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Background: Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high‐risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored. Objectives: To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP. Search strategy: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023. Selection criteria: We included placebo‐controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications. Data collection and analysis: We extracted absolute event numbers for HDP and pre‐eclampsia in women receiving vaginal progesterone or placebo, and meta‐analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology. Main results: The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53–0.93, 2 RCTs, n = 4431 women, I2 = 0%; moderate‐certainty evidence) and pre‐eclampsia (RR 0.61, 95% CI 0.41–0.92, 3 RCTs, n = 5267 women, I2 = 0%; moderate‐certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67–2.12, 3 RCTs, n = 1602 women, I2 = 9%; low‐certainty evidence) or pre‐eclampsia (RR 0.97, 95% CI 0.71–1.31, 5 RCTs, n = 4274 women, I2 = 0%; low‐certainty evidence). Conclusions: Our systematic review found first‐trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre‐eclampsia. [ABSTRACT FROM AUTHOR]

Problem: Recurrent implantation failure (RIF) after multiple embryo transfers remains a vexing problem and immunomodulators have been used with conflicting results. This study aims to assess the effect of immunomodulation therapy on live birth rate (LBR) in women with RIF undergoing assisted reproduction treatment (ART). Method of study design: This is a retrospective cohort study in multicentre network of private assisted conception units in the UK. The study included women who had at least two failed attempts of embryo transfers at CARE fertility network in the period from 1997 to 2018. Women in the treatment group had immunomodulator drugs in the form of corticosteroids, low molecular weight heparin (LMWH), and intravenous intralipid (IVIL) infusions, either separately or in combination, after immunological testing, in addition to standard ART whilst women in the control group had only ART without immunomodulators. The primary outcome was LBR per cycle. Secondary outcomes included the rates of clinical pregnancy (CPR), cumulative live birth (CLBR), and miscarriage. Results: A total of 27 163 ART cycles fulfilled the inclusion criteria, of which 5083 had immunomodulation treatment in addition to standard ART treatment, and 22 080 had standard ART treatment alone. Women in the treatment group were significantly older (mean age 38.5 vs. 37.1 years, p <.001), and had a higher number of previous failed ART cycles (mean 4.3 vs. 3.8, p <.01). There was a higher LBR in women who received immunomodulation therapy when compared with the control group (20.9% vs. 15.8%, odds ratio [OR] 1.4, 95% confidence interval [CI] 1.29–1.53, p <.001). Multivariate regression analysis showed that immunomodulation treatment was a significant independent predictor of live birth after adjusting for other confounders (adjusted OR [aOR] 1.33, 95% CI 1.15–1.54, p <.001). Survival analysis showed a higher CLBR in the treatment group (adjusted hazard ratio [aHR] 1.78, 95% CI 1.62–1.94, p <.001). Conclusion(s): This study provides evidence of a potential beneficial effect of immunomodulation therapy in women with RIF after immunological testing. There remains a need for high quality, adequately powered multicentre RCTs to robustly address the role of immunomodulation in women with RIF. There is also an urgent need for standardised screening tests for immune disorders that could preclude implantation. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether a Bayesian interpretation might help prevent misinterpretation of statistical findings and support authors to differentiate evidence of no effect from statistical uncertainty. Design: A Bayesian re‐analysis to determine posterior probabilities of clinically important effects (e.g., a large effect is set at a 4 percentage point difference and a trivial effect to be within a 0.5 percentage point difference). Posterior probabilities greater than 95% are considered as strong statistical evidence, and less than 95% as inconclusive. Sample: 150 major women's health trials with binary outcomes. Main Outcome Measures: Posterior probabilities of large, moderate, small and trivial effects. Results: Under frequentist methods, 48 (32%) were statistically significant (p‐value ≤ 0.05) and 102 (68%) statistically non‐significant. The frequentist and Bayesian point estimates and confidence intervals showed strong concordance. Of the statistically non‐significant trials (n = 102), the Bayesian approach classified the majority (94, 92%) as inconclusive, neither able to confirm or refute effectiveness. A small number of statistically non‐significant findings (8, 8%) were classified as having strong statistical evidence of an effect. Conclusions: Whilst almost all trials report confidence intervals, in practice most statistical findings are interpreted on the basis of statistical significance, mostly concluding evidence of no effect. Findings here suggest the majority are likely uncertain. A Bayesian approach could help differentiate evidence of no effect from statistical uncertainty. [ABSTRACT FROM AUTHOR]

Objective: To investigate the compatibility of oxytocin and tranexamic acid injection products when mixed for the purpose of co‐administration by intravenous infusion. Design: Compatibility testing. Setting: Hospitals taking part in a multicentre postpartum haemorrhage treatment (E‐MOTIVE) trial in Kenya, Nigeria, Tanzania and South Africa. Sample: Oxytocin and tranexamic acid products. Methods: The compatibility of two sentinel products of oxytocin injection and tranexamic acid injection in 200‐mL infusion bags of both 0.9% w/v saline and Ringer's lactate solution was assessed. We analysed all tranexamic acid–oxytocin combinations, and each evaluation was conducted for up to 3 h. Subsequently, the compatibility of multiple tranexamic acid products with reference oxytocin products when mixed in 0.9% w/v saline over a period of 1 h was investigated. Main outcome measures: Concentration of oxytocin over time after mixing with tranexamic acid products. Results: We found significant interaction between certain oxytocin and tranexamic acid products after mixing them in vitro and observing for 1 h. The interaction substantially impacted oxytocin content leading to reduction in concentration (14.8%–29.0%) immediately on mixing (t = 0 min). In some combinations, the concentration continued to decline throughout the stability assessment period. Oxytocin loss was observed in 7 out of 22 (32%) of combinations tested. Conclusions: In a clinical setting, mixing certain oxytocin and tranexamic acid products before administration may result in an underdosing of oxytocin, compromising care in an emergency life‐threatening situation. The mixing of oxytocin and tranexamic acid injection products for co‐administration with intravenous infusion fluids should be avoided until the exact nature of the observed interaction and its implications are understood. [ABSTRACT FROM AUTHOR]

Plain language summary: The thyroid is a gland located in the neck and is important for many processes in the body. Problems with the thyroid gland are common in women of reproductive age. It is essential to have a normal working thyroid gland in order to achieve a successful pregnancy. One of the most common problems with the thyroid is underactivity (known as hypothyroidism). An early, mild form of an underactive thyroid is called subclinical hypothyroidism. Often people with this condition do not have any symptoms. Another common problem is thyroid autoimmunity. Here, the immune system attacks the thyroid gland, sometimes leading to the development of abnormal thyroid function. This can be diagnosed by the presence of proteins in the bloodstream called antibodies. Mild thyroid problems and the presence of high levels of thyroid antibodies have been linked to miscarriage and premature birth. There is debate in medicine about whether there should be routine testing of thyroid function both in the general population and in individuals who are trying for a baby. In addition, the strategies used to manage certain thyroid problems are questioned. Discussions around testing and subsequent management particularly relate to women with a history of subfertility or repeated miscarriages. This Scientific Impact Paper provides information on thyroid testing and the management of mild thyroid problems and thyroid antibodies in women with a history of subfertility or recurrent miscarriages, using the latest evidence and guidelines. It concludes that there may be a role for treating these women with thyroxine tablets (the hormone produced by the thyroid gland) when subclinical hypothyroidism is present, and gives guidance on the cut‐off levels for treatment. [ABSTRACT FROM AUTHOR]

