Diagnosis and management of selective fetal growth restriction in monochorionic twin pregnancies: A cross-sectional international survey.

OBJECTIVE: To identify current practices in the management of selective fetal growth restriction (sFGR) in monochorionic diamniotic (MCDA) twin pregnancies. DESIGN: Cross-sectional survey. SETTING: International. POPULATION: Clinicians involved in the management of MCDA twin pregnancies with sFGR. METHODS: A structured, self-administered survey. MAIN OUTCOME MEASURES: Clinical practices and attitudes to diagnostic criteria and management strategies. RESULTS: Overall, 62.8% (113/180) of clinicians completed the survey; of which, 66.4% (75/113) of the respondents reported that they would use an estimated fetal weight (EFW) of <10th centile for the smaller twin and an inter-twin EFW discordance of >25% for the diagnosis of sFGR. For early-onset type I sFGR, 79.8% (75/94) of respondents expressed that expectant management would be their routine practice. On the other hand, for early-onset type II and type III sFGR, 19.3% (17/88) and 35.7% (30/84) of respondents would manage these pregnancies expectantly, whereas 71.6% (63/88) and 57.1% (48/84) would refer these pregnancies to a fetal intervention centre or would offer fetal intervention for type II and type III cases, respectively. Moreover, 39.0% (16/41) of the respondents would consider fetoscopic laser surgery (FLS) for early-onset type I sFGR, whereas 41.5% (17/41) would offer either FLS or selective feticide, and 12.2% (5/41) would exclusively offer selective feticide. For early-onset type II and type III sFGR cases, 25.9% (21/81) and 31.4% (22/70) would exclusively offer FLS, respectively, whereas 33.3% (27/81) and 32.9% (23/70) would exclusively offer selective feticide. CONCLUSIONS: There is significant variation in clinician practices and attitudes towards the management of early-onset sFGR in MCDA twin pregnancies, especially for type II and type III cases, highlighting the need for high-level evidence to guide management.

Neurodevelopmental outcomes at 2 years in children who received sildenafil therapy in utero: The STRIDER randomised controlled trial.

OBJECTIVE: Severe early-onset fetal growth restriction (FGR) causes stillbirth, neonatal death and neurodevelopmental impairment. Poor maternal spiral artery remodelling maintains vasoactive responsiveness but is susceptible to treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, which may improve perinatal outcomes. DESIGN: Superiority, double-blind randomised controlled trial. SETTING: A total of 20 UK fetal medicine units. POPULATION: Pregnancies affected by FGR, defined as an abdominal circumference below the tenth centile with absent end-diastolic flow in the umbilical artery between 22+0 and 29+6 weeks of gestation. METHODS: Treatment with sildenafil (25 mg three times/day) or placebo until delivery or 32 weeks of gestation. MAIN OUTCOME MEASURES: All infants alive at hospital discharge were assessed for cardiovascular function and cognitive, speech/language and neuromotor impairment at 2 years of age. The primary outcome was survival without cerebral palsy or neurosensory impairment, or a Bayley-III composite score of >85. RESULTS: In total, 135 women were randomised between November 2014 and July 2016 (70 to sildenafil and 65 to placebo). We previously published that there was no improvement in time to delivery or perinatal outcomes with sildenafil. In all, 75 babies (55.5%) were discharged alive, with 61 infants eligible for follow-up (32 sildenafil and 29 placebo). One infant died (placebo), three mothers declined and ten mothers were uncontactable. There was no difference in neurodevelopment or blood pressure following treatment with sildenafil. Infants who received sildenafil had a larger head circumference at 2 years of age (median difference 49.2 cm, IQR 46.4-50.3, vs 47.2 cm, 95% CI 44.7-48.9 cm). CONCLUSIONS: Sildenafil therapy did not prolong pregnancy or improve perinatal outcomes and did not improve infant neurodevelopment in FGR survivors. Therefore, sildenafil should not be prescribed for this condition.

Oral misoprostol alone, compared with oral misoprostol followed by oxytocin, in women induced for hypertension of pregnancy: A multicentre randomised trial.

