Perioperative pharmacological interventions for fetal immobilisation during fetal surgery and invasive procedures.

BACKGROUND: Developments in ultrasound assessment of pregnancy has resulted in the increasing diagnosis of antenatal fetal issues. Many structural fetal conditions as well as complications associated with multiple pregnancies have the potential for in-utero treatment to improve both pregnancy and neonatal outcomes. Procedures such as laser ablation for twin-twin syndrome or cord occlusion for selective fetal termination require fetal immobilisation. Immobilisation of the fetus can occur through administration of medication to the mother or directly to the fetus. This improves procedural success and reduces the ongoing risk to the pregnancy. Evidence regarding the best medication and mode of delivery helps to ensure the optimal decision is made for both the mother and the fetus. OBJECTIVES: To assess the effects of perioperative pharmacological interventions for fetal immobilisation during fetal surgery and invasive procedures on fetal, neonatal, and maternal outcomes.  SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 May 2021), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) which compared different classes of medication administered to the mother or fetus to allow in-utero procedures to be performed. We also included cluster-randomised trials but excluded cross-over trials. DATA COLLECTION AND ANALYSIS: We used the standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. MAIN RESULTS: One study with three trial reports met the inclusion criteria. This involved 54 women with a multiple pregnancy. The study was conducted in a tertiary European hospital maternal-fetal medicine unit and compared remifentanil to diazepam for fetal immobilisation and maternal sedation during fetoscopic surgery.   Low-certainty evidence suggested that remifentanil may reduce fetal movement more than diazepam for two outcomes of fetal movement, one of fetal immobilisation at 40 minutes using a visual analogue score (VAS) (where 0 = immobile and 100 = baseline mobility), and one of gross body and limb movements (score was absolute number of movements), both assessed by a sonographer evaluating a taped ultrasound sequence (mean difference (MD) -65.00, 95% confidence interval (CI) -69.38 to -60.62 and MD -10.00, 95% CI -11.62 to -8.38; 1 study, 50 women).  Surgeons may also report being more satisfied with the procedure when using remifentanil rather than diazepam (risk ratio (RR) 2.88, 95% CI 1.60 to 5.15; 1 study, 50 women; low-certainty evidence). However, maternal respiratory rate may decrease more during the surgical procedure with remifentanil compared with diazepam (MD -6.00, 95% CI -8.29 to -3.71; 1 study, 50 women; low-certainty evidence). Maternal sedation may also be worse with remifentanil compared with diazepam (RR 0.09, 95% CI 0.01 to 0.65; 1 study, 50 women; low-certainty evidence) measured using an observer assessment of alertness/sedation (where a score of < 4 equates to profound sedation and > 4 equates to insufficient sedation). Perinatal mortality and time taken to perform the procedure were not reported in the trial.  We prespecified 20 outcomes and planned to use GRADE for 6 of them, all other outcomes were not able to be reported against for the purpose of meta-analysis due to data not being provided or unable to be interpreted. We assessed the included study at low risk of selection bias (appropriate random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (outcome assessors were blinded), attrition bias (incomplete outcome data minimal), and reporting bias.  Our GRADE assessment for certainty of the evidence indicates that there is low certainty of the evidence. AUTHORS' CONCLUSIONS: We were only able to include one study with a small number of women, from a single centre, a European tertiary hospital. This study was published in 2005 with an abstract of this trial published in 2004. This study evaluated two intravenous medications administered to the mother - remifentanil and diazepam. This study reported our prespecified primary outcome but only evaluated several of our secondary outcomes, which limited further assessment. Low-certainty evidence suggested that remifentanil may be better at reducing fetal movements and surgeons were more satisfied with the procedure. However, maternal sedation and depression of breathing may be worse with remifentanil.  Further high-quality RCTs assessing both fetal and maternal medications are required to evaluate their efficacy for fetal immobilisation as well as safety for both mother and fetus.

