Vaginal dinoprostone versus Foley catheter for induction of labor at term with an unfavorable cervix: an open-label randomized controlled trial.

BACKGROUND: Induction of labor with mechanical methods or pharmacological agents is used in about 20-30% of all pregnant women. We specialized in comparing the effectiveness and safety of dinoprostone versus transcervical Foley catheter for induction of labor in term pregnant women with an unfavorable cervix with adequate samples. OBJECTIVE: To compare the effectiveness and safety of dinoprostone versus transcervical Foley catheter for induction of labor in term pregnant women with an unfavorable cervix. STUDY DESIGN: This is a parallel, open-label randomized controlled trial in two maternal centers in Shanghai, China between October 2019 and July 2022. Women with a singleton pregnancy in cephalic presentation at term and an unfavorable cervix (Bishop score < 6) scheduled for induction of labor were eligible. 1,860 women were randomly allocated to cervical ripening with either a dinoprostone vaginal insert (10mg) or a 60cc Foley catheter for up to 24 hours. The primary outcomes were vaginal delivery rate and time to vaginal delivery. Secondary outcomes included time to delivery and maternal and neonatal morbidity. Analysis was done from an intention-to-treat perspective. The trial was registered with the China trial registry (CTR2000038435). RESULTS: The vaginal birth rates were 72.8% (677/930) vs. 69.9% (650/930) in vaginal dinoprostone and Foley catheter, respectively (aRR 1.04, 95% CI 0.98 to 1.10, risk difference: 0.03). Time to vaginal delivery was not significantly different between the two groups (sub-distribution hazard ratio 1.11, 95% CI 0.99-1.24). Vaginal dinoprostone was more likely complicated with hyperstimulation with fetal heart rate changes (5.8% vs. 2.8%, aRR 2.09, 95% CI 1.32-3.31) and placenta abruption (0.9% vs. 0.1%, aRR: 8.04, 95% CI 1.01-64.15), while Foley catheter was more likely complicated with suspected intrapartum infection (5.1% vs. 8.2 %, aRR: 0.62, 95% CI 0.44-0.88) and postpartum infection (1.4% vs. 3.7%, aRR: 0.38, 95% CI 0.20-0.72). The composite of poor neonatal outcomes was not significantly different between the two groups (4.5% vs. 3.8%, aRR 1.21, 95% CI 0.78 to 1.88), while more neonatal asphyxia occurred in the dinoprostone group (1.2% vs. 0.2%, aRR 5.39, 95% CI 1.22 to 23.92). In a subgroup analysis, vaginal dinoprostone decreased vaginal birth rate slightly in multiparous women (90.6% vs. 97.0%, aRR 0.93, 95% CI 0.88 to 0.99). CONCLUSIONS: In term pregnant women with an unfavorable cervix, induction of labor with vaginal dinoprostone or Foley catheter has similar effectiveness. Foley catheter leads to better safety for neonates, while it may result in a higher risk of maternal infection. Furthermore, Foley catheter should be preferred in multiparous women.

Regional variation in health care substitution for intrauterine device insertion: a retrospective cohort study.

BACKGROUND: Rising health care costs are a major concern in most Western countries. The substitution of healthcare stands as a strategic approach aimed at mitigating costs while offering medical services in proximity to patients' residences. An illustrative instance involves the migration of outpatient hospital care to primary care settings. Notably, the insertion of intrauterine devices (IUDs) can be safely executed within primary care contexts. In order to establish a pragmatic objective for the rate of IUD substitution, we conducted an evaluation of regional disparities in healthcare substitution pertaining to the insertion of intrauterine devices. Furthermore, we investigated disparities in the follow-up ultrasound and reinsertion of IUDs between primary and secondary healthcare environments. METHODS: All women who underwent IUD insertion in Dutch primary care (by general practitioners and midwives) and secondary care (by hospital physicians) between January 1, 2016, and December 31, 2020 were included. The main outcome measures were the case-mix adjusted IUD insertion rates at the regional level by care setting and the proportions requiring follow-up ultrasound and IUD reinsertion within three months. RESULTS: Of the 840,766 IUD placements, 74% were inserted in primary care and 26% in secondary care. The proportion inserted in primary care increased from 70% in 2016 to 77% in 2020. The observed substitution rate ranged from 58 to 82% between regions. Compared with health care professionals in primary care, those in secondary care performed more ultrasounds to verify IUD placement (23% vs. 3%; p-value < 0.01) and more IUD reinsertions within three months (6% vs. 2%; p-value < 0.01). CONCLUSIONS: IUDs are increasingly being inserted in Dutch primary care, with peak regional IUD insertion care substitution rates at ≥ 80%. IUD insertion care substitution to primary care appears to be associated with significantly fewer women having follow-up ultrasound or IUD reinsertion within three months.

Neurodevelopmental outcomes of school-age children conceived after hysterosalpingography with oil-based or water-based iodinated contrast: long-term follow-up of a nationwide randomized controlled trial.

STUDY QUESTION: Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children's neurodevelopment compared with exposure to water-based alternatives? SUMMARY ANSWER: Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives. WHAT IS KNOWN ALREADY: HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women's iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG. STUDY DESIGN, SIZE, DURATION: This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012-2014; NTR3270). Of 369 children born <6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: The study included 69 children aged 6-9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups. MAIN RESULTS AND THE ROLE OF CHANCE: School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant. LIMITATIONS, REASONS FOR CAUTION: The small sample size of this follow-up study limited statistical power. This study provides evidence for the absence of large-sized differences between preconceptional exposure to the two contrast media types but does not rule out more subtle effects on neurodevelopment compared to naturally conceived children without preconceptional exposure to HSG. WIDER IMPLICATIONS OF THE FINDINGS: This study contributes to our knowledge about the long-term effects of different types of iodinated contrast media used in fertility work-up, indicating that choosing oil-based over water-based iodinated contrast media is unlikely to have major effect on the long-term neurodevelopmental outcomes of children conceived shortly after HSG. However, further research should focus on the overall safety of iodine exposure during HSG, comparing children conceived after HSG to those conceived naturally as both types of contrast contain high amounts of iodine. STUDY FUNDING/COMPETING INTEREST(S): The original H2Oil randomized controlled trial was an investigator-initiated study that was funded by the two academic hospitals now merged into the Amsterdam University Medical Centre. The current follow-up study (Neuro-H2Oil) is funded through a research grant awarded to the authors by the Amsterdam Reproduction & Development (AR&D) research institute. S.K. is funded by a AMC MD/PhD Scholarship from the Amsterdam UMC. S.K. reports holding voluntary roles in the civil society organizations Universities Allied for Essential Medicines and People's Health Movement. V.M. reports receiving travel and speaker fees as well as research grants from Guerbet, Merck and Ferring. K.D. reports receiving travel and speaker fees as well as research grants from Guerbet. BWM is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy, travel support and research funding from Merck, consultancy for Organon and Norgine, and holding stock from ObsEva. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: NCT05168228.

The effect of prior hysterosalpingo-foam sonography or hysterosalpingography on tubal patency: a secondary analysis of a randomized controlled trial.

STUDY QUESTION: Does hysterosalpingo-foam sonography (HyFoSy) prior to hysterosalpingography (HSG) or HSG prior to HyFoSy affect visible tubal patency when compared HSG or HyFoSy alone? SUMMARY ANSWER: Undergoing either HyFoSy or HSG prior to tubal patency testing by the alternative method does not demonstrate a significant difference in visible tubal patency when compared to HyFoSy or HSG alone. WHAT IS KNOWN ALREADY: HyFoSy and HSG are two commonly used visual tubal patency tests with a high and comparable diagnostic accuracy for evaluating tubal patency. These tests may also improve fertility, although the underlying mechanism is still not fully understood. One of the hypotheses points to a dislodgment of mucus plugs that may have disrupted the patency of the Fallopian tubes. STUDY DESIGN, SIZE, DURATION: This is a secondary analysis of the randomized controlled FOAM study, in which women underwent tubal patency testing by HyFoSy and HSG, randomized for order of the procedure. Participants either had HyFoSy first and then HSG, or vice versa. Here, we evaluate the relative effectiveness of tubal patency testing by HyFoSy or HSG prior to the alternative tubal patency testing method on visible tubal patency, compared to each method alone. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women aged between 18 and 41 years scheduled for tubal patency testing were eligible for participating in the FOAM study. Women with anovulatory cycles, endometriosis, or with a partner with male infertility were excluded. To evaluate the effect HyFoSy on tubal patency, we relied on HSG results by comparing the proportion of women with bilateral tubal patency visible on HSG in those who underwent and who did not undergo HyFoSy prior to their HSG (HyFoSy prior to HSG versus HSG alone). To evaluate the effect of HSG on tubal patency, we relied on HyFoSy results by comparing the proportion of women with bilateral tubal patency visible on HyFoSy in those who underwent and who did not undergo HSG prior to their HyFoSy (HSG prior to HyFoSy versus HyFoSy alone). MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, we randomized 1160 women (576 underwent HyFoSy first followed by HSG, and 584 underwent HSG first followed by HyFoSy). Among the women randomized to HyFoSy prior to HSG, bilateral tubal patency was visible on HSG in 467/537 (87%) women, compared with 472/544 (87%) women who underwent HSG alone (risk difference 0.2%; 95% CI: -3.8% to 4.2%). Among the women randomized to HSG prior to HyFoSy, bilateral tubal patency was visible on HyFoSy in 394/471 (84%) women, compared with 428/486 (88%) women who underwent HyFoSy alone (risk difference -4.4%; 95% CI: -8.8% to 0.0%). LIMITATIONS, REASONS FOR CAUTION: The results of this secondary analysis should be interpreted as exploratory and cannot be regarded as definitive evidence. Furthermore, it has to be noted that pregnancy outcomes were not considered in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: Tubal patency testing by either HyFoSy or HSG, prior to the alternative tubal patency testing method does not significantly affect visible tubal patency, when compared to alternative method alone. This suggests that both methods may have comparable abilities to dislodge mucus plugs in the Fallopian tubes. STUDY FUNDING/COMPETING INTEREST(S): The FOAM study was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, or interpretation of the data. H.R.V. reports consultancy fees from Ferring. M.v.W. received a travel grant from Oxford University Press in the role of Deputy Editor for Human Reproduction and participates in a Data Safety and Monitoring Board as an independent methodologist in obstetrics studies in which she has no other role. M.v.W. is coordinating editor of Cochrane Fertility and Gynaecology. B.W.J.M. received an investigator grant from NHMRC (GNT1176437) and research funding from Merck KGaA. B.W.J.M. reports consultancy for Organon and Merck KGaA, and travel support from Merck KGaA. B.W.J.M. reports holding stocks of ObsEva. V.M. received research grants from Guerbet, Merck and Ferring and travel and speaker fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.

The Individual Participant Data Integrity Tool for assessing the integrity of randomised trials.

Increasing concerns about the trustworthiness of research have prompted calls to scrutinise studies' Individual Participant Data (IPD), but guidance on how to do this was lacking. To address this, we developed the IPD Integrity Tool to screen randomised controlled trials (RCTs) for integrity issues. Development of the tool involved a literature review, consultation with an expert advisory group, piloting on two IPD meta-analyses (including 73 trials with IPD), preliminary validation on 13 datasets with and without known integrity issues, and evaluation to inform iterative refinements. The IPD Integrity Tool comprises 31 items (13 study-level, 18 IPD-specific). IPD-specific items are automated where possible, and are grouped into eight domains, including unusual data patterns, baseline characteristics, correlations, date violations, patterns of allocation, internal and external inconsistencies, and plausibility of data. Users rate each item as having either no issues, some/minor issue(s), or many/major issue(s) according to decision rules, and justification for each rating is recorded. Overall, the tool guides decision-making by determining whether a trial has no concerns, some concerns requiring further information, or major concerns warranting exclusion from evidence synthesis or publication. In our preliminary validation checks, the tool accurately identified all five studies with known integrity issues. The IPD Integrity Tool enables users to assess the integrity of RCTs via examination of IPD. The tool may be applied by evidence synthesists, editors and others to determine whether an RCT should be considered sufficiently trustworthy to contribute to the evidence base that informs policy and practice.

Development of the individual participant data integrity tool for assessing the integrity of randomised trials using individual participant data.

Increasing integrity concerns in medical research have prompted the development of tools to detect untrustworthy studies. Existing tools primarily assess published aggregate data (AD), though scrutiny of individual participant data (IPD) is often required to detect trustworthiness issues. Thus, we developed the IPD Integrity Tool for detecting integrity issues in randomised trials with IPD available. This manuscript describes the development of this tool. We conducted a literature review to collate and map existing integrity items. These were discussed with an expert advisory group; agreed items were included in a standardised tool and automated where possible. We piloted this tool in two IPD meta-analyses (including 116 trials) and conducted preliminary validation checks on 13 datasets with and without known integrity issues. We identified 120 integrity items: 54 could be conducted using AD, 48 required IPD, and 18 were possible with AD, but more comprehensive with IPD. An initial reduced tool was developed through consensus involving 13 advisors, featuring 11 AD items across four domains, and 12 IPD items across eight domains. The tool was iteratively refined throughout piloting and validation. All studies with known integrity issues were accurately identified during validation. The final tool includes seven AD domains with 13 items and eight IPD domains with 18 items. The quality of evidence informing healthcare relies on trustworthy data. We describe the development of a tool to enable researchers, editors, and others to detect integrity issues using IPD. Detailed instructions for its application are published as a complementary manuscript in this issue.

Early magnesium discontinuation postpartum and eclampsia risk: A systematic review and meta-analysis.

INTRODUCTION: The optimal duration of magnesium administration postpartum for prevention of eclampsia has not yet been established. Our objective was to investigate the effect of early discontinuation of postpartum magnesium on the rates of postpartum eclampsia compared to continuation for 24-hours postpartum. MATERIAL AND METHODS: Searches were performed using keywords related to "preeclampsia" and "magnesium sulfate" from inception of database until August 2023. Randomized controlled trials of women with preeclampsia were included if they received magnesium prior to delivery and were randomized to early discontinuation versus 24-hours of magnesium postpartum. The primary outcome was the rate of postpartum eclampsia. RESULTS: Nine RCTs with 2183 women were included with five different magnesium administration time frames. In total, seven patients with postpartum eclampsia were reported in three studies. Eclampsia rates were not different between the two groups (5/1088 (0.5 %) after early discontinuation, versus 2/1095 (0.2 %) in the 24-hour group; RR 2.25, 95 % CI 0.5-9.9, I2 = 0 %, 8 studies, 2183 participants). A number needed to treat was calculated; 374 women would need to receive 24-hours of magnesium postpartum to prevent one episode of postpartum eclampsia. The early discontinuation group had a significant decrease in time to ambulation (-9.1 h, 95 % CI -14.7 - (-3.6), I2 = 98 %, 3 studies, 1509 participants) and breastfeeding (-8.4 h, 95 % CI -12.0 - (-4.8), I2 = 98 %, 2 studies, 1397 participants). CONCLUSIONS: Early magnesium discontinuation postpartum, usually ≤6 h or none at all, did not significantly increase the rate of postpartum eclampsia, however this study is likely underpowered to demonstrate a difference. The number needed to treat is similar to the number needed to treat for antepartum preeclampsia without severe features, for which magnesium is not recommended. The largest proportion of women did not receive magnesium postpartum after receiving at least 8 h of magnesium intrapartum (e.g., loading and maintenance dose). Thus, it is reasonable to consider not using magnesium postpartum, particularly if a woman has received similar adequate dose prior to delivery.

PhIGFBP-1 to predict preterm birth in asymptomatic women: A systematic review and meta-analysis.

