Preterm prelabour rupture of membranes before 23 weeks' gestation: prospective observational study.

Objective: To describe perinatal and maternal outcomes of preterm prelabour rupture of membranes (PPROM) before 23 weeks' gestation in a national cohort. Design: Prospective observational study. Setting: National population based cohort study with the UK Obstetric Surveillance System (UKOSS), a research infrastructure of all 194 obstetric units in the UK, 1 September 2019 to 28 February 2021. Participants: 326 women with singleton and 38 with multiple pregnancies with PPROM between 16+0 and 22+6 weeks+days' gestation. Main outcome measures: Perinatal outcomes of live birth, survival to discharge from hospital, and severe morbidity, defined as intraventricular haemorrhage grade 3 or 4, or requiring supplemental oxygen at 36 weeks' postmenstrual age, or both. Maternal outcomes were surgery for removal of the placenta, sepsis, admission to an intensive treatment unit, and death. Clinical data included rates of termination of pregnancy for medical reasons. Results: Perinatal outcomes were calculated with all terminations of pregnancy for medical reasons excluded, and a worst-best range was calculated assuming that all terminations for medical reasons and those with missing data would have died (minimum value) or all would be liveborn (maximum value). For singleton pregnancies, the live birth rate was 44% (98/223), range 30-62% (98/326-201/326), perinatal survival to discharge from hospital was 26% (54/207), range 17-53% (54/326-173/326), and 18% (38/207), range 12-48% (38/326-157/326) of babies survived without severe morbidity. The rate of maternal sepsis was 12% (39/326) in singleton and 29% (11/38) in multiple pregnancies (P=0.004). Surgery for removal of the placenta was needed in 20% (65/326) and 16% (6/38) of singleton and twin pregnancies, respectively. Five women became severely unwell with sepsis; two died and another three required care in the intensive treatment unit. Conclusions: In this study, 26% of women who had very early PPROM with expectant management had babies that survived to discharge from hospital. Morbidity and mortality rates were high for both mothers and neonates. Maternal sepsis is a considerable risk that needs more research. These data should be used in counselling families with PPROM before 23 weeks' gestation, and currently available guidelines should be updated accordingly.

Association of maternal prenatal copper concentration with gestational duration and preterm birth: a multicountry meta-analysis.

BACKGROUND: Copper (Cu), an essential trace mineral regulating multiple actions of inflammation and oxidative stress, has been implicated in risk for preterm birth (PTB). OBJECTIVES: This study aimed to determine the association of maternal Cu concentration during pregnancy with PTB risk and gestational duration in a large multicohort study including diverse populations. METHODS: Maternal plasma or serum samples of 10,449 singleton live births were obtained from 18 geographically diverse study cohorts. Maternal Cu concentrations were determined using inductively coupled plasma mass spectrometry. The associations of maternal Cu with PTB and gestational duration were analyzed using logistic and linear regressions for each cohort. The estimates were then combined using meta-analysis. Associations between maternal Cu and acute-phase reactants (APRs) and infection status were analyzed in 1239 samples from the Malawi cohort. RESULTS: The maternal prenatal Cu concentration in our study samples followed normal distribution with mean of 1.92 µg/mL and standard deviation of 0.43 µg/mL, and Cu concentrations increased with gestational age up to 20 wk. The random-effect meta-analysis across 18 cohorts revealed that 1 µg/mL increase in maternal Cu concentration was associated with higher risk of PTB with odds ratio of 1.30 (95% confidence interval [CI]: 1.08, 1.57) and shorter gestational duration of 1.64 d (95% CI: 0.56, 2.73). In the Malawi cohort, higher maternal Cu concentration, concentrations of multiple APRs, and infections (malaria and HIV) were correlated and associated with greater risk of PTB and shorter gestational duration. CONCLUSIONS: Our study supports robust negative association between maternal Cu and gestational duration and positive association with risk for PTB. Cu concentration was strongly correlated with APRs and infection status suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB. Therefore, maternal Cu could be used as potential marker of integrated inflammatory pathways during pregnancy and risk for PTB.

Which events are experienced as traumatic by obstetricians and gynaecologists, and why? A qualitative analysis from a cross-sectional survey and in-depth interviews.