Nifedipine for primary dysmenorrhoea.

BACKGROUND: Dysmenorrhoea (period pain) is a common condition with a substantial impact on the well-being and productivity of women. Primary dysmenorrhoea is defined as recurrent, cramping pelvic pain that occurs with periods, in the presence of a normal uterus, ovaries and fallopian tubes. It is thought to be caused by uterine contractions (cramps) associated with a high level of production of local chemicals such as prostaglandins. The muscle of the uterus (the myometrium) responds to these high levels of prostaglandins by contracting forcefully, causing low oxygen levels and consequently pain. Nifedipine is a calcium channel blocker in widespread clinical use for preterm labour due to its ability to inhibit uterine contractions in that setting. This review addresses whether this effect of nifedipine also helps with relief of the uterine contractions during menstruation OBJECTIVES: To assess the effectiveness and safety of nifedipine for primary dysmenorrhoea. SEARCH METHODS: We searched for all published and unpublished randomised controlled trials (RCTs) of nifedipine for dysmenorrhoea, without language restriction and in consultation with the Cochrane Gynaecology and Fertility Group (CGF) Information Specialist. The following databases were searched to 25 November 2021: the Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. Also searched were the international trial registers: ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal, the Web of Science, OpenGrey, LILACS database, PubMed and Google Scholar. We checked the reference lists of relevant articles. SELECTION CRITERIA: We included RCTs comparing nifedipine with placebo for the treatment of primary dysmenorrhoea. DATA COLLECTION AND ANALYSIS: The primary outcomes to be assessed were pain, and health-related quality of life. Secondary outcomes were adverse effects, satisfaction, and need for additional medication. The two review authors independently assessed the included trials. There were insufficient data to allow meaningful meta-analysis. MAIN RESULTS: The evidence assessed was of very low quality overall. We examined three small RCTs, with a total of 106 participants. Data for analysis could be extracted from only two of these trials (with a total of 66 participants); two trials were published in the 1980s, and the third in 1993. Nifedipine may be effective for "any pain relief" compared to placebo in women with primary dysmenorrhoea (odds ratio (OR) 9.04, 95% confidence interval (CI) 2.61 to 31.31; 2 studies, 66 participants; very low-quality evidence). The evidence suggests that if the rate of pain relief using placebo is 40%, the rate using nifedipine would be between 64% and 95%. For the outcome of "good" or "excellent" pain relief, nifedipine may be more effective than placebo; the confidence interval was very wide (OR 43.78, 95% CI 5.34 to 259.01; 2 studies, 66 participants; very low-quality evidence). We are uncertain if the use of nifedipine was associated with less requirement for additional analgesia use than placebo (OR 0.54, 95% CI 0.07 to 4.20, 1 study, 42 participants; very low-quality evidence). Participants indicated that they would choose to use nifedipine over their previous analgesic if the option was available. There were similar levels of adverse effects and menstruation-related symptoms in the placebo and intervention groups (OR 0.94, 95% CI 0.08 to 10.90; 1 study, 24 participants; very low-quality evidence); if the chance of adverse effects with placebo is 80%, the rate using nifedipine would be between 24% and 98%. There were no results regarding formal assessment of health-related quality of life. AUTHORS' CONCLUSIONS: The evidence is insufficient to confirm whether nifedipine is a possible medical treatment for primary dysmenorrhoea. The trials included in this review had very low numbers and were of low quality. Notably, there was a large imbalance in numbers randomised between placebo and treatment groups in one of the two trials with data available for analysis. While there was no evidence of a difference noted in adverse effects between groups, more data from larger participant numbers are needed for this outcome. Larger, more well-conducted trials are required to elucidate the potential role of nifedipine in the treatment of this common condition, as it could be a useful addition to the therapeutic options available if shown to be well tolerated and effective. The safety of nifedipine in women of reproductive age is well established from trials of its use in preterm labour, and clinicians are accustomed to off-label use for this indication. The drug is inexpensive and readily available. Other options for relief of primary dysmenorrhoea are not suitable for all women; NSAIDs and the oral contraceptive pill (OCP) are contraindicated for some women, and the OCP is not suitable for women who are trying to conceive. In addition, the trials examined suggest there may be a participant preference for nifedipine.

