Magnesium Sulfate Before Preterm Birth for Neuroprotection: An Updated Cochrane Systematic Review.

OBJECTIVE: To systematically review the evidence for the effectiveness and safety of magnesium sulfate as a fetal neuroprotective agent when given to individuals at risk of preterm birth. DATA SOURCES: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (through March 17, 2023), and reference lists of relevant studies. METHODS OF STUDY SELECTION: Randomized controlled trials (RCTs) assessing magnesium sulfate for fetal neuroprotection in pregnant participants at risk of imminent preterm birth were eligible. Two authors assessed RCTs for inclusion, extracted data, and evaluated risk of bias, trustworthiness, and evidence certainty (GRADE [Grading of Recommendations Assessment, Development and Evaluation]). TABULATION, INTEGRATION, AND RESULTS: We included six RCTs (5,917 pregnant participants and 6,759 fetuses at less than 34 weeks of gestation at randomization). They were conducted in high-income countries (two in the United States, two across Australia and New Zealand, and one each in Denmark and France) and commenced between 1995 and 2018. Primary outcomes: up to 2 years of corrected age, magnesium sulfate compared with placebo reduced the risk of cerebral palsy (risk ratio [RR] 0.71, 95% CI, 0.57-0.89; six RCTs, 6,107 children) and death or cerebral palsy (RR 0.87, 95% CI, 0.77-0.98; six RCTs, 6,481 children) (high-certainty evidence). Magnesium sulfate had little or no effect on death up to 2 years of corrected age (moderate-certainty evidence) or these outcomes at school age (low-certainty evidence). Although there was little or no effect on death or cardiac or respiratory arrest for pregnant individuals (low-certainty evidence), magnesium sulfate increased adverse effects severe enough to stop treatment (RR 3.21, 95% CI, 1.88-5.48; three RCTs, 4,736 participants; moderate-certainty evidence). Secondary outcome: magnesium sulfate reduced the risk of severe neonatal intraventricular hemorrhage (moderate-certainty evidence). CONCLUSION: Magnesium sulfate for preterm fetal neuroprotection reduces cerebral palsy and death or cerebral palsy for children. Further research is required on longer-term benefits and harms for children, effect variation by participant and treatment characteristics, and the generalizability of findings to low- and middle-income countries. SYSTEMATIC REVIEW REGISTRATION: The review protocol was based on a standard Cochrane Pregnancy and Childbirth template and our previous Cochrane Systematic Review (doi: 10.1002/14651858.CD004661.pub3; published before the introduction of PROSPERO).

Lifestyle and sociodemographic risk factors for stillbirth by region of residence in South Australia: a retrospective cohort study.

BACKGROUND: Stillbirth rates remain a global priority and in Australia, progress has been slow. Risk factors of stillbirth are unique in Australia due to large areas of remoteness, and limited resource availability affecting the ability to identify areas of need and prevalence of factors associated with stillbirth. This retrospective cohort study describes lifestyle and sociodemographic factors associated with stillbirth in South Australia (SA), between 1998 and 2016. METHODS: All restigered births in SA between 1998 ad 2016 are included. The primary outcome was stillbirth (birth with no signs of life ≥ 20 weeks gestation or ≥ 400 g if gestational age was not reported). Associations between stillbirth and lifestyle and sociodemographic factors were evaluated using multivariable logistic regression and described using adjusted odds ratios (aORs). RESULTS: A total of 363,959 births (including 1767 stillbirths) were included. Inadequate antenatal care access (assessed against the Australian Pregnancy Care Guidelines) was associated with the highest odds of stillbirth (aOR 3.93, 95% confidence interval (CI) 3.41-4.52). Other factors with important associations with stillbirth were plant/machine operation (aOR, 1.99; 95% CI, 1.16-2.45), birthing person age ≥ 40 years (aOR, 1.92; 95% CI, 1.50-2.45), partner reported as a pensioner (aOR, 1.83; 95% CI, 1.12-2.99), Asian country of birth (aOR, 1.58; 95% CI, 1.19-2.10) and Aboriginal/Torres Strait Islander status (aOR, 1.50; 95% CI, 1.20-1.88). The odds of stillbirth were increased in regional/remote areas in association with inadequate antenatal care (aOR, 4.64; 95% CI, 2.98-7.23), birthing age 35-40 years (aOR, 1.92; 95% CI, 1.02-3.64), Aboriginal and/or Torres Strait Islander status (aOR, 1.90; 95% CI, 1.12-3.21), paternal occupations: tradesperson (aOR, 1.69; 95% CI, 1.17-6.16) and unemployment (aOR, 4.06; 95% CI, 1.41-11.73). CONCLUSION: Factors identified as independently associated with stillbirth odds include factors that could be addressed through timely access to adequate antenatal care and are likely relevant throughout Australia. The identified factors should be the target of stillbirth prevention strategies/efforts. SThe stillbirth rate in Australia is a national concern. Reducing preventable stillbirths remains a global priority.

Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus.

