Siobhan Quenby

STUDY QUESTION: Does preconceptual doxycycline prevent miscarriage in women with recurrent miscarriage (RM) and chronic endometritis (CE) defined by CD138+ stromal cells? SUMMARY ANSWER: Preconceptual doxycycline was not associated with improved livebirth rates in women with CE and a history of RM. WHAT IS KNOWN ALREADY: CE is characterised by asymptomatic endometrial inflammation and has been associated with RM. Some national and international RM guidelines advise testing and treating for CE with antibiotics, most commonly doxycycline, whereas others do not. STUDY DESIGN, SIZE, DURATION: Definitions of CE vary widely; in this study, all CD138+ cells, not only morphological plasma cells were included in the assessment. This was an adaptive, multi-centre, parallel-arm, double-blind, placebo-controlled, randomised trial. Recruitment started on January 2020, and follow-up finished on October 2023. Of 2178 women screened, 505 were positive for CD138 and 438 were randomised. A subgroup (202) had repeat endometrial biopsies in the luteal phase of their treatment cycle analysed. A screen negative group (208) were followed up in their first pregnancies. Screen positive women were randomised using an online web tool to preconceptual doxycycline 100 mg or an identical placebo from day 1 of the menstrual cycle, twice daily for 14 days. Patients, their clinicians and outcome assessors were blinded to treatment allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women, aged ≥18 to <42 years with ≥2 consecutive first trimester miscarriages were recruited in specialist RM clinics from 27 UK sites. Screening was by luteal phase endometrial biopsy with immunohistochemistry for CD138. The primary outcome was cumulative live birth and pregnancies ≥24 + 0 weeks gestation at cessation of the trial. Secondary outcomes included first pregnancy outcome, time to first conception and pregnancy complication rates. A prospective Bayesian analysis with no prior information was undertaken to estimate posterior probabilities. MAIN RESULTS AND THE ROLE OF CHANCE: There were 113/219 (52%) cumulative livebirths or ongoing pregnancies in the doxycycline group and 109/219 (50%) in the placebo group (adjusted Relative Risk (aRR)1.02; Credible Interval (CrI) 0.85–1.21). Sensitivity analysis did not influence these results. In the CE negative group, there were 62/208 (30%) livebirths or ongoing first pregnancies compared to 89/219 (41%) in the placebo group (aRR 0.73; CrI 0.56–0.95). The amount and pattern of CD138 staining varied equally before and after placebo (98 paired biopsies) and doxycycline (104 paired biopsies) treatments. LIMITATIONS, REASONS FOR CAUTION: In keeping with the adaptive Bayesian design, the trial was stopped at interim analyses. Whilst a higher-than-expected prevalence of CD138+ CE occurred in this study, a sensitivity analysis increasing the diagnostic threshold did not alter the findings. The second biopsies occurred within the treatment menstrual cycle; hence, we did not exclude a difference in CD138+ CE after menstruation. A few participants obtained additional doxycycline; however, a sensitivity analysis excluding these showed no difference in outcome. WIDER IMPLICATIONS OF THE FINDINGS: Neither the primary nor secondary outcome measures supported the use of doxycycline in the management of CD138+ CE in this first placebo-controlled trial. Similar differences in CD138 expression before and after placebo or doxycycline suggesting inter-cycle variation may account for previously reported findings. FUNDING: This study was funded by the Efficacy and Mechanism Evaluation Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership (Funder reference: 17/60/22). DISCLOSURES: All authors declare no competing interests. TRIAL REGISTRATION NUMBER: ISRCTN 2394773 https://doi.org/10.1186/ISRCTN23947730 TRIAL REGISTRATION DATE: 12 September 2019 DATE OF FIRST PATIENT’S ENROLMENT: 3 January 2020