OBJECTIVE: To assess whether, in those requiring continuing uterine stimulation after cervical ripening with oral misoprostol and membrane rupture, augmentation with low-dose oral misoprostol is superior to intravenous oxytocin. DESIGN: Open-label, superiority randomised trial. SETTING: Government hospitals in India. POPULATION: Women who were induced for hypertensive disease in pregnancy and had undergone cervical ripening with oral misoprostol, but required continuing stimulation after artificial membrane rupture. METHODS: Participants received misoprostol (25 micrograms, orally, 2-hourly) or titrated oxytocin through an infusion pump. All women had one-to-one care; fetal monitoring was conducted using a mixture of intermittent and continuous electronic fetal monitoring. MAIN OUTCOME MEASURES: Caesarean birth. RESULTS: A total of 520 women were randomised and the baseline characteristics were comparable between the groups. The caesarean section rate was not reduced with the use of misoprostol (misoprostol, 84/260, 32.3%, vs oxytocin, 71/260, 27.3%; aOR 1.23; 95% CI 0.81-1.85; P = 0.33). The interval from randomisation to birth was somewhat longer with misoprostol (225 min, 207-244 min, vs 194 min, 179-210 min; aOR 1.137; 95% CI 1.023-1.264; P = 0.017). There were no cases of hyperstimulation in either arm. The rates of fetal heart rate abnormalities and maternal side effects were similar. Fewer babies in the misoprostol arm were admitted to the special care unit (10 vs 21 in the oxytocin group; aOR 0.463; 95% CI 0.203-1.058; P = 0.068) and there were no neonatal deaths in the misoprostol group, compared with three neonatal deaths in the oxytocin arm. Women's acceptability ratings were high in both study groups. CONCLUSIONS: Following cervical preparation with oral misoprostol and membrane rupture, the use of continuing oral misoprostol for augmentation did not significantly reduce caesarean rates, compared with the use of oxytocin. There were no hyperstimulation or significant adverse events in either arm of the trial.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

INTRODUCTION: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. METHODS AND ANALYSIS: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare. ETHICS AND DISSEMINATION: The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

Introduction: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INSPECT-SR project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare related interventions. Methods and analysis: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: 1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, 2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, 3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in 4) a consensus meeting to select checks to be included in a draft tool and to determine its format, 5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies, and will help patients by protecting them from the influence of false data on their healthcare.

Few randomized trials in preterm birth prevention meet predefined usefulness criteria.

OBJECTIVES: We operationalized a research usefulness tool identified through literature searches and consensus and examined if randomized controlled trials (RCTs) addressing preterm birth prevention met predefined criteria for usefulness. STUDY DESIGN AND SETTING: The usefulness tool included eight criteria combining 13 items. RCTs were evaluated for compliance with each item by multiple assessors (reviewer agreement 95-98%). Proportions of compliances with 95% confidence interval (CI) were calculated and change over time was assessed using â‰§ 2010 as a cutoff. RESULTS: Among 347 selected RCTs, published within 56 preterm birth Cochrane reviews, only 36 (10%, 95% CI = 7-14%) met more than half of the usefulness criteria. Compared to trials before 2010, recent trials used composite or surrogate (less informative) outcomes more often (13% vs. 25%, relative risk 1.91, 95% CI = 1.21-3.00). Only 16 trials reflected real practice (pragmatism) in design (5%, 95% CI = 3-7%), with no improvements over time. No trials reported involvement of mothers to reflect patients' research priorities and outcomes selection. Recent trials were more transparent. CONCLUSION: Few preterm birth prevention RCTs met more than half of the usefulness criteria but most of usefulness criteria are improving after 2010. Use of informative outcomes, patient centeredness, pragmatism and transparency should be key targets for future research planning.

Cohort profile: Improved Pregnancy Outcomes via Early Detection (IMPROvED), an International Multicentre Prospective Cohort.