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.

Skin and subcutaneous fascia closure at caesarean section to reduce wound complications: the closure randomised trial.

BACKGROUND: Wound infection is a common complication following caesarean section. Factors influencing the risk of infection may include the suture material for skin closure, and closure of the subcutaneous fascia. We assessed the effect of skin closure with absorbable versus non-absorbable suture, and closure versus non-closure of the subcutaneous fascia on risk of wound infection following Caesarean section. METHODS: Women undergoing caesarean birth at an Adelaide maternity hospital were eligible for recruitment to a randomised trial using a 2 × 2 factorial design. Women were randomised to either closure or non-closure of the subcutaneous fascia and to subcuticular skin closure with an absorbable or non-absorbable suture. Participants were randomised to each of the two interventions into one of 4 possible groups: Group 1 - non-absorbable skin suture and non-closure of the subcutaneous fascia; Group 2 - absorbable skin suture and non-closure of the subcutaneous fascia; Group 3 - non-absorbable skin suture and closure of the subcutaneous fascia; and Group 4 - absorbable skin suture and closure of the subcutaneous fascia. The primary outcomes were reported wound infection and wound haematoma or seroma within the first 30 days after birth. RESULTS: A total of 851 women were recruited and randomised, with 849 women included in the analyses (Group 1: 216 women; Group 2: 212 women; Group 3: 212 women; Group 4: 211 women). In women who underwent fascia closure, there was a statistically significant increase in risk of wound infection within 30 days post-operatively for those who had skin closure with an absorbable suture (Group 4), compared with women who had skin closure with a non-absorbable suture (Group 3) (adjusted RR 2.17; 95% CI 1.05, 4.45; p = 0.035). There was no significant difference in risk of wound infection for absorbable vs non-absorbable sutures in women who did not undergo fascia closure. CONCLUSION: The combination of subcutaneous fascia closure and skin closure with an absorbable suture may be associated with an increased risk of reported wound infection after caesarean section. TRIAL REGISTRATION: Prospectively registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12608000143325 , on the 20th March, 2008.

Intravenous or oral iron for treating iron deficiency anaemia during pregnancy: systematic review and meta-analysis.

OBJECTIVES: To compare the effects on perinatal maternal and neonatal outcomes of intravenous and oral iron therapy as first-line treatment of iron deficiency anaemia (IDA) in pregnant women. STUDY DESIGN: A meta-analysis, applying fixed and random effects models, of randomised controlled trials (RCTs) that compared the effects of intravenous and oral iron therapy for pregnant women with IDA. DATA SOURCES: MEDLINE, EMBASE, Scopus, Cochrane Register of Controlled Trials, Web of Science; bibliographies of identified articles. DATA SYNTHESIS: Fifteen eligible studies with a total of 1938 participants were identified. Each was at high risk of bias in at least one domain; ten were undertaken in low or middle income countries. Evidence (from nine RCTs) that intravenous iron was superior to oral iron in reducing the need for blood transfusion at delivery was low quality (Peto odds ratio, 0.19 [95% CI, 0.05-0.78]; number needed to treat, 95 [95% CI, 81-348]). Evidence that intravenous iron was superior to oral iron in increasing neonatal birthweight (eight RCTs: mean difference, 58 g; 95% CI, 4-112 g) or reducing the rate of breastfeeding cessation within 24 months of delivery (one RCT: hazard ratio, 0.70; 95% CI, 0.50-0.99) was of low or very low quality. While intravenous iron treatment was superior to oral iron for improving maternal haematological parameters at delivery, their effects on neonatal haematological parameters were similar. CONCLUSIONS: There is no strong evidence that first-line therapy with intravenous iron is superior to oral administration for treating IDA in pregnant women. The few identified differences in outcomes were small in magnitude and from studies at high risk of bias. REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO), CRD42019120652.