OBJECTIVE: To assess the prognostic value of cervicovaginal phosphorylated insulin-like growth factor-binding protein 1 (phIGFBP-1) to predict preterm birth in asymptomatic women during the second trimester of pregnancy. STUDY DESIGN: This is a systematic review and meta-analysis of prognostic factor studies. We searched MEDLINE and Embase to identify cohort studies on the prognostic value of mid-trimester phIGFBP-1 on preterm birth in asymptomatic women. We included studies with singleton and twin gestations if they did not receive treatment to reduce the risk of preterm birth. Two reviewers independently screened the titles and abstracts, evaluated full-text articles, extracted the data and performed the risk of bias assessment using the QUIPS tool. The primary outcome was preterm birth < 37 weeks' gestation. We conducted random-effects meta-analyses, with subgroup analyses on populations with different preterm birth risks. RESULTS: We included 17 studies with a total of 7618 participants. PhIGFBP-1 positive was associated with higher odds of preterm birth (12 studies, 7466 participants, OR 3.87, 95 %CI 1.60-9.32, I2 87 %). When stratifying by population, phIGFBP-1 positive was associated with higher odds of preterm birth in women with no prior history of preterm birth (6 studies, OR 4.43, 95 %CI 2.50-7.84) but not in women with risk factors for preterm birth (6 studies, OR 1.59, 95 %CI 0.57-4.42). Risk of bias due to confounding was high in included studies. CONCLUSIONS: While the prognostic value of PhIGFBP-1 in the prediction of preterm birth is a prognostic research question, it has been often treated as a diagnostic research question in the literature. PhIGFBP-1 may be a potential biomarker to predict PTB during mid-trimester in asymptomatic women, especially for women with low risk of PTB. However, the clinical value of phIGFBP-1 remains limited due to bias in confounding. Future research should use the prognostic research framework to address such questions on biomarkers to maximise the clinical implications.

Addition of operative hysteroscopy to vacuum aspiration for the management of early pregnancy loss after in vitro fertilization.

OBJECTIVE: To investigate whether operative hysteroscopy in addition to vacuum aspiration for the management of early pregnancy loss effectively increases the success rate of subsequent frozen embryo transfer. DESIGN: Propensity score-matched cohort study. SETTING: Academic hospital. PATIENT(S): Women with a miscarriage at 5-16 gestational weeks during an in vitro fertilization cycle in Peking University Third Hospital from 2015 to 2022. INTERVENTION(S): Hysteroscopy plus vacuum aspiration vs. conventional vacuum aspiration. MAIN OUTCOME MEASURE(S): Live birth rate in the subsequent frozen embryo transfer. RESULT(S): A total of 347 women who underwent vacuum aspiration plus hysteroscopy and 2,562 women who underwent conventional vacuum aspiration were included in the analysis. After propensity score matching (1:1 ratio), 325 women were included in each group. Compared with women who underwent vacuum aspiration, those who underwent vacuum aspiration plus hysteroscopy were associated with a lower rate of live birth in the propensity score-based matched cohort (22% vs. 30%; adjusted odds ratio, 0.68 [0.47-0.97]). Biochemical, clinical, and multiple pregnancy rates were not significantly different, as was the miscarriage rate. In the overall cohort, 11 women experienced surgery reintervention in the vacuum aspiration group (0.4%), whereas none required surgery reintervention in the vacuum aspiration plus hysteroscopy group. CONCLUSION(S): Women who underwent vacuum aspiration plus hysteroscopy may be associated with lower rates of live birth than those who underwent vacuum aspiration. Further studies are necessary to establish this relationship definitively.

Modelling and comparing the use of IVF and ICSI in Australia.

PURPOSE: This study estimates the need of IVF/ICSI in Australia as compared to its actual uptake. METHODS: We created a model estimating for the annual demand for IVF/ICSI in a hypothetical infertile population, using demographic data from medical literature and Australian government databases. For each category of infertility (tubal, severe male, endometriosis, anovulation and unexplained), our estimated need for IVF/ICSI was compared to the actual IVF/ICSI uptake (ANZARD 2019). The model consisted of three categories depending on couples' cause of infertility, i.e. couples with absolute indications for IVF/ICSI (couples with severe male factor infertility and tubal obstruction); couples with anovulatory infertility (couples with ovulation disorders) and couples with ovulatory infertility (couples suffering from unexplained infertility and endometriosis). The model was applied to each of these categories to determine the number of couples that would require IVF/ICSI treatment after failing to conceive naturally or after following alternative treatment plans. The main outcomes of this study were the estimate of IVF/ICSI cycles and the difference between the estimate and the reported number of IVF/ICSI cycles (2019 ANZARD report). RESULTS: We estimated that approximately 35,300 couples required IVF/ICSI treatment in Australia in 2019, while in 2019 according to ANZARD, 46,000 couples underwent IVF/ICSI. A higher uptake of IVF/ICSI cycles than expected was specifically reported in couples with unexplained infertility, ovulation disorders and endometriosis, while for tubal and severe male infertility uptake seemed adequate. CONCLUSION: In Australia, there seems to be overservicing of IVF/ICSI, specifically for unexplained, ovulatory and endometriosis-related infertility.

Characteristics of preterm births during COVID-19 mitigation measures.

BACKGROUND: During the COVID-19 pandemic, mitigation measures were associated with a reduction in preterm birth rates; while not clearly proven, this observation has sparked significant interest. AIM: To understand the cause of this reduction by exploring the characteristics of preterm birth cohorts. MATERIAL AND METHODS: We performed a retrospective cohort study where we compared women who delivered preterm in three Melbourne maternity hospitals and conceived between November 2019 and February 2020 (mitigation measures-exposed cohort) to women who delivered preterm and conceived between November 2018 and February 2019 (non-exposed cohort). We compared maternal characteristics, pregnancy complications, antenatal interventions, intrapartum care, and indications for delivery. RESULTS: In the exposed cohort, 252/3129 women delivered preterm (8.1%), vs 298/3154 (9.4%) in the non-exposed cohort (odds ratio (OR) 0.84, 95% CI 0.70-1.00, P = 0.051). The baseline characteristic of two cohorts were comparable. Rates of spontaneous preterm labour (sPTL) without preterm pre-labour rupture of membranes (PPROM) were lower in the exposed cohort (13.1% vs 24.2%, OR 0.47, P = 0.001) while PPROM occurred more often (48.0% vs 35.6%, OR 1.67, P = 0.003). With a non-statistically significant prolongation of pregnancy in the cohort exposed to mitigation measures for both sPTL without PPROM (35.4 vs 34.9 weeks, P = 0.703) and PPROM (35.6 vs 34.9 weeks, P = 0.184). The rate of spontaneous labour after PPROM was higher in the exposed cohort compared to the non-exposed cohort (40.1% vs 24.1%, OR 2.09, P < 0.001). CONCLUSION: The reduction in preterm delivery during mitigation measures may have been driven by a reduction in spontaneous labour without PPROM, which seemed to result in more PPROM later in pregnancy.

Panel stacking is a threat to consensus statement validity.

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members toward one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but nonfinancial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analyzing in depth a recent high-impact Delphi consensus statement on COVID-19 recommendations as a case example. We demonstrate that many of the selected panel members and at least 35% of the core panel members had advocated toward COVID-19 elimination (Zero-COVID) during the pandemic and were leading members of aggressive advocacy groups. These advocacy conflicts were not declared in the Delphi consensus publication, with rare exceptions. Therefore, we propose that consensus statements should always require rigorous evidence synthesis and maximal transparency on potential biases toward advocacy or lobbyist groups to be valid. While advocacy can have many important functions, its biased impact on consensus panels should be carefully avoided.

Livebirth rate after one frozen embryo transfer in ovulatory women starting with natural, modified natural, or artificial endometrial preparation in Viet Nam: an open-label randomised controlled trial.

BACKGROUND: Use of frozen embryo transfer (FET) in in-vitro fertilisation (IVF) has increased. However, the best endometrial preparation protocol for FET cycles is unclear. We compared natural and modified natural cycle strategies with an artificial cycle strategy for endometrial preparation before FET. METHODS: In this randomised, open-label study, we recruited ovulatory women aged 18-45 years at a hospital in Ho Chi Minh City, Viet Nam, who were randomly allocated (1:1:1) to natural, modified natural, or artificial cycle endometrial preparation using a computer-generated random list and block randomisation. The trial was not masked due to the nature of the study interventions. In natural cycles, no oestrogen, progesterone, or human chorionic gonadotropin (hCG) was used. In modified natural cycles, hCG was used to trigger ovulation. In artificial cycles, oral oestradiol valerate (8 mg/day from day 2-4 of menstruation) and vaginal progesterone (800 mg/day starting when endometrial thickness was ≥7 mm) were used. Embryos were vitrified, and then one or two day-3 embryos or one day-5 embryo were warmed and transferred under ultrasound guidance. If the first FET cycle was cancelled, subsequent cycles were performed with artificial endometrial preparation. The primary endpoint was livebirth after one FET. This trial is registered at ClinicalTrials.gov, NCT04804020. FINDINGS: Between March 22, 2021, and March 14, 2023, 4779 women were screened and 1428 were randomly assigned (476 to each group). 99 first FET cycles were cancelled in each of the natural and modified cycle groups, versus none in the artificial cycle group. The livebirth rate after one FET was 174 (37%) of 476 in the natural cycle strategy group, 159 (33%) of 476 in the modified natural cycle strategy group, and 162 (34%) of 476 in the artificial cycle strategy group (relative risk 1·07 [95% CI 0·87-1·33] for natural vs artificial cycle strategy, and 0·98 [0·79-1·22] for modified natural vs artificial cycle strategy). Maternal and neonatal outcomes did not differ significantly between groups, as the power to detect small differences was low. INTERPRETATION: Although the livebirth rate was similar after natural, modified natural, and artificial cycle endometrial preparation strategies in ovulatory women undergoing FET IVF, no definitive conclusions can be made regarding the comparative safety of the three approaches. FUNDING: None.

Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial.

INTRODUCTION: Preterm pre-eclampsia is a leading cause of maternal morbidity and mortality. The Pre-eclampsia Intervention 2 (PI 2) trial suggested that metformin sustained release (XR) may prolong gestation by a week in pregnant women undergoing expectant management (7.6 days, geometric mean ratio 1.39, 95% CI 0.99 to 1.95; p=0.057). These findings should be confirmed with a larger sample size, and we need to know if such a prolongation improves neonatal outcome. Here, we describe the protocol for such a follow-up trial. METHODS: The PI 3 trial is a phase III, intention-to-treat, double-blind, placebo-controlled randomised clinical trial to assess if metformin XR can prolong gestation and improve neonatal outcomes in women undergoing expectant management for preterm pre-eclampsia. We will recruit women who are between 26+0 and 31+6 weeks pregnant. Women will be randomised to receive either 3 g metformin XR or an identical placebo in divided daily doses. The primary outcome is prolongation of pregnancy. Secondary outcomes are neonatal birth weight and length of neonatal care admission (an indicator of neonatal health at birth). All other outcomes will be exploratory. We will record tolerability and adverse events. We plan a sample size of 500 participants to be powered for the primary and secondary outcomes. ETHICS AND DISSEMINATION: PI 3 has ethical approval (Health Research Ethics Committee 2, Stellenbosch University, Protocol number M21/03/007, Project ID 21639, Federal Wide Assurance Number 00001372, Institutional Review Board Number IRB0005239), and is registered with the Pan African Clinical Trial Registry (PACTR202104532026017) and the South African Medicine Control Council (20211211). Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: PACTR202104532026017).

A 24-Months Follow-Up Study of Individuals With Endometriosis Using Transvaginal Ultrasound.

STUDY OBJECTIVE: To investigate the progression of deep infiltrating endometriosis using transvaginal ultrasound surveillance of patients undergoing conservative management. DESIGN: Retrospective single cohort. SETTING: Australian tertiary university hospital PATIENTS: One hundred twenty two women with endometriosis proven on transvaginal ultrasound who had not undergone surgical management. INTERVENTIONS: The progression of endometriosis lesions demonstrated on transvaginal ultrasound in women receiving conservative management over the course of 24 months. MEASUREMENTS AND MAIN RESULTS: A total of 122 patients fulfilled the inclusion criteria. All women had 2 ultrasounds that were performed at least 6 months apart. The median follow-up time was 490.5 days (255.4-725.6). At second scan, 22% (95% CI: 15-30%) of cohort experienced an increase in the number of endometriosis nodules compared to first scan, with 51% (95% CI: 42-60%) remaining static while 27% (95% CI: 19-35%) experienced a decrease. While there was no statistically significant difference in the volumes of uterosacral ligament, retro cervical, and bowel endometriosis, endometrioma volumes were significantly lower at second scan (Median = 3.24 mL, IQR = 0.6-16.87) as compared to the first scan (Median = 7.41 mL, IQR = 2.04-28.95), p <.001. CONCLUSION: Individuals with deep infiltrating endometriosis are unlikely to see significant disease progression over time. Both surgical and nonsurgical interventions are effective in managing endometriosis in terms of endometriotic nodule size and number, as measured by ultrasound.

[Not all published data are reliable: fabricated data in medical research]. / Niet alle gepubliceerde data zijn betrouwbaar.

For a long time, the reliability of medical-scientific research was, without further verification, based on real data. It is becoming increasingly clear that this assumption is unjustified and that probably at least 25% of published randomized clinical trials are based on unreliable and sometimes even fabricated data. After giving a number of examples, it is discussed what the reader can do about this problem. More importantly, editors and publishers should no longer rely on whistle-blowers but take action themselves. If this does not happen, external parties must intervene. Society cannot afford (medical) science that is based on unreliable data.

Study protocol for two randomised controlled trials evaluating the effects of Cerclage in the reduction of extreme preterm birth and perinatal mortality in twin pregnancies with a short cervix or dilatation: the TWIN Cerclage studies.

INTRODUCTION: Twin pregnancies have a high risk of extreme preterm birth (PTB) at less than 28 weeks of gestation, which is associated with increased risk of neonatal morbidity and mortality. Currently there is a lack of effective treatments for women with a twin pregnancy and a short cervix or cervical dilatation. A possible effective surgical method to reduce extreme PTB in twin pregnancies with an asymptomatic short cervix or dilatation at midpregnancy is the placement of a vaginal cerclage. METHODS AND ANALYSIS: We designed two multicentre randomised trials involving eight hospitals in the Netherlands (sites in other countries may be added at a later date). Women older than 16 years with a twin pregnancy at <24 weeks of gestation and an asymptomatic short cervix of ≤25 mm or cervical dilatation will be randomly allocated (1:1) to both trials on vaginal cerclage and standard treatment according to the current Dutch Society of Obstetrics and Gynaecology guideline (no cerclage). Permuted blocks sized 2 and 4 will be used to minimise the risk of disbalance. The primary outcome measure is PTB of <28 weeks. Analyses will be by intention to treat. The first trial is to demonstrate a risk reduction from 25% to 10% in the short cervix group, for which 194 patients need to be recruited. The second trial is to demonstrate a risk reduction from 80% to 35% in the dilatation group and will recruit 44 women. A cost-effectiveness analysis will be performed from a societal perspective. ETHICS AND DISSEMINATION: This study has been approved by the Research Ethics Committees in the Netherlands on 3/30/2023. Participants will be required to sign an informed consent form. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT05968794.

Data integrity of 14 randomised controlled trials.

BACKGROUND: A review of the literature on iron treatments for iron-deficient anaemia in pregnancy indicated duplication of baseline and outcome tables in two separate randomised controlled trials (RCTs) that share only a single author. AIM: To assess the integrity of randomised clinical trials from Dr A.M. Darwish, Assiut University, Egypt. DESIGN: Assessment of Research Integrity. METHODS: We tabulated the characteristics of studies, compared baseline and outcome tables between articles and looked for implausible findings. We used the distribution of baseline p-values to assess whether the summary statistics of baseline characteristics were consistent with properly conducted randomisation. RESULTS: We identified 14 RCTs (1,405 participants) published between October 2004 and September 2019. Two pairs of studies showed considerable similarities in baseline characteristics, while another pair of studies was plagiarized. The analysis of baseline p-values indicated a low probability that all the studies featured randomised treatment allocation. CONCLUSION: Our analysis of the RCTs of Dr Darwish suggests possible integrity problems. We recommend a critical investigation of the studies that have not been retracted. Until that has been completed, these studies should not be used to inform clinical practice.