OBJECTIVES: To explore the events perceived as traumatic by obstetricians and gynaecologists (O&G), and to examine factors contributing to the perception of trauma. DESIGN: Mixed methods: cross-sectional survey and in-depth interviews. SAMPLE AND SETTING: Fellows, members and trainees of the Royal College of Obstetricians and Gynaecologists (RCOG). METHODS: An online survey was distributed to 6300 fellows (May-June 2017), members and trainees of RCOG; 1095 (17%) completed surveys were returned. Of these, 728 (66%) reported work-related trauma experience, with 525 providing a brief description of an event. Forty-three participants with trauma experience were purposively sampled and completed an in-depth interview (October 2017-March 2018), which were analysed using Template Analysis. Information regarding the scale and impact of trauma experience is presented elsewhere. The present analysis provides new information describing the events and perceptions of why events were traumatic. PRIMARY OUTCOME MEASURES: The nature of traumatic events in this clinical setting, taken from survey descriptions of perceived traumatic events and information from the in-depth interviews. RESULTS: Events perceived as traumatic by O&G were similar between consultants, trainees and other RCOG members no longer working in O&G. Maternal or neonatal death/stillbirth, haemorrhage and events involving a difficult delivery were most frequently reported. Sudden and unpredictable events, perceived preventability, acute sensory experiences and high emotionality contributed to trauma perception. Respondents' trauma was compounded by an absence of support, involvement in investigation procedures and pre-existing relationships with a recipient of care. CONCLUSIONS: Identification of events most likely to be perceived as traumatic, and wider circumstances contributing to the perception of trauma, provide a basis on which to focus preventative and supportive strategies for O&G. Training on the nature of traumatic events, self-help for early stress responses, processing support and rapid access to trauma-focused psychological input (where required) are needed.

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.

Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis.

BACKGROUND: Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations. METHODS: Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis. FINDINGS: In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi. INTERPRETATION: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.

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.

Plasma long-chain omega-3 fatty acid status and risk of recurrent early spontaneous preterm birth: a prospective observational study.

INTRODUCTION: A 2018 Cochrane review found that omega-3 supplementation in pregnancy was associated with a risk reduction of early preterm birth of 0.58; prompting calls for universal supplementation. Recent analysis suggests the benefit may be confined to women with a low baseline omega-3 fatty acid status. However, the contemporary omega-3 fatty acid status of pregnant women in the UK is largely unknown. This is particularly pertinent for women with a previous preterm birth, in whom a small relative risk reduction would have a larger reduction of absolute risk. This study aimed to assess the omega-3 fatty acid status of a UK pregnant population and determine the association between the long-chain omega-3 fatty acids and recurrent spontaneous early preterm birth. MATERIAL AND METHODS: A total of 283 high-risk women with previous early preterm birth were recruited to the prospective observational study in Liverpool, UK. Additionally, 96 pregnant women with previous term births and birth ≥39+0  weeks in the index pregnancy provided a low-risk population sample. Within the high-risk group we assessed the odds ratio of recurrent early preterm birth compared with birth at ≥37+0  weeks of gestation according to plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) at 15-22 weeks of gestation. RESULTS: Our participants had low EPA+DHA; 62% (143/229) of women with previous preterm birth and 69% (68/96) of the population sample had levels within the lowest two quintiles of a previously published pregnancy cohort. We found no association between long-chain omega-3 status and recurrent early preterm birth (n = 51). The crude odds ratio of a recurrent event was 0.91 (95% CI 0.38-2.15, p = 0.83) for women in the lowest, compared with the highest three quintiles of EPA+DHA. CONCLUSIONS: In the majority of our participants, levels of long-chain omega-3 were low; within the range that may benefit from supplementation. However, levels showed no association with risk of recurrent early spontaneous preterm birth. This could be because our population levels were too low to show benefit in being omega-3 "replete"; or else omega-3 levels may be of lesser importance in recurrent early preterm birth.

Controversies in the prevention of spontaneous preterm birth in asymptomatic women: an evidence summary and expert opinion.

Preterm birth prevention is multifaceted and produces many nuanced questions. This review addresses six important clinical questions about preterm birth prevention as voted for by members of the UK Preterm Clinical Network. The questions cover the following areas: preterm birth prevention in 'low-risk' populations; screening for asymptomatic genital tract infection in women at high risk of preterm birth; cervical length screening with cerclage or vaginal pessary in situ; cervical shortening whilst using progesterone; use of vaginal progesterone in combination with cervical cerclage; and optimal advice about intercourse for women at high risk of preterm birth.

Cervical pessary for short cervix in high risk pregnant women: 5 years experience in a single centre.

