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

Effect of QUiPP prediction algorithm on treatment decisions in women with a previous preterm birth: a prospective cohort study.

OBJECTIVE:The QUiPP algorithm combines cervical length, quantitative fetal fibronectin (qfFN) and medical history to quantify risk of preterm birth. We assessed the utility of QUiPP to inform preterm birth prevention treatment decisions. DESIGN:A prospective cohort study with a subsequent impact assessment using the QUiPP risk of birth before 34 weeks gestation. SETTING:A UK TERTIARY REFERRAL HOSPITAL: SAMPLE: 119 women with previous spontaneous preterm birth (sPTB) or preterm premature rupture of membranes (PPROM) before 34 weeks gestation. METHODS:Cervical length and qfFN were measured at 19+0 - 23+0 weeks gestation. Clinical management was based on history and cervical length. After birth, clinicians were unblinded to qfFN results and QUiPP analysis was undertaken. MAIN OUTCOME MEASURES:Predictive statistics of QUiPP algorithm using 10% risk of sPTB before 34+0 weeks as treatment threshold. RESULTS:Fifteen of 119 women (13%) had PPROM or sPTB before 34 weeks. Of these 53% (8/15) had QUiPP risk of sPTB before 34+0 weeks above 10%. Applying this treatment threshold in practice would have doubled our treatment rate (20% vs 42%). QUIPP threshold of 10% had positive likelihood ratio (LR) of 1.3 (95% CI 0.76-2.18), and negative LR of 0.8 (95% CI 0.45-1.40) for predicting sPTB before 34+0 weeks. CONCLUSIONS:Use of the QUiPP algorithm in this population may lead to substantial increase in interventions without evidence that currently available treatment options are beneficial for this particular group. This article is protected by copyright. All rights reserved

Inequalities and stillbirth in the UK: a meta-narrative review

Objective To review what is known about the relationship between stillbirth and inequalities from different disciplinary perspectives to inform stillbirth prevention strategies. Design Systematic review using the meta-narrative method. Setting Studies undertaken in the UK. Data sources Scoping phase: experts in field, exploratory electronic searches and handsearching. Systematic searches phase: Nine databases with no geographical or date restrictions. Non-English language studies were excluded. Study selection Any investigation of stillbirth and inequalities with a UK component. Data extraction and synthesis Three authors extracted data and assessed study quality. Data were summarised, tabulated and presented graphically before synthesis of the unfolding storyline by research tradition; and then of the commonalities, differences and interplays between narratives into resultant summary meta-themes. Results Fifty-four sources from nine distinctive research traditions were included. The evidence of associations between social inequalities and stillbirth spanned 70 years. Across research traditions, there was recurrent evidence of the social gradient remaining constant or increasing, fuelling repeated calls for action (meta-theme 1: something must be done). There was less evidence of an effective response to these calls. Data pertaining to socioeconomic, area and ethnic disparities were routinely collected, but not consistently recorded, monitored or reported in relation to stillbirth (meta-theme 2: problems of precision). Many studies stressed the interplay of socioeconomic status, deprivation or ethnicity with aggregated factors including heritable, structural, environmental and lifestyle factors (meta-theme 3: moving from associations towards intersectionality and intervention(s)). No intervention studies were identified. Conclusion Research investigating inequalities and stillbirth in the UK is underdeveloped. This is despite repeated evidence of an association between stillbirth risk and poverty, and stillbirth risk, poverty and ethnicity. A specific research forum is required to lead the development of research and policy in this area, which can harness the multiple relevant research perspectives and address the intersections between different policy areas. PROSPERO registration number CRD42017079228

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 UK pregnant omega-3 fatty acid status 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 obstervational 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 to birth at ≥37⁺⁰ weeks gestation according to plasma eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) at 15-22 weeks 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 to 2.15, p=0.83) for women in the lowest, compared to 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.Laura Goodfellow, Angharad Care, Jane Harrold, Andrew Sharp, Jelena Ivandic, Borna Poljak ... et al

