Publications by authors named "Jim G Thornton"

75 Publications

An investigation of seven other publications by the first author of a retracted paper due to doubts about data integrity.

Eur J Obstet Gynecol Reprod Biol 2021 Apr 18. Epub 2021 Apr 18.

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia. Electronic address:

Background: In 2019, a randomized controlled trial (RCT) authored by Dr. Ismail was retracted due to concerns about data integrity. Since there are no policies in place to investigate other publications of authors of retracted studies, we investigated Dr. Ismail's other trials.

Methods: We searched for RCTs authored by Dr. Ismail. We made pairwise comparisons of values in baseline and outcome tables between trials. We assessed whether the distributions of baseline characteristics were compatible with properly conducted randomization, using Monte Carlo simulations and the Kolmogorov-Smirnov test. We read the publications carefully for unusual features.

Results: Dr. Ismail was author in eight published and one unpublished trial. In three of his first author studies we found multiple identical values in the baseline and/or outcome tables from different trials. At least some of the trials were unlikely to have followed a proper randomization process. There were a number of other unusual features in the papers we reviewed.

Conclusions: It is probable that other trials published by Dr. Ismail contain questionable data. We call for a thorough investigation of the original trial data and related official documents. Our exercise suggests that the practice to assess research integrity should include all publications of authors with retracted fabricated articles.
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http://dx.doi.org/10.1016/j.ejogrb.2021.04.018DOI Listing
April 2021

Should all pregnant women be offered testing for group B streptococcus?

BMJ 2021 04 26;373:n882. Epub 2021 Apr 26.

University of Nottingham, Nottingham, UK.

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http://dx.doi.org/10.1136/bmj.n882DOI Listing
April 2021

Fetal umbilical artery Doppler as a tool for universal third trimester screening: A systematic review and meta-analysis of diagnostic test accuracy.

Placenta 2021 Mar 22;108:47-54. Epub 2021 Mar 22.

Department of Obstetrics and Gynaecology, University of Cambridge; NIHR Cambridge Comprehensive Biomedical Research Centre, CB2 2SW, United Kingdom. Electronic address:

The objective of this study was to investigate the accuracy of universal third trimester umbilical artery (UA) Doppler to predict adverse pregnancy outcome at term. We searched Medline, EMBASE, the Cochrane library and ClinicalTrials.gov from inception to October 2020 and we also analyzed previously unpublished data from a prospective cohort study of nulliparous women, the Pregnancy Outcome Prediction (POP) study. We included studies that performed a third-trimester ultrasound scan in unselected, low or mixed risk populations, excluding studies which only included high risk pregnancies. Meta-analysis was performed using the hierarchal summary receiver operating characteristic curve (HSROC) analysis and bivariate logit-normal models. We identified 13 studies (including the POP study) involving 67,764 pregnancies which met our inclusion criteria. The overall quality was variable and only six studies (N = 5777 patients) blinded clinicians to the UA Doppler result. The summary sensitivity and positive likelihood ratio (LR) for small for gestational age (SGA; birthweight <10th centile) were 21.7% (95% CI 13.2-33.6%) and 2.65 (95% CI 1.89-3.72) respectively. The summary positive LR for NICU admission and metabolic acidosis were 1.35 (95% CI 0.93-1.97) and 1.34 (95% CI 0.86-2.08) respectively. The results were similar in the POP study: associations with SGA (positive LR 2.66 [95% CI 2.11-3.36]) and severe SGA (birthweight <3rd centile; positive LR 3.27 [95% CI 2.29-4.68]) but no statistically significant association with neonatal morbidity. We conclude that third trimester UA Doppler has moderate predictive accuracy for small for gestational age but not for indicators of neonatal morbidity in unselected and low risk pregnancies.
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http://dx.doi.org/10.1016/j.placenta.2021.03.011DOI Listing
March 2021

Evaluating the influence of progesterone concentration and time of exposure on in vitro endometrial decidualisation.

Mol Cell Endocrinol 2021 05 11;528:111242. Epub 2021 Mar 11.

Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK. Electronic address:

This study aimed to evaluate the influence of progesterone (concentration and time of exposure) on endometrial decidualisation using an in vitro model cell line: Human Endometrial Stromal Cells (HESCs). HESCs exposed to progesterone (1 and 10 μM) had higher percentages of decidualised cells and higher expression of the decidual marker (Insulin Like Growth Factor Binding Protein 1 (IGFBP1)) compared with those exposed to (0.1 μM). Among those HESCs cultured with 1 μM progesterone for 11 days, the highest rate of morphological differentiation (40-50%) occurred between days 7-9 and IGFBP1 peaked on day 7. The cell-cycle pathway was significantly down-regulated in HESCs exposed to at least 1 μM progesterone regardless of the incubation period. We conclude that exposure to high progesterone concentration for 7-9 days is essential to maximise the process of decidualisation.
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http://dx.doi.org/10.1016/j.mce.2021.111242DOI Listing
May 2021

Universal late pregnancy ultrasound screening to predict adverse outcomes in nulliparous women: a systematic review and cost-effectiveness analysis.

Health Technol Assess 2021 Feb;25(15):1-190

The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Background: Currently, pregnant women are screened using ultrasound to perform gestational aging, typically at around 12 weeks' gestation, and around the middle of pregnancy. Ultrasound scans thereafter are performed for clinical indications only.

Objectives: We sought to assess the case for offering universal late pregnancy ultrasound to all nulliparous women in the UK. The main questions addressed were the diagnostic effectiveness of universal late pregnancy ultrasound to predict adverse outcomes and the cost-effectiveness of either implementing universal ultrasound or conducting further research in this area.

Design: We performed diagnostic test accuracy reviews of five ultrasonic measurements in late pregnancy. We conducted cost-effectiveness and value-of-information analyses of screening for fetal presentation, screening for small for gestational age fetuses and screening for large for gestational age fetuses. Finally, we conducted a survey and a focus group to determine the willingness of women to participate in a future randomised controlled trial.

Data Sources: We searched MEDLINE, EMBASE and the Cochrane Library from inception to June 2019.

Review Methods: The protocol for the review was designed a priori and registered. Eligible studies were identified using keywords, with no restrictions for language or location. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Health economic modelling employed a decision tree analysed via Monte Carlo simulation. Health outcomes were from the fetal perspective and presented as quality-adjusted life-years. Costs were from the perspective of the public sector, defined as NHS England, and the costs of special educational needs. All costs and quality-adjusted life-years were discounted by 3.5% per annum and the reference case time horizon was 20 years.