Prenatal administration of progestogens for preventing spontaneous preterm birth in women with a multiple pregnancy.

BACKGROUND: Multiple pregnancy is a strong risk factor for preterm birth, and more than 50% of women with a twin pregnancy will give birth prior to 37 weeks' gestation. Infants born preterm are recognised to be at increased risk of many adverse health outcomes, contributing to more than half of overall perinatal mortality. Progesterone is produced naturally in the body and has a role in maintaining pregnancy, although it is not clear whether administering progestogens to women with multiple pregnancy at high risk of early birth is effective and safe. Since publication of this new review in Issue 10, 2017, we have now moved one study (El-Refaie 2016) from included to studies awaiting classification, pending clarification about the study data. OBJECTIVES: To assess the benefits and harms of progesterone administration for the prevention of preterm birth in women with a multiple pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (1 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials examining the administration of a progestogen by any route for the prevention of preterm birth in women with multiple pregnancy. We did not include quasi-randomised or cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed reports identified by the search for eligibility, extracted data, assessed risk of bias and graded the quality of the evidence. MAIN RESULTS: We included 16 trials, which all compared either vaginal or intramuscular (IM) progesterone with a placebo or no treatment, and involved a total of 4548 women. The risk of bias for the majority of included studies was low, with the exception of three studies that had inadequate blinding, or significant loss to follow-up or both, or were not reported well enough for us to make a judgement. We graded the evidence low to high quality, with downgrading for statistical heterogeneity, design limitations in some of the studies contributing data, and imprecision of the effect estimate. 1 IM progesterone versus no treatment or placebo More women delivered at less than 34 weeks' gestation in the IM progesterone group compared with placebo (risk ratio (RR) 1.54, 95% confidence interval (CI) 1.06 to 2.26; women = 399; studies = 2; low-quality evidence). Although the incidence of perinatal death in the progesterone group was higher, there was considerable uncertainty around the effect estimate and high heterogeneity between studies (average RR 1.45, 95% CI 0.60 to 3.51; infants = 3089; studies = 6; I2 = 71%; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up. There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (RR 1.05, 95% CI 0.98 to 1.13; women = 2010; studies = 5; high-quality evidence); preterm birth less than 28 weeks (RR 1.08, 95% CI 0.75 to 1.55; women = 1920; studies = 5; moderate-quality evidence); infant birthweight less than 2500 g (RR 0.99, 95% CI 0.90 to 1.08; infants = 4071; studies = 5; I2 = 76%, moderate-quality evidence)). No childhood outcomes were reported in the trials. 2 Vaginal progesterone versus no treatment or placebo by dose There were no clear group differences in incidence of preterm birth before 34 weeks (average RR 0.90, 95% CI 0.66 to 1.23; women = 1503; studies = 5; I2 = 36%; low-quality evidence). Although fewer births before 34 weeks appeared to occur in the progesterone group, the CIs crossed the line of no effect. Incidence of perinatal death was higher in the progesterone group, although there was considerable uncertainty in the effect estimate and the quality of the evidence was low for this outcome (RR 1.23, 95% CI 0.74 to 2.06; infants = 2287; studies = 3; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up. There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (average RR 0.97, 95% CI 0.89 to 1.06; women = 1597; studies = 6; moderate-quality evidence); preterm birth less than 28 weeks (RR 1.53, 95% CI 0.79 to 2.97; women = 1345; studies = 3; low-quality evidence); infant birthweight less than 2500 g (average RR 0.95, 95% CI 0.84 to 1.07; infants = 2640; studies = 3; I2 = 66%, moderate-quality evidence)). No childhood outcomes were reported in the trials. For secondary outcomes, there were no clear group differences found in any of the other maternal outcomes except for caesarean section, where women who received vaginal progesterone did not have as many caesarean sections as those in the placebo group, although the difference between groups was not large (8%) (RR 0.92, 95% CI 0.86 to 0.98; women = 1919; studies = 5; I2 = 0%). There were no clear group differences found in any of the infant outcomes except for mechanical ventilation, which was required by fewer infants whose mothers had received the vaginal progesterone (RR 0.70, 95% CI 0.52 to 0.94; infants = 2695; studies = 4). AUTHORS' CONCLUSIONS: Overall, for women with a multiple pregnancy, the administration of progesterone (either IM or vaginal) does not appear to be associated with a reduction in risk of preterm birth or improved neonatal outcomes. Future research could focus on a comprehensive individual participant data meta-analysis including all of the available data relating to both IM and vaginal progesterone administration in women with a multiple pregnancy, before considering the need to conduct trials in subgroups of high-risk women (for example, women with a multiple pregnancy and a short cervical length identified on ultrasound).