Amnioinfusion in preterm premature rupture of membranes (AMIPROM): a randomised controlled trial of amnioinfusion versus expectant management in very early preterm premature rupture of membranes – a pilot study

BACKGROUND: Fetal survival is severely compromised when the amniotic membrane ruptures between 16 and 24 weeks of pregnancy. Reduced amniotic fluid levels are associated with poor lung development, whereas adequate levels lead to better perinatal outcomes. Restoring amniotic fluid by means of ultrasound-guided amnioinfusion (AI) may be of benefit in improving perinatal and long-term outcomes in children of pregnancies with this condition. OBJECTIVE: The AI in preterm premature rupture of membranes (AMIPROM) pilot study was conducted to assess the feasibility of recruitment, the methods for conduct and the retention through to long-term follow-up of participants with very early rupture of amniotic membranes (between 16 and 24 weeks of pregnancy). It was also performed to assess outcomes and collect data to inform a larger, more definitive, clinical trial. DESIGN: A prospective, non-blinded randomised controlled trial. A computer-generated random sequence using a 1 : 1 ratio was used. Randomisation was stratified for pregnancies in which the amniotic membrane ruptured between 16(+0) and 19(+6) weeks' gestation and 20(+0) and 24(+0) weeks' gestation. The randomisation sequence was generated in blocks of four. Telephone randomisation and intention-to-treat analysis were used. SETTING: Four UK hospital-based fetal medicine units - Liverpool Women's NHS Trust, St. Mary's Hospital, Manchester, Birmingham Women's NHS Foundation Trust and Wirral University Hospitals Trust. PARTICIPANTS: Women with confirmed preterm prelabour rupture of membranes between 16(+0) and 24(+0) weeks' gestation. Women with multiple pregnancies, resultant fetal abnormalities or obstetric indication for immediate delivery were excluded. INTERVENTIONS: Participants were randomly allocated to either serial weekly transabdominal AI or expectant management (Exp) until 37 weeks of pregnancy, if the deepest pool of amniotic fluid was < 2 cm. MAIN OUTCOME MEASURE: Short-term maternal, pregnancy and neonatal outcomes and long-term outcomes for the child were studied. Long-term respiratory morbidity was assessed using validated respiratory questionnaires at 6, 12 and 18 months of age and infant lung function was assessed at approximately 12 months of age. Neurodevelopment was assessed using Bayley's Scale of Infant Development II at a corrected age of 2 years. RESULTS: Fifty-eight women were randomised and two were excluded from the analysis owing to termination of pregnancy for lethal anomaly, leaving 56 participants (28 serial AI, 28 Exp) recruited between 2002 and 2009, with annual recruitment rates varying between 2 and 14. Recruitment to the study improved significantly from 2007 with National Institute for Health Research (NIHR) funding. There was no significant difference in perinatal mortality [19/28 vs. 19/28; relative risk (RR) 1.0; 95% confidence interval (CI) 0.70 to 1.43], maternal morbidity or neonatal morbidity. The overall chance of surviving without long-term respiratory or neurodevelopmental disability is 4/56 (7.1%): 4/28 (14.3%) in the AI arm and 0/28 in the expectant arm (0%) (RR 9.0; 95% CI 0.51 to 159.70). CONCLUSIONS: This pilot study found no major differences in maternal, perinatal or pregnancy outcomes. The study was not designed to show a difference between the arms and the number of survivors was too small to draw any conclusions about long-term outcomes. It does signal, however, that a larger, definitive, study to evaluate AI for improvement in healthy survival is indicated. The results suggest that, with appropriate funding, such a study is feasible. A larger, definitive, study with full health economic analysis and patient perspective assessment is required to show whether AI can improve the healthy survivor rate

Vaginal bacterial load in the second trimester is associated with early preterm birth recurrence: a nested case-control study