Results: Umbilical artery Doppler flow velocimetry, cerebroplacental ratio, severe oligohydramnios and borderline oligohydramnios were all either non-predictive or weakly predictive of the risk of neonatal morbidity (summary positive likelihood ratios between 1 and 2) and were all weakly predictive of the risk of delivering a small for gestational age infant (summary positive likelihood ratios between 2 and 4). Suspicion of fetal macrosomia is strongly predictive of the risk of delivering a large infant, but it is only weakly, albeit statistically significantly, predictive of the risk of shoulder dystocia. Very few studies blinded the result of the ultrasound scan and most studies were rated as being at a high risk of bias as a result of treatment paradox, ascertainment bias or iatrogenic harm. Health economic analysis indicated that universal ultrasound for fetal presentation only may be both clinically and economically justified on the basis of existing evidence. Universal ultrasound including fetal biometry was of borderline cost-effectiveness and was sensitive to assumptions. Value-of-information analysis indicated that the parameter that had the largest impact on decision uncertainty was the net difference in cost between an induced delivery and expectant management.

Limitations: The primary literature on the diagnostic effectiveness of ultrasound in late pregnancy is weak. Value-of-information analysis may have underestimated the uncertainty in the literature as it was focused on the internal validity of parameters, which is quantified, whereas the greatest uncertainty may be in the external validity to the research question, which is unquantified.

Conclusions: Universal screening for presentation at term may be justified on the basis of current knowledge. The current literature does not support universal ultrasonic screening for fetal growth disorders.

Future Work: We describe proof-of-principle randomised controlled trials that could better inform the case for screening using ultrasound in late pregnancy.

Study Registration: This study is registered as PROSPERO CRD42017064093.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 15. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958245PMC
February 2021

Haemostatic and thrombo-embolic complications in pregnant women with COVID-19: a systematic review and critical analysis.

BMC Pregnancy Childbirth 2021 Feb 5;21(1):108. Epub 2021 Feb 5.

Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK.

Background: As pregnancy is a physiological prothrombotic state, pregnant women may be at increased risk of developing coagulopathic and/or thromboembolic complications associated with COVID-19.

Methods: Two biomedical databases were searched between September 2019 and June 2020 for case reports and series of pregnant women with a diagnosis of COVID-19 based either on a positive swab or high clinical suspicion where no swab had been performed. Additional registry cases known to the authors were included. Steps were taken to minimise duplicate patients. Information on coagulopathy based on abnormal coagulation test results or clinical evidence of disseminated intravascular coagulation (DIC), and on arterial or venous thrombosis, were extracted using a standard form. If available, detailed laboratory results and information on maternal outcomes were analysed.

Results: One thousand sixty-three women met the inclusion criteria, of which three (0.28, 95% CI 0.0 to 0.6) had arterial and/or venous thrombosis, seven (0.66, 95% CI 0.17 to 1.1) had DIC, and a further three (0.28, 95% CI 0.0 to 0.6) had coagulopathy without meeting the definition of DIC. Five hundred and thirty-seven women (56%) had been reported as having given birth and 426 (40%) as having an ongoing pregnancy. There were 17 (1.6, 95% CI 0.85 to 2.3) maternal deaths in which DIC was reported as a factor in two.

Conclusions: Our data suggests that coagulopathy and thromboembolism are both increased in pregnancies affected by COVID-19. Detection of the former may be useful in the identification of women at risk of deterioration.
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http://dx.doi.org/10.1186/s12884-021-03568-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863033PMC
February 2021

Authors' reply re: Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: a systematic review and critical analysis.

BJOG 2021 03 28;128(4):769. Epub 2020 Dec 28.

Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK.

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http://dx.doi.org/10.1111/1471-0528.16436DOI Listing
March 2021

Perinatal death in a term fetal growth restriction randomized controlled trial: the paradox of prior risk and consent.

Am J Obstet Gynecol MFM 2020 11 24;2(4):100239. Epub 2020 Sep 24.

Leiden University Medical Center, Leiden, the Netherlands.

Background: The disproportionate intrauterine growth intervention trial at term was an intention to treat analysis and compared labor induction with expectant monitoring in pregnancies complicated by fetal growth restriction at term and showed equivalence for neonatal outcomes.

Objective: To evaluate trial participation bias and to examine the generalizability of the results of an obstetrical randomized trial.

Study Design: We used data from participants and nonparticipants of a randomized controlled trial-the disproportionate intrauterine growth intervention trial at term (n=1116) -to perform a secondary analysis. This study compared induction of labor and expectant management in women with term growth restriction. Data were collected in the same manner for both groups. Baseline characteristics and neonatal and maternal outcomes were compared. The primary outcome was a composite measure of adverse neonatal outcome. Secondary outcomes were delivery by cesarean delivery and instrumental vaginal delivery; length of stay in the neonatal intensive care, neonatal ward, and the maternal hospital; and maternal morbidity.

Results: Nonparticipants were older, had a lower body mass index, had a higher level of education, smoked less, and preferred expectant management. The time between study inclusion and labor onset was shorter in participants than in nonparticipants. Notably, 4 perinatal deaths occurred among nonparticipants and none among participants. Among nonparticipants, there were more children born with a birthweight below the third centile. The nonparticipants who had expectant management were monitored less frequently than the participants in both the intervention and the expectant arm.

Conclusion: We found less favorable outcomes and more perinatal deaths in nonparticipants. Protocol-driven management, differences between participants and nonparticipants, or the fact that nonparticipants had a preference for expectant management might explain the findings.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100239DOI Listing
November 2020

A novel non-antimicrobial treatment of bacterial vaginosis: An open label two-private centre study.

Eur J Obstet Gynecol Reprod Biol 2021 Jan 24;256:419-424. Epub 2020 Nov 24.

Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Skåne University Hospital, Lund University, Sweden.

Background: Bacterial vaginosis (BV) is the most common cause of vaginal discharge. It is caused by an imbalance in the normal vaginal microbiota. Symptoms include an offensive odour. Standard oral or vaginal antimicrobial treatments have high immediate cure rates but almost as high recurrence rates. pHyph, a vaginal pessary, contains glucono-delta-lactone (GDL) and sodium gluconate (NaG) which restore normal pH and disrupt the associated biofilm.

Aim: To investigate the clinical performance of pHyph, for both treatment and recurrence prevention. Design An open-label, single arm, multi-centre first in women study.

Setting: Two private gynaecology clinics in Skåne County, Southern Sweden.