Nutrition During Pregnancy, Lactation and Early Childhood and its Implications for Maternal and Long-Term Child Health: The Early Nutrition Project Recommendations.

BACKGROUND: A considerable body of evidence accumulated especially during the last decade, demonstrating that early nutrition and lifestyle have long-term effects on later health and disease ("developmental or metabolic programming"). METHODS: Researchers involved in the European Union funded international EarlyNutrition research project consolidated the scientific evidence base and existing recommendations to formulate consensus recommendations on nutrition and lifestyle before and during pregnancy, during infancy and early childhood that take long-term health impact into account. Systematic reviews were performed on published dietary guidelines, standards and recommendations, with special attention to long-term health consequences. In addition, systematic reviews of published systematic reviews on nutritional interventions or exposures in pregnancy and in infants and young children aged up to 3 years that describe effects on subsequent overweight, obesity and body composition were performed. Experts developed consensus recommendations incorporating the wide-ranging expertise from additional 33 stakeholders. FINDINGS: Most current recommendations for pregnant women, particularly obese women, and for young children do not take long-term health consequences of early nutrition into account, although the available evidence for relevant consequences of lifestyle, diet and growth patterns in early life on later health and disease risk is strong. INTERPRETATION: We present updated recommendations for optimized nutrition before and during pregnancy, during lactation, infancy and toddlerhood, with special reference to later health outcomes. These recommendations are developed for affluent populations, such as women and children in Europe, and should contribute to the primary prevention of obesity and associated non-communicable diseases.

Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes.