What is the relationship between constitutive CD138 expression in the endometrium and the reproductive tract microbiota composition? The presence of CD138⁺ cells in endometrial stroma is cycle-dependent and associated with impaired luteal phase endometrial timing but not altered vaginal or endometrial microbial composition. CD138-diagnosed chronic endometritis (CE) is associated with adverse reproductive outcomes including recurrent pregnancy loss (RPL) in uncontrolled studies. However, CD138 is constitutively expressed in the endometrium, potentially confounding the reported associations between CE, adverse endometrial function, and early pregnancy loss. Translational cohort study of a subset of 103 samples derived from 737 women embedded within the CERM trial, a double-blinded, randomized interventional trial evaluating the impact of pre-pregnancy antibiotic treatment for CE in RPL patients. Women aged ≥18 to 200 CD138-positive stromal cells/10 mm²) in 26 out of 27 proliferative endometrial samples. While CD138 immunoreactivity in the stroma declines markedly following ovulation (Mann–Whitney U-test; P < 0.005), gene expression analysis demonstrated a reduction in SDC1 expression encoding CD138/syndecan-1, across the menstrual cycle. When compared to CD138-negative samples, conspicuous diffuse staining in the stromal compartment was associated with significantly earlier endometrial histological dating (P < 0.01) and lower molecular timing ratios (P < 0.01). Poor correlation between CD138 and immunoreactivity was demonstrated. Sequencing of paired vaginal and ectocervical swabs and endometrial Tao brush samples collected from 114 patients demonstrated tightly interconnected microbial composition throughout the reproductive tract. No significant difference in vaginal, ectocervical, or endometrial community state type with CD138 expression was demonstrated. Analysis of supernatants of vaginal and ectocervical swabs and Tao Brush revealed an inverse correlation between the severity of stromal CD138 immunoreactivity in endometrial stroma and secreted levels of IL-10, TNF-α, and VEGF (q < 0.05). Microbial and Metataxonomic raw data are available in the European Nucleotide Archive (Projects PRJEB83331 and PRJEB83332). This study relied on patient-reported ovulation-based timing. This was, however, associated with the provision of validated ovulation tests. In addition, the study is limited by lack of collection of data on the underlying fertility-related co-morbidities due to exclusion of known contributory co-morbidities at the point of recruitment. This study challenges the purported relationship between CD138⁺ CE and the pathophysiology of CE-associated RPL. The findings indicate endometrial CD138 levels are non-immune and non-bacterial driven and are associated with endometrial immaturity. CD138-based CE testing and treatment should not be performed outside of a research context. Funding was provided by the Efficacy and Mechanism Evaluation (EME) Programme a National Institute for Health and Care Research and Medical Research Council partnership (17/60/22). Further funding was from Tommy’s National Centre for Miscarriage Research, and the Imperial National Institute for Health and Care Research Biomedical Research Centre Pregnancy and Prematurity Theme. G.D.S.C. is supported by the Genesis Research Trust. All authors report no direct conflict of interest. ISRCTN23947730.

Objective: Fetal size and gestational age are essential factors to consider when determining the timing of delivery between mothers and obstetricians in term pregnancies. Previous studies have shown that both fetal size and gestational age have associations with cognitive or academic outcomes. This study aimed to determine whether the association between gestational age (37–41 weeks) and child intelligence is moderated by fetal size in term‐born children. Methods: Data were harmonized for four national cohorts in the USA, UK, Ireland, and Australia. Predictors included fetal size and gestational age. Fetal size was calculated using Fenton's chart and grouped into three categories: Large for gestational age (LGA) (>90th percentile), appropriate for gestational age (AGA) (10th to 90th percentile), and small for gestational age (SGA) (Z ‐score, equivalent to a 3.45 IQ difference) was found in SGA‐born children who were born at 37 weeks compared to 41 weeks. Conclusion: The association between gestation and child IQ at age 5 was not moderated by fetal size in term‐born children. Regardless of gestational age at term, SGA (but not LGA) is consistently and unfavorably associated with poorer cognitive outcomes. The IQ at age 5 was only clinically meaningfully decreased in SGA children born at 37 weeks.

