Background: Cervical ripening in labour induction using a combination of methods is gaining popularity, but the effectiveness and safety of this approach are not clear. Objective: To compare the effectiveness, perinatal and maternal safety of cervical ripening in the induction of labour (IOL) using a balloon catheter with concurrent low-dose vaginal misoprostol (combined group) versus low-dose vaginal misoprostol alone. Search Strategy: MEDLINE, Embase, Emcare, Scopus, Cochrane Library, WHO ICTRP and clinicaltrials.gov. Selection Criteria: Randomised controlled trials (RCTs), viable singleton gestation, no language restrictions, published and unpublished data. Data Collection and Analysis: Systematic search, screening for trustworthiness and study quality, and an individual participant data (IPD) meta-analysis were conducted. Main Results: Eight of 22 RCTs provided IPD, of which three were excluded due to trustworthiness concerns after IPD checking (604 women). Thirteen of 22 RCTs (59.1%) were identified as ‘ not meeting trustworthiness criteria’. This IPD meta-analysis included five RCTs (649 women): two had prospective, another two had retrospective trial registrations, and one RCT was unregistered. Vaginal delivery rate, composite adverse perinatal and maternal outcomes were comparable between the two groups in the IPD meta-analysis. Vaginal delivery rate, based on aggregate data from eight RCTs ‘meeting trustworthiness criteria’ (IPD and non-IPD), had an Odds Ratio (OR) of 1.07 (95% CI 0.68;1.68). In comparison, data from thirteen RCTs ‘not meeting trustworthiness criteria’ (IPD and non-IPD) showed an OR of 1.25 (95% CI 0.88;1.77). Conclusions: Based on trustworthy data, the effectiveness of the combined group and the low-dose vaginal misoprostol group is likely to be comparable. We are uncertain about the safety of using a balloon catheter with concurrent low-dose vaginal misoprostol due to low data retrieval and trustworthiness concerns among the underlying RCTs.

Objective: To investigate the effects of aspirin on the distribution of birthweight and its impact on the rates of large-for-gestational age (LGA) neonates. Design: Secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention (ASPRE) trial. Setting: Thirteen hospitals in England, Spain, Belgium, Greece, Italy, and Israel. Population: Participants of the ASPRE trial at increased risk of preterm pre-eclampsia (PE) who had a live birth. Methods: We compared the birthweight distributions and the rates of LGA neonates between the trial groups. Analyses were stratified according to the presence of pre-existing diabetes mellitus and the development of pre-eclampsia, and logistic regression was used to investigate independent predictors of LGA neonates. Main Outcome Measures: Birthweight distribution and rate of LGA neonates. Results: Among 1,571 singleton, live neonates (777 from the aspirin group and 794 from the placebo group), aspirin was associated with a shift in birthweight from below 2,500 to between 2,500 and 4,000 grams, and birthweight percentile from below the 25 th to between the 25 th and 75 th percentiles, with no significant increase in LGA neonates (5.5% vs. 6.2%, p=0.667). Logistic regression demonstrated a significant interaction between treatment and pre-existing diabetes (p-value 0.034), and a positive association between maternal weight and LGA neonates (adjusted odds ratio 1.040, 95% confidence interval 1.030 – 1.051, p<0.001). Conclusions: Aspirin use is associated with increased birthweight without increasing the rate of LGA neonates. Among women with pre-existing diabetes, however, aspirin may lead to a higher rate of LGA neonates.

Background: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality. Uterotonics are the mainstay of PPH prevention. Objectives: To compare the efficacy of misoprostol and oxytocin for the prevention of PPH, and to evaluate the trustworthiness of trials comparing these uterotonics. Search strategy and selection criteria: Seven databases were searched for peer-reviewed literature, meeting the inclusion criteria of randomized controlled trials (RCTs) comparing misoprostol and oxytocin for the prevention of PPH. Data Collection and Analysis: Data were collected by two independent reviewers. Individual participant data (IPD) was meta-analyzed for outcomes PPH≥500mL and PPH≥1000mL. RCTs that did not share IPD were classified as trustworthy or not and were included in an aggregate data meta-analysis according to trustworthiness. Main results: Of 79 eligible RCTs, ten (12.7%) provided IPD, of which six were included. Analysis of IPD showed PPH≥500mL to be significantly higher in the misoprostol than the oxytocin group (2,022 women, aOR 1.84, 95% CI 1.43- 2.34). For PPH≥1000mL, analysis of IPD showed misoprostol and oxytocin were comparable (2022 women, OR 1.14, 95% CI 0.68- 1.91). Of the 69 studies that did not provide IPD, 23 (33.3%) were assessed as trustworthy. Analysis of trustworthy data (IPD and 23 aggregate data RCTs) showed no difference between misoprostol and oxytocin for PPH≥500mL (24,334 women, OR 1.01, 95% CI 0.69- 1.49), while misoprostol significantly increased the risk for PPH≥1000 (25,249 women, OR 1.36, 95% CI 1.16- 1.59). Conclusions: Of 79 RCTs comparing misoprostol and oxytocin for the prevention of PPH, 36.7% met trustworthiness criteria. Analysis of trustworthy data suggests oxytocin is superior to misoprostol for preventing PPH.

Background: Pregnancies complicated by placental insufficiency are characterised by increased oxidative stress. It has been suggested that melatonin has antioxidant properties and contributes to the maintenance of placental homeostasis. Objective: To systematically review the available literature about melatonin in pregnancies complicated by placental insufficiency, specifically preeclampsia and fetal growth restriction, exploring three different aspects: 1) maternal melatonin levels; 2) expression and activity of melatonin placental receptors; 3) effects of maternal melatonin administration. Search strategy: PubMed (Medline) and Scopus were searched until December 2020. Selection criteria: Published literature in English language describing the role of melatonin in pregnancies complicated by placental insufficiency, with a specific focus on preeclampsia and fetal growth restriction. Data collection and analysis: Identified studies were screened and assessed independently by two authors. Data were extracted and compiled in a qualitative evidence synthesis. Main results: Pregnancies complicated by placental insufficiency show a significant reduction in maternal systemic serum melatonin levels and a significant reduction in the expression of placental melatonin receptors. Melatonin administration in pregnancy seems safe and may reduce oxidative stress. Conclusion: The circadian pattern of melatonin secretion seems to be altered in pregnancies complicated by placental insufficiency. This is reflected by lower production of melatonin, with consequent lower systemic and placental concentrations, and lower expression of melatonin receptors, thus reducing the local release of the indole and its autocrine function. Funding: None Keywords: Melatonin, Preeclampsia, Fetal growth restriction, Placental insufficiency, Review.