BACKGROUND: There has been considerable interest in providing antenatal dietary and lifestyle advice for women with obesity or who are overweight during pregnancy, as a strategy to limit gestational weight gain and improve maternal and infant health. However, such antenatal interventions appear to have a modest effect on gestational weight gain and other clinical pregnancy and birth outcomes and additional strategies are required.Metformin is an oral insulin-sensitising medication that acts to decrease blood glucose concentrations. Metformin is commonly used in the treatment of type 2 diabetes mellitus and polycystic ovarian syndrome, and is being used increasingly in the treatment of gestational diabetes, having been shown to result in decreased rates of caesarean birth and neonatal hypoglycaemia. Metformin may be an adjuvant therapy to current antenatal strategies in pregnant women with obesity or who are overweight, acting to reduce glucose production in the liver and improve glucose uptake in smooth muscle cells, and therefore improve the overall metabolic health of women in pregnancy and reduce the risk of known adverse pregnancy outcomes. OBJECTIVES: To evaluate the role of metformin in pregnant women with obesity or who are overweight, on maternal and infant outcomes, including adverse effects of treatment and costs. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (11 October 2017), and reference lists of retrieved studies. SELECTION CRITERIA: All published and unpublished randomised controlled trials evaluating metformin use (compared with placebo or no metformin) in women with obesity or who are overweight in pregnancy for improving outcomes, alone or in combination with other interventions were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We included three studies which randomised women (1099) with a body mass index (BMI) of 30 kg/m2 (1 study) and 35 kg/m2 (2 studies), with outcomes available for 1034 participants. None of the studies assessed women with a BMI between 25 kg/m2and 29.9 kg/m2, therefore we could not assess the use of metformin in women considered overweight. We did not identify studies of metformin in combination with another treatment. Two other studies are ongoing.All three included studies were randomised controlled trials and compared metformin with placebo, commencing early in the second trimester. Doses ranged from 500 mg twice daily to 3.0 g per day. All three studies (two in the UK, one in Egypt) included women attending hospitals for antenatal care.Two studies were generally at a low risk of bias across the majority of domains. We assessed the third study as being at an unclear risk of selection bias, performance and detection bias due to insufficient information in the report. We assessed the trial as being at a low risk of attrition bias and other bias; we felt it was at a high risk of reporting bias.The primary outcome for this review was infant birthweight large-for-gestational-age (> 90th centile for gestational age and infant sex). Women who received metformin or placebo had a similar risk of their baby being born large for his or her gestational age (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.30; 2 studies, 831 infants; high-quality evidence).Women who received metformin may have a slightly lower gestational weight gain (mean difference (MD) -2.60 kg, 95% CI -5.29 to 0.10; 3 studies, 899 women; low-quality evidence).Metformin may make little or no difference in the risk of women developing gestational hypertension (average RR 1.02, 95% CI 0.54 to 1.94; 3 studies, 1040 women; low-quality evidence) or pre-eclampsia (RR 0.74, 95% CI 0.09 to 6.28; 2 studies, 840 women; low-quality evidence). Metformin probably makes little or no difference in the risk of women developing gestational diabetes (RR 0.85, 95% CI 0.61 to 1.19; 3 studies, 892 women; moderate-quality evidence).One study of 400 women reported women receiving metformin were more likely to experience any adverse effect compared with women receiving placebo (RR 1.63, 95% CI 1.27 to 2.08; 1 study, 400 women). Adverse effects included abdominal pain, diarrhoea, or headache. When considering individual side effects, women receiving metformin were more likely to experience diarrhoea than women receiving placebo (RR 2.34, 95% CI 1.74 to 3.14; 797 women; 2 studies, 797 women; high-quality evidence). No other important differences were identified between Metformin and placebo for other maternal secondary outcomes, including: caesarean birth, birth before 37 weeks of pregnancy, shoulder dystocia, perineal tear, or postpartum haemorrhage.In terms of other infant outcomes, there was little or no difference in the infant birthweight (MD 6.39 g, 95% CI -81.15 to 93.92; 2 studies, 834 infants; high-quality evidence). There were no other important differences identified for other infant secondary outcomes in this review: hypoglycaemia (low blood sugar); hyperbilirubinaemia (jaundice); Apgar score less than 7 at five minutes; or stillbirth and neonatal death. Only one study reported admission to the neonatal intensive care unit (NICU), indicating similar rates of admission between women receiving metformin or placebo; no other admission data were reported to assess differences in costs. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of metformin for women with obesity in pregnancy for improving maternal and infant outcomes. Metformin was, however, associated with increased risk of adverse effects, particularly diarrhoea. The quality of the evidence in this review varied from high to low, with downgrading decisions based on study limitations and inconsistency.There were only a small number of studies included in this review. Furthermore, none of the included studies included women categorised as 'overweight' and no trials looked at metformin in combination with another treatment.Future research is required in order to further evaluate the role of metformin therapy in pregnant women with obesity or who are overweight, as a strategy to improve maternal and infant health, alone or as an adjuvant to dietary and lifestyle advice.

Safety and efficacy of intravenous iron polymaltose, iron sucrose and ferric carboxymaltose in pregnancy: A systematic review.

BACKGROUND: Intravenous (IV) iron in pregnancy is useful where oral iron is not tolerated or a rapid replenishment of iron is required. AIMS: To review the literature on the efficacy and safety of different IV iron preparations in the management of antenatal iron-deficiency anaemia (IDA). MATERIALS AND METHODS: We searched MEDLINE, Embase and Scopus from inception to June 2016. Eligible studies were randomised controlled trials (RCTs) and observational studies, involving administration of IV iron (ferric carboxymaltose (FCM), iron polymaltose (IPM) or iron sucrose (IS)), regardless of comparator, to manage antenatal IDA. Two independent reviewers selected studies, extracted data and assessed quality. RESULTS: A total of 47 studies were eligible (21 RCTs and 26 observational studies), investigating IS (n = 2635; 41 studies), FCM (n = 276; four studies) and IPM (n = 164; three studies). All IV preparations resulted in significant improvements in haematological parameters, with a median increase of 21.8 g/L at 3-4 weeks and 30.1 g/L by delivery, but there was no evidence of any associated improvements in clinical outcomes. A greater median increase in Hb was observed with a high (25 g/L; range: 20-39.6 g/L) compared with low dose (20 g/L; range: 6.2-50.3 g/L). The median prevalence of adverse drug reactions for IPM (2.2%; range: 0-4.5%) was lower than FCM (5.0%; range: 0-20%) and IS (6.7%; range: 0-19.5%). CONCLUSION: While IV iron in pregnancy improves haematological parameters, there is an absence of evidence for improvements in important maternal or perinatal outcomes. No single preparation of IV iron appeared to be superior, with the current IV iron preparation of choice largely determined by cost and convenience around administration.

Use of intravenous iron polymaltose in the management of iron deficiency in pregnancy: A retrospective cohort study.

BACKGROUND: Intravenous iron polymaltose (IPM) is commonly utilised in pregnancy when oral treatment is not tolerated or where rapid replenishment of iron stores is required, but data on use in pregnancy is scarce. AIM: To examine the use, safety and efficacy of intravenous IPM in pregnancy. METHODS: Retrospective cohort study of pregnant women administered intravenous IPM between January 2014 and January 2016 at a Tertiary teaching hospital in Adelaide, Australia. Data on maternal characteristics, intravenous iron infusion details, and haematological parameters were collected from case notes and electronic records. Main outcome measures included indication for intravenous iron infusion, prevalence of infusion reactions, change in haemoglobin and correction of anaemia prior to delivery. RESULTS: Intravenous IPM was administered in 213 pregnancies, 62.0% of women with iron deficiency anaemia (IDA) and the remainder (38.0%) with non-anaemic iron deficiency. Adverse drug reactions (ADRs) occurred in 24% of women, of which 32% required infusion cessation. Anaemia was still present at delivery among 7%, and 17% of women with mild, and moderate/severe anaemia respectively. Approximately one in five anaemic women received an intravenous IPM dose below that recommended by the local guideline, particularly in women with a body mass index ≥ 25 kg/m2 compared with <25 kg/m2 (30.9% vs 6.3%; P < 0.001). Doses 'at recommended' resulted in a greater increase in haemoglobin from treatment until delivery than doses 'below recommended' (adjusted beta coefficient 8.4 g/L; 95% CI 2.7-14.1 g/L). CONCLUSION: Intravenous IPM is effective in treating IDA in pregnancy but is associated with a high prevalence of ADRs and treatment cessation.

Evaluation of a smartphone nutrition and physical activity application to provide lifestyle advice to pregnant women: The SNAPP randomised trial.

