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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Induction of labour for improving birth outcomes for women at or beyond term.

BACKGROUND: Beyond term, the risks of stillbirth or neonatal death increase. 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 OBJECTIVES: To assess the effects of a policy of labour induction at or beyond term compared with a policy of awaiting spontaneous labour or until an indication for birth induction of labour is identified) on pregnancy outcomes for infant and mother. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (9 October 2017), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) conducted in pregnant women at or beyond term, 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 are not eligible for inclusion in this review.We included pregnant women at or beyond term. Since a risk factor at this stage of pregnancy would normally require an intervention, only trials including women at low risk for complications were eligible. We accepted the trialists' definition of 'low risk'. 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 reviewers independently assessed trials for inclusion, assessed risk of bias and extracted data. Data were checked for accuracy. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: In this updated review, we included 30 RCTs (reporting on 12,479 women). The trials took place in Norway, China, Thailand, the USA, Austria, Turkey, Canada, UK, India, Tunisia, Finland, Spain, Sweden and the Netherlands. They were generally at a 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) 0.33, 95% confidence interval (CI) 0.14 to 0.78; 20 trials, 9960 infants; moderate-quality evidence). There were two perinatal deaths in the labour induction policy group compared with 16 perinatal deaths in the expectant management group. The number needed to treat to for an additional beneficial outcome (NNTB) with induction of labour in order to prevent one perinatal death was 426 (95% CI 338 to 1337). There were fewer stillbirths in the induction group (RR 0.33, 95% CI 0.11 to 0.96; 20 trials, 9960 infants; moderate-quality evidence); there was one stillbirth in the induction policy arm and 10 in the expectant management group.For women in the policy of induction arms of trials, there were fewer caesarean sections compared with expectant management (RR 0.92, 95% CI 0.85 to 0.99; 27 trials, 11,738 women; moderate-quality evidence); and a corresponding marginal increase in operative vaginal births with induction (RR 1.07, 95% CI 0.99 to 1.16; 18 trials, 9281 women; moderate-quality evidence). There was no evidence of a difference between groups for perineal trauma (RR 1.09, 95% CI 0.65 to 1.83; 4 trials; 3028 women; low-quality evidence), postpartum haemorrhage (RR 1.09 95% CI 0.92 to 1.30, 5 trials; 3315 women; low-quality evidence), or length of maternal hospital stay (average mean difference (MD) -0.34 days, 95% CI -1.00 to 0.33; 5 trials; 1146 women; Tau² = 0.49; I² 95%; very low-quality evidence).Rates of neonatal intensive care unit (NICU) admission were lower (RR 0.88, 95% CI 0.77 to 1.01; 13 trials, 8531 infants; moderate-quality evidence) and fewer babies had Apgar scores less than seven at five minutes in the induction groups compared with expectant management (RR 0.70, 95% CI 0.50 to 0.98; 16 trials, 9047 infants; moderate-quality evidence).There was no evidence of a difference for neonatal trauma (RR 1.18, 95% CI 0.68 to 2.05; 3 trials, 4255 infants; low-quality evidence), for induction compared with expectant management.Neonatal encephalopathy, neurodevelopment at childhood follow-up, breastfeeding at discharge and postnatal depression were not reported by any trials.In subgroup analyses, no clear differences between timing of induction (< 41 weeks versus ≥ 41 weeks' gestation) or by state of cervix were seen for perinatal death, stillbirth, NICU admission, caesarean section, or perineal trauma. However, operative vaginal birth was more common in the inductions at < 41 weeks' gestation subgroup compared with inductions at later gestational ages. The majority of trials (about 75% of participants) adopted a policy of induction at ≥ 41 weeks (> 287 days) gestation for the intervention arm. AUTHORS' CONCLUSIONS: A policy of labour induction at or beyond term compared with expectant management is associated with fewer perinatal deaths and fewer caesarean sections; but more operative vaginal births. NICU admissions were lower and fewer babies had low Apgar scores with induction. No important differences were seen for most of the other maternal and infant outcomes.Most of the important outcomes assessed using GRADE had a rating of moderate or low-quality evidence - with downgrading decisions generally due to study limitations such as lack of blinding (a condition inherent in comparisons between a policy of acting and of waiting), or imprecise effect estimates. One outcome (length of maternal stay) was downgraded further to very low-quality evidence due to inconsistency.Although the absolute risk of perinatal death is small, it may be helpful to offer women appropriate counselling to help choose between scheduled induction for a post-term pregnancy or monitoring without (or later) induction).The optimal timing of offering induction of labour to women at or beyond term warrants further investigation, as does further exploration of risk profiles of women and their values and preferences. Individual participant meta-analysis is likely to help elucidate the role of factors, such as parity, in influencing outcomes of induction compared with expectant management.