Methods: Twenty four adult women with confirmed bacterial vaginosis received the investigational product for self-administration on days 0, 2, 4, and 6 and were assessed on day 7. Clinical cure was defined as absence of three of four Amsel's criteria (pH excluded) on day 7. Safety and tolerability were also recorded. Those not cured by day 7 received a prolonged treatment protocol. Results There were three withdrawals, two before the day 7 assessment. 18/22 (82 %) were clinically cured at day 7. The pessary was well tolerated. Recurrence rates at 14 days in patients cured at day 7 after receiving standard study treatment (n = 18) were 1/18 (5.6 %) with no additional recurrences reported at 35 days. Three of four patients not cured at 7 days received continued treatment (day 7, 9, 11, and 13), but none were cured at 14 days.

Conclusion: pHyph has the potential for both high cure rates and a reduction in recurrence.
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http://dx.doi.org/10.1016/j.ejogrb.2020.11.059DOI Listing
January 2021

Universal third-trimester ultrasonic screening using fetal macrosomia in the prediction of adverse perinatal outcome: A systematic review and meta-analysis of diagnostic test accuracy.

PLoS Med 2020 10 13;17(10):e1003190. Epub 2020 Oct 13.

Department of Obstetrics and Gynaecology, University of Cambridge, NIHR Cambridge Comprehensive Biomedical Research Centre, Cambridge, United Kingdom.

Background: The effectiveness of screening for macrosomia is not well established. One of the critical elements of an effective screening program is the diagnostic accuracy of a test at predicting the condition. The objective of this study is to investigate the diagnostic effectiveness of universal ultrasonic fetal biometry in predicting the delivery of a macrosomic infant, shoulder dystocia, and associated neonatal morbidity in low- and mixed-risk populations.

Methods And Findings: We conducted a predefined literature search in Medline, Excerpta Medica database (EMBASE), the Cochrane library and ClinicalTrials.gov from inception to May 2020. No language restrictions were applied. We included studies where the ultrasound was performed as part of universal screening and those that included low- and mixed-risk pregnancies and excluded studies confined to high risk pregnancies. We used the estimated fetal weight (EFW) (multiple formulas and thresholds) and the abdominal circumference (AC) to define suspected large for gestational age (LGA). Adverse perinatal outcomes included macrosomia (multiple thresholds), shoulder dystocia, and other markers of neonatal morbidity. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was carried out using the hierarchical summary receiver operating characteristic (ROC) and the bivariate logit-normal (Reitsma) models. We identified 41 studies that met our inclusion criteria involving 112,034 patients in total. These included 11 prospective cohort studies (N = 9986), one randomized controlled trial (RCT) (N = 367), and 29 retrospective cohort studies (N = 101,681). The quality of the studies was variable, and only three studies blinded the ultrasound findings to the clinicians. Both EFW >4,000 g (or 90th centile for the gestational age) and AC >36 cm (or 90th centile) had >50% sensitivity for predicting macrosomia (birthweight above 4,000 g or 90th centile) at birth with positive likelihood ratios (LRs) of 8.74 (95% confidence interval [CI] 6.84-11.17) and 7.56 (95% CI 5.85-9.77), respectively. There was significant heterogeneity at predicting macrosomia, which could reflect the different study designs, the characteristics of the included populations, and differences in the formulas used. An EFW >4,000 g (or 90th centile) had 22% sensitivity at predicting shoulder dystocia with a positive likelihood ratio of 2.12 (95% CI 1.34-3.35). There was insufficient data to analyze other markers of neonatal morbidity.

Conclusions: In this study, we found that suspected LGA is strongly predictive of the risk of delivering a large infant in low- and mixed-risk populations. However, it is only weakly (albeit statistically significantly) predictive of the risk of shoulder dystocia. There was insufficient data to analyze other markers of neonatal morbidity.
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http://dx.doi.org/10.1371/journal.pmed.1003190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553291PMC
October 2020

Letter of response (2) - Data integrity of 35 randomised controlled trials in women' health.

Eur J Obstet Gynecol Reprod Biol 2020 12 30;255:261-262. Epub 2020 Aug 30.

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia.

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http://dx.doi.org/10.1016/j.ejogrb.2020.08.050DOI Listing
December 2020

Timing and mode of delivery with advancing maternal age.

Best Pract Res Clin Obstet Gynaecol 2021 Jan 29;70:101-111. Epub 2020 Jun 29.

Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Queen's Medical Centre, Derby Road, Nottingham, NG7 2UH, UK. Electronic address:

In 2017, 23% of all live births in the United Kingdom were to women aged over 35 years. Decisions around the timing of delivery for such women must balance the risks of prolongation of the pregnancy and of iatrogenic harm from timed delivery. Women of advanced maternal age have a small age-related elevated risk of term stillbirth. Antenatal monitoring and the route of delivery should not differ from those for younger women. The induction of labour at 39 weeks for such women does not appear to increase the risk of emergency caesarean section or to have any short-term adverse effects on mother or baby. There have been no studies on the long-term effects of induction in this group. Nevertheless, it seems reasonable to offer women of advanced maternal age, induction of labour at 39 weeks where resources are available to safely provide this.
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http://dx.doi.org/10.1016/j.bpobgyn.2020.06.005DOI Listing
January 2021

The UK Obstetric Anal Sphincter Injury (OASI) Care Bundle: A critical review.

Midwifery 2020 Nov 18;90:102801. Epub 2020 Jul 18.

Professor of Midwifery, Associate Dean Research and HDR, Midwifery Discipline Lead, School of Nursing and Midwifery, Building EB/LG Room 34, Parramatta South Campus, Western Sydney University, Sydney, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.midw.2020.102801DOI Listing
November 2020

Pharmacological interventions for treating intrahepatic cholestasis of pregnancy.

Cochrane Database Syst Rev 2020 07 27;7:CD000493. Epub 2020 Jul 27.

Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK.

Background: Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been largely empiric. As ICP is an uncommon condition (incidence less than 2% a year), many trials have been small. Synthesis, including recent larger trials, will provide more evidence to guide clinical practice. This review is an update of a review first published in 2001 and last updated in 2013.

Objectives: To assess the effects of pharmacological interventions to treat women with intrahepatic cholestasis of pregnancy, on maternal, fetal and neonatal outcomes.

Search Methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 December 2019), and reference lists of retrieved studies.

Selection Criteria: Randomised or quasi-randomised controlled trials, including cluster-randomised trials and trials published in abstract form only, that compared any drug with placebo or no treatment, or two drug intervention strategies, for women with a clinical diagnosis of intrahepatic cholestasis of pregnancy.

