This study addresses the research question “Is early stillbirth associated with modifiable factors?” It specifically aims to:
1. Identify modifiable risk factors for early stillbirth that are amenable to public health campaigns or adaptation of antenatal care.
2. Confirm or refute whether the range of factors associated with late stillbirth are independently associated with early stillbirth, including (but not limited to) supine sleep position, caffeine intake and reduced fetal movement.
3. Explore interactions between maternal/parental characteristics (especially those relating to health inequalities including ethnicity and socioeconomic deprivation), fetal factors (including fetal growth restriction, reduced fetal movements) and early stillbirth risk.
4. Determine whether exposures associated with early stillbirth vary by cause of death.
Study design
A prospective case-control study of people who experience ES (n=316) and those who have a contemporaneous ongoing pregnancy at the same gestation (n=632) will be conducted. The methodology of the previous MiNESS study (26) has been adapted for application to ES in a multicentre study taking place in 40-60 UK maternity units. Most research sites will be located in England, but participating sites are welcomed from Northern Ireland, Scotland and Wales. Maternity units of varying location (urban or rural), size and level of maternity or neonatal care provided on site. Local research midwifery teams will be supported by a central research midwife coordinator based in Manchester. A case-control study is the most appropriate, efficient, design to study relatively rare disorders such as stillbirths and can evaluate multiple exposures in the same study. Routine data studies lack detailed information regarding pregnancy exposures (e.g., sleep practices, caffeine consumption).
Ethical approval has been obtained from the Seasonal Research Ethics Committee (23/LO/0622). Recruitment will occur between September 2023 and August 2025. Initial results will be available by March 2026.
Sample size
ES occurs in ~0.3% of births (27). Recruiting 316 cases and 632 controls will detect associations between ES and exposures of interest with an odds ratio ≥1.5 (i.e., an associated fetal death rate of 0.45% or more) with 80% power and 5% significance level, where 30-60% of participants are exposed. Individual early stillbirth subtypes (preterm delivery, unexplained in utero, explainable in utero) are expected to occur in a 1:1:1 ratio. If these are differentially affected by certain exposures, the sample size is adequate to detect subtype-specific associations with an odds ratio ≥2. Larger effect sizes are expected in relation to subtype-specific risk factors compared to overall analyses, as subgroup effects will be attenuated by patient heterogeneity in the latter. With ~1,450 UK ES without congenital anomalies per year, by recruiting in multiple locations we believe this recruitment target can be achieved within 24 months.
Inclusion criteria
Overall inclusion criteria: People receiving pregnancy care and/or giving birth in a singleton pregnancy, between 20-28 weeks of pregnancy in a participating maternity unit during the study period. Case participants are defined as those where baby was diagnosed to have died before/during or immediately after labour between 20+0 and 27+6 weeks of pregnancy. Control participants are defined as those with an ongoing pregnancy at a group-matched gestation.
Participant recruitment
All pregnant people receiving antenatal care at participating hospitals will be made aware of the ongoing study, its purpose, and that they may be invited to participate prior to any recruitment approach being made. This information will take the form of study awareness posters displayed in hospital/community antenatal clinic and ultrasound department waiting areas, and a brief study awareness leaflet to be distributed at/after the routine 16-week antenatal clinic appointment.
Bereaved mothers/parents will be approached prior to discharge from the maternity unit by a member of the clinical care team. A brief description of the study will be provided by their midwife, bereavement midwife or doctor, and consent to contact obtained to allow contact from a research midwife. Initial introduction to the study by a clinician known to the participant was viewed favourably by participants in MiNESS (29) and the study-specific PPI group. Potential control participants will be identified from the maternity unit patient list using a bespoke random identification algorithm generated based on local historic case gestation mix. Pregnant people identified using this algorithm will be invited to participate as control participants following a normal routine fetal anatomy scan (18+0 to 20+6 weeks’ gestation (28)), providing a brief description of the study in the same way. This approach may be made by a clinician known to the potential participant or by a research midwife, many of whom recruited to the previous MiNESS study and are experienced in discussing stillbirth research with pregnant individuals. If the individual declines participation or cannot be contacted, another potential control participant will be identified and approached in the same manner until a suitable control participant is recruited. Written information about the study will be provided to and discussed with all participants by a trained research midwife. A mutually agreed date (within six weeks of ES or target gestation) and mode (online video consultation or face to face) for interview will be agreed.
Data collection
During the interview the research midwife will obtain informed consent to participate and administer a bespoke study questionnaire (Appendix 1), facilitated by use of interpreter if required. The questionnaire captures data on the social and demographic characteristics of the participant and any partner, past obstetric and medical history, medication and supplement use, use of nicotine/tobacco products, alcohol, recreational substances or caffeine, stress, violence and sleep practices. We aim to interview all participants as close to the interview reference date (date of ES diagnosis or randomly allocated gestation for controls). Distress protocols will be followed if required during/after interview. Following interview, the local research team will extract routinely recorded data from contemporaneous medical records (maternal biometry, antenatal and post-mortem investigation results, healthcare episodes).
Statistical analysis
Unadjusted associations between the outcome (ES) and each exposure will be estimated by logistic regression. Additional logistic regression models, adjusted for confounding variables, will consider multiple exposures in relation to ES. A separate logistic model, including a bespoke set of confounding variables will be used for each exposure variable to avoid spurious inferences (30). All models will include age, first pregnancy, self-declared ethnic group, smoking, obesity, diabetes, and hypertension. Both unadjusted and adjusted estimates and 95% confidence intervals will be presented for all exposure variables. Likelihood Ratio Testing will be used to test for an effect of each exposure. Secondary analyses will be conducted by ES subtype (preterm delivery, unexplained in utero, explainable in utero) and repeated including only babies without sign of life after birth. Study data will be compared with national data (MBRRACE UK; via co-applicant Smith) to assess generalisability (19). Fully anonymised individual patient data will be made available via an online research data repository with publication of the primary research findings.
Potential challenges
The interview will take place within the first few weeks following a bereavement (which is recognised to be an extremely traumatic and difficult period). There is the potential for participation in this study to exacerbate the grieving process. Individuals approached to take part as control participants may be dissuaded from participating due to a fear of "tempting fate” and may experience distress in relation to mention of the potential of stillbirth. Researchers will be trained to uphold the dignity of (potential) participants at all times and to provide support. Feedback from participants in the original MiNESS, Auckland Stillbirth and Sydney stillbirth studies suggests that participants appreciated taking part in the research; further, non-participants also viewed the invitation to research positively. (29, 31) Members of the public with lived experience of both ES and healthy pregnancy have been involved in the conceptualisation and design of the study to improve acceptability and participation rates and will continue to oversee the successful conduct of the study, interpretation and dissemination of its findings.
Exclusion criteria
1) Presence of a known significant congenital anomaly (as informed by the NHS Fetal Anomaly Screening Programme (27)); pregnancies where significant congenital anomaly is diagnosed after participation will be excluded from data analysis.
2) Multifetal pregnancy
3) Inability to consent despite provision of translation services
4) Participant age <16 years
5) Cases: Attempted postnatal transfer of the infant to neonatal services (survival-focused care); resuscitation attempts alone are not an exclusion