Objective To assess the association between vaginal microbiome (VMB) composition and recurrent early spontaneous preterm birth (sPTB)/preterm prelabour rupture of membranes (PPROM). Design Nested case-control study. Setting UK tertiary referral hospital. Sample High-risk women with previous sPTB/PPROM Methods Vaginal swabs collected between 15-22 weeks gestation were analysed by 16S rRNA gene sequencing and 16S quantitative PCR. Main outcome measure Recurrent early sPTB/PPROM. Results 28/109 high-risk women had anaerobic vaginal dysbiosis, with the remainder dominated by lactobacilli ( L. iners 36/109, L. crispatus 23/109, or other 22/109). VMB type, diversity, and stability were not associated with recurrence. Women with a recurrence, compared to those without, had a higher median vaginal bacterial load (8.64 vs. 7.89 log 10 cells/μl, adjusted odds ratio (aOR)=1.90, 95% confidence interval (CI)=1.01-3.56, p=0.047) and estimated Lactobacillus concentration (8.59 vs. 7.48 log 10 cells/μl, aOR=2.35, CI=1.20-4.61, p=0.013). A higher recurrence risk was associated with higher median bacterial loads for each VMB type after stratification, although statistical significance was reached only for L. iners -domination (aOR=3.44, CI=1.06-11.15, p=0.040). Women with anaerobic dysbiosis or L. iners -domination had a higher median vaginal bacterial load than women with a VMB dominated by L. crispatus or other lactobacilli (8.54, 7.96, 7.63, and 7.53 log 10 cells/μl, respectively). Conclusions Vaginal bacterial load is associated with early sPTB/PPROM recurrence. Domination by lactobacilli other than L. iners may protect women from developing high bacterial loads. Future PTB studies should quantify vaginal bacteria and yeasts. Funding Wellbeing of Women, London, UK Tweetable abstract Increased vaginal bacterial load in the second trimester may be associated with recurrent early spontaneous preterm birth

Consortium for the Study of Pregnancy Treatments (Co-OPT): An international birth cohort to study the effects of antenatal corticosteroids

BACKGROUND: Antenatal corticosteroids (ACS) are widely prescribed to improve outcomes following preterm birth. Significant knowledge gaps surround their safety, long-term effects, optimal timing and dosage. Almost half of women given ACS give birth outside the "therapeutic window" and have not delivered over 7 days later. Overtreatment with ACS is a concern, as evidence accumulates of risks of unnecessary ACS exposure. METHODS: The Consortium for the Study of Pregnancy Treatments (Co-OPT) was established to address research questions surrounding safety of medications in pregnancy. We created an international birth cohort containing information on ACS exposure and pregnancy and neonatal outcomes by combining data from four national/provincial birth registers and one hospital database, and follow-up through linked population-level data from death registers and electronic health records. RESULTS AND DISCUSSION: The Co-OPT ACS cohort contains 2.28 million pregnancies and babies, born in Finland, Iceland, Israel, Canada and Scotland, between 1990 and 2019. Births from 22 to 45 weeks' gestation were included; 92.9% were at term (≥ 37 completed weeks). 3.6% of babies were exposed to ACS (67.0% and 77.9% of singleton and multiple births before 34 weeks, respectively). Rates of ACS exposure increased across the study period. Of all ACS-exposed babies, 26.8% were born at term. Longitudinal childhood data were available for 1.64 million live births. Follow-up includes diagnoses of a range of physical and mental disorders from the Finnish Hospital Register, diagnoses of mental, behavioural, and neurodevelopmental disorders from the Icelandic Patient Registers, and preschool reviews from the Scottish Child Health Surveillance Programme. The Co-OPT ACS cohort is the largest international birth cohort to date with data on ACS exposure and maternal, perinatal and childhood outcomes. Its large scale will enable assessment of important rare outcomes such as perinatal mortality, and comprehensive evaluation of the short- and long-term safety and efficacy of ACS

Consortium for the Study of Pregnancy Treatments (Co-OPT) : An international birth cohort to study the effects of antenatal corticosteroids