Data Collection And Analysis: The review authors independently assessed trials for eligibility and risks of bias. We independently extracted data and checked these for accuracy. We assessed the certainty of the evidence using the GRADE approach.

Main Results: We included 26 trials involving 2007 women. They were mostly at unclear to high risk of bias. They assessed nine different pharmacological interventions, resulting in 14 different comparisons. We judged two placebo-controlled trials of ursodeoxycholic acid (UDCA) in 715 women to be at low risk of bias. The ten different pharmacological interventions were: agents believed to detoxify bile acids (UCDA) and S-adenosylmethionine (SAMe); agents used to bind bile acids in the intestine (activated charcoal, guar gum, cholestyramine); Chinese herbal medicines (yinchenghao decoction (YCHD), salvia, Yiganling and Danxioling pill (DXLP)), and agents aimed to reduce bile acid production (dexamethasone) Compared with placebo, UDCA probably results in a small improvement in pruritus score measured on a 100 mm visual analogue scale (VAS) (mean difference (MD) -7.64 points, 95% confidence interval (CI) -9.69 to -5.60 points; 2 trials, 715 women; GRADE moderate certainty), where a score of zero indicates no itch and a score of 100 indicates severe itching. The evidence for fetal distress and stillbirth were uncertain, due to serious limitations in study design and imprecision (risk ratio (RR) 0.70, 95% CI 0.35 to 1.40; 6 trials, 944 women; RR 0.33, 95% CI 0.08 to 1.37; 6 trials, 955 women; GRADE very low certainty). We found very few differences for the other comparisons included in this review. There is insufficient evidence to indicate if SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction, Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with intrahepatic cholestasis of pregnancy.

Authors' Conclusions: When compared with placebo, UDCA administered to women with ICP probably shows a reduction in pruritus. However the size of the effect is small and for most pregnant women and clinicians, the reduction may fall below the minimum clinically worthwhile effect. The evidence was unclear for other adverse fetal outcomes, due to very low-certainty evidence. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, YCHD, DXLP, Salvia, Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. There are no trials of the efficacy of topical emollients. Further high-quality trials of other interventions are needed in order to identify effective treatments for maternal itching and preventing adverse perinatal outcomes. It would also be helpful to identify those women who are mostly likely to respond to UDCA (for example, whether bile acid concentrations affect how women with ICP respond to treatment with UDCA).
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http://dx.doi.org/10.1002/14651858.CD000493.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389072PMC
July 2020

Letter of response - Data integrity of 35 randomised controlled trials in women' health.

Eur J Obstet Gynecol Reprod Biol 2020 12 13;255:260. Epub 2020 Jun 13.

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia.

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http://dx.doi.org/10.1016/j.ejogrb.2020.06.007DOI Listing
December 2020

The risks of a range of maternal pregnancy choices, expressed as "baby micromorts" (risk of death per million births).

Eur J Obstet Gynecol Reprod Biol 2020 Aug 28;251:194-198. Epub 2020 May 28.

Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham City Hospital, NG5 1PB, United Kingdom. Electronic address:

Objective: To present the risks of baby death from various maternal choices on a common scale.

Design: Review of published data.

Methods: Mortality calculated as the attributable risk per activity, expressed in "baby micromorts", the number of one in a million chances of the baby dying.

Results: Amniocentesis and chorionic villous sampling carry procedure related risks of 9142 (-600 to 19,000) and 37,902 (23,302 to 52,502) micromorts respectively. Smoking carries a risk of 0.21 micromorts per cigarette or 300 micromorts for a woman smoking 5/day throughout pregnancy. Drinking a unit of alcohol in the first trimester carries a risk of 400 micromorts via miscarriage or 19,200 micromorts for a woman drinking 4 units/week in the first trimester. The risk per unit due to stillbirth is only about 19 or 3,710 micromorts when drinking 5 units/week throughout pregnancy. Cocaine use carries a risk of about 45 micromorts per single use; 3,630 micromorts using cocaine twice/week during pregnancy. For low risk women in the UK, planned first birth at home carries an additional 843 (-200 to 2620) micromorts compared with in hospital, and planned vaginal breech birth an additional 5870 (-4400 to 18,500), compared with planned caesarean. The risk of delaying conception by a year varies by age group. For women aged 35-39 the risk increases by 220 (-430 to 870) micromorts each year versus 600 (-800 to 2000) micromorts for women aged over 40. Compared with the above, the risk from the mother eating a serving of unpasteurised cheese, is negligible at 0.00026 micromorts.

Conclusions: This way of expressing risk may help put choices which pregnant women make into perspective, although it needs evaluating in well conducted experimental studies.
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http://dx.doi.org/10.1016/j.ejogrb.2020.05.051DOI Listing
August 2020

Data integrity of 35 randomised controlled trials in women' health.

Eur J Obstet Gynecol Reprod Biol 2020 Jun 11;249:72-83. Epub 2020 Apr 11.

Department of Obstetrics and Gynecology, Monash University, Clayton, Australia.

While updating a systematic review on the topic of ovulation of induction, we observed unusual similarities in a number of randomised controlled trials (RCTs) published by two authors from the same institute in the same disease spectrum in a short period of time. We therefore undertook a focused analysis of the data integrity of all RCTs published by the two authors. We made pairwise comparisons to find identical or similar values in baseline characteristics and outcome tables between trials. We also assessed whether baseline characteristics were compatible with chance, using Monte Carlo simulations and Kolmogorov-Smirnov test. For 35 trials published between September 2006 and January 2016, we found a large number of similarities in both the baseline characteristics and outcomes of 26. Analysis of the baseline characteristics of the trials indicated that their distribution was unlikely to be the result of proper randomisation. The procedures demonstrated in this paper may help to assess data integrity in future attempts to verify the authenticity of published RCTs.
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http://dx.doi.org/10.1016/j.ejogrb.2020.04.016DOI Listing
June 2020

Ursodeoxycholic acid for adverse perinatal outcomes - Authors' reply.

Lancet 2020 03;395(10226):780-781

Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK.

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http://dx.doi.org/10.1016/S0140-6736(19)32970-8DOI Listing
March 2020

Childbirth experience questionnaire 2: Validating its use in the United Kingdom.

Eur J Obstet Gynecol Reprod Biol X 2020 Jan 3;5:100097. Epub 2019 Oct 3.

Division of Obstetrics and Gynaecology, University of Nottingham, Maternity Department, Nottingham City Hospital, Nottingham, NG5 1PB, UK.