BACKGROUND: Magnesium sulphate is a common therapy in perinatal care. Its benefits when given to women at risk of preterm birth for fetal neuroprotection (prevention of cerebral palsy for children) were shown in a 2009 Cochrane review. Internationally, use of magnesium sulphate for preterm cerebral palsy prevention is now recommended practice. As new randomised controlled trials (RCTs) and longer-term follow-up of prior RCTs have since been conducted, this review updates the previously published version. OBJECTIVES: To assess the effectiveness and safety of magnesium sulphate as a fetal neuroprotective agent when given to women considered to be at risk of preterm birth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 17 March 2023, as well as reference lists of retrieved studies. SELECTION CRITERIA: We included RCTs and cluster-RCTs of women at risk of preterm birth that assessed prenatal magnesium sulphate for fetal neuroprotection compared with placebo or no treatment. All methods of administration (intravenous, intramuscular, and oral) were eligible. We did not include studies where magnesium sulphate was used with the primary aim of preterm labour tocolysis, or the prevention and/or treatment of eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed RCTs for inclusion, extracted data, and assessed risk of bias and trustworthiness. Dichotomous data were presented as summary risk ratios (RR) with 95% confidence intervals (CI), and continuous data were presented as mean differences with 95% CI. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included six RCTs (5917 women and their 6759 fetuses alive at randomisation). All RCTs were conducted in high-income countries. The RCTs compared magnesium sulphate with placebo in women at risk of preterm birth at less than 34 weeks' gestation; however, treatment regimens and inclusion/exclusion criteria varied. Though the RCTs were at an overall low risk of bias, the certainty of evidence ranged from high to very low, due to concerns regarding study limitations, imprecision, and inconsistency. Primary outcomes for infants/children: Up to two years' corrected age, magnesium sulphate compared with placebo reduced cerebral palsy (RR 0.71, 95% CI 0.57 to 0.89; 6 RCTs, 6107 children; number needed to treat for additional beneficial outcome (NNTB) 60, 95% CI 41 to 158) and death or cerebral palsy (RR 0.87, 95% CI 0.77 to 0.98; 6 RCTs, 6481 children; NNTB 56, 95% CI 32 to 363) (both high-certainty evidence). Magnesium sulphate probably resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.96, 95% CI 0.82 to 1.13; 6 RCTs, 6759 children); major neurodevelopmental disability (RR 1.09, 95% CI 0.83 to 1.44; 1 RCT, 987 children); or death or major neurodevelopmental disability (RR 0.95, 95% CI 0.85 to 1.07; 3 RCTs, 4279 children) (all moderate-certainty evidence). At early school age, magnesium sulphate may have resulted in little to no difference in death (fetal, neonatal, or later) (RR 0.82, 95% CI 0.66 to 1.02; 2 RCTs, 1758 children); cerebral palsy (RR 0.99, 95% CI 0.69 to 1.41; 2 RCTs, 1038 children); death or cerebral palsy (RR 0.90, 95% CI 0.67 to 1.20; 1 RCT, 503 children); and death or major neurodevelopmental disability (RR 0.81, 95% CI 0.59 to 1.12; 1 RCT, 503 children) (all low-certainty evidence). Magnesium sulphate may also have resulted in little to no difference in major neurodevelopmental disability, but the evidence is very uncertain (average RR 0.92, 95% CI 0.53 to 1.62; 2 RCTs, 940 children; very low-certainty evidence). Secondary outcomes for infants/children: Magnesium sulphate probably reduced severe intraventricular haemorrhage (grade 3 or 4) (RR 0.76, 95% CI 0.60 to 0.98; 5 RCTs, 5885 infants; NNTB 92, 95% CI 55 to 1102; moderate-certainty evidence) and may have resulted in little to no difference in chronic lung disease/bronchopulmonary dysplasia (average RR 0.92, 95% CI 0.77 to 1.10; 5 RCTs, 6689 infants; low-certainty evidence). Primary outcomes for women: Magnesium sulphate may have resulted in little or no difference in severe maternal outcomes potentially related to treatment (death, cardiac arrest, respiratory arrest) (RR 0.32, 95% CI 0.01 to 7.92; 4 RCTs, 5300 women; low-certainty evidence). However, magnesium sulphate probably increased maternal adverse effects severe enough to stop treatment (average RR 3.21, 95% CI 1.88 to 5.48; 3 RCTs, 4736 women; moderate-certainty evidence). Secondary outcomes for women: Magnesium sulphate probably resulted in little to no difference in caesarean section (RR 0.96, 95% CI 0.91 to 1.02; 5 RCTs, 5861 women) and postpartum haemorrhage (RR 0.94, 95% CI 0.80 to 1.09; 2 RCTs, 2495 women) (both moderate-certainty evidence). Breastfeeding at hospital discharge and women's views of treatment were not reported. AUTHORS' CONCLUSIONS: The currently available evidence indicates that magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus, compared with placebo, reduces cerebral palsy, and death or cerebral palsy, in children up to two years' corrected age, and probably reduces severe intraventricular haemorrhage for infants. Magnesium sulphate may result in little to no difference in outcomes in children at school age. While magnesium sulphate may result in little to no difference in severe maternal outcomes (death, cardiac arrest, respiratory arrest), it probably increases maternal adverse effects severe enough to stop treatment. Further research is needed on the longer-term benefits and harms for children, into adolescence and adulthood. Additional studies to determine variation in effects by characteristics of women treated and magnesium sulphate regimens used, along with the generalisability of findings to low- and middle-income countries, should be considered.

Neonatal magnesium sulphate for neuroprotection: A systematic review and meta-analysis.

AIM: To review the evidence of the effects of neonatal magnesium sulphate for neuroprotection in perinatal asphyxia and hypoxic-ischaemic encephalopathy (HIE). METHOD: This was a systematic review of randomized controlled trials (RCTs) (with meta-analysis) and non-RCTs assessing magnesium sulphate for treating perinatal asphyxia and HIE at 35 weeks or more gestation (primary outcomes: neonatal death and death or long-term major neurodevelopmental disability). RESULTS: Twenty-five RCTs (2099 infants) and four non-RCTs (871 infants) were included, 23 in low- and middle-income countries (LMICs). In RCTs, reductions in neonatal death with magnesium sulphate versus placebo or no treatment (risk ratio [RR] = 0.68; 95% confidence interval [CI] = 0.53-0.86; 13 RCTs), and magnesium sulphate with melatonin versus melatonin alone (RR = 0.74; 95% CI = 0.58-0.95; one RCT) were observed. No difference in neonatal death was seen for magnesium sulphate with therapeutic hypothermia versus therapeutic hypothermia alone (RR = 0.66, 95% CI = 0.34-1.26; three RCTs), or magnesium sulphate versus phenobarbital (RR = 3.00; 95% CI = 0.86-10.46; one RCT). No reduction in death or long-term neurodevelopmental disability (RR = 0.52; 95% CI = 0.14-1.89; one RCT) but reductions in several short-term adverse outcomes were observed with magnesium sulphate. Evidence was low- to very-low certainty because of risk of bias and imprecision. INTERPRETATION: Given the uncertainty of the current evidence, further robust neonatal magnesium sulphate research is justified. This may include high-quality studies to determine stand-alone effects in LMICs and effects with and after therapeutic hypothermia in high-income countries.

Scleral Buckle Removal: Long-Term Patient Outcomes.