Treatments for women with gestational diabetes mellitus: an overview of Cochrane systematic reviews.

BACKGROUND: Successful treatments for gestational diabetes mellitus (GDM) have the potential to improve health outcomes for women with GDM and their babies. OBJECTIVES: To provide a comprehensive synthesis of evidence from Cochrane systematic reviews of the benefits and harms associated with interventions for treating GDM on women and their babies. METHODS: We searched the Cochrane Database of Systematic Reviews (5 January 2018) for reviews of treatment/management for women with GDM. Reviews of pregnant women with pre-existing diabetes were excluded.Two overview authors independently assessed reviews for inclusion, quality (AMSTAR; ROBIS), quality of evidence (GRADE), and extracted data. MAIN RESULTS: We included 14 reviews. Of these, 10 provided relevant high-quality and low-risk of bias data (AMSTAR and ROBIS) from 128 randomised controlled trials (RCTs), 27 comparisons, 17,984 women, 16,305 babies, and 1441 children. Evidence ranged from high- to very low-quality (GRADE). Only one effective intervention was found for treating women with GDM.EffectiveLifestyle versus usual careLifestyle intervention versus usual care probably reduces large-for-gestational age (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.50 to 0.71; 6 RCTs, N = 2994; GRADE moderate-quality).PromisingNo evidence for any outcome for any comparison could be classified to this category.Ineffective or possibly harmful Lifestyle versus usual careLifestyle intervention versus usual care probably increases the risk of induction of labour (IOL) suggesting possible harm (average RR 1.20, 95% CI 0.99 to 1.46; 4 RCTs, N = 2699; GRADE moderate-quality).Exercise versus controlExercise intervention versus control for return to pre-pregnancy weight suggested ineffectiveness (body mass index, BMI) MD 0.11 kg/m², 95% CI -1.04 to 1.26; 3 RCTs, N = 254; GRADE moderate-quality).Insulin versus oral therapyInsulin intervention versus oral therapy probably increases the risk of IOL suggesting possible harm (RR 1.3, 95% CI 0.96 to 1.75; 3 RCTs, N = 348; GRADE moderate-quality).Probably ineffective or harmful interventionsInsulin versus oral therapyFor insulin compared to oral therapy there is probably an increased risk of the hypertensive disorders of pregnancy (RR 1.89, 95% CI 1.14 to 3.12; 4 RCTs, N = 1214; GRADE moderate-quality).InconclusiveLifestyle versus usual careThe evidence for childhood adiposity kg/m² (RR 0.91, 95% CI 0.75 to 1.11; 3 RCTs, N = 767; GRADE moderate-quality) and hypoglycaemia was inconclusive (average RR 0.99, 95% CI 0.65 to 1.52; 6 RCTs, N = 3000; GRADE moderate-quality).Exercise versus controlThe evidence for caesarean section (RR 0.86, 95% CI 0.63 to 1.16; 5 RCTs, N = 316; GRADE moderate quality) and perinatal death or serious morbidity composite was inconclusive (RR 0.56, 95% CI 0.12 to 2.61; 2 RCTs, N = 169; GRADE moderate-quality).Insulin versus oral therapyThe evidence for the following outcomes was inconclusive: pre-eclampsia (RR 1.14, 95% CI 0.86 to 1.52; 10 RCTs, N = 2060), caesarean section (RR 1.03, 95% CI 0.93 to 1.14; 17 RCTs, N = 1988), large-for-gestational age (average RR 1.01, 95% CI 0.76 to 1.35; 13 RCTs, N = 2352), and perinatal death or serious morbidity composite (RR 1.03; 95% CI 0.84 to 1.26; 2 RCTs, N = 760). GRADE assessment was moderate-quality for these outcomes.Insulin versus dietThe evidence for perinatal mortality was inconclusive (RR 0.74, 95% CI 0.41 to 1.33; 4 RCTs, N = 1137; GRADE moderate-quality).Insulin versus insulinThe evidence for insulin aspart versus lispro for risk of caesarean section was inconclusive (RR 1.00, 95% CI 0.91 to 1.09; 3 RCTs, N = 410; GRADE moderate quality).No conclusions possibleNo conclusions were possible for: lifestyle versus usual care (perineal trauma, postnatal depression, neonatal adiposity, number of antenatal visits/admissions); diet versus control (pre-eclampsia, caesarean section); myo-inositol versus placebo (hypoglycaemia); metformin versus glibenclamide (hypertensive disorders of pregnancy, pregnancy-induced hypertension, death or serious morbidity composite, insulin versus oral therapy (development of type 2 diabetes); intensive management versus routine care (IOL, large-for-gestational age); post- versus pre-prandial glucose monitoring (large-for-gestational age). The evidence ranged from moderate-, low- and very low-quality. AUTHORS' CONCLUSIONS: Currently there is insufficient high-quality evidence about the effects on health outcomes of relevance for women with GDM and their babies for many of the comparisons in this overview comparing treatment interventions for women with GDM. Lifestyle changes (including as a minimum healthy eating, physical activity and self-monitoring of blood sugar levels) was the only intervention that showed possible health improvements for women and their babies. Lifestyle interventions may result in fewer babies being large. Conversely, in terms of harms, lifestyle interventions may also increase the number of inductions. Taking insulin was also associated with an increase in hypertensive disorders, when compared to oral therapy. There was very limited information on long-term health and health services costs. Further high-quality research is needed.

Neonatal interventions for preventing cerebral palsy: an overview of Cochrane Systematic Reviews.

BACKGROUND: Cerebral palsy is an umbrella term that encompasses disorders of movement and posture attributed to non-progressive disturbances occurring in the developing foetal or infant brain. As there are diverse risk factors and aetiologies, no one strategy will prevent cerebral palsy. Therefore, there is a need to systematically consider all potentially relevant interventions for prevention. OBJECTIVES: PrimaryTo summarise the evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions for preventing cerebral palsy (reducing cerebral palsy risk).SecondaryTo summarise the evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions that may increase cerebral palsy risk. METHODS: We searched the Cochrane Database of Systematic Reviews (27 November 2016) for reviews of neonatal interventions reporting on cerebral palsy. Two review authors assessed reviews for inclusion, extracted data, and assessed review quality (using AMSTAR and ROBIS) and quality of the evidence (using the GRADE approach). Reviews were organised by topic; findings were summarised in text and were tabulated. Interventions were categorised as effective (high-quality evidence of effectiveness); possibly effective (moderate-quality evidence of effectiveness); ineffective (high-quality evidence of harm); probably ineffective (moderate-quality evidence of harm or lack of effectiveness); and no conclusions possible (low- to very low-quality evidence). MAIN RESULTS: Forty-three Cochrane Reviews were included. A further 102 reviews pre-specified the outcome cerebral palsy, but none of the included randomised controlled trials (RCTs) reported this outcome. Included reviews were generally of high quality and had low risk of bias, as determined by AMSTAR and ROBIS. These reviews involved 454 RCTs; data for cerebral palsy were available from 96 (21%) RCTs involving 15,885 children. Review authors considered interventions for neonates with perinatal asphyxia or with evidence of neonatal encephalopathy (3); interventions for neonates born preterm and/or at low or very low birthweight (33); and interventions for other specific groups of 'at risk' neonates (7). Quality of evidence (GRADE) ranged from very low to high.Interventions for neonates with perinatal asphyxia or with evidence of neonatal encephalopathyEffective interventions: high-quality evidence of effectivenessResearchers found a reduction in cerebral palsy following therapeutic hypothermia versus standard care for newborns with hypoxic ischaemic encephalopathy (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.54 to 0.82; seven trials; 881 children).No conclusions possible: very low-quality evidenceOne review observed no clear differences in cerebral palsy following