Objective: To validate the Childbirth Experience Questionnaire 2 (CEQ2) in the UK to see if it is an effective tool for evaluating labour experience.

Study Design: The CEQ2 and part of the Care Quality Commission Maternity Survey (2010) was sent to 475 women one month and six weeks after birth. It was tested for face validity among 25 postnatal mothers. Demographic data and delivery data was used to establish construct validity using the method of known-groups validation. The results of the scored CEQ2 sent out twice were used to measure test-retest reliability by calculating the quadratic weighted index of agreement between the two scores. Criterion validity was measured by calculating the Pearson correlation coefficient for the CEQ2 and Maternity Survey scores.

Results: Face validity of the CEQ2 in a UK population was demonstrated with all respondents stating it was easy to understand and complete. A statistically significantly higher CEQ2 score for subgroups of women known to report a better birth outcome demonstrated construct validity. A weighted kappa of 0.55 demonstrated test-retest reliability. A Pearson correlation co-efficient of 0.56 demonstrated a moderate correlation between the results of the CEQ2 and the results of the 'gold standard' assessment of childbirth experience in the UK: the Maternity Survey and hence criterion validity.

Conclusions: This study demonstrates that the Childbirth Experience Questionnaire version 2 (CEQ2) is a valid and reliable measure of childbirth experience in the UK population.
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http://dx.doi.org/10.1016/j.eurox.2019.100097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994391PMC
January 2020

Mode of birth and long-term sexual health: a follow-up study of mothers in the Danish National Birth Cohort.

BMJ Open 2019 11 3;9(11):e029517. Epub 2019 Nov 3.

Department of Clinical Research, Research Unit of Obstetrics and Gynecology, Syddansk Universitet, Odense, Denmark.

Objectives: To investigate the relation between mode of birth and women's long-term sexual health.

Design: Maternal follow-up of the Danish National Birth Cohort (1996-2002) in 2013-2014 including questions on sexual health. Logistic regression was used to relate registry-based information about mode of birth and perineal tears with data on sexual problems.

Setting: Denmark.

Participants: Of 82 569 eligible mothers in the Danish National Birth Cohort, 43 639 (53%) completed the follow-up. Of these, 37 417 women had a partner, and answered at least one question on sexual health.

Main Outcome Measures: Self-reported sexual health.

Results: Participants were on average 44 years old, and 16 years after their first birth. The frequency of sexual problems among women with only spontaneous vaginal births, the reference group, was 37%. For women who only had caesarean sections, more problems were reported (OR 1.18; 95% CI 1.09 to 1.28). For women who had a spontaneous vaginal birth subsequent to a caesarean, and for women with only vaginal births who had experienced one or more instrumental vaginal births, the odds of sexual problems did not differ from women with only spontaneous vaginal births (OR 1.00; 95% CI 0.91 to 1.11) and (OR 1.01; 95% CI 0.95 to 1.08), respectively.

Conclusions: These findings indicate that caesarean section does not protect against long-term sexual problems. Rather, vaginal birth, even after caesarean section, was associated with fewer long-term sexual problems.
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http://dx.doi.org/10.1136/bmjopen-2019-029517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858091PMC
November 2019

Management of non-severe pregnancy hypertension - A summary of the CHIPS Trial (Control of Hypertension in Pregnancy Study) research publications.

Pregnancy Hypertens 2019 Oct 15;18:156-162. Epub 2019 Oct 15.

Department of Women and Children's Health, King's College London, UK.

The international CHIPS Trial (Control of Hypertension In Pregnancy Study) enrolled 987 women with chronic (75%) or gestational (25%) hypertension. Pre-eclampsia developed in 48%; women remained on their allocated BP control and delivered an average of two weeks later. 'Less tight' control (target diastolic BP 100 mmHg) achieved BP that was 6/5mmHg higher (p < 0.001) than 'tight' control (target diastolic 85 mmHg, BP achieved 133/85 mmHg). 'Less tight' (vs. 'tight') control resulted in similar adverse perinatal outcomes (31.5% vs. 30.7%; p = 0.84) that balanced birthweight < 10th percentile (16.1% vs. 19.8%; p = 0.14) against preterm birth (35.6% vs. 31.5%; p = 0.18). 12-month follow-up revealed no compelling evidence for developmental programming of child growth. However, 'less tight' (vs. 'tight') control resulted in more severe maternal hypertension (40.6% vs. 27.5%; p < 0.001), and more women with platelets < 100 × 10/L (4.3% vs. 1.6%; p = 0.02) or symptomatic elevated liver enzymes (4.3% vs. 1.8%; p = 0.03), with no difference in serious maternal complications (3.7% vs. 2.0%; p = 0.17). Labetalol was the drug of choice. Methyldopa did not result in inferior outcomes. Post-hoc, severe hypertension, independent of pre-eclampsia, was associated with heightened increased risk of adverse outcomes, and in 'less tight' control, of serious maternal complications. At no gestational age at initiation of BP control was 'less tight' superior to 'tight'. Women in both groups were equally satisfied with care. 'Less tight' control tended to be more expensive by CAD$6000 (p =0.07) based on neonatal care costs. Collectively, CHIPS publications have provided evidence that women with non-severe pregnancy hypertension should receive 'tight' BP control achieved by a simple algorithm.
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http://dx.doi.org/10.1016/j.preghy.2019.08.166DOI Listing
October 2019

Ursodeoxycholic acid versus placebo in women with intrahepatic cholestasis of pregnancy (PITCHES): a randomised controlled trial.

Lancet 2019 09 1;394(10201):849-860. Epub 2019 Aug 1.

Division of Child Health, Obstetrics and Gynaecology, University of Nottingham, Nottingham, UK.

Background: Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy.

Methods: We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806.

Findings: Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62-1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment.

Interpretation: Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered.

Funding: National Institute for Health Research Efficacy and Mechanism Evaluation Programme.
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http://dx.doi.org/10.1016/S0140-6736(19)31270-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739598PMC
September 2019

Trials of antenatal corticosteroids for preterm fetal lung maturity: a review of the potential for selective outcome reporting.

Eur J Obstet Gynecol Reprod Biol 2019 May 11;236:58-68. Epub 2019 Mar 11.

Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham City Hospital, NG5 1PB, United Kingdom.

Objective: To measure the extent to which the evidence underpinning prenatal corticosteroids for preterm fetal lung maturity is at risk of bias due to selective outcome reporting.