PURPOSE: Scleral buckling has been a reliable treatment option in the repair of primary rhegmatogenous retinal detachments. Occasionally, patients require scleral buckles (SBs) to be removed for various reasons. While outcomes of SB removal have been investigated in this subset of patients, there has not been any large patient series to reach any conclusions. Long-term sequelae of SB removal are debated in the literature, specifically around the risk of redetachment. DESIGN: We performed a retrospective, observational study to evaluate the clinical indications for, and outcomes of, SB removal. PARTICIPANTS: No control patients in this retrospective, observational study. METHODS: Eighty-six individuals with a history of SB removal from June 1, 2000, to January 1, 2021, were followed from a large academic center and a private, retina-only practice in Chicago. Exclusion criteria were age of < 18 years and unplanned or self-explanted SB removal. MAIN OUTCOME MEASURES: Data extracted included patient symptoms before SB removal, indications for removal, resolution of symptoms following removal, rate of redetachment, and rate of additional ocular surgery. Secondary outcomes included identifying factors associated with poorer outcomes. RESULTS: Eighty-six eyes with history of SB removal were included with an average follow-up of 4 years. Approximately 60% were males and the mean age at the time of SB removal was 59 years. Leading indications for removal were exposure (61.63%), infection (20.93%), and diplopia/strabismus (19.77%). The average time from SB placement to removal was 12.28 ± 11.16 years. Most patients requiring SB removal presented with symptoms, specifically of pain and discomfort (65.12%), diplopia (22.09%), and drainage/discharge (18.60%). Of these patients, 86.59% experienced symptom resolution following SB removal. Notably, 6.56% (4 eyes) of all eyes with at least 1 year of follow-up experienced a redetachment requiring surgery. Within this subset, the average time from SB placement to removal was 2.05 ± 2.01 years and time to redetachment following removal was 15.95 ± 25.71 months. Nine percent of all eyes required additional strabismus or oculoplastic surgery. CONCLUSIONS: Scleral buckle removal provides a high rate of symptomatic relief and low risk of subsequent detachment. Nevertheless, close monitoring is warranted to monitor for recurrent retinal detachments. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

CHARACTERISTICS, OUTCOMES, AND OPTICAL COHERENCE TOMOGRAPHY FEATURES OF MACULAR HOLE AFTER RHEGMATOGENOUS RETINAL DETACHMENT REPAIR.

PURPOSE: To investigate full-thickness macular holes (FTMHs) that develop after rhegmatogenous retinal detachment (RRD) repair. METHODS: Retrospective consecutive case series of patients who underwent RRD repair between 2015 and 2021 and subsequently developed FTMH. Twenty-three patients (23 eyes) were included. All eyes underwent pars plana vitrectomy + membrane peel for macular hole (MH) repair. RESULTS: The mean age at RRD diagnosis was 62 years and 52% were male. In total, 78% were macula-off RRDs. Fourteen eyes (60.9%) underwent pars plana vitrectomy alone, 7 (30.4%) underwent pars plana vitrectomy and scleral buckling, 1 (4.3%) underwent scleral buckling only, and 1 (4.3%) underwent pneumatic retinopexy. Median time from RRD repair to MH diagnosis was 116 days. Macula-off RRDs had a significantly lower time to MH diagnosis (mean 154 days, P < 0.05) than macula-on RRDs (mean 875 days). Twenty-one MH (91%) had optical coherence tomography evidence of an epiretinal membrane. Mean logMAR visual acuity at MH diagnosis was 1.05 (∼20/224) and significantly improved to 0.66 (∼20/91) at the final follow-up ( P < 0.001); 100% of MHs closed by the final follow-up. CONCLUSION: Pars plana vitrectomy for MH after RRD repair has a high closure rate and leads to significant VA improvement. MH formation after RRD repair may be associated with macula-off detachments and epiretinal membrane. Macula-off RRDs develop MH faster than macula-on RRDs.

VITREOUS SEEDING OF RENAL CELL CARCINOMA IN A PATIENT RECEIVING CHECKPOINT INHIBITORS.

PURPOSE: To describe a case of vitreous seeding with tractional retinal detachment as a result of metastatic renal cell carcinoma in a patient on systemic checkpoint inhibitors. METHODS: Case report. RESULTS: A 44-year-old Hispanic woman with a history of renal cell carcinoma with metastases to the lungs, adrenal glands, hilar lymph nodes, and peritoneum presented with a complaint of severe floaters and blurry vision of the right eye for two months. She was found to have dense, web-like vitreous opacities and a peripheral tractional retinal detachment of the right eye. Pars plana vitrectomy, membrane peeling, endolaser, air-fluid exchange, gas injection, and vitreous biopsy were performed. The vitreous and membranes were sent for cytology with stains, including AE1/AE3, PAX-8, CK-7, CA-IX, AMACR, and S-100. Cytology revealed crowded groups of glandular cells, some in papillary-like formations. Positive stains included AE1/AE3, PAX-8, CK-7, CA-IX, and AMACR. CONCLUSION: Cytology and pathology demonstrated that vitreous seeding of metastatic renal cell carcinoma without an ocular mass lesion. It is hypothesized that the use of checkpoint inhibitors played a role in allowing for the atypical and previously unreported seeding of renal cell carcinoma to the vitreous.

Pharmacologic Mydriasis Secondary to Topical Glycopyrronium Tosylate Cloths: Clinical Characterization From a Multicenter Analysis.

BACKGROUND: Topical glycopyrronium tosylate (GT) is an anticholinergic medication for treatment of axillary hyperhidrosis. Pharmacologic mydriasis and anisocoria from topical GT has been reported and may be underrecognized. This study aims to clinically characterize patients presenting with pharmacologic mydriasis from exposure to this medication. METHODS: This study is a retrospective observational case series. A multicenter chart review of 16 patients diagnosed with pharmacologic mydriasis secondary to topical GT was performed. RESULTS: Eight patients (50.0%) were age 18 years and younger, and 14 patients (87.5%) were female. Unilateral mydriasis (anisocoria) occurred in 14 patients (87.5%). Fourteen patients (87.5%) did not initially volunteer topical GT as a "medication," and the history of topical GT exposure needed to be elicited with further questioning. Hand hygiene details were known for 12 patients, and all reported that they did not wash their hands after GT application. Six patients (37.5%) were soft contact lens users. One patient had possible exposure through a family member's use of the medication. Ocular symptoms were common (blurry vision [11 patients, 68.8%] and eye dryness [7 patients, 43.8%]), but systemic anticholinergic symptoms were uncommon (such as constipation [1 patient, 6.3%] and urinary symptoms [3 patients, 18.8%]). CONCLUSIONS: Mydriasis associated with topical GT seems to be a consequence of local exposure rather than systemic toxicity. Because patients may not volunteer topical GT as a medication, eliciting a history of exposure often requires further specific questioning. Soft contact lens wear and poor postapplication hand hygiene seem to be associated with mydriasis in GT use.

Post-COVID Wernicke's presenting as bilateral vision loss.

PURPOSE: This case report represents poor nutritional intake and vomiting secondary to COVID-19 resulting in Wernicke's syndrome and blindness. OBSERVATIONS: We report the case of a 36 year old with a post-COVID episode of acute-subacute onset bilateral blindness ultimately diagnosed as Wernicke's syndrome based on MRI findings and clinical response to high dose IV thiamine supplementation. CONCLUSIONS AND IMPORTANCE: Given this patient's dramatic presentation of no light perception vision in both eyes and resolution of symptoms with treatment, it is reasonable to consider thiamine deficiency in any individual who presents with acute-subacute onset vision loss, particularly when the history is suggestive of potential nutritional deficiency.