therapeutic hypothermia versus standard care.Interventions for neonates born preterm and/or at low or very low birthweightPossibly effective interventions: moderate-quality evidence of effectivenessResearchers found a reduction in cerebral palsy with prophylactic methylxanthines (caffeine) versus placebo for endotracheal extubation in preterm infants (RR 0.54, 95% CI 0.32 to 0.92; one trial; 644 children).Probably ineffective interventions: moderate-quality evidence of harmResearchers reported an increase in cerebral palsy (RR 1.45, 95% CI 1.06 to 1.98; 12 trials; 1452 children) and cerebral palsy in assessed survivors (RR 1.50, 95% CI 1.13 to 2.00; 12 trials; 959 children) following early (at less than eight days of age) postnatal corticosteroids versus placebo or no treatment for preventing chronic lung disease in preterm infants.Probably ineffective interventions: moderate-quality evidence of lack of effectivenessTrial results showed no clear differences in cerebral palsy following ethamsylate versus placebo for prevention of morbidity and mortality in preterm or very low birthweight infants (RR 1.13, 95% CI 0.64 to 2.00; three trials, 532 children); volume expansion versus no treatment (RR 0.76, 95% CI 0.48 to 1.20; one trial; 604 children); gelatin versus fresh frozen plasma (RR 0.94, 95% CI 0.52 to 1.69; one trial, 399 children) for prevention of morbidity and mortality in very preterm infants; prophylactic indomethacin versus placebo for preventing mortality and morbidity in preterm infants (RR 1.04, 95% CI 0.77 to 1.40; four trials; 1372 children); synthetic surfactant versus placebo for respiratory distress syndrome in preterm infants (RR 0.76, 95% CI 0.55 to 1.05; five trials; 1557 children); or prophylactic phototherapy versus standard care (starting phototherapy when serum bilirubin reached a pre-specified level) for preventing jaundice in preterm or low birthweight infants (RR 0.96, 95% CI 0.50 to 1.85; two trials; 756 children).No conclusions possible: low- to very low-quality evidenceNo clear differences in cerebral palsy were observed with interventions assessed in 21 reviews.Interventions for other specific groups of 'at risk' neonatesNo conclusions possible: low- to very low-quality evidenceReview authors observed no clear differences in cerebral palsy with interventions assessed in five reviews. AUTHORS' CONCLUSIONS: This overview summarises evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions on cerebral palsy, and can be used by researchers, funding bodies, policy makers, clinicians, and consumers to aid decision-making and evidence translation. To formally assess other benefits and/or harms of included interventions, including impact on risk factors for cerebral palsy, review of the included Reviews is recommended.Therapeutic hypothermia versus standard care for newborns with hypoxic ischaemic encephalopathy can prevent cerebral palsy, and prophylactic methylxanthines (caffeine) versus placebo for endotracheal extubation in preterm infants may reduce cerebral palsy risk. Early (at less than eight days of age) postnatal corticosteroids versus placebo or no treatment for preventing chronic lung disease in preterm infants may increase cerebral palsy risk.Cerebral palsy is rarely identified at birth, has diverse risk factors and aetiologies, and is diagnosed in approximately one in 500 children. To date, only a small proportion of Cochrane Systematic Reviews assessing neonatal interventions have been able to report on this outcome. There is an urgent need for long-term follow-up of RCTs of such interventions addressing risk factors for cerebral palsy (through strategies such as data linkage with registries) and for consideration of the use of relatively new interim assessments (including the General Movements Assessment). Such RCTs must be rigorous in their design and must aim for consistency in cerebral palsy outcome measurement and reporting to facilitate pooling of data and thus to maximise research efforts focused on prevention.

Omega-3 fatty acid addition during pregnancy.