Study Design: Five biomedical databases (Medline, ClinicalTrials.gov, Embase, OVID and HMIC) were searched for trials published between February 2016 and September 2017. Randomised trials of prenatal steroids for women at risk of preterm birth were identified. For each, we recorded the registration status and timing, and whether the registered primary outcome had been reported. For unregistered trials, we estimated the potential for selective outcome reporting indirectly by tabulating all reported outcomes and by comparing the first outcome reported in the methods to the first in the results section.

Results: Twenty seven trials were identified. Only three (11%) trials had been registered. All three reported their pre-specified primary outcome. Among the unregistered trials, thirteen (54%) had different first reported outcomes in the methods and results sections, and among all trials many different outcomes were reported suggesting considerable potential for selective reporting. However, the single outcome of respiratory distress syndrome, albeit defined in different ways, was reported in all but two trials. This is reassuring evidence that the beneficial effect of steroids on this outcome has not been exaggerated by selective outcome reporting.

Conclusion: We conclude that the evidence that steroids reduce respiratory distress syndrome is secure.
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http://dx.doi.org/10.1016/j.ejogrb.2019.02.031DOI Listing
May 2019

Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta-analyses.

Lancet 2019 03 14;393(10174):899-909. Epub 2019 Feb 14.

Department of Obstetrics and Gynecology, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv, Israel.

Background: Intrahepatic cholestasis of pregnancy is associated with adverse perinatal outcomes, but the association with the concentration of specific biochemical markers is unclear. We aimed to quantify the adverse perinatal effects of intrahepatic cholestasis of pregnancy in women with increased serum bile acid concentrations and determine whether elevated bile acid concentrations were associated with the risk of stillbirth and preterm birth.

Methods: We did a systematic review by searching PubMed, Web of Science, and Embase databases for studies published from database inception to June 1, 2018, reporting perinatal outcomes for women with intrahepatic cholestasis of pregnancy when serum bile acid concentrations were available. Inclusion criteria were studies defining intrahepatic cholestasis of pregnancy based upon pruritus and elevated serum bile acid concentrations, with or without raised liver aminotransferase concentrations. Eligible studies were case-control, cohort, and population-based studies, and randomised controlled trials, with at least 30 participants, and that reported bile acid concentrations and perinatal outcomes. Studies at potential higher risk of reporter bias were excluded, including case reports, studies not comprising cohorts, or successive cases seen in a unit; we also excluded studies with high risk of bias from groups selected (eg, a subgroup of babies with poor outcomes were explicitly excluded), conference abstracts, and Letters to the Editor without clear peer review. We also included unpublished data from two UK hospitals. We did a random effects meta-analysis to determine risk of adverse perinatal outcomes. Aggregate data for maternal and perinatal outcomes were extracted from case-control studies, and individual patient data (IPD) were requested from study authors for all types of study (as no control group was required for the IPD analysis) to assess associations between biochemical markers and adverse outcomes using logistic and stepwise logistic regression. This study is registered with PROSPERO, number CRD42017069134.

Findings: We assessed 109 full-text articles, of which 23 studies were eligible for the aggregate data meta-analysis (5557 intrahepatic cholestasis of pregnancy cases and 165 136 controls), and 27 provided IPD (5269 intrahepatic cholestasis of pregnancy cases). Stillbirth occurred in 45 (0·83%) of 4936 intrahepatic cholestasis of pregnancy cases and 519 (0·32%) of 163 947 control pregnancies (odds ratio [OR] 1·46 [95% CI 0·73-2·89]; I=59·8%). In singleton pregnancies, stillbirth was associated with maximum total bile acid concentration (area under the receiver operating characteristic curve [ROC AUC]) 0·83 [95% CI 0·74-0·92]), but not alanine aminotransferase (ROC AUC 0·46 [0·35-0·57]). For singleton pregnancies, the prevalence of stillbirth was three (0·13%; 95% CI 0·02-0·38) of 2310 intrahepatic cholestasis of pregnancy cases in women with serum total bile acids of less than 40 μmol/L versus four (0·28%; 0·08-0·72) of 1412 cases with total bile acids of 40-99 μmol/L (hazard ratio [HR] 2·35 [95% CI 0·52-10·50]; p=0·26), and versus 18 (3·44%; 2·05-5·37) of 524 cases for bile acids of 100 μmol/L or more (HR 30·50 [8·83-105·30]; p<0·0001).

Interpretation: The risk of stillbirth is increased in women with intrahepatic cholestasis of pregnancy and singleton pregnancies when serum bile acids concentrations are of 100 μmol/L or more. Because most women with intrahepatic cholestasis of pregnancy have bile acids below this concentration, they can probably be reassured that the risk of stillbirth is similar to that of pregnant women in the general population, provided repeat bile acid testing is done until delivery.

Funding: Tommy's, ICP Support, UK National Institute of Health Research, Wellcome Trust, and Genesis Research Trust.
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http://dx.doi.org/10.1016/S0140-6736(18)31877-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396441PMC
March 2019

Ursodeoxycholic acid versus placebo in the treatment of women with intrahepatic cholestasis of pregnancy (ICP) to improve perinatal outcomes: protocol for a randomised controlled trial (PITCHES).

Trials 2018 Nov 27;19(1):657. Epub 2018 Nov 27.

University of Nottingham, Nottingham, UK.

Background: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy and presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver function tests. ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid and intrauterine death. Some clinicians treat ICP with ursodeoxycholic acid (UDCA) to improve maternal pruritus and biochemical abnormalities. However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question.

Methods: The PITCHES trial is a triple-masked, placebo-controlled randomised trial, to evaluate UDCA versus placebo in women with ICP between 20 + 0 to 40 + 6 weeks' gestation. The primary objective of the trial is to determine if UDCA treatment of women with ICP between 20 + 0 and 40 + 6 weeks' gestation reduces the primary perinatal outcome: a composite of perinatal death (as defined by in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (less than 37 weeks' gestation) or neonatal unit admission for at least 4 h (from infant delivery until hospital discharge). The secondary objectives of the trial are (1) to investigate the effect of UDCA on other short-term outcomes for both mother and infant and (2) to assess the impact of UDCA on health care resource use, in terms of the total number of nights for mother and infant, together with level of care.

Discussion: Current practice in the UK at the time of trial commencement for the treatment of ICP is inconsistent, with some units routinely prescribing UDCA, others prescribing very little and the remainder offering it variably. Our previous pilot trial of UDCA in women with ICP demonstrated that the trial would be feasible, and the research question remains active and unanswered. Results are highly likely to influence clinical practice, through direct management and impact on national and international guidelines.