Antenatal magnesium sulfate to prevent cerebral palsy.

Magnesium sulfate given to women before birth at <30 weeks' gestation reduces the risk of cerebral palsy in their children. Our study aimed to assess the impact of a local quality improvement programme, primarily using plan-do-study-act cycles, to increase the use of antenatal magnesium sulfate. After implementing our quality improvement programme, an average of 86% of babies delivered at <30 weeks' gestation were exposed to antenatal magnesium sulfate compared with a historical baseline rate of 63%. Our study strengthens the case for embedding quality improvement programmes in maternal perinatal care to reduce the impact of cerebral palsy on families and society.

Antenatal magnesium sulphate for preventing cerebral palsy: An economic evaluation of the impact of a quality improvement program.

Previous work demonstrated that implementing a quality improvement (QI) program improves the uptake of guideline-recommended antenatal magnesium sulphate, a critical intervention known to reduce cerebral palsy risk. Here we estimate potential cost savings attributable to the improved uptake. By expanding coverage from 63 to 83% of eligible women, we estimated that five children potentially would not have received a diagnosis of cerebral palsy, a potential cost saving of $AU4.8 million in lifetime healthcare costs. Our findings strengthen the case for embedding QI approaches in perinatal care to reduce the incidence of cerebral palsy.

Maternal vaccines during the Covid-19 pandemic:A qualitative interview study with UK pregnant women.

BACKGROUND: There is suboptimal uptake of recommended maternal vaccines (pertussis and influenza) during pregnancy in the UK. The Covid-19 pandemic has impacted healthcare services, and potentially vaccine coverage, and brought the need for new vaccines to be tested and rolled out. OBJECTIVES: To explore: i) the impact of the Covid-19 pandemic on pregnant women's access to, and attitudes towards, routine maternal vaccines and; ii) women's attitudes towards testing Covid-19 vaccines on pregnant women and their personal willingness to take part in such a trial. DESIGN: Qualitative interview study with pregnant women in the Bristol and surrounding area (UK). METHODS: Semi-structured telephone/videoconference interviews were conducted (following a topic guide), transcribed verbatim and subjected to thematic analysis. RESULTS: Thirty-one pregnant women (selected for demographic range) were interviewed in April/May 2020. Participants felt the pandemic had elevated the importance of routine maternal vaccines, though women were concerned about safety management around appointment attendance. Women were wary of receiving a new Covid-19 vaccine, with most perceiving it as riskier than Covid-19 itself. CONCLUSIONS: It is important to maximise the safety and efficiency of maternity appointments to encourage uptake of routine maternal vaccines, and to communicate this well. For pregnant women to gain a new vaccine or participate in a vaccine trial, they need to be convinced that the risk posed by the virus is greater than any risk of receiving a new vaccine.

Pregnant women's experiences of social distancing behavioural guidelines during the Covid-19 pandemic 'lockdown' in the UK, a qualitative interview study.

BACKGROUND: Covid-19 triggered the rapid roll-out of mass social distancing behavioural measures for infection control. Pregnant women were categorised as 'at risk' requiring extra vigilance with behavioural guidelines. Their understanding and ability to adhere to recommendations was unknown. OBJECTIVES: To complete a behavioural analysis of the determinants of recommended social distancing behaviour in pregnant women, according to the 'capability, opportunity, motivation and behaviour' ('COM-B') model to inform the development of recommendations/materials to support pregnant women in understanding and adhering to behavioural guidelines. DESIGN: Qualitative interview study with pregnant women in the Bristol area (UK). METHODS: Semi-structured telephone/videoconference interviews were conducted following a topic guide informed by the COM-B model, transcribed verbatim and subjected to framework analysis. Infographic materials were iteratively produced with stakeholder consultation, to support pregnant women. RESULTS: Thirty-one women participated (selected for demographic range). Women reported adhering to social distancing recommendations and intended to continue. COM-B analysis identified gaps in understanding around risk, vulnerability, and the extent of required social distancing, as well as facilitators of social distancing behaviour (e.g. social support, motivation to stay safe, home environment/resources). Additional themes around detrimental mental health effects and changes to maternity healthcare from the social distancing measures were identified. Infographic resources (plus midwife report) addressing women's key concerns were produced and disseminated. CONCLUSIONS: The COM-B model provided useful details of determinants of pregnant women's adherence to social distancing behaviours. The confusion of what being 'at risk' meant and varying interpretation of what was expected indicates a need for greater clarity around categories and guidance. The loss of maternity care and negative mental health effects of social distancing suggest a growing area of unmet health needs to be addressed in future.

Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period.