Purpose: To describe single center clinical experience with cervical pessary used for high-risk pregnant women who also had short cervix. We have focused on the techniques to optimize efficacy and minimize the risk of complications and side effects related to pessary insertion, removal, and pregnancy management.Methods: This is an audit from specialist preterm birth prevention clinic in Liverpool Women's Hospital, United Kingdom for the period between January 2013 and December 2017. We also conducted postal survey in November 2015 to evaluate women's experience with vaginal pessary.Results: Out of 235 women who were treated for short cervix, 129 (55%) had cervical pessary as a first line treatment. Overall, 50% of treated women reached term. 17 women (13%) needed additional treatment, 9 women had pessary reinserted (7%), and 53 (41%) had pessary removed before 36 weeks, mainly due to ruptured membranes. Significant vaginal discharge and pelvic discomfort were reported by 14 and 7% women, respectively. 89% of treated women would recommend the pessary treatment to others.Conclusions: Whilst the cervical pessary continues to be evaluated in clinical trials, our experience suggests that pessary is quite easy to insert and remove and is well tolerated by the women.

Activity levels in mothers and their preschool children.

OBJECTIVES: To investigate the association between objectively measured maternal and preschool-aged children's physical activity, determine how this association differs by demographic and temporal factors, and identify factors associated with maternal activity levels. METHODS: In the UK Southampton Women's Survey, physical activity levels of 554 4-year-olds and their mothers were measured concurrently by using accelerometry for ≤7 days. Two-level mixed-effects linear regression was used to model the association between maternal and children's minutes spent sedentary, in light (LPA) and moderate-to-vigorous physical activity (MVPA). Linear regression was used to investigate correlates of maternal activity. RESULTS: Mother-child daily activity levels were positively associated at all activity intensities (sedentary, LPA, and MVPA; all P < .001). The association for sedentary time was stronger for normal-weight children (versus those who were overweight/obese), and those attending preschool part-time (versus full-time). The mother-child association for LPA differed by maternal education and was stronger at the weekend (versus weekdays). The opposite was true for MVPA. Sedentary time and MVPA were most strongly associated in mornings, with LPA most strongly associated in the evenings. Maternal BMI, age leaving school, number and age of children at home, and working hours were independently associated with maternal daily sedentary time and LPA. CONCLUSIONS: Physical activity levels in mothers and their 4-year-old children are directly associated, with associations at different activity intensities influenced by temporal and demographic factors. Influences on maternal physical activity levels also differ by activity intensity. Providing targeted interventions for mothers of young children may increase both groups' activity.

Regulation of placental calcium transport and offspring bone health.

Osteoporosis causes considerable morbidity and mortality in later life, and the risk of the disease is strongly determined by peak bone mass, which is achieved in early adulthood. Poor intrauterine and early childhood growth are associated with reduced peak bone mass, and increased risk of osteoporotic fracture in older age. In this review we describe the regulatory aspects of intrauterine bone development, and then summarize the evidence relating early growth to later fracture risk. Physiological systems include vitamin D, parathyroid hormone, leptin, GH/IGF-1; finally the potential role of epigenetic processes in the underlying mechanisms will be explored. Thus factors such as maternal lifestyle, diet, body build, physical activity, and vitamin D status in pregnancy all appear to influence offspring bone mineral accrual. These data demonstrate a likely interaction between environmental factors and gene expression, a phenomenon ubiquitous in the natural world (developmental plasticity), as the potential key process. Intervention studies are now required to test the hypotheses generated by these epidemiological and physiological findings, to inform potential novel public health interventions aimed at improving childhood bone health and reducing the burden of osteoporotic fracture in future generations.

Maternal diet, behaviour and offspring skeletal health.

Osteoporotic fracture has a major impact upon health, both in terms of acute and long term disability and economic cost. Peak bone mass, achieved in early adulthood, is a major determinant of osteoporosis risk in later life. Poor early growth predicts reduced bone mass, and so risk of fracture in later life. Maternal lifestyle, body build and 25(OH) vitamin D status predict offspring bone mass. Recent work has suggested epigenetic mechanisms as key to these observations. This review will explore the role of the early environment in determining later osteoporotic fracture risk.

Nondrug treatments for psychogenic nonepileptic seizures: what's the evidence?

OBJECTIVE: The purpose of this Cochrane Review was to establish the evidence base for treatment of psychogenic nonepileptic seizures. METHODS: Six hundred eight references were identified using a search strategy designed with the support of the Cochrane Review Epilepsy Group library. The search employed Medline and PsychInfo, and included hand searches of relevant journals (Seizure, Epilepsia, Epilepsy &Behavior, Epilepsy Research). RESULTS: Three studies were found that met the inclusion criteria; two used hypnosis and one used paradoxical therapy. None included detailed reports of improved seizure frequency or quality of life, although reduction in seizure frequency was mentioned. All three studies concluded that the intervention used was beneficial in the treatment of psychogenic nonepileptic seizures. CONCLUSIONS: The limited number of studies and poor methodology preclude these results from being generalizable. There is a need for well-designed clinical trials to identify the most suitable treatments for this population.