Background: Improved Pregnancy Outcomes via Early Detection (IMPROvED) is a multi-centre, European phase IIa clinical study. The primary aim of IMPROvED is to enable the assessment and refinement of innovative prototype preeclampsia risk assessment tests based on emerging biomarker technologies. Here we describe IMPROvED's profile and invite researchers to collaborate. Methods: A total of 4,038 low-risk nulliparous singleton pregnancies were recruited from maternity units in Ireland (N=1,501), United Kingdom (N=1,108), The Netherlands (N=810), and Sweden (N=619) between November 2013 to August 2017. Participants were interviewed by a research midwife at ~11 weeks (optional visit), ~15 weeks, ~20 weeks, ~34 weeks' gestation (optional visit), and postpartum (within 72-hours following delivery). Findings to date: Clinical data included information on maternal sociodemographic, medical history, and lifestyle factors collected at ~15 weeks' gestation, and maternal measurements, collected at each study visit. Biobank samples included blood, urine, and hair collected at each study visit throughout pregnancy in all units plus umbilical cord/blood samples collected at birth in Ireland and Sweden. A total of 74.0% (N=2,922) had an uncomplicated pregnancy, 3.1% (N=122) developed preeclampsia, 3.6% (N=143) had a spontaneous preterm birth, and 10.5% (N=416) had a small for gestational age baby. We evaluated a panel of metabolite biomarkers and a panel of protein biomarkers at 15 weeks and 20 weeks' gestation for preeclampsia risk assessment. Their translation into tests with clinical application, as conducted by commercial entities, was hampered by technical issues and changes in test requirements. Work on the panel of proteins was abandoned, while work on the use of metabolite biomarkers for preeclampsia risk assessment is ongoing. Future plans: In accordance with the original goals of the IMPROvED study, the data and biobank are now available for international collaboration to conduct high quality research into the cause and prevention of adverse pregnancy outcomes.

Foetal loss after chorionic villus sampling and amniocentesis in twin pregnancies: A multicentre retrospective cohort study.

OBJECTIVE: We aimed to determine foetal losses for DCDA and MCDA twins following transabdominal CVS or amniocentesis performed <22+0  weeks. METHODS: Retrospective cohort study conducted in the UK and Belgium 01/01/00-01/06/20. Cases with unknown chorionicity, monochorionic complications or complex procedures were excluded. Uncomplicated DCDA and MCDA twins without invasive procedures were identified as controls. We reported foetal losses <24+0  weeks and losses of genetically and structurally normal foetuses. RESULTS: Outcomes were compared for DCDA foetuses; 258 after CVS with 3406 controls, 406 after amniocentesis with 3390 controls plus MCDA foetuses, 98 after CVS with 1124 controls, and 160 after amniocentesis with 1122 controls. There were more losses <24+0  weeks with both procedures in DCDA (CVS RR 5.54 95% CI 3.38-9.08, amniocentesis RR 2.36 95% CI 1.22-4.56) and MCDA twins (CVS RR 5.14 95% CI 2.51-10.54, amniocentesis RR 7.01 95% CI 3.86-12.74). Losses of normal foetuses were comparable to controls (DCDA CVS RR 0.39 95% CI 0.05-2.83, DCDA amniocentesis RR 1.16 95% CI 0.42-3.22, MCDA CVS RR 2.3 95% CI 0.71-7.56, and MCDA amniocentesis RR 1.93 95% CI 0.59-6.38). CONCLUSIONS: This study indicates increased foetal losses for DCDA and MCDA twins following CVS and amniocentesis with uncertain risk to normal foetuses.

Amnioinfusion versus Usual Care in Women with Prelabor Rupture of Membranes in Midtrimester: A Systematic Review and Meta-Analysis of Short- and Long-Term Outcomes.