BACKGROUND: Venous thromboembolism (VTE), although rare, is a major cause of maternal mortality and morbidity. Some women are at increased risk of VTE during pregnancy and the early postnatal period (e.g. caesarean section, family history of VTE, or thrombophilia), and so prophylaxis may be considered. As some methods of prophylaxis carry risks of adverse effects, and risk of VTE is often low, benefits of thromboprophylaxis may be outweighed by harms. OBJECTIVES: To assess the effects of thromboprophylaxis during pregnancy and the early postnatal period on the risk of venous thromboembolic disease and adverse effects in women at increased risk of VTE. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (18 October 2019). In addition, we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports (18 October 2019). SELECTION CRITERIA: Randomised trials comparing one method of thromboprophylaxis with placebo or no treatment, or two (or more) methods of thromboprophylaxis. DATA COLLECTION AND ANALYSIS: At least two review authors assessed trial eligibility, extracted data, assessed risk of bias, and judged certainty of evidence for selected critical outcomes (using GRADE). We conducted fixed-effect meta-analysis and reported data (all dichotomous) as summary risk ratios (RRs) with 95% confidence intervals (CIs). MAIN RESULTS: Twenty-nine trials (involving 3839 women), overall at moderate to high risk of bias were included. Trials were conducted across the antenatal, peripartum and postnatal periods, with most in high-income countries. Interventions included types and regimens of heparin (low molecular weight heparin (LMWH) and unfractionated heparin (UFH)), hydroxyethyl starch (HES), and compression stockings or devices. Data were limited due to a small number of trials in comparisons and/or few or no events reported. All critical outcomes (assessed for comparisons of heparin versus no treatment/placebo, and LMWH versus UFH) were considered to have very low-certainty evidence, downgraded mainly for study limitations and imprecise effect estimates.  Maternal death was not reported in most studies. Antenatal (± postnatal) prophylaxis For the primary outcomes symptomatic thromboembolic events pulmonary embolism (PE) and/or deep vein thrombosis (DVT), and the critical outcome of adverse effects sufficient to stop treatment, the evidence was very uncertain.  Symptomatic thromboembolic events: - heparin versus no treatment/placebo (RR 0.39; 95% CI 0.08 to 1.98; 4 trials, 476 women; very low-certainty evidence); - LMWH versus UFH (RR 0.47; 95% CI 0.09 to 2.49; 4 trials, 404 women; very low-certainty evidence); Symptomatic PE: - heparin versus no treatment/placebo (RR 0.33; 95% CI 0.02 to 7.14; 3 trials, 187 women; very low-certainty evidence); - LMWH versus UFH (no events; 3 trials, 287 women); Symptomatic DVT: - heparin versus no treatment/placebo (RR 0.33; 95% CI 0.04 to 3.10; 4 trials, 227 women; very low-certainty evidence); - LMWH versus UFH (no events; 3 trials, 287 women); Adverse effects sufficient to stop treatment: - heparin versus no treatment/placebo (RR 0.49; 95% CI 0.05 to 5.31; 1 trial, 139 women; very low-certainty evidence); - LMWH versus UFH (RR 0.07; 95% CI 0.01 to 0.54; 2 trials, 226 women; very low-certainty evidence). Peripartum/postnatal prophylaxis Vaginal or caesarean birth When UFH and no treatment were compared, the effects on symptomatic thromboembolic events (RR 0.16; 95% CI 0.02 to 1.36; 1 trial, 210 women; very low-certainty evidence), symptomatic PE (RR 0.16; 95% CI 0.01 to 3.34; 1 trial, 210 women; very low-certainty evidence), and symptomatic DVT  (RR 0.27; 95% CI 0.03 to 2.55; 1 trial, 210 women; very low-certainty evidence) were very uncertain.  Maternal death and adverse effects sufficient to stop treatment were not reported. Caesarean birth Symptomatic thromboembolic events: - heparin versus no treatment/placebo (RR 1.30; 95% CI 0.39 to 4.27; 4 trials, 840 women; very low-certainty evidence); - LMWH versus UFH (RR 0.33; 95% CI 0.01 to 7.99; 3 trials, 217 women; very low-certainty evidence); Symptomatic PE: - heparin versus no treatment/placebo (RR 1.10; 95% CI 0.25 to 4.87; 4 trials, 840 women; very low-certainty evidence); - LMWH versus UFH (no events; 3 trials, 217 women);  Symptomatic DVT: - heparin versus no treatment/placebo (RR 1.30; 95% CI 0.24 to 6.94; 5 trials, 1140 women; very low-certainty evidence); LMWH versus UFH (RR 0.33; 95% CI 0.01 to 7.99; 3 trials, 217 women; very low-certainty evidence); Maternal death: - heparin versus placebo (no events, 1 trial, 300 women); Adverse effects sufficient to stop treatment: - heparin versus placebo (no events;  1 trial, 140 women). Postnatal prophylaxis No events were reported for LMWH versus no treatment/placebo for: symptomatic thromboembolic events, symptomatic PE and symptomatic DVT (all 2 trials, 58 women), or maternal death (1 trial, 24 women). Adverse effects sufficient to stop treatment were not reported. We were unable to conduct subgroup analyses due to lack of data. Sensitivity analysis including the nine studies at low risk of bias did not impact overall findings. AUTHORS' CONCLUSIONS: The evidence is very uncertain about benefits and harms of VTE thromboprophylaxis in women during pregnancy and the early postnatal period at increased risk of VTE. Further high-quality very large-scale randomised trials are needed to determine effects of currently used treatments in women with different VTE risk factors. As sufficiently large definitive trials are unlikely to be funded, secondary data analyses based on high-quality registry data are important.

Aspirin (single dose) for perineal pain in the early postpartum period.

BACKGROUND: Perineal trauma, due to spontaneous tears, surgical incision (episiotomy), or in association with operative vaginal birth, is common after vaginal birth, and is often associated with postpartum perineal pain. Birth over an intact perineum may also lead to perineal pain. There are adverse health consequences associated with perineal pain for the women and their babies in the short- and long-term, and the pain may interfere with newborn care and the establishment of breastfeeding. Aspirin has been used in the management of postpartum perineal pain, and its effectiveness and safety should be assessed. This is an update of the review, last published in 2017. OBJECTIVES: To determine the effects of a single dose of aspirin (acetylsalicylic acid), including at different doses, in the relief of acute postpartum perineal pain. SEARCH METHODS: For this update, we searched the Cochrane Pregnancy and Childbirth's Trials Register (4 October 2019), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (4 October 2019) and screened reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), assessing single dose aspirin compared with placebo, no treatment, a different dose of aspirin, or single dose paracetamol or acetaminophen, for women with perineal pain in the early postpartum period. We planned to include cluster-RCTs, but none were identified. We excluded quasi-RCTs and cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of the included RCTs. Data were checked for accuracy. The certainty of the evidence for the main comparison (aspirin versus placebo) was assessed using the GRADE approach. MAIN RESULTS: We included 17 RCTs, 16 of which randomised 1132 women to aspirin or placebo; one RCT did not report numbers of women. Two RCTs (of 16) did not contribute data to meta-analyses. All women had perineal pain post-episiotomy, and were not breastfeeding. Studies were published between 1967 and 1997, and the risk of bias was often unclear, due to poor reporting. We included four comparisons: aspirin versus placebo (15 RCTs); 300 mg versus 600 mg aspirin (1 RCT); 600 mg versus 1200 mg aspirin (2 RCTs); and 300 mg versus 1200 mg aspirin (1 RCT). Aspirin versus placebo Aspirin may result in more women reporting adequate pain relief four to eight hours after administration compared with placebo (risk ratio (RR) 2.03, 95% confidence interval (CI) 1.69 to 2.42; 13 RCTs, 1001 women; low-certainty evidence). It is uncertain whether aspirin compared with placebo has an effect on the need for additional pain relief (RR 0.25, 95% CI 0.17 to 0.37; 10 RCTs, 744 women; very low-certainty evidence), or maternal adverse effects (RR 1.08, 95% CI 0.57 to 2.06; 14 RCTs, 1067 women; very low-certainty evidence), four to eight hours after administration. Analyses based on dose did not reveal any clear subgroup differences. 300 mg versus 600 mg aspirin It is uncertain whether over four hours after administration, 300 mg compared with 600 mg aspirin has an effect on adequate pain relief (RR 0.82, 95% CI 0.36 to 1.86; 1 RCT, 81 women) or the need for additional pain relief (RR 0.68, 95% CI 0.12 to 3.88; 1 RCT, 81 women). There were no maternal adverse effects in either aspirin group. 600 mg versus 1200 mg aspirin It is uncertain whether over four to eight hours after administration, 600 mg compared with 1200 mg aspirin has an effect on adequate pain relief (RR 0.85, 95% CI 0.52 to 1.39; 2 RCTs, 121 women), the need for additional pain relief (RR 1.32, 95% CI 0.30 to 5.68; 2 RCTs, 121 women), or maternal adverse effects (RR 3.00, 95% CI 0.13 to 69.52; 2 RCTs, 121 women). 300 mg versus 1200 mg aspirin It is uncertain whether over four hours after administration, 300 mg compared with 1200 mg aspirin has an effect on adequate pain relief (RR 0.62, 95% CI 0.29 to 1.32; 1 RCT, 80 women) or need for additional pain relief (RR 2.00, 95% CI 0.19 to 21.18; 1 RCT, 80 women). There were no maternal adverse effects in either aspirin group. None of the included RCTs reported on neonatal adverse effects. No RCTs reported on secondary review outcomes of: prolonged hospitalisation due to perineal pain; re-hospitalisation due to perineal pain; fully breastfeeding at discharge; mixed feeding at discharge; fully breastfeeding at six weeks; mixed feeding at six weeks; perineal pain at six weeks; maternal views; or maternal postpartum depression. AUTHORS' CONCLUSIONS: Single dose aspirin may increase adequate pain relief in women with perineal pain post-episiotomy compared with placebo. It is uncertain whether aspirin has an effect on the need for additional analgesia, or on maternal adverse effects, compared with placebo. We downgraded the certainty of the evidence because of study limitations (risk of bias), imprecision, and publication bias. Aspirin may be considered for use in non-breastfeeding women with post-episiotomy perineal pain. Included RCTs excluded breastfeeding women, so there was no evidence to assess the effects of aspirin on neonatal adverse effects or breastfeeding. Future RCTs should be designed to ensure low risk of bias, and address gaps in the evidence, such as the secondary outcomes established for this review. Current research has focused on women with post-episiotomy pain; future RCTs could be extended to include women with perineal pain associated with spontaneous tears or operative birth.

