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During the implantation window, the endometrium becomes poised to transition to a pregnant state, a process driven by differentiation of stromal cells into decidual cells (DC). Perturbations in this process, termed decidualization, leads to breakdown of the feto-maternal interface and miscarriage, but the underlying mechanisms are poorly understood. Here, we reconstructed the decidual pathway at single-cell level in vitro and demonstrate that stromal cells first mount an acute stress response before emerging as DC or senescent DC (snDC). In the absence of immune cell-mediated clearance of snDC, secondary senescence transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in peri-implantation endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage. Lucas, Vrljicak et al characterise how the cycling endometrium transitions to a pregnant state. Through single-cell analysis of endometrial stromal cells and timed endometrial biopsies they identify DIO2 and SCARA5 as markers of a divergent decidual response.

IntroductionLarge-for-gestational age (LGA) fetuses have an increased risk of shoulder dystocia. This can lead to adverse neonatal outcomes and death. Early induction of labour in women with a fetus suspected to be macrosomic may mitigate the risk of shoulder dystocia. The Big Baby Trial aims to find if induction of labour at 38+0–38+4 weeks’ gestation, in pregnancies with suspected LGA fetuses, reduces the incidence of shoulder dystocia.Methods and analysisThe Big Baby Trial is a multicentre, prospective, individually randomised controlled trial of induction of labour at 38+0 to 38+4 weeks’ gestation vs standard care as per each hospital trust (median gestation of delivery 39+4) among women whose fetuses have an estimated fetal weight >90th customised centile according to ultrasound scan at 35+0 to 38+0 weeks’ gestation. There is a parallel cohort study for women who decline randomisation because they opt for induction, expectant management or caesarean section. Up to 4000 women will be recruited and randomised to induction of labour or to standard care. The primary outcome is the incidence of shoulder dystocia; assessed by an independent expert group, blind to treatment allocation, from delivery records. Secondary outcomes include birth trauma, fractures, haemorrhage, caesarean section rate and length of inpatient stay. The main trial is ongoing, following an internal pilot study. A qualitative reporting, health economic evaluation and parallel process evaluation are included.Ethics and disseminationThe study received a favourable opinion from the South West—Cornwall and Plymouth Health Research Authority on 23/03/2018 (IRAS project ID 229163). Study results will be reported in the National Institute for Health Research journal library and published in an open access peer-reviewed journal. We will plan dissemination events for key stakeholders.Trial registration numberISRCTN18229892.

Elvira Grandone and colleagues are correct that about half of the pregnancy losses might have been because of fetal aneuploidy.4 Had LMWH prevented euploid losses, we would have expected some difference in livebirth rates, because aneuploidy losses are distributed randomly between the intervention and control groups. The ALIFE2 trial1 is consistent with a meta-analysis of the subgroups of women with inherited thrombophilia who were included in previous randomised controlled trials of women with recurrent miscarriages, which showed no benefit of LMWH.5 We adhere to the principle of first, do no harm, and with the strong evidence of an absence of effect, LMWH should not be prescribed to prevent recurrent miscarriages in women with inherited thrombophilia. ALIFE2 recruited women who were at high risk of pregnancy loss, with 92 (28%) of 326 women having a further loss. Because LMWH did not prevent pregnancy loss, we recommend that future research is aimed at assessing non-thrombotic causes and treatments.

Full dilatation caesarean sections (CS) have increased risk of uterine extensions, which leads to cervical trauma that has been associated with an increased risk of spontaneous preterm birth (sPTB) in a subsequent pregnancy. The aim of this study was to determine if CS at full dilatation increased the risk of sPTB in a subsequent pregnancy in our unit. A historical cohort study was performed on women delivered by emergency CS between 2008–2015 (n = 5808) in a university hospital who had a subsequent pregnancy in this time frame (n = 1557). Women were classified into two exposure groups; those who were 6–9 cm and those fully dilated at index CS. The reference group was CS at 0–5 cm dilated. The primary outcome was sPTB < 37 weeks’ gestation. CS at 6–9 cm or fully dilated did not significantly increase the odds of sPTB in a subsequent pregnancy (aOR 1.64, 95% CI: 0.83–3.28, p = 0.158; aOR 1.86, 95% CI: 0.91–3.83; p = 0.090, respectively). However, a short interpregnancy interval of <1 year significantly increased the odds of sPTB in a subsequent pregnancy (aOR 3.10, 95% CI: 1.71–5.61). This study has found a short interpregnancy interval following a CS conferred a higher risk of sPTB than full dilatation CS. This finding highlights postnatal contraception and increased surveillance of women with short interpregnancy interval post CS as possible interventions to reduce sPTB.

Anticoagulant therapy might reduce the number of miscarriages and adverse pregnancy outcomes in women with recurrent pregnancy loss and inherited thrombophilia. We aimed to assess use of low-molecular-weight heparin (LMWH) versus standard care in this population. The ALIFE2 trial was an international open-label, randomised controlled trial undertaken in hospitals in the UK (n=26), the Netherlands (n=10), the USA (n=2), Belgium (n=1), and Slovenia (n=1). Women aged 18–42 years who had two or more pregnancy losses and confirmed inherited thrombophilia, and who were trying to conceive or were already pregnant (≤7 weeks' gestation), were eligible for inclusion. Women were randomly assigned (1:1) to use low-dose LMWH or not (alongside standard care in both groups) once they had a positive urine pregnancy test. LMWH was started at or before 7 weeks' gestation and continued until the end of pregnancy. The primary outcome measure was livebirth rate, assessed in all women with available data. Safety outcomes included bleeding episodes, thrombocytopenia, and skin reactions, and were assessed in all randomly assigned women who reported a safety event. The trial was registered within the Dutch Trial Register (NTR3361) and EudraCT (UK: 2015-002357-35). Between Aug 1, 2012, and Jan 30, 2021, 10 625 women were assessed for eligibility, 428 were registered, and 326 conceived and were randomly assigned (164 to LMWH and 162 to standard care). 116 (72%) of 162 women with primary outcome data in the LMWH group and 112 (71%) of 158 in the standard care group had livebirths (adjusted odds ratio 1·08, 95% CI 0·65 to 1·78; absolute risk difference, 0·7%, 95% CI –9·2% to 10·6%). 39 (24%) of 164 women in the LMWH group and 37 (23%) of 162 women in the standard care group reported adverse events. LMWH did not result in higher livebirth rates in women who had two or more pregnancy losses and confirmed inherited thrombophilia. We do not advise use of LMWH in women with recurrent pregnancy loss and inherited thrombophilia, and we advise against screening for inherited thrombophilia in women with recurrent pregnancy loss. National Institute for Health and Care Research and the Netherlands Organization for Health Research and Development.