INTRODUCTION: Midtrimester prelabor rupture of membranes (PROM) between 16 and 24 weeks of gestational age is a major obstetric complication with high rates of perinatal morbidity and mortality. Amnioinfusion has been proposed in women with midtrimester PROM to target oligohydramnios and subsequently enhance pulmonary development and perinatal outcomes. MATERIAL AND METHODS: The purpose of this study was to perform a systematic review and meta-analysis including all randomized clinical trials investigating amnioinfusion versus no intervention in women with PROM between 16+0 and 24+0 weeks of gestational age. Databases Central, Embase, Medline, ClinicalTrials.gov and references of identified articles were searched from inception of database to December 2021. The primary outcome was perinatal mortality. Secondary outcomes included neonatal, maternal, and long-term developmental outcomes as defined in the core outcome set for preterm birth studies. Summary measures were reported as pooled relative risk (RR) or mean difference with corresponding 95% confidence interval (CI). RESULTS: Two studies (112 patients, 56 in the amnioinfusion group and 56 in the no intervention group) were included in this review. Pooled perinatal mortality was 66.1% (37/56) in the amnioinfusion group compared with 71.4% (40/56) in no intervention group (RR 0.92, 95% CI: 0.72-1.19). Other neonatal and maternal core outcomes were similar in both groups, although due to the relatively small number of events and wide CIs, there is a possibility that amnioinfusion can be associated with clinically important benefits and harms. Long-term healthy survival was seen in 35.7% (10/28) of children assessed for follow-up and treated with amnioinfusion versus 28.6% (8/28) after no intervention (RR 1.30, 95% CI: 0.47-3.60, "best case scenario"). CONCLUSIONS: Based on these findings, the benefits of amnioinfusion for midtrimester PROM <24 weeks of gestational age are unproven, and the potential harms remain undetermined.

Robert's uterus (asymmetric septate uterus): a rare congenital Müllerian duct anomaly.

Müllerian anomalies such as Robert's uterus, which was first described by the French gynaecologist Dr Helene Robert in 1969, are rare clinical entities and have been reported in <3% of the female population. Robert's uterus is a rare phenomenon with a relative dearth of reported cases. Affected individuals may present with pelvic pain and dysmenorrhoea that intensifies near menses or acutely, with severe abdominal pain to the emergency department. They are also associated with adverse pregnancy outcomes, abnormal fetal presentation, preterm labour, recurrent pregnancy loss and infertility. Although ultrasound has a role in its initial assessment, MRI is the best modality to further delineate its anatomy. It is typically managed via laparotomy and total horn resection, endometrectomy of the blind cavity or abdominal metroplasty. The authors present the case of a 40-year-old woman at 19+3 weeks gestation with acute onset of left-sided abdominal pain. A transvaginal ultrasound and MRI of the pelvis confirmed a Robert's uterus with a viable pregnancy in the upper left horn. She developed a ruptured horn with significant haemoperitoneum. An emergency laparotomy was performed and a non-viable fetus was evident. Only a few cases of pregnancy in the blind hemicavity have been reported so far. This case also highlights the importance of considering this diagnosis in young females presenting with dysmenorrhoea and normal menstrual flow. It is imperative to render a prompt diagnosis, as minimally invasive procedures may be more effective if detected before the formation of adnexal endometriomas.

Interventions to prevent spontaneous preterm birth in women with singleton pregnancy who are at high risk: systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy of bed rest, cervical cerclage (McDonald, Shirodkar, or unspecified type of cerclage), cervical pessary, fish oils or omega fatty acids, nutritional supplements (zinc), progesterone (intramuscular, oral, or vaginal), prophylactic antibiotics, prophylactic tocolytics, combinations of interventions, placebo or no treatment (control) to prevent spontaneous preterm birth in women with a singleton pregnancy and a history of spontaneous preterm birth or short cervical length. DESIGN: Systematic review with bayesian network meta-analysis. DATA SOURCES: The Cochrane Pregnancy and Childbirth Group's Database of Trials, the Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, relevant journals, conference proceedings, and registries of ongoing trials. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials of pregnant women who are at high risk of spontaneous preterm birth because of a history of spontaneous preterm birth or short cervical length. No language or date restrictions were applied. OUTCOMES: Seven maternal outcomes and 11 fetal outcomes were analysed in line with published core outcomes for preterm birth research. Relative treatment effects (odds ratios and 95% credible intervals) and certainty of evidence are presented for outcomes of preterm birth <34 weeks and perinatal death. RESULTS: Sixty one trials (17 273 pregnant women) contributed data for the analysis of at least one outcome. For preterm birth <34 weeks (40 trials, 13 310 pregnant women) and with placebo or no treatment as the comparator, vaginal progesterone was associated with fewer women with preterm birth <34 weeks (odds ratio 0.50, 95% credible interval 0.34 to 0.70, high certainty of evidence). Shirodkar cerclage showed the largest effect size (0.06, 0.00 to 0.84), but the certainty of evidence was low. 17OHPC (17α-hydroxyprogesterone caproate; 0.68, 0.43 to 1.02, moderate certainty), vaginal pessary (0.65, 0.39 to 1.08, moderate certainty), and fish oil or omega 3 (0.30, 0.06 to 1.23, moderate certainty) might also reduce preterm birth <34 weeks compared with placebo or no treatment. For the fetal outcome of perinatal death (30 trials, 12 119 pregnant women) and with placebo or no treatment as the comparator, vaginal progesterone was the only treatment that showed clear evidence of benefit for this outcome (0.66, 0.44 to 0.97, moderate certainty). 17OHPC (0.78, 0.50 to 1.21, moderate certainty), McDonald cerclage (0.59, 0.33 to 1.03, moderate certainty), and unspecified cerclage (0.77, 0.53 to 1.11, moderate certainty) might reduce perinatal death rates, but credible intervals could not exclude the possibility of harm. Only progesterone treatments are associated with reduction in neonatal respiratory distress syndrome, neonatal sepsis, necrotising enterocolitis, and admission to neonatal intensive care unit compared with controls. CONCLUSION: Vaginal progesterone should be considered the preventative treatment of choice for women with singleton pregnancy identified to be at risk of spontaneous preterm birth because of a history of spontaneous preterm birth or short cervical length. Future randomised controlled trials should use vaginal progesterone as a comparator to identify better treatments or combination treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020169006.

Genome and transcriptome profiling of spontaneous preterm birth phenotypes.

Preterm birth (PTB) occurs before 37 weeks of gestation. Risk factors include genetics and infection/inflammation. Different mechanisms have been reported for spontaneous preterm birth (SPTB) and preterm birth following preterm premature rupture of membranes (PPROM). This study aimed to identify early pregnancy biomarkers of SPTB and PPROM from the maternal genome and transcriptome. Pregnant women were recruited at the Liverpool Women's Hospital. Pregnancy outcomes were categorised as SPTB, PPROM (≤ 34 weeks gestation, n = 53), high-risk term (HTERM, ≥ 37 weeks, n = 126) or low-risk (no history of SPTB/PPROM) term (LTERM, ≥ 39 weeks, n = 188). Blood samples were collected at 16 and 20 weeks gestation from which, genome (UK Biobank Axiom array) and transcriptome (Clariom D Human assay) data were acquired. PLINK and R were used to perform genetic association and differential expression analyses and expression quantitative trait loci (eQTL) mapping. Several significant molecular signatures were identified across the analyses in preterm cases. Genome-wide significant SNP rs14675645 (ASTN1) was associated with SPTB whereas microRNA-142 transcript and PPARG1-FOXP3 gene set were associated with PPROM at week 20 of gestation and is related to inflammation and immune response. This study has determined genomic and transcriptomic candidate biomarkers of SPTB and PPROM that require validation in diverse populations.

Maternal selenium levels and whole genome screen in recurrent spontaneous preterm birth population: A nested case control study.

OBJECTIVE: To establish if low maternal selenium (Se) was associated with sPTB in women with recurrent sPTB and identify genetic link with maternal Se levels. DESIGN: Nested case-control study. SETTING: Tertiary Maternity Hospital. POPULATION: Plasma and whole blood from pregnant women with history of early sPTB/PPROM < 34+0 and European ancestry were obtained at 20 weeks (range 15-24 weeks). 'Cases' were recurrent PTB/PPROM < 34+0 weeks and term (≥37+0) deliveries were classified as 'high-risk controls.' Women with previous term births and index birth ≥ 39 weeks were 'low-risk controls'. METHODS: Maternal plasma Se measured by ICP-MS was used as a continuous phenotype in a GWAS analysis. Se was added to a logistic regression model using PTB predictor variables. MAIN OUTCOME MEASURES: Maternal Se concentration, recurrent early sPTB/PPROM. RESULTS: 53/177 high-risk women had a recurrent sPTB/PPROM < 34+0weeks and were 2.7 times more likely to have a Se level < 83.3 ppm at 20weeks of pregnancy compared with low-risk term controls (n = 179), (RR 2.7, 95%CI 1.5-4.8; p = .001). One SNP from a non-coding region (FOXN3 intron variant, rs55793422) reached genome-wide significance level (p = 3.73E-08). Targeted analysis of Se gene variant did not show difference between preterm and term births. (χ2 test, OR = 0.95; 95%CI = 0.59-1.56; p = 0.82). When Se levels were added to a clinical prediction model, only an additional 5% of cases (n = 3) and 0.6% (n = 1) of controls were correctly identified. CONCLUSIONS: Low plasma Se is associated with sPTB risk but is not sufficiently predictive at individual patient level. We did not find a genetic association between maternal Se levels and Se-related genes.

The Induction with Foley OR Misoprostol (INFORM) Study dataset. A dataset of 602 women with hypertensive disease in pregnancy, in India, randomised to either Foley catheter or oral misoprostol for induction of labour.

OBJECTIVES: Induction of labour (IOL), or starting labour artificially, can be a lifesaving intervention for pregnant women and their babies, and rates are rising significantly globally. As rates increase, it becomes increasingly important to fully evaluate all available data, especially that from low income settings where the potential benefits and harms are greater. The goal of this paper is to describe the datasets collected as part of the Induction with Foley OR Misoprostol (INFORM) Study, a randomised trial comparing two of the recommended methods of cervical ripening for labour induction, oral misoprostol and Foley catheter, in women being induced for hypertension in pregnancy, at two sites in India during 2013-15. DATA DESCRIPTION: This dataset includes comprehensive data on 602 women who underwent IOL for hypertensive disorders in pregnancy. Women were randomly assigned to cervical ripening with oral misoprostol or a transcervical Foley catheter in two government hospitals in India. The main dataset has 367 variables including monitoring during the induction of labour, medications administered, timing and mode of delivery, measures of neonatal morbidity and mortality, maternal mortality and morbidity, maternal satisfaction and health economic data. The dataset is anonymised and available on ReShare.

Metabolic profiling of maternal serum of women at high-risk of spontaneous preterm birth using NMR and MGWAS approach.

Preterm birth (PTB) is a leading global cause of infant mortality. Risk factors include genetics, lifestyle choices and infection. Understanding the mechanism of PTB could aid the development of novel approaches to prevent PTB. This study aimed to investigate the metabolic biomarkers of PTB in early pregnancy and the association of significant metabolites with participant genotypes. Maternal sera collected at 16 and 20 weeks of gestation, from women who previously experienced PTB (high-risk) and women who did not (low-risk controls), were analysed using 1H nuclear magnetic resonance (NMR) metabolomics and genome-wide screening microarray. ANOVA and probabilistic neural network (PNN) modelling were performed on the spectral bins. Metabolomics genome-wide association (MGWAS) of the spectral bins and genotype data from the same participants was applied to determine potential metabolite-gene pathways. Phenylalanine, acetate and lactate metabolite differences between PTB cases and controls were obtained by ANOVA and PNN showed strong prediction at week 20 (AUC = 0.89). MGWAS identified several metabolite bins with strong genetic associations. Cis-eQTL analysis highlighted TRAF1 (involved in the inflammatory pathway) local to a non-coding SNP associated with lactate at week 20 of gestation. MGWAS of a well-defined cohort of participants highlighted a lactate-TRAF1 relationship that could potentially contribute to PTB.