Induction of labour at or beyond 37 weeks' gestation.

BACKGROUND: Risks of stillbirth or neonatal death increase as gestation continues beyond term (around 40 weeks' gestation). It is unclear whether a policy of labour induction can reduce these risks. This Cochrane Review is an update of a review that was originally published in 2006 and subsequently updated in 2012 and 2018. OBJECTIVES: To assess the effects of a policy of labour induction at or beyond 37 weeks' gestation compared with a policy of awaiting spontaneous labour indefinitely (or until a later gestational age, or until a maternal or fetal indication for induction of labour arises) on pregnancy outcomes for the infant and the mother. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (17 July 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) conducted in pregnant women at or beyond 37 weeks, comparing a policy of labour induction with a policy of awaiting spontaneous onset of labour (expectant management). We also included trials published in abstract form only. Cluster-RCTs, quasi-RCTs and trials using a cross-over design were not eligible for inclusion in this review. We included pregnant women at or beyond 37 weeks' gestation. Since risk factors at this stage of pregnancy would normally require intervention, only trials including women at low risk for complications, as defined by trialists, were eligible. The trials of induction of labour in women with prelabour rupture of membranes at or beyond term were not considered in this review but are considered in a separate Cochrane Review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, assessed risk of bias and extracted data. Data were checked for accuracy. We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: In this updated review, we included 34 RCTs (reporting on over 21,000 women and infants) mostly conducted in high-income settings. The trials compared a policy to induce labour usually after 41 completed weeks of gestation (> 287 days) with waiting for labour to start and/or waiting for a period before inducing labour. The trials were generally at low to moderate risk of bias. Compared with a policy of expectant management, a policy of labour induction was associated with fewer (all-cause) perinatal deaths (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.15 to 0.64; 22 trials, 18,795 infants; high-certainty evidence). There were four perinatal deaths in the labour induction policy group compared with 25 perinatal deaths in the expectant management group. The number needed to treat for an additional beneficial outcome (NNTB) with induction of labour, in order to prevent one perinatal death, was 544 (95% CI 441 to 1042). There were also fewer stillbirths in the induction group (RR 0.30, 95% CI 0.12 to 0.75; 22 trials, 18,795 infants; high-certainty evidence); two in the induction policy group and 16 in the expectant management group. For women in the policy of induction arms of trials, there were probably fewer caesarean sections compared with expectant management (RR 0.90, 95% CI 0.85 to 0.95; 31 trials, 21,030 women; moderate-certainty evidence); and probably little or no difference in operative vaginal births with induction (RR 1.03, 95% CI 0.96 to 1.10; 22 trials, 18,584 women; moderate-certainty evidence). Induction may make little or difference to perineal trauma (severe perineal tear: RR 1.04, 95% CI 0.85 to 1.26; 5 trials; 11,589 women; low-certainty evidence). Induction probably makes little or no difference to postpartum haemorrhage (RR 1.02, 95% CI 0.91 to 1.15, 9 trials; 12,609 women; moderate-certainty evidence), or breastfeeding at discharge (RR 1.00, 95% CI 0.96 to 1.04; 2 trials, 7487 women; moderate-certainty evidence). Very low certainty evidence means that we are uncertain about the effect of induction or expectant management on the length of maternal hospital stay (average mean difference (MD) -0.19 days, 95% CI -0.56 to 0.18; 7 trials; 4120 women; Tau² = 0.20; I² = 94%). Rates of neonatal intensive care unit (NICU) admission were lower (RR 0.88, 95% CI 0.80 to 0.96; 17 trials, 17,826 infants; high-certainty evidence), and probably fewer babies had Apgar scores less than seven at five minutes in the induction groups compared with expectant management (RR 0.73, 95% CI 0.56 to 0.96; 20 trials, 18,345 infants; moderate-certainty evidence). Induction or expectant management may make little or no difference for neonatal encephalopathy (RR 0.69, 95% CI 0.37 to 1.31; 2 trials, 8851 infants; low-certainty evidence, and probably makes little or no difference for neonatal trauma (RR 0.97, 95% CI 0.63 to 1.49; 5 trials, 13,106 infants; moderate-certainty evidence) for induction compared with expectant management. Neurodevelopment at childhood follow-up and postnatal depression were not reported by any trials. In subgroup analyses, no differences were seen for timing of induction (< 40 versus 40-41 versus > 41 weeks' gestation), by parity (primiparous versus multiparous) or state of cervix for any of the main outcomes (perinatal death, stillbirth, NICU admission, caesarean section, operative vaginal birth, or perineal trauma). AUTHORS' CONCLUSIONS: There is a clear reduction in perinatal death with a policy of labour induction at or beyond 37 weeks compared with expectant management, though absolute rates are small (0.4 versus 3 deaths per 1000). There were also lower caesarean rates without increasing rates of operative vaginal births and there were fewer NICU admissions with a policy of induction. Most of the important outcomes assessed using GRADE had high- or moderate-certainty ratings. While existing trials have not yet reported on childhood neurodevelopment, this is an important area for future research. The optimal timing of offering induction of labour to women at or beyond 37 weeks' gestation needs further investigation, as does further exploration of risk profiles of women and their values and preferences. Offering women tailored counselling may help them make an informed choice between induction of labour for pregnancies, particularly those continuing beyond 41 weeks - or waiting for labour to start and/or waiting before inducing labour.

Interventions to prevent women from developing gestational diabetes mellitus: an overview of Cochrane Reviews.

BACKGROUND: The prevalence of gestational diabetes mellitus (GDM) is increasing, with approximately 15% of pregnant women affected worldwide, varying by country, ethnicity and diagnostic thresholds. There are associated short- and long-term health risks for women and their babies. OBJECTIVES: We aimed to summarise the evidence from Cochrane systematic reviews on the effects of interventions for preventing GDM. METHODS: We searched the Cochrane Database of Systematic Reviews (6 August 2019) with key words 'gestational diabetes' OR 'GDM' to identify reviews pre-specifying GDM as an outcome. We included reviews of interventions in women who were pregnant or planning a pregnancy, irrespective of their GDM risk status. Two overview authors independently assessed eligibility, extracted data and assessed quality of evidence using ROBIS and GRADE tools. We assigned interventions to categories with graphic icons to classify the effectiveness of interventions as: clear evidence of benefit or harm (GRADE moderate- or high-quality evidence with a confidence interval (CI) that did not cross the line of no effect); clear evidence of no effect or equivalence (GRADE moderate- or high-quality evidence with a narrow CI crossing the line of no effect); possible benefit or harm (low-quality evidence with a CI that did not cross the line of no effect or GRADE moderate- or high-quality evidence with a wide CI); or unknown benefit or harm (GRADE low-quality evidence with a wide CI or very low-quality evidence). MAIN RESULTS: We included 11 Cochrane Reviews (71 trials, 23,154 women) with data on GDM. Nine additional reviews pre-specified GDM as an outcome, but did not identify GDM data in included trials. Ten of the 11 reviews were judged to be at low risk of bias and one review at unclear risk of bias. Interventions assessed included diet, exercise, a combination of diet and exercise, dietary supplements, pharmaceuticals, and management of other health problems in pregnancy. The quality of evidence ranged from high to very low. Diet Unknown benefit or harm: there was unknown benefit or harm of dietary advice versus standard care, on the risk of GDM: risk ratio (RR) 0.60, 95% CI 0.35 to 1.04; 5 trials; 1279 women; very low-quality evidence. There was unknown benefit or harm of a low glycaemic index diet versus a moderate-high glycaemic index diet on the risk of GDM: RR 0.91, 95% CI 0.63 to 1.31; 4 trials; 912 women; low-quality evidence. Exercise Unknown benefit or harm: there was unknown benefit or harm for exercise interventions versus standard antenatal care on the risk of GDM: RR 1.10, 95% CI 0.66 to 1.84; 3 trials; 826 women; low-quality evidence. Diet and exercise combined Possible benefit: combined diet and exercise interventions during pregnancy versus standard care possibly reduced the risk of GDM: RR 0.85, 95% CI 0.71 to 1.01; 19 trials; 6633 women; moderate-quality evidence. Dietary supplements Clear evidence of no effect: omega-3 fatty acid supplementation versus none in pregnancy had no effect on the risk of GDM: RR 1.02, 95% CI 0.83 to 1.26; 12 trials; 5235 women; high-quality evidence. Possible benefit: myo-inositol supplementation during pregnancy versus control possibly reduced the risk of GDM: RR 0.43, 95% CI 0.29 to 0.64; 3 trials; 502 women; low-quality evidence. Possible benefit: vitamin D supplementation versus placebo or control in pregnancy possibly reduced the risk of GDM: RR 0.51, 95% CI 0.27 to 0.97; 4 trials; 446 women; low-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of probiotic with dietary intervention versus placebo with dietary intervention (RR 0.37, 95% CI 0.15 to 0.89; 1 trial; 114 women; very low-quality evidence), or probiotic with dietary intervention versus control (RR 0.38, 95% CI 0.16 to 0.92; 1 trial; 111 women; very low-quality evidence) on the risk of GDM. There was unknown benefit or harm of vitamin D + calcium supplementation versus placebo (RR 0.33, 95% CI 0.01 to 7.84; 1 trial; 54 women; very low-quality evidence) or vitamin D + calcium + other minerals versus calcium + other minerals (RR 0.42, 95% CI 0.10 to 1.73; 1 trial; 1298 women; very low-quality evidence) on the risk of GDM. Pharmaceutical Possible benefit: metformin versus placebo given to obese pregnant women possibly reduced the risk of GDM: RR 0.85, 95% CI 0.61 to 1.19; 3 trials; 892 women; moderate-quality evidence. Unknown benefit or harm:eight small trials with low- to very low-quality evidence showed unknown benefit or harm for heparin, aspirin, leukocyte immunisation or IgG given to women with a previous stillbirth on the risk of GDM. Management of other health issues Clear evidence of no effect: universal versus risk based screening of pregnant women for thyroid dysfunction had no effect on the risk of GDM: RR 0.93, 95% CI 0.70 to 1.25; 1 trial; 4516 women; moderate-quality evidence. Unknown benefit or harm: there was unknown benefit or harm of using fractional exhaled nitrogen oxide versus a clinical algorithm to adjust asthma therapy on the risk of GDM: RR 0.74, 95% CI 0.31 to 1.77; 1 trial; 210 women; low-quality evidence. There was unknown benefit or harm of pharmacist led multidisciplinary approach to management of maternal asthma versus standard care on the risk of GDM: RR 5.00, 95% CI 0.25 to 99.82; 1 trial; 58 women; low-quality evidence. AUTHORS' CONCLUSIONS: No interventions to prevent GDM in 11 systematic reviews were of clear benefit or harm. A combination of exercise and diet, supplementation with myo-inositol, supplementation with vitamin D and metformin were of possible benefit in reducing the risk of GDM, but further high-quality evidence is needed. Omega-3-fatty acid supplementation and universal screening for thyroid dysfunction did not alter the risk of GDM. There was insufficient high-quality evidence to establish the effect on the risk of GDM of diet or exercise alone, probiotics, vitamin D with calcium or other vitamins and minerals, interventions in pregnancy after a previous stillbirth, and different asthma management strategies in pregnancy. There is a lack of trials investigating the effect of interventions prior to or between pregnancies on risk of GDM.