The benefits and harms of early induction of labour to reduce shoulder dystocia in fetuses suspected to be large for gestational age (LGA) are uncertain. We aimed to investigate whether early induction of labour is associated with a reduced risk of shoulder dystocia compared with standard care. In this open-label, randomised controlled phase 3 trial, women aged ≥18 years with a suspected LGA fetus (estimated fetal weight >90th customised percentile) as identified by ultrasound scan between 35 weeks and 0 days (35+0 weeks) of gestation and 38+0 weeks' gestation, recruited from 106 hospitals across England, Scotland, and Wales in the UK, were randomly assigned (1:1) by web app to standard care or induction of labour between 38+0 weeks' gestation and 38+4 weeks' gestation using minimisation, balancing site, estimated fetal weight percentile (≤95th EFW percentile or >95th EFW percentile), and maternal age (≤35 years or >35 years). Key exclusion criteria included drug-treated diabetes, gestational diabetes, and elective caesarean section or induction already planned or indicated for any reason. Our primary outcome was incidence of shoulder dystocia, assessed by a masked independent expert adjudication panel who reviewed participants' delivery notes. Induction of labour was anticipated to result in birth 10·5 days earlier with a 300 g lower birthweight on average than standard care. We did an intention-to-treat (ITT) analysis in all participants for whom we had primary outcome data, and a per-protocol analysis in participants in the induction group who went into labour or were induced at 38+0 to 38+4 weeks' gestation versus participants in the standard care group who had not started labour, been induced, or had an elective caesarean section before 38+4 weeks' gestation. This study was registered with ISRCTN (18229892) and is no longer recruiting. Between June 8, 2018, and Oct 25, 2022, 2893 women were randomly assigned to induction of labour (n=1447) or standard care (n=1446); the trial was terminated before the target of 4000 participants was reached on advice of the data monitoring committee following the lower-than-expected incidence of shoulder dystocia in the standard care group. Two participants in the induction group and seven in the standard care group had missing data for the primary outcome and were excluded from the ITT analysis. In the ITT analysis, 33 (2·3%) of 1445 babies in the induction group versus 44 (3·1%) of 1439 in the standard care group had shoulder dystocia (risk ratio [RR] 0·75 [95% CI 0·51–1·09]; p=0·14) with a mean difference of –6·0 days' (95% CI –6·3 to –5·6) gestation and –163·6 g (–190·0 to –137·1) birthweight between trial groups. 355 (24·6%) of 1446 mothers in the standard care group were induced, delivered, or went into labour at or before 38+4 weeks' gestation. In the per-protocol analysis, 27 (2·3%) of 1180 babies in the induction group versus 40 (3·7%) of 1074 in the standard care group had shoulder dystocia (RR 0·62 [0·41–0·92]; p=0·019), and there was a mean difference of –8·1 days' (–8·4 to –7·9) gestation and –213·3 g (–242·0 to –184·6) birthweight between trial groups. One neonatal death occurred from perinatal asphyxia after shoulder dystocia in the standard care group, and one neonatal death occurred following sepsis and congenital pneumonia in the induction group. 88 (6·1%) of 1447 mothers in the induction group had an adverse event versus 108 (7·5%) of 1446 in the standard care group (RR 0·81 [0·62 to 1·06]; p=0·13). Similar numbers of serious adverse events were reported in both groups. No significant difference in incidence of shoulder dystocia was found between trial groups in the ITT analysis, probably due to the high proportion of earlier-than-expected deliveries in the standard care group reducing the intended between-group differences in gestational age and birthweight. However, in the per-protocol analysis, compared with all deliveries after 38+4 weeks' gestation, induction of labour between 38+0 weeks' gestation and 38+4 weeks' gestation did show a significant reduction in shoulder dystocia. This study provides pregnant women with suspected LGA fetuses and their clinicians important information about choices and decision making for timing and mode of birth. National Institute for Health and Care Research Health Technology Assessment Programme.

Breakdown of the feto-maternal interface in early pregnancy causes miscarriage. The cycling endometrium becomes poised to transition to a pregnant state during the midluteal implantation window, coinciding with differentiation of stromal cells into decidual cells (DC) and emergence of senescent decidual cells (snDC). Emerging evidence suggests that DC engage uterine natural killer cells to eliminate their senescent counterparts, thus enabling formation of a robust decidual matrix in pregnancy. To examine if failure to constrain snDC during the peri-implantation window increases the risk of miscarriage, we reconstructed the decidual pathway at single-cell level in vitro and demonstrated that, without immune surveillance, secondary senescence rapidly transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identified DIO2 and SCARA5 as marker genes of a diverging decidual response in vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in luteal phase endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage.