Objective
To evaluate whether a particular group of women with intrahepatic cholestasis of pregnancy (ICP), based on their presenting characteristics, would benefit from treatment with ...ursodeoxycholic acid (UDCA).
Design
Secondary analysis of the PITCHES trial (ISRCTN91918806).
Setting
United Kingdom.
Population or Sample
527 women with ICP.
Methods
Subgroup analyses were performed to determine whether baseline bile acid concentrations or baseline itch scores moderated a woman’s response to treatment with UDCA.
Main outcome measures
Bile acid concentration and itch score.
Results
In women with baseline bile acid concentrations less than 40 μmol/l, treatment with UDCA resulted in increased post‐randomisation bile acid concentrations (geometric mean ratio 1.19, 95% CI 1.00–1.41, P = 0.048). A test of interaction showed no significance (P = 0.647). A small, clinically insignificant difference was seen in itch response in women with a high baseline itch score (–6.0 mm, 95% CI −11.80 to −0.21, P = 0.042), with a test of interaction not showing significance (P = 0.640). Further subgroup analyses showed no significance. Across all women there was a weak relationship between bile acid concentrations and itch severity.
Conclusions
There was no subgroup of women with ICP in whom a beneficial effect of treatment with UDCA on bile acid concentration or itch score could be identified. This confirms that its routine use in women with this condition for improvement of bile acid concentration or itch score should be reconsidered.
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PITCHES: No group of women with ICP has been found in whom UDCA reduces bile acid concentrations or pruritus.
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PITCHES: No group of women with ICP has been found in whom UDCA reduces bile acid concentrations or pruritus.
Background
Progestogens have been evaluated in numerous trials and meta‐analyses, many of which concluded they were effective. However, two large trials PROMISE and OPPTIMUM have recently concluded ...that progesterone was ineffective. This raises the possibility that earlier studies and reviews had been biased by either selective publication or selective choice of outcomes, so called “P‐hacking”.
Objectives
To compare the findings all progestogen trials and systematic reviews with those of trials with pre‐registered primary outcomes which avoided selective outcome reporting.
Search strategy
Search of PubMed, the Cochrane Library and trial registries. Registration PROSPERO CRD42016035303.
Selection criteria
Systematic reviews of randomised trials comparing progestogen with placebo in pregnancy and the individual trials included in those reviews. The subset of trials reporting a pre‐registered primary outcome were compared with the totality of trials and reviews.
Data collection and analysis
For reviews all outcomes were included. For individual trials all outcomes reported in the systematic reviews were included. For the comparison group we recorded the registered primary outcome from trials that were either registered before they started, or registered during the recruitment phase and also double blind.
Main results
Nineteen of twenty‐nine meta‐analyses concluded that progestogens were effective. Twenty‐two trials reported their pre‐registered primary outcomes. There was no effect of progesterone on primary registered dichotomous outcome RR 1.00 (95% CI 0.94–1.07). Only one of the 22 showed a nominally statistically significant benefit.
Author's conclusions
When evaluated in registered double‐blind trials with analysis restricted to predefined primary outcomes, progestational agents in pregnancy are ineffective.
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Progestogens to prevent pregnancy loss, an example of P‐hacking.
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Progestogens to prevent pregnancy loss, an example of P‐hacking.
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.
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.
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.
We searched MEDLINE, EMBASE and the Cochrane Library from inception to June 2019.
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.
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.
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.
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.
We describe proof-of-principle randomised controlled trials that could better inform the case for screening using ultrasound in late pregnancy.
This study is registered as PROSPERO CRD42017064093.
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.
Background
Women with a suspected large‐for‐dates fetus or a fetus with suspected macrosomia (birthweight greater than 4000 g) are at risk of operative birth or caesarean section. The baby is also at ...increased risk of shoulder dystocia and trauma, in particular fractures and brachial plexus injury. Induction of labour may reduce these risks by decreasing the birthweight, but may also lead to longer labours and an increased risk of caesarean section.
Objectives
To assess the effects of a policy of labour induction at or shortly before term (37 to 40 weeks) for suspected fetal macrosomia on the way of giving birth and maternal or perinatal morbidity.
Search methods
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2016), contacted trial authors and searched reference lists of retrieved studies.
Selection criteria
Randomised trials of induction of labour for suspected fetal macrosomia.
Data collection and analysis
Review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We contacted study authors for additional information. For key outcomes the quality of the evidence was assessed using the GRADE approach.
Main results
We included four trials, involving 1190 women. It was not possible to blind women and staff to the intervention, but for other 'Risk of bias' domains these studies were assessed as being at low or unclear risk of bias.
Compared to expectant management, there was no clear effect of induction of labour for suspected macrosomia on the risk of caesarean section (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.76 to 1.09; 1190 women; four trials, moderate‐quality evidence) or instrumental delivery (RR 0.86, 95% CI 0.65 to 1.13; 1190 women; four trials, low‐quality evidence). Shoulder dystocia (RR 0.60, 95% CI 0.37 to 0.98; 1190 women; four trials, moderate‐quality evidence), and fracture (any) (RR 0.20, 95% CI 0.05 to 0.79; 1190 women; four studies, high‐quality evidence) were reduced in the induction of labour group. There were no clear differences between groups for brachial plexus injury (two events were reported in the control group in one trial, low‐quality evidence). There was no strong evidence of any difference between groups for measures of neonatal asphyxia; low five‐minute infant Apgar scores (less than seven) or low arterial cord blood pH (RR 1.51, 95% CI 0.25 to 9.02; 858 infants; two trials, low‐quality evidence; and, RR 1.01, 95% CI 0.46 to 2.22; 818 infants; one trial, moderate‐quality evidence, respectively).
Mean birthweight was lower in the induction group, but there was considerable heterogeneity between studies for this outcome (mean difference (MD) ‐178.03 g, 95% CI ‐315.26 to ‐40.81; 1190 infants; four studies; I2 = 89%).
For outcomes assessed using GRADE, we based our downgrading decisions on high risk of bias from lack of blinding and imprecision of effect estimates.
Authors' conclusions
Induction of labour for suspected fetal macrosomia has not been shown to alter the risk of brachial plexus injury, but the power of the included studies to show a difference for such a rare event is limited. Also antenatal estimates of fetal weight are often inaccurate so many women may be worried unnecessarily, and many inductions may not be needed. Nevertheless, induction of labour for suspected fetal macrosomia results in a lower mean birthweight, and fewer birth fractures and shoulder dystocia. The observation of increased use of phototherapy in the largest trial, should also be kept in mind.
Findings from trials included in the review suggest that to prevent one fracture it would be necessary to induce labour in 60 women. Since induction of labour does not appear to alter the rate of caesarean delivery or instrumental delivery, it is likely to be popular with many women. In settings where obstetricians can be reasonably confident about their scan assessment of fetal weight, the advantages and disadvantages of induction at or near term for fetuses suspected of being macrosomic should be discussed with parents.
Although some parents and doctors may feel the evidence already justifies induction, others may justifiably disagree. Further trials of induction shortly before term for suspected fetal macrosomia are needed. Such trials should concentrate on refining the optimum gestation of induction, and improving the accuracy of the diagnosis of macrosomia.
Second-stage caesarean sections, of which there are around 34,000 per year in the UK, have greater maternal and perinatal morbidity than those in the first stage. The fetal head is often deeply ...impacted in the maternal pelvis, and extraction can be difficult. Numerous techniques are reported, but the superiority of one over another is contentious and there is no national guidance.
To determine the feasibility of a randomised trial of different techniques for managing an impacted fetal head during emergency caesarean.
A scoping study with five work packages: (1) national surveys to determine current practice and acceptability of research in this area, and a qualitative study to determine acceptability to women who have experienced a second-stage caesarean; (2) a national prospective observational study to determine incidence and rate of complications; (3) a Delphi survey and consensus meeting on choice of techniques and outcomes for a trial; (4) the design of a trial; and (5) a national survey and qualitative study to determine acceptability of the proposed trial.
Secondary care.
Health-care professionals, pregnant women, women who have had a second-stage caesarean, and parents.
Most (244/279, 87%) health-care professionals believe that a trial in this area would help guide their practice, and 90% (252/279) would be willing to participate in such a trial. Thirty-eight per cent (98/259) of parents reported that they would take part. Women varied in which technique they thought was most acceptable. Our observational study found that impacted head is common (occurring in 16% of second-stage caesareans) and leads to both maternal (41%) and neonatal (3.5%) complications. It is most often treated by an assistant pushing the head up vaginally. We designed a randomised clinical trial comparing the fetal pillow with the vaginal push technique. The vast majority of health-care professionals, 83% of midwives and 88% of obstetricians, would be willing to participate in the trial proposed, and 37% of parents reported that they would take part. Our qualitative study found that most participants thought the trial would be feasible and acceptable.
Our survey is subject to the limitation that, although responses refer to contemporaneous real cases, they are self-reported by the surgeon and collected after the event. Willingness to participate in a hypothetical trial may not translate into recruitment to a real trial.
We proposed a trial to compare a new device, the fetal pillow, with a long-established procedure, the vaginal push technique. Such a trial would be widely supported by health-care professionals. We recommend that it be powered to test an effect on important short term maternal and baby outcomes which would require 754 participants per group. Despite the well-known difference between intent and action, this would be feasible within the UK.
We recommend a randomised controlled trial of two techniques for managing an impacted fetal head with an in-built internal pilot phase and alongside economic and qualitative substudies.
This study is registered as Research Registry 4942.
This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 27, No. 6. See the NIHR Journals Library website for further project information.
Blast injury is common in current warfare, but little is known about the effects of blast-related mild traumatic brain injury (mTBI). Profile analyses were conducted investigating differences in ...self-reported postconcussive (PC) symptoms in 339 veteran outpatients with mTBI histories reporting current symptoms based on mechanism of injury (blast only, nonblast only, or both blast and nonblast), number of blast injuries, and distance from the blast. Veterans with any blast-related mTBI history were younger and reported higher posttraumatic stress symptoms than veterans with nonblast-related mTBI histories, with a marginally significant difference in posttraumatic stress symptom report between veterans reporting blast-related mTBI only and those reporting nonblast-related mTBI. The groups did not differ in terms of PC symptom severity or PC symptom cluster profiles. Among veterans with blast-related mTBI histories, PC symptom report did not vary by number of blast-related mTBIs or proximity to blast. Overall, posttraumatic stress symptoms accounted for a substantial portion of variance in PC symptom report. In veteran outpatients with remote mTBI histories who have enduring symptom complaints related to the mTBI, mechanism of injury did not clearly contribute to differential PC symptom severity or PC symptom cluster profile. Proximal rather than distal factors may be important intervention targets in returning symptomatic veterans with mTBI histories.
Objective
To examine the association between pre‐eclampsia definition and pregnancy outcome.
Design
Secondary analysis of Control of Hypertension in Pregnancy Study (CHIPS) trial data.
Setting
...International multicentre randomised controlled trial (RCT).
Population
In all, 987 women with non‐severe non‐proteinuric pregnancy hypertension.
Methods
We evaluated the association between pre‐eclampsia definitions and adverse pregnancy outcomes, stratified by hypertension type and blood pressure control.
Main outcome measures
Main CHIPS trial outcomes: primary (perinatal loss or high‐level neonatal care for >48 hours), secondary (serious maternal complications), birthweight <10th centile, severe maternal hypertension, delivery at <34 or <37 weeks, and maternal hospitalisation before birth.
Results
Of 979/987 women with informative data, 280 (28.6%) progressed to pre‐eclampsia defined restrictively by new proteinuria, and 471 (48.1%) to pre‐eclampsia defined broadly as proteinuria or one/more maternal symptoms, signs or abnormal laboratory tests. The broad (versus restrictive) definition had significantly higher sensitivities (range 62–79% versus 36–50%), lower specificities (range 53–65% versus 72–82%), and similar or higher diagnostic odds ratios and ‘true‐positive’ to ‘false‐positive’ ratios. Stratified analyses showed similar results. Addition of available fetoplacental manifestations (stillbirth or birthweight <10th centile) to the broad pre‐eclampsia definition improved sensitivity (74–87%).
Conclusions
A broad (versus restrictive) pre‐eclampsia definition better identifies women who develop adverse pregnancy outcomes. These findings should be replicated in a prospective study within routine healthcare to ensure that the anticipated increase in surveillance and intervention in a larger number of women with pre‐eclampsia is associated with improved outcomes, reasonable costs and congruence with women's values.
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A broad (versus restrictive) pre‐eclampsia definition better identifies the risk of adverse pregnancy outcomes.
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A broad (versus restrictive) pre‐eclampsia definition better identifies the risk of adverse pregnancy outcomes.
This article includes Author Insights, a video available at https://vimeo.com/rcog/authorinsights16602
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