Objectives: Recombinant granulocyte colony‐stimulating factor (G‐CSF) is frequently administered to patients with cancer to enhance granulocyte recovery post‐chemotherapy. Clinical trials have also used G‐CSF to modulate myeloid cell function in pregnancy and inflammatory diseases. Although the contribution of G‐CSF to expanding normal granulocytes is well known, the effect of this cytokine on the phenotype and function of immunosuppressive granulocytic cells remains unclear. Here, we investigate the impact of physiological and iatrogenic G‐CSF on an as yet undescribed granulocyte phenotype and ensuing outcome on T cells in the settings of cancer and pregnancy. Methods: Granulocytes from patients treated with recombinant G‐CSF, patients with late‐stage cancer and women enrolled on a trial of recombinant G‐CSF were phenotyped by flow cytometry. The ability and mechanism of polarised granulocytes to suppress T‐cell proliferation were assessed by cell proliferation assays, flow cytometry and ELISA. Results: We observed that G‐CSF leads to a significant upregulation of CD14 expression on CD15+ granulocytes. These CD15+CD14+ cells are identified in the blood of patients with patients undergoing neutrophil mobilisation with recombinant G‐CSF, and physiologically in women early in pregnancy or in those treated as a part of a clinical trial. Immunohistochemistry of tumor tissue or placental tissue identified the expression of G‐CSF. The G‐CSF upregulates the release of reactive oxygen species (ROS) in CD15+CD14+ cells leading to the suppression of T‐cell proliferation. Conclusions: G‐CSF induces a population of ROS+ immunosuppressive CD15+CD14+ granulocytes. Strategies for how recombinant G‐CSF can be scheduled to reduce effects on T‐cell therapies should be developed in future clinical studies. [ABSTRACT FROM AUTHOR]

Objective: Stillbirth is a potentially preventable complication of pregnancy. Identifying women at high risk of stillbirth can guide decisions on the need for closer surveillance and timing of delivery in order to prevent fetal death. Prognostic models have been developed to predict the risk of stillbirth, but none has yet been validated externally. In this study, we externally validated published prediction models for stillbirth using individual participant data (IPD) meta-analysis to assess their predictive performance.Methods: MEDLINE, EMBASE, DH-DATA and AMED databases were searched from inception to December 2020 to identify studies reporting stillbirth prediction models. Studies that developed or updated prediction models for stillbirth for use at any time during pregnancy were included. IPD from cohorts within the International Prediction of Pregnancy Complications (IPPIC) Network were used to validate externally the identified prediction models whose individual variables were available in the IPD. The risk of bias of the models and cohorts was assessed using the Prediction study Risk Of Bias ASsessment Tool (PROBAST). The discriminative performance of the models was evaluated using the C-statistic, and calibration was assessed using calibration plots, calibration slope and calibration-in-the-large. Performance measures were estimated separately in each cohort, as well as summarized across cohorts using random-effects meta-analysis. Clinical utility was assessed using net benefit.Results: Seventeen studies reporting the development of 40 prognostic models for stillbirth were identified. None of the models had been previously validated externally, and the full model equation was reported for only one-fifth (20%, 8/40) of the models. External validation was possible for three of these models, using IPD from 19 cohorts (491 201 pregnant women) within the IPPIC Network database. Based on evaluation of the model development studies, all three models had an overall high risk of bias, according to PROBAST. In the IPD meta-analysis, the models had summary C-statistics ranging from 0.53 to 0.65 and summary calibration slopes ranging from 0.40 to 0.88, with risk predictions that were generally too extreme compared with the observed risks. The models had little to no clinical utility, as assessed by net benefit. However, there remained uncertainty in the performance of some models due to small available sample sizes.Conclusions: The three validated stillbirth prediction models showed generally poor and uncertain predictive performance in new data, with limited evidence to support their clinical application. The findings suggest methodological shortcomings in their development, including overfitting. Further research is needed to further validate these and other models, identify stronger prognostic factors and develop more robust prediction models. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Objective: To determine the accuracy of ultrasonographically estimated fetal weight (EFW) and abdominal circumference (AC) in the prediction of macrosomia. Design: Systematic quantitative review. Methods: Studies were identified without language restrictions from MEDLINE (1966-2003), EMBASE (1980-2003), Cochrane Library (2003:4), SCISEARCH (1974-2003) and manual searching of bibliographies of known primary and review articles. Studies were selected if accuracy of ultrasonographically EFW or AC was evaluated for predicting macrosomia using birthweight as the reference standard. Data were extracted on study characteristics, quality and accuracy. Data were pooled to produce summary receiver operating characteristic curves (sROC) for studies with various test thresholds. Summary likelihood ratios for positive (LR+) and negative (LR-) test results were generated for an EFW of 4000 g and an AC of 36 cm for predicting birthweight of over 4000 g. Main Outcome Measures: Birthweight over various thresholds. Results: There were 36 primary articles consisting of 63 accuracy studies (51 evaluating the accuracy of EFW, and 12 accuracy of fetal AC), including a total of 19,117 women. The sROC area for EFW was not different from the area for fetal AC (0.87 vs 0.85, P= 0.91). For predicting a birthweight of over 4000 g, the summary LRs were 5.7 (95% CI: 4.3 to 7.6) for a positive test and 0.48 (95% CI: 0.38 to 0.60) for a negative test, using Hadlock's method of ultrasonographically estimating fetal weight. For ultrasound fetal AC of 36 cm, the respective LRs for predicting a birthweight over 4000 g were 6.9 (95% CI: 5.2 to 9.0) and 0.37 (0.30-0.45). Conclusion: There is no difference in accuracy between ultrasonographically EFW and AC in the prediction of a macrosomic baby at birth. A positive test result is more accurate for ruling in macrosomia than a negative test result for ruling it out. [ABSTRACT FROM AUTHOR]

Reviews tubal evaluation tests for their inter- and intra-observer reliability, accuracy to predict tubal blockage and disease, prognostic value for treatment-independent pregnancies, effectiveness to improve pregnancy outcome and possible complications. Review of the related literature; Selection of the studies in two-stage process; Discussion on the hysterosalpingography test; Information on fertiloscopy.

The article discusses the launch of the United Kingdom Early Pregnancy Surveillance Service (UKEPSS) in February 14, 2014 which aimed to investigate uncommon disorders in emergency gynaecology and early pregnancy in Great Britain. It states the use of UKEPPS platform in the nationwide collaboration to improve knowledge and provide better care in women. It also mentions the significant of research outputs and improvement in patient care under the healthcare system National Health Service (NHS).

The article discusses various reports published within the issue, including one on the risks off women who have gestational diabetes mellitus to have diabetes in the future and another on the implications of obesity for pregnancy.

Presents information on the system set up for registering protocols for systematic reviews of clinical studies that will be published in "BJOG: An International Journal of Obstetrics and Gynaecology." Types of clinical studies being reviewed in the journal; Benefits of the protocols to readers and systematic reviewers of studies; Availability of instructions for registering review protocols.

Provides information on registering protocols for studies of test accuracy with "BJOG: An International Journal of Obstetrics and Gynaecology. Objective of the BJOG for setting up facilities for clinical researchers to register their randomized controlled trial protocols for electronic publication; Requirements for reporting test accuracy studies.

Background: Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored., Objectives: To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP., Search Strategy: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023., Selection Criteria: We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications., Data Collection and Analysis: We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology., Main Results: The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I 2  = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I 2  = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I 2  = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I 2  = 0%; low-certainty evidence)., Conclusions: Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To investigate whether a Bayesian interpretation might help prevent misinterpretation of statistical findings and support authors to differentiate evidence of no effect from statistical uncertainty., Design: A Bayesian re-analysis to determine posterior probabilities of clinically important effects (e.g., a large effect is set at a 4 percentage point difference and a trivial effect to be within a 0.5 percentage point difference). Posterior probabilities greater than 95% are considered as strong statistical evidence, and less than 95% as inconclusive., Sample: 150 major women's health trials with binary outcomes., Main Outcome Measures: Posterior probabilities of large, moderate, small and trivial effects., Results: Under frequentist methods, 48 (32%) were statistically significant (p-value ≤ 0.05) and 102 (68%) statistically non-significant. The frequentist and Bayesian point estimates and confidence intervals showed strong concordance. Of the statistically non-significant trials (n = 102), the Bayesian approach classified the majority (94, 92%) as inconclusive, neither able to confirm or refute effectiveness. A small number of statistically non-significant findings (8, 8%) were classified as having strong statistical evidence of an effect., Conclusions: Whilst almost all trials report confidence intervals, in practice most statistical findings are interpreted on the basis of statistical significance, mostly concluding evidence of no effect. Findings here suggest the majority are likely uncertain. A Bayesian approach could help differentiate evidence of no effect from statistical uncertainty., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To develop core outcome sets (COS) for miscarriage management and prevention., Design: Modified Delphi survey combined with a consensus development meeting., Setting: International., Population: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention., Methods: Modified Delphi method and modified nominal group technique., Results: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes., Conclusions: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Objective: To investigate the compatibility of oxytocin and tranexamic acid injection products when mixed for the purpose of co-administration by intravenous infusion., Design: Compatibility testing., Setting: Hospitals taking part in a multicentre postpartum haemorrhage treatment (E-MOTIVE) trial in Kenya, Nigeria, Tanzania and South Africa., Sample: Oxytocin and tranexamic acid products., Methods: The compatibility of two sentinel products of oxytocin injection and tranexamic acid injection in 200-mL infusion bags of both 0.9% w/v saline and Ringer's lactate solution was assessed. We analysed all tranexamic acid-oxytocin combinations, and each evaluation was conducted for up to 3 h. Subsequently, the compatibility of multiple tranexamic acid products with reference oxytocin products when mixed in 0.9% w/v saline over a period of 1 h was investigated., Main Outcome Measures: Concentration of oxytocin over time after mixing with tranexamic acid products., Results: We found significant interaction between certain oxytocin and tranexamic acid products after mixing them in vitro and observing for 1 h. The interaction substantially impacted oxytocin content leading to reduction in concentration (14.8%-29.0%) immediately on mixing (t = 0 min). In some combinations, the concentration continued to decline throughout the stability assessment period. Oxytocin loss was observed in 7 out of 22 (32%) of combinations tested., Conclusions: In a clinical setting, mixing certain oxytocin and tranexamic acid products before administration may result in an underdosing of oxytocin, compromising care in an emergency life-threatening situation. The mixing of oxytocin and tranexamic acid injection products for co-administration with intravenous infusion fluids should be avoided until the exact nature of the observed interaction and its implications are understood., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

The use of tranexamic acid for postpartum hemorrhage has entered obstetrical practice globally with the evidence-based expectation of saving lives. This improvement in the care of women with postpartum hemorrhage has come at a price. For the anesthetist, having tranexamic acid ampoules close at hand would seem an obvious strategy to facilitate its use during cesarean delivery, an important setting for severe hemorrhage. Tragically, we have identified a number of recent instances of inadvertent intrathecal administration of tranexamic acid instead of local anesthetic for spinal anesthesia. Reported cases of this catastrophic error seem to be increasing. The profound neurotoxicity of tranexamic acid causes rapid-onset convulsions, with mortality of 50%. How can these tragic errors be averted? Drug safety alerts have been issued by the US Food and Drug Administration and the World Health Organization, but that is not enough. We recommend extensive dissemination of information to raise awareness of this potential hazard, and local hospital protocols to ensure that tranexamic acid is stored separately from anesthetic drugs, preferably outside the operating room and with an auxiliary warning label. Implementation of safety strategies on a very large scale will be needed to ensure that the life-saving potential of tranexamic acid is not eclipsed by drug-error mortality., (© 2022 The Authors. Published by Elsevier Inc /Elsevier B.V./ Wiley on behalf of The International Federation of Gynecology and Obstetrics (FIGO) / John Wiley & Son Ltd.)

The thyroid is a gland located in the neck and is important for many processes in the body. Problems with the thyroid gland are common in women of reproductive age. It is essential to have a normal working thyroid gland in order to achieve a successful pregnancy. One of the most common problems with the thyroid is underactivity (known as hypothyroidism). An early, mild form of an underactive thyroid is called subclinical hypothyroidism. Often people with this condition do not have any symptoms. Another common problem is thyroid autoimmunity. Here, the immune system attacks the thyroid gland, sometimes leading to the development of abnormal thyroid function. This can be diagnosed by the presence of proteins in the bloodstream called antibodies. Mild thyroid problems and the presence of high levels of thyroid antibodies have been linked to miscarriage and premature birth. There is debate in medicine about whether there should be routine testing of thyroid function both in the general population and in individuals who are trying for a baby. In addition, the strategies used to manage certain thyroid problems are questioned. Discussions around testing and subsequent management particularly relate to women with a history of subfertility or repeated miscarriages. This Scientific Impact Paper provides information on thyroid testing and the management of mild thyroid problems and thyroid antibodies in women with a history of subfertility or recurrent miscarriages, using the latest evidence and guidelines. It concludes that there may be a role for treating these women with thyroxine tablets (the hormone produced by the thyroid gland) when subclinical hypothyroidism is present, and gives guidance on the cut-off levels for treatment., (© 2022 Royal College of Obstetricians and Gynaecologists.)