In every menstrual cycle, progesterone acting on estrogen-primed endometrium elicits an inflammatory decidual reaction, rendering it poised for embryo implantation and transformation into the decidua of pregnancy. Here, we show that the sequential functions of the decidual reaction—implantation and decidualization—pivot on the time-sensitive loss of progesterone-resistant DIO2 ⁺ stromal cells that form a specialized implantation niche and reciprocal expansion of progesterone-dependent PLA2G2A ⁺ predecidual cells. Simultaneously, uterine natural killer (uNK) cell proliferation results in the accumulation of immunotolerant subsets. Examination of endometrial biopsies from 924 women revealed that the recurrence risk of miscarriage closely aligns with the incidence of a weakened or stalled decidual reaction, more so than poor uNK cell expansion. Analysis of paired biopsies obtained in different cycles and modeling in assembloids intimated that prior miscarriages disrupt intercycle endometrial homeostasis and calibration of the decidual reaction. Our findings show that erosion of the decidual reaction following a miscarriage drives the recurrence risk irrespective of maternal age.

Introduction: Early induction of labor (37⁺⁰–38⁺⁶ gestational weeks) in large‐for‐gestational‐age infants may reduce perinatal risks such as shoulder dystocia, but it may also increase the long‐term risks of reduced cognitive abilities. This systematic review aimed to evaluate the cognitive and academic outcomes of large‐for‐gestational‐age children born early term vs full term (combined or independent exposures).Material and Methods: The protocol was registered in the PROSPERO database under the registration no. CRD42024528626. Five databases were searched from their inception until March 27, 2024, without language restrictions. Studies reporting childhood cognitive or academic outcomes after early term or large‐for‐gestational‐age births were included. Two reviewers independently screened the selected studies. One reviewer extracted the data, and the other double‐checked the data. The risk of bias was assessed using the Newcastle‐Ottawa Quality Assessment Scale. In addition to narrative synthesis, meta‐analyses were conducted where possible.Results: Of the 2505 identified articles, no study investigated early‐term delivery in large‐for‐gestational‐age babies. Seventy‐six studies involving 11 460 016 children investigated the effects of either early‐term delivery or large‐for‐gestational‐age. Children born at 37 weeks of gestation (standard mean difference, −0.13; 95% confidence interval, −0.21 to −0.05), but not at 38 weeks (standard mean difference, −0.04; 95% confidence interval, −0.08 to 0.002), had lower cognitive scores than those born at 40 weeks. Large‐for‐gestational‐age children had slightly higher cognitive scores than appropriate‐for‐gestational‐age children (standard mean difference, 0.06; 95% confidence interval, 0.01–0.11). Similar results were obtained using the outcomes of either cognitive impairment or academic performance.Conclusions: No study has investigated the combined effect of early‐term delivery on cognitive scores in large‐for‐gestational‐age babies. Early‐term delivery may have a very small detrimental effect on cognitive scores, whereas being large for gestational age may have a very small benefit. However, evidence from randomized controlled trials or observational studies is required.

Introduction Interventional clinical trials in recurrent miscarriage use varying expected effect sizes to inform their sample size calculations. Often these are not informed by what stakeholders consider a meaningful treatment effect. Adaptive trial designs may integrate stakeholder views on trial success and futility but the criteria to inform this is lacking. This study aims to understand relevant stakeholder views of what is considered a worthwhile treatment effect for miscarriage prevention interventions and what is acceptable stopping criteria in miscarriage clinical trials. Methods and analysis The study is designed as a cross-sectional online anonymous survey. The survey presents different scenarios to respondents relating to varying target differences and probability thresholds and explores success and futility criteria for clinical trials. The survey was developed with personal and public involvement (PPI) through focus groups and a PPI partner. Eligible participants will be those with a personal history of miscarriage, including partners, and healthcare professionals who manage patients who experience a miscarriage. Convenience, snowball and purposive sampling techniques will be employed to invite eligible participants to complete the survey. The survey will be accepting responses for an initial 2-week pilot to check validity, prior to being open for a further 12 weeks. Descriptive analyses and linear regression analyses will synthesise the survey results. Ethics and dissemination Ethical approval was obtained from the NHS Research Ethics Committee North West—Greater Manchester East (23/NW/0322) on 30 January 2024. Informed consent will be obtained prior to survey completion. No personal identifying information will be collected. The results will be published in a relevant scientific journal and communicated through our institutional website.