Acknowledgments We are grateful to the Co-OPT collaborators from Finland, Iceland, Israel, Nova Scotia, and Scotland, who have provided high-quality patient data, without which the Co-OPT ACS cohort would not have been possible. We acknowledge Public Health Scotland for providing us with a secure data analytical platform in which to undertake this research and are particularly grateful to Anna Schneider who has been the data controller for this project. Co-OPT collaborators: Karel Allegaert (Belgium), Jasper Been (Netherlands), David Burgner (Australia), Sohinee Bhattacharya (UK), Kate Duhig (UK), Kristjana Einarsdóttir (Iceland), John Fahey (Canada), Lani Florian (UK), Abigail Fraser (UK), Mika Gissler (Finland), Cynthia Gyamfi-Bannerman (USA), Bo Jacobsson (Sweden), Eyal Krispin (Israel), Stefan Kuhle (Canada), Marius Lahti-Pulkkinen (Finland), Jessica Miller (Australia), Ben Mol (Australia), Sarah Murray (UK), Jane Norman (UK), Lars Henning Pedersen (Denmark), Richard Riley (UK), Devender Roberts (UK), Ewoud Schuit (Netherlands), Aziz Sheikh (UK), Ting Shi (UK), Joshua Vogel (Australia), Rachael Wood (UK), John Wright (UK), Helga Zoega (Australia). Funding Information: The Co-OPT ACS study is funded through a Wellcome Trust Clinical Career Development Fellowship grant (Funding Reference number 209560/Z/17) awarded to Sarah J Stock. The funders had no role in study design, data collection, data analysis, decision to publish, or preparation of the manuscript. The Sponsor of the study is the University of Edinburgh (www.ed.ac. uk), Sponsor reference AC19119. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.Peer reviewedPublisher PD

Vicariance and dispersal in southern hemisphere freshwater fish clades: a palaeontological perspective

Widespread fish clades that occur mainly or exclusively in fresh water represent a key target of biogeographical investigation due to limited potential for crossing marine barriers. Timescales for the origin and diversification of these groups are crucial tests of vicariant scenarios in which continental break‐ups shaped modern geographic distributions. Evolutionary chronologies are commonly estimated through node‐based palaeontological calibration of molecular phylogenies, but this approach ignores most of the temporal information encoded in the known fossil record of a given taxon. Here, we review the fossil record of freshwater fish clades with a distribution encompassing disjunct landmasses in the southern hemisphere. Palaeontologically derived temporal and geographic data were used to infer the plausible biogeographic processes that shaped the distribution of these clades. For seven extant clades with a relatively well‐known fossil record, we used the stratigraphic distribution of their fossils to estimate confidence intervals on their times of origin. To do this, we employed a Bayesian framework that considers non‐uniform preservation potential of freshwater fish fossils through time, as well as uncertainty in the absolute age of fossil horizons. We provide the following estimates for the origin times of these clades: Lepidosireniformes [125–95 million years ago (Ma)]; total‐group Osteoglossomorpha (207–167 Ma); Characiformes (120–95 Ma; a younger estimate of 97–75 Ma when controversial Cenomanian fossils are excluded); Galaxiidae (235–21 Ma); Cyprinodontiformes (80–67 Ma); Channidae (79–43 Ma); Percichthyidae (127–69 Ma). These dates are mostly congruent with published molecular timetree estimates, despite the use of semi‐independent data. Our reassessment of the biogeographic history of southern hemisphere freshwater fishes shows that long‐distance dispersals and regional extinctions can confound and erode pre‐existing vicariance‐driven patterns. It is probable that disjunct distributions in many extant groups result from complex biogeographic processes that took place during the Late Cretaceous and Cenozoic. Although long‐distance dispersals likely shaped the distributions of several freshwater fish clades, their exact mechanisms and their impact on broader macroevolutionary and ecological dynamics are still unclear and require further investigation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148368/1/brv12473_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148368/2/brv12473.pd