Trial Registration: ISRCTN registry, ID: ISRCTN91918806 . Prospectively registered on 27 August 2015.
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http://dx.doi.org/10.1186/s13063-018-3018-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260710PMC
November 2018

Maternal position in the second stage of labour for women with epidural anaesthesia.

Cochrane Database Syst Rev 2018 11 9;11:CD008070. Epub 2018 Nov 9.

Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham City Hospital NHS Trust, Hucknall Road, Nottingham, Nottinghamshire, UK, NG5 1PB.

Background: Epidural analgesia in labour prolongs the second stage and increases instrumental delivery. It has been suggested that a more upright maternal position during all or part of the second stage may counteract these adverse effects. This is an update of a Cochrane Review published in 2017.

Objectives: To assess the effects of different birthing positions (upright or recumbent) during the second stage of labour, on maternal and fetal outcomes for women with epidural analgesia.

Search Methods: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (5 June 2018), and the reference lists of retrieved studies.

Selection Criteria: All randomised or quasi-randomised trials including pregnant women (primigravidae or multigravidae) in the second stage of induced or spontaneous labour receiving epidural analgesia of any kind. Cluster-randomised controlled trials would have been eligible for inclusion but we found none. Studies published in abstract form only were also eligible.We assumed the experimental intervention to be maternal use of any upright position during the second stage of labour, compared with the control condition of remaining in any recumbent position.

Data Collection And Analysis: Two review authors independently assessed trials for inclusion, assessed risks of bias, and extracted data. We contacted study authors to obtain missing data. We assessed the quality of the evidence using the GRADE approach.We carried out a planned sensitivity analysis of the three studies with low risks of bias for allocation concealment and incomplete outcome data reporting, and further excluded one study with a co-intervention (this was not prespecified).

Main Results: We include eight randomised controlled trials, involving 4464 women, comparing upright positions versus recumbent positions in this update. Five were conducted in the UK, one in France and two in Spain.The largest UK trial accounted for three-quarters of all review participants, and we judged it to have low risk of bias. We assessed two other trials as being at low risk of selection and attrition bias. We rated four studies at unclear or high risk of bias for both selection and attrition bias and one study as high risk of bias due to a co-intervention. The trials varied in their comparators, with five studies comparing different positions (upright and recumbent), two comparing ambulation with (recumbent) non-ambulation, and one study comparing postural changes guided by a physiotherapist to a recumbent position.Overall, there may be little or no difference between upright and recumbent positions for our combined primary outcome of operative birth (caesarean or instrumental vaginal): average risk ratio (RR) 0.86, 95% confidence interval (CI) 0.70 to 1.07; 8 trials, 4316 women; I = 78%; low-quality evidence. It is uncertain whether the upright position has any impact on caesarean section (RR 0.94, 95% CI 0.61 to 1.46; 8 trials, 4316 women; I = 47%; very low-quality evidence), instrumental vaginal birth (RR 0.90, 95% CI 0.72 to 1.12; 8 trials, 4316 women; I = 69%) and the duration of the second stage of labour (mean difference (MD) 6.00 minutes, 95% CI -37.46 to 49.46; 3 trials, 456 women; I = 96%), because we rated the quality of the evidence as very low for these outcomes. Maternal position in the second stage of labour probably makes little or no difference to postpartum haemorrhage (PPH), (PPH requiring blood transfusion): RR 1.20, 95% CI 0.83 to 1.72; 1 trial, 3093 women; moderate-quality evidence. Maternal satisfaction with the overall childbirth experience was slightly lower in the upright group: RR 0.95, 95% CI 0.92 to 0.99; 1 trial, 2373 women. Fewer babies were born with low cord pH in the upright group: RR 0.43, 95% CI 0.20 to 0.90; 2 trials, 3159 infants; moderate-quality evidence.The results were less clear for other maternal or fetal outcomes, including trauma to the birth canal requiring suturing (average RR 1.00, 95% CI 0.89 to 1.13; 3 trials, 3266 women; I = 46%; low-quality evidence), abnormal fetal heart patterns requiring intervention (RR 1.69, 95% CI 0.32 to 8.84; 1 trial, 107 women; very low-quality evidence), or admission to neonatal intensive care unit (RR 0.54, 95% CI 0.02 to 12.73; 1 trial, 66 infants; very low-quality evidence). However, the CIs around some of these estimates were wide, and we cannot rule out clinically important effects.In our sensitivity analysis of studies at low risk of bias, upright positions increase the chance of women having an operative birth: RR 1.11, 95% CI 1.03 to 1.20; 3 trials, 3609 women; high-quality evidence. In absolute terms, this equates to 63 more operative births per 1000 women (from 17 more to 115 more). This increase appears to be due to the increase in caesarean section in the upright group (RR 1.29; 95% CI 1.05 to 1.57; 3 trials, 3609 women; high-quality evidence), which equates to 25 more caesarean sections per 1000 women (from 4 more to 49 more). In the sensitivity analysis there was no clear impact on instrumental vaginal births: RR 1.08, 95% CI 0.91 to 1.30; 3 trials, 3609 women; low-quality evidence.

Authors' Conclusions: There may be little or no difference in operative birth between women who adopt recumbent or supine positions during the second stage of labour with an epidural analgesia. However, the studies are heterogeneous, probably related to differing study designs and interventions, differing adherence to the allocated intervention and possible selection and attrition bias. Sensitivity analysis of studies at low risk of bias indicated that recumbent positions may reduce the need for operative birth and caesarean section, without increasing instrumental delivery. Mothers may be more satisfied with their experience of childbirth by adopting a recumbent position. The studies in this review looked at left or right lateral and semi-recumbent positions. Recumbent positions such as flat on the back or lithotomy are not generally used due to the possibility of aorto-caval compression, although we acknowledge that these recumbent positions were not the focus of trials included in this review.
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http://dx.doi.org/10.1002/14651858.CD008070.pub4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517130PMC
November 2018

Interventionist versus expectant care for severe pre-eclampsia between 24 and 34 weeks' gestation.

Cochrane Database Syst Rev 2018 10 5;10:CD003106. Epub 2018 Oct 5.

Department of Obstetrics and Gynaecology, The Royal Wolverhampton Hospitals NHS Trust, New Cross Hospital, Wednesfield, Wolverhampton, West Midlands, UK, WV10 0QP.