Linking data from a large clinical trial with the Australian Cerebral Palsy Register.

AIM: To link data from a large maternal perinatal trial with the Australian Cerebral Palsy Register (ACPR) to identify children with cerebral palsy (CP). METHOD: Deidentified data from the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO4 ) and the ACPR were linked. Children born from 1996 to 2000 at Australian hospitals who survived and had 2-year paediatric assessments were included. Children identified with CP in: (1) both the ACTOMgSO4 (2y) and the ACPR (5y), (2) the ACTOMgSO4 only, and (3) the ACPR only were compared. RESULTS: We included 913 children (492 males, 421 females; mean gestational age at birth 27.8wks [standard deviation 2.1wks]; range 23.0-40.0wks). Eighty-four children received a CP diagnosis: 35 by the ACTOMgSO4 and the ACPR, 29 by the ACTOMgSO4 only, and 20 by the ACPR only. The ACTOMgSO4 diagnosed 76.2% (95% confidence interval [CI] 65.9-84.1) and the ACPR identified 65.5% (95% CI 54.7-74.9). Children born in states/territories with long-standing versus more recently established registers were more likely to be included on the ACPR (p<0.05). INTERPRETATION: Linking deidentified perinatal trial data with the ACPR was achieved. Limitations of both strategies for identifying children with CP in this era (late 1990s and early 2000s) probably explain many of the differences observed, and inform future linkage studies and evaluations of CP-preventive interventions. WHAT THIS PAPER ADDS: Randomized trial data were linked with the Australian Cerebral Palsy Register. Trial (2y) and register (up to 5y) diagnoses of cerebral palsy (CP) differed. States with long-standing registers were more likely to include children with CP.

Protocol for a longitudinal, prospective cohort study investigating the biology of uterine fibroids and endometriosis, and patients' quality of life: the FENOX study.

INTRODUCTION: Millions of women suffer from the consequences of endometriosis and uterine fibroids, with fibroids the cause for over 50% of hysterectomies in the USA, and direct costs for their treatment estimated at between US$4 and US$9 billion. Endometriosis commonly affects millions of women worldwide predominantly during reproductive age, with severe menstrual and non-menstrual pain and subfertility the main symptoms. Due to the 'unhappy triad' of endometriosis-lack of awareness, lack of clinically relevant biomarkers and the unspecific nature of symptoms-women wait on average for 8-12 years before the definitive endometriosis diagnosis is made. Treatment options for both conditions are not satisfactory at the moment, especially with a view to preserving fertility for the women and families affected. In the Fibroids and Endometriosis Oxford (FENOX) study, we combine the investigation of fibroids and endometriosis, and plan to collect high-quality tissue samples and medical data of participants over a time frame of 5 years after surgical intervention. METHODS AND ANALYSIS: Biological samples such as blood, saliva, urine, fat, peritoneal fluid and-if found-endometrial tissue or fibroids as well as detailed clinical and intraoperative data will be collected from women undergoing surgery and participating in the study after informed consent. We plan to recruit up to 1200 participants per disease arm (ie, endometriosis and uterine fibroids) over 5 years. Participants will fill in detailed and validated questionnaires on their medical history and quality of life, with follow-ups for 5 years. Enrolment started on 2 April 2018, and FENOX will close on 31 March 2028. We will analyse the biological samples using state-of-the-art molecular biology methods and correlate the findings with the medical records and questionnaire data. ETHICS AND DISSEMINATION: The findings will be published in high-ranking journals in the field and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN13560263.

Antenatal magnesium sulphate and adverse neonatal outcomes: A systematic review and meta-analysis.

BACKGROUND: There is widespread, increasing use of magnesium sulphate in obstetric practice for pre-eclampsia, eclampsia, and preterm fetal neuroprotection; benefit for preventing preterm labour and birth (tocolysis) is unproven. We conducted a systematic review and meta-analysis to assess whether antenatal magnesium sulphate is associated with unintended adverse neonatal outcomes. METHODS AND FINDINGS: CINAHL, Cochrane Library, LILACS, MEDLINE, Embase, TOXLINE, and Web of Science, were searched (inceptions to 3 September 2019). Randomised, quasi-randomised, and non-randomised trials, cohort and case-control studies, and case reports assessing antenatal magnesium sulphate for pre-eclampsia, eclampsia, fetal neuroprotection, or tocolysis, compared with placebo/no treatment or a different magnesium sulphate regimen, were included. The primary outcome was perinatal death. Secondary outcomes included pre-specified and non-pre-specified adverse neonatal outcomes. Two reviewers screened 5,890 articles, extracted data, and assessed risk of bias following Cochrane Handbook and RTI Item Bank guidance. For randomised trials, pooled risk ratios (RRs) or mean differences, with 95% confidence intervals (CIs), were calculated using fixed- or random-effects meta-analysis. Non-randomised data were tabulated and narratively summarised. We included 197 studies (40 randomised trials, 138 non-randomised studies, and 19 case reports), of mixed quality. The 40 trials (randomising 19,265 women and their babies) were conducted from 1987 to 2018 across high- (16 trials) and low/middle-income countries (23 trials) (1 mixed). Indications included pre-eclampsia/eclampsia (24 trials), fetal neuroprotection (7 trials), and tocolysis (9 trials); 18 trials compared magnesium sulphate with placebo/no treatment, and 22 compared different regimens. For perinatal death, no clear difference in randomised trials was observed between magnesium sulphate and placebo/no treatment (RR 1.01; 95% CI 0.92 to 1.10; 8 trials, 13,654 babies), nor between regimens. Eleven of 138 non-randomised studies reported on perinatal death. Only 1 cohort (127 babies; moderate to high risk of bias) observed an increased risk of perinatal death with >48 versus ≤48 grams magnesium sulphate exposure for tocolysis. No clear secondary adverse neonatal outcomes were observed in randomised trials, and a very limited number of possible adverse outcomes warranting further consideration were identified in non-randomised studies. Where non-randomised studies observed possible harms, often no or few confounders were controlled for (moderate to high risk of bias), samples were small (200 babies or fewer), and/or results were from subgroup analyses. Limitations include missing data for important outcomes across most studies, heterogeneity of included studies, and inclusion of published data only. CONCLUSIONS: Our findings do not support clear associations between antenatal magnesium sulphate for beneficial indications and adverse neonatal outcomes. Further large, high-quality studies (prospective cohorts or individual participant data meta-analyses) assessing specific outcomes, or the impact of regimen, pregnancy, or birth characteristics on these outcomes, would further inform safety recommendations. PROSPERO: CRD42013004451.