC Capital Investment in Human Tissue Banking and Linked Data in Partnership with Charities Award (MR/R014167/1). NH was funded by a NIHR Doctoral Research Fellowship (DRF-2013-06-171).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

INSIGHT (IRAS: 117589) was reviewed and approved by London City and East Research Ethics Committee (REC: 13/LO/0393).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present work are contained in the manuscript.