Background: Severe pre-eclampsia can cause significant mortality and morbidity for both mother and child, particularly when it occurs remote from term, between 24 and 34 weeks' gestation. The only known cure for this disease is delivery. Some obstetricians advocate early delivery to ensure that the development of serious maternal complications, such as eclampsia (fits) and kidney failure are prevented. Others prefer a more expectant approach, delaying delivery in an attempt to reduce the mortality and morbidity for the child that is associated with being born too early.

Objectives: To evaluate the comparative benefits and risks of a policy of early delivery by induction of labour or by caesarean section, after sufficient time has elapsed to administer corticosteroids, and allow them to take effect; with a policy of delaying delivery (expectant care) for women with severe pre-eclampsia between 24 and 34 weeks' gestation.

Search Methods: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) on 27 November 2017, and reference lists of retrieved studies.

Selection Criteria: Randomised trials comparing the two intervention strategies for women with early onset, severe pre-eclampsia. Trials reported in an abstract were eligible for inclusion, as were cluster-trial designs. We excluded quasi-randomised trials.

Data Collection And Analysis: Three review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. We assessed the quality of the evidence for specified outcomes using the GRADE approach.

Main Results: We included six trials, with a total of 748 women in this review. All trials included women in whom there was no overriding indication for immediate delivery in the fetal or maternal interest. Half of the trials were at low risk of bias for methods of randomisation and allocation concealment; and four trials were at low risk for selective reporting. For most other domains, risk of bias was unclear. There were insufficient data for reliable conclusions about the comparative effects on most outcomes for the mother. Two studies reported on maternal deaths; neither study reported any deaths (two studies; 320 women; low-quality evidence). It was uncertain whether interventionist care reduced eclampsia (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.06 to 15.58; two studies; 359 women) or pulmonary oedema (RR 0.45, 95% CI 0.07 to 3.00; two studies; 415 women), because the quality of the evidence for these outcomes was very low. Evidence from two studies suggested little or no clear difference between the interventionist and expectant care groups for HELLP (haemolysis, elevated liver enzymes, and low platelets) syndrome (RR 1.09, 95% CI 0.62 to 1.91; two studies; 359 women; low-quality evidence). No study reported on stroke. With the addition of data from two studies for this update, there was now evidence to suggest that interventionist care probably made little or no difference to the incidence of caesarean section (average RR 1.01, 95% CI 0.91 to 1.12; six studies; 745 women; Heterogeneity: Tau² = 0.01; I² = 63%).For the baby, there was insufficient evidence to draw reliable conclusions about the effects on perinatal deaths (RR 1.11, 95% CI 0.62 to 1.99; three studies; 343 women; low-quality evidence). Babies whose mothers had been allocated to the interventionist group had more intraventricular haemorrhage (RR 1.94, 95% CI 1.15 to 3.29; two studies; 537 women; moderate-quality evidence), more respiratory distress caused by hyaline membrane disease (RR 2.30, 95% CI 1.39 to 3.81; two studies; 133 women), required more ventilation (RR 1.50, 95% CI 1.11 to 2.02; two studies; 300 women), and were more likely to have a lower gestation at birth (mean difference (MD) -9.91 days, 95% CI -16.37 to -3.45 days; four studies; 425 women; Heterogeneity: Tau² = 31.74; I² = 76%). However, babies whose mothers had been allocated to the interventionist group were no more likely to be admitted to neonatal intensive care (average RR 1.19, 95% CI 0.89 to 1.60; three studies; 400 infants; Heterogeneity: Tau² = 0.05; I² = 84%). Babies born to mothers in the interventionist groups were more likely to have a longer stay in the neonatal intensive care unit (MD 7.38 days, 95% CI -0.45 to 15.20 days; three studies; 400 women; Heterogeneity: Tau² = 40.93, I² = 85%) and were less likely to be small-for-gestational age (RR 0.38, 95% CI 0.24 to 0.61; three studies; 400 women). There were no clear differences between the two strategies for any other outcomes.

Authors' Conclusions: This review suggested that an expectant approach to the management of women with severe early onset pre-eclampsia may be associated with decreased morbidity for the baby. However, this evidence was based on data from only six trials. Further large, high-quality trials are needed to confirm or refute these findings, and establish if this approach is safe for the mother.
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http://dx.doi.org/10.1002/14651858.CD003106.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517196PMC
October 2018

Reduced fetal movement intervention Trial-2 (ReMIT-2): protocol for a pilot randomised controlled trial of standard care informed by the result of a placental growth factor (PlGF) blood test versus standard care alone in women presenting with reduced fetal movement at or after 36 weeks gestation.

Trials 2018 Oct 1;19(1):531. Epub 2018 Oct 1.

Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester, M13 9WL, UK.

Background: Forty percent of babies who are stillborn born die after 36 weeks gestation and have no lethal structural abnormality. Maternal perception of reduced fetal movement (RFM) is associated with stillbirth and is related to abnormal placental structure and function. The ultimate objective of this trial is to assess whether for women with RFM, intervention directed by measurement of placental biochemical factors in addition to standard care improves pregnancy outcome compared with standard care alone. This is the protocol for a pilot trial to determine the feasibility of a definitive trial and also provide proof of concept that informing care by measurement of placental factors improves neonatal outcomes.

Methods: ReMIT-2 is a multicentre, pilot randomised controlled trial of care informed by results of an additional placental factor blood test versus standard care alone for women presenting with RFM at or after 36 weeks gestation. Participants will be randomised 1:1 to the intervention arm where the blood test result is revealed and acted on, or to the control arm where the blood sample is not tested immediately and therefore the result cannot be acted on. All participants will be followed up six weeks after delivery to assess their health status and views of the trial, along with healthcare costs. A sub-group will be interviewed within 16 weeks after delivery to further explore their views of the trial. Outcomes to determine feasibility of a definitive trial include number of potentially eligible women, proportion lost to follow-up, clinical characteristics at randomisation, reasons for non-recruitment, compliance with the trial intervention and views of participants and clinicians about the trial. Proof of concept outcomes include: rates of induction of labour; Caesarean birth; and a composite neonatal outcome of stillbirths and deaths before discharge, 5-min Apgar score < 7, umbilical artery pH < 7.05 and admission to neonatal unit for > 48 h.

Discussion: Results from this pilot trial will help determine whether a large definitive trial is feasible. Such a study would provide evidence to guide management of women with RFM and reduce stillbirths.

Trial Registration: ISRCTN Registry, ISRCTN12067514 . Registered on 8 September 2017.
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http://dx.doi.org/10.1186/s13063-018-2859-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167841PMC
October 2018