BACKGROUND: Higher intakes of foods containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA), such as fish, during pregnancy have been associated with longer gestations and improved perinatal outcomes. This is an update of a review that was first published in 2006. OBJECTIVES: To assess the effects of omega-3 LCPUFA, as supplements or as dietary additions, during pregnancy on maternal, perinatal, and neonatal outcomes and longer-term outcomes for mother and child. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 August 2018), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing omega-3 fatty acids (as supplements or as foods, stand-alone interventions, or with a co-intervention) during pregnancy with placebo or no omega-3, and studies or study arms directly comparing omega-3 LCPUFA doses or types. Trials published in abstract form were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data, assessed risk of bias in trials and assessed quality of evidence for prespecified birth/infant, maternal, child/adult and health service outcomes using the GRADE approach. MAIN RESULTS: In this update, we included 70 RCTs (involving 19,927 women at low, mixed or high risk of poor pregnancy outcomes) which compared omega-3 LCPUFA interventions (supplements and food) compared with placebo or no omega-3. Overall study-level risk of bias was mixed, with selection and performance bias mostly at low risk, but there was high risk of attrition bias in some trials. Most trials were conducted in upper-middle or high-income countries; and nearly half the trials included women at increased/high risk for factors which might increase the risk of adverse maternal and birth outcomes.Preterm birth < 37 weeks (13.4% versus 11.9%; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early preterm birth < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to 0.77; 9 RCTs, 5204 participants; high-quality evidence) were both lower in women who received omega-3 LCPUFA compared with no omega-3. Prolonged gestation > 42 weeks was probably increased from 1.6% to 2.6% in women who received omega-3 LCPUFA compared with no omega-3 (RR 1.61 95% CI 1.11 to 2.33; 5141 participants; 6 RCTs; moderate-quality evidence).For infants, there was a possibly reduced risk of perinatal death (RR 0.75, 95% CI 0.54 to 1.03; 10 RCTs, 7416 participants; moderate-quality evidence: 62/3715 versus 83/3701 infants) and possibly fewer neonatal care admissions (RR 0.92, 95% CI 0.83 to 1.03; 9 RCTs, 6920 participants; moderate-quality evidence - 483/3475 infants versus 519/3445 infants). There was a reduced risk of low birthweight (LBW) babies (15.6% versus 14%; RR 0.90, 95% CI 0.82 to 0.99; 15 trials, 8449 participants; high-quality evidence); but a possible small increase in large-for-gestational age (LGA) babies (RR 1.15, 95% CI 0.97 to 1.36; 6 RCTs, 3722 participants; moderate-quality evidence, for omega-3 LCPUFA compared with no omega-3. Little or no difference in small-for-gestational age or intrauterine growth restriction (RR 1.01, 95% CI 0.90 to 1.13; 8 RCTs, 6907 participants; moderate-quality evidence) was seen.For the maternal outcomes, there is insufficient evidence to determine the effects of omega-3 on induction post-term (average RR 0.82, 95% CI 0.22 to 2.98; 3 trials, 2900 participants; low-quality evidence), maternal serious adverse events (RR 1.04, 95% CI 0.40 to 2.72; 2 trials, 2690 participants; low-quality evidence), maternal admission to intensive care (RR 0.56, 95% CI 0.12 to 2.63; 2 trials, 2458 participants; low-quality evidence), or postnatal depression (average RR 0.99, 95% CI 0.56 to 1.77; 2 trials, 2431 participants; low-quality evidence). Mean gestational length was greater in women who received omega-3 LCPUFA (mean difference (MD) 1.67 days, 95% CI 0.95 to 2.39; 41 trials, 12,517 participants; moderate-quality evidence), and pre-eclampsia may possibly be reduced with omega-3 LCPUFA (RR 0.84, 95% CI 0.69 to 1.01; 20 trials, 8306 participants; low-quality evidence).For the child/adult outcomes, very few differences between antenatal omega-3 LCPUFA supplementation and no omega-3 were observed in cognition, IQ, vision, other neurodevelopment and growth outcomes, language and behaviour (mostly low-quality to very low-quality evidence). The effect of omega-3 LCPUFA on body mass index at 19 years (MD 0, 95% CI -0.83 to 0.83; 1 trial, 243 participants; very low-quality evidence) was uncertain. No data were reported for development of diabetes in the children of study participants. AUTHORS' CONCLUSIONS: In the overall analysis, preterm birth < 37 weeks and early preterm birth < 34 weeks were reduced in women receiving omega-3 LCPUFA compared with no omega-3. There was a possibly reduced risk of perinatal death and of neonatal care admission, a reduced risk of LBW babies; and possibly a small increased risk of LGA babies with omega-3 LCPUFA.For our GRADE quality assessments, we assessed most of the important perinatal outcomes as high-quality (e.g. preterm birth) or moderate-quality evidence (e.g. perinatal death). For the other outcome domains (maternal, child/adult and health service outcomes) GRADE ratings ranged from moderate to very low, with over half rated as low. Reasons for downgrading across the domain were mostly due to design limitations and imprecision.Omega-3 LCPUFA supplementation during pregnancy is an effective strategy for reducing the incidence of preterm birth, although it probably increases the incidence of post-term pregnancies. More studies comparing omega-3 LCPUFA and placebo (to establish causality in relation to preterm birth) are not needed at this stage. A further 23 ongoing trials are still to report on over 5000 women, so no more RCTs are needed that compare omega-3 LCPUFA against placebo or no intervention. However, further follow-up of completed trials is needed to assess longer-term outcomes for mother and child, to improve understanding of metabolic, growth and neurodevelopment pathways in particular, and to establish if, and how, outcomes vary by different types of omega-3 LCPUFA, timing and doses; or by characteristics of women.

Care prior to and during subsequent pregnancies following stillbirth for improving outcomes.

BACKGROUND: Stillbirth affects at least 2.6 million families worldwide every year and has enduring consequences for parents and health services. Parents entering a subsequent pregnancy following stillbirth face a risk of stillbirth recurrence, alongside increased risks of other adverse pregnancy outcomes and psychosocial challenges. These parents may benefit from a range of interventions to optimise their short- and longer-term medical health and psychosocial well-being. OBJECTIVES: To assess the effects of different interventions or models of care prior to and during subsequent pregnancies following stillbirth on maternal, fetal, neonatal and family health outcomes, and health service utilisation. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (6 June 2018), along with ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (18 June 2018). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-randomised controlled trials (qRCTs). Trials using a cluster-randomised design were eligible for inclusion, but we found no such reports. We included trials published as abstract only, provided sufficient information was available to allow assessment of trial eligibility and risk of bias. We excluded cross-over trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and undertook data extraction and 'Risk of bias' assessments. We extracted data from published reports, or sourced data directly from trialists. We checked the data for accuracy and resolved discrepancies by discussion or correspondence with trialists, or both. We conducted an assessment of the quality of the evidence using the GRADE approach. MAIN RESULTS: We included nine RCTs and one qRCT, and judged them to be at low to moderate risk of bias. Trials were carried out between the years 1964 and 2015 and took place predominantly in high-income countries in Europe. All trials assessed medical interventions; no trials assessed psychosocial interventions or incorporated psychosocial aspects of care. Trials evaluated the use of antiplatelet agents (low-dose aspirin (LDA) or low-molecular-weight heparin (LMWH), or both), third-party leukocyte immunisation, intravenous immunoglobulin, and progestogen. Trial participants were women who were either pregnant or attempting to conceive following a pregnancy loss, fetal death, or adverse outcome in a previous pregnancy.We extracted data for 222 women who had experienced a previous stillbirth of 20 weeks' gestation or more from the broader trial data sets, and included them in this review. Our GRADE assessments of the quality of evidence ranged from very low to low, due largely to serious imprecision in effect estimates as a result of small sample sizes, low numbers of events, and wide confidence intervals (CIs) crossing the line of no effect. Most of the analyses in this review were not sufficiently powered to detect differences in the outcomes assessed. The results presented are therefore largely uncertain.Main comparisonsLMWH versus no treatment/standard care (three RCTs, 123 women, depending on the outcome)It was uncertain whether LMWH reduced the risk of stillbirth (risk ratio (RR) 2.58, 95% CI 0.40 to 16.62; 3 trials; 122 participants; low-quality evidence), adverse perinatal outcome (RR 0.81, 95% CI 0.20 to 3.32; 2 trials; 77 participants; low-quality evidence), adverse maternal psychological effects (RR 1.00, 95% CI 0.07 to 14.90; 1 trial; 40 participants; very low-quality evidence), perinatal mortality (RR 2.58, 95% CI 0.40 to 16.62; 3 trials; 122 participants; low-quality evidence), or any preterm birth (< 37 weeks) (RR 1.01, 0.58 to 1.74; 3 trials; 114 participants; low-quality evidence). No neonatal deaths were reported in the trials assessed and no data were available for maternal-infant attachment. There was no clear evidence of a difference between the groups among the remaining secondary outcomes.LDA versus placebo (one RCT, 24 women)It was uncertain whether LDA reduced the risk of stillbirth (RR 0.85, 95% CI 0.06 to 12.01), neonatal death (RR 0.29, 95% CI 0.01 to 6.38), adverse perinatal outcome (RR 0.28, 95% CI 0.03 to 2.34), perinatal mortality, or any preterm birth (< 37 weeks) (both of the latter RR 0.42, 95% CI 0.04 to 4.06; all very low-quality evidence). No data were available for adverse maternal psychological effects or maternal-infant attachment. LDA appeared to be associated with an increase in birthweight (mean difference (MD) 790.00 g, 95% CI 295.03 to 1284.97 g) when compared to placebo, but this result was very unstable due to the extremely small sample size. Whether LDA has any effect on the remaining secondary outcomes was also uncertain.Other comparisonsLDA appeared to be associated with an increase in birthweight when compared to LDA + LMWH (MD -650.00 g, 95% CI -1210.33 to -89.67 g; 1 trial; 29 infants), as did third-party leukocyte immunisation when compared to placebo (MD 1195.00 g, 95% CI 273.35 to 2116.65 g; 1 trial, 4 infants), but these results were again very unstable due to extremely small sample sizes. The effects of the interventions on the remaining outcomes were also uncertain. AUTHORS' CONCLUSIONS: There is insufficient evidence in this review to inform clinical practice about the effectiveness of interventions to improve care prior to and during subsequent pregnancies following a stillbirth. There is a clear and urgent need for well-designed trials addressing this research question. The evaluation of medical interventions such as LDA, in the specific context of stillbirth prevention (and recurrent stillbirth prevention), is warranted. However, appropriate methodologies to evaluate such therapies need to be determined, particularly where clinical equipoise may be lacking. Careful trial design and multicentre collaboration is necessary to carry out trials that would be sufficiently large to detect differences in statistically rare outcomes such as stillbirth and neonatal death. The evaluation of psychosocial interventions addressing maternal-fetal attachment and parental anxiety and depression is also an urgent priority. In a randomised-trial context, such trials may allocate parents to different forms of support, to determine which have the greatest benefit with the least financial cost. Importantly, consistency in nomenclature and in data collection across all future trials (randomised and non-randomised) may be facilitated by a core outcomes data set for stillbirth research. All future trials should assess short- and longer-term psychosocial outcomes for parents and families, alongside economic costs of interventions.

Interventions for investigating and identifying the causes of stillbirth.

BACKGROUND: Identification of the causes of stillbirth is critical to the primary prevention of stillbirth and to the provision of optimal care in subsequent pregnancies. A wide variety of investigations are available, but there is currently no consensus on the optimal approach. Given their cost and potential to add further emotional burden to parents, there is a need to systematically assess the effect of these interventions on outcomes for parents, including psychosocial outcomes, economic costs, and on rates of diagnosis of the causes of stillbirth. OBJECTIVES: To assess the effect of different tests, protocols or guidelines for investigating and identifying the causes of stillbirth on outcomes for parents, including psychosocial outcomes, economic costs, and rates of diagnosis of the causes of stillbirth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (31 August 2017), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (15 May 2017). SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs. We planned to include studies published as abstract only, provided there was sufficient information to allow us to assess study eligibility. We planned to exclude cross-over trials.Participants included parents (including mothers, fathers, and partners) who had experienced a stillbirth of 20 weeks' gestation or greater.This review focused on interventions for investigating and identifying the causes of stillbirth. Such interventions are likely to be diverse, but could include:* review of maternal and family history, and current pregnancy and birth history;* clinical history of present illness;* maternal investigations (such as ultrasound, amniocentesis, antibody screening, etc.);* examination of the stillborn baby (including full autopsy, partial autopsy or noninvasive components, such as magnetic resonance imaging (MRI), computerised tomography (CT) scanning, and radiography);* umbilical cord examination;* placental examination including histopathology (microscopic examination of placental tissue); and* verbal autopsy (interviews with care providers and support people to ascertain causes, without examination of the baby).We planned to include trials assessing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth, compared with the absence of a test, protocol or guideline, or usual care (further details are presented in the Background, see Description of the intervention).We also planned to include trials comparing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth with another, for example, the use of a limited investigation protocol compared with a comprehensive investigation protocol. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility independently. MAIN RESULTS: We excluded five studies that were not RCTs. There were no eligible trials for inclusion in this review. AUTHORS' CONCLUSIONS: There is currently a lack of RCT evidence regarding the effectiveness of interventions for investigating and identifying the causes of stillbirth. Seeking to determine the causes of stillbirth is an essential component of quality maternity care, but it remains unclear what impact these interventions have on the psychosocial outcomes of parents and families, the rates of diagnosis of the causes of stillbirth, and the care and management of subsequent pregnancies following stillbirth. Due to the absence of trials, this review is unable to inform clinical practice regarding the investigation of stillbirths, and the specific investigations that would determine the causes.Future RCTs addressing this research question would be beneficial, but the settings in which the trials take place, and their design, need to be given careful consideration. Trials need to be conducted with the utmost care and consideration for the needs, concerns, and values of parents and families. Assessment of longer-term psychosocial variables, economic costs to health services, and effects on subsequent pregnancy care and outcomes should also be considered in any future trials.

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. OBJECTIVES: To determine the efficacy of a single dose of aspirin (acetylsalicylic acid), including at different doses, in the relief of acute postpartum perineal pain. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (30 August 2016), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (31 May 2016) and 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/acetaminophen for women with perineal pain in the early postpartum period. We planned to include cluster-RCTs but none were identified. Quasi-RCTs and cross-over studies were not eligible for inclusion in this review. 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 quality of the evidence for the main comparison (aspirin versus placebo) was assessed using the GRADE approach. MAIN RESULTS: We included 17 RCTs, with 16 involving 1132 women randomised to aspirin or placebo (one RCT did not report numbers of women). Two RCTs (of 16) did not contribute data to review 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 (data from 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). Primary outcomes Aspirin versus placeboMore women who received aspirin experienced adequate pain relief compared with women who received placebo over four to eight hours after administration (risk ratio (RR) 2.03, 95% confidence intervals (CI) 1.69 to 2.42; 13 RCTs, 1001 women; low-quality evidence). Women who received aspirin were less likely to need additional pain relief over four to eight hours after administration (RR 0.25, 95% CI 0.17 to 0.37; 10 RCTs, 744 women; very low-quality evidence). There was no difference in maternal adverse effects over four to eight hours post-administration (RR 1.08, 95% CI 0.57 to 2.06; 14 RCTs, 1067 women; very low-quality evidence). Subgroup analyses based on dose did not reveal any clear subgroup differences.There was no clear difference over four hours after administration between 300 mg and 600 mg aspirin for adequate pain relief (RR 0.82, 95% CI 0.36 to 1.86; 1 RCT, 81 women) or 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.There was no clear difference over four to eight hours after administration between 600 mg and 1200 mg aspirin for adequate pain relief (RR 0.85, 95% CI 0.52 to 1.39; 2 RCTs, 121 women), 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).There was no clear difference over four hours after administration between 300 mg and 1200 mg aspirin for 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. Secondary outcomesNo studies reported on secondary review outcomes: 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; maternal postpartum depression. AUTHORS' CONCLUSIONS: We found low-quality evidence to suggest that single dose aspirin compared with placebo can increase pain relief in women with perineal pain post-episiotomy. Very low-quality evidence also suggested that aspirin can reduce the need for additional analgesia, without increasing maternal adverse effects. Evidence was downgraded based on study limitations (risk of bias), imprecision, and publication bias or both. RCTs excluded breastfeeding women so there is no evidence to assess the effects of aspirin on neonatal adverse effects or breastfeeding.With international guidance recommending mothers initiate breastfeeding within one hour of birth, and exclusively breastfeed for the first six months, the evidence from this review is not applicable to current recommended best practice. Aspirin may be considered for use in non-breastfeeding women with post-episiotomy perineal pain. Although formal assessment was beyond the remit of this review, current guidance suggests that other analgesic drugs (including paracetamol) should be considered first for postpartum perineal pain. Such agents are the focus of other reviews in this series on drugs for perineal pain in the early postpartum period. It is considered most likely that if RCTs are conducted in the future they could compare aspirin with other pain relievers. Future RCTs should be designed to ensure high methodological quality, 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 women with perineal pain associated with spontaneous tears or operative birth.