Our objective was to evaluate the impact of a smartphone application as an adjunct to face-to-face consultations in facilitating dietary and physical activity change among pregnant women. This multicentre, nested randomised trial involved pregnant women with a body mass index ≥18.5 kg/m2 , with a singleton pregnancy between 10 and 20 weeks' gestation, and participating in 2 pregnancy nutrition-based randomised trials across metropolitan Adelaide, South Australia. All women participating in the SNAPP trial received a comprehensive dietary, physical activity, and behavioural intervention, as part of the GRoW or OPTIMISE randomised trials. Women were subsequently randomised to either the "Lifestyle Advice Only Group," where women received the above intervention, or the "Lifestyle Advice plus Smartphone Application Group," where women were additionally provided access to the smartphone application. The primary outcome was healthy eating index (HEI) assessed by maternal food frequency questionnaire completed at trial entry, and 28 and 36 weeks' gestation. Analyses were performed using intention-to-treat principles, with statistical significance at p = .05. One hundred sixty-two women participated: 77 allocated to the Lifestyle Advice plus Smartphone Application Group and 85 to the Lifestyle Advice Only Group. Mean difference in HEI score at 28 weeks of pregnancy was 0.01 (CI [-2.29, 2.62]) and at 36 weeks of pregnancy -1.16 (CI [-4.60, 2.28]). There was no significant additional benefit from the provision of the smartphone application in improving HEI score (p = .452). Although all women improved dietary quality across pregnancy, use of the smartphone application was poor. Our findings do not support addition of the smartphone application.

The effect of an antenatal lifestyle intervention in overweight and obese women on circulating cardiometabolic and inflammatory biomarkers: secondary analyses from the LIMIT randomised trial.

BACKGROUND: Maternal overweight and obesity during pregnancy is associated with insulin resistance, hyperglycaemia, hyperlipidaemia and a low-grade state of chronic inflammation. The aim of this pre-specified analysis of secondary outcome measures was to evaluate the effect of providing antenatal dietary and lifestyle advice on cardiometabolic and inflammatory biomarkers. METHODS: We conducted a multicentre trial in which pregnant women who were overweight or obese were randomised to receive either Lifestyle Advice or Standard Care. We report a range of pre-specified secondary maternal and newborn cardiometabolic and inflammatory biomarker outcomes. Maternal whole venous blood was collected at trial entry (mean 14 weeks gestation; non-fasting), at 28 weeks gestation (fasting), and at 36 weeks gestation (non-fasting). Cord blood was collected after birth and prior to the delivery of the placenta. A range of cardiometabolic and inflammatory markers were analysed (total cholesterol, triglycerides, non-esterified fatty acids, high-density lipoprotein cholesterol, insulin, glucose, leptin, adiponectin, C-reactive protein, granulocyte macrophage-colony stimulating factor, interferon gamma, TNF-α, and interleukins 1ß, 2, 4, 5, 6, 8, and 10). Participants were analysed in the groups to which they were randomised, and were included in the analyses if they had a measure at any time point. RESULTS: One or more biological specimens were available from 1951 women (989 Lifestyle Advice and 962 Standard Care), with cord blood from 1174 infants (596 Lifestyle Advice and 578 Standard Care). There were no statistically significant differences in mean cardiometabolic and inflammatory marker concentrations across pregnancy and in infant cord blood between treatment groups. Estimated treatment group differences were close to zero, with 95% confidence intervals spanning a range of differences that were short of clinical relevance. There was no evidence to suggest that the intervention effect was modified by maternal BMI category. CONCLUSIONS: Despite our findings, it will be worth considering potential relationships between cardiometabolic and inflammatory markers and clinical outcomes, including longer-term infant health and adiposity. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426 ; Date Registered 09/03/2007).

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.

Regimens of ultrasound surveillance for twin pregnancies for improving outcomes.

BACKGROUND: Increased ultrasound surveillance of twin pregnancies has become accepted practice due to the higher risk of complications. There is no current consensus however as to the method and frequency of ultrasound monitoring that constitutes optimal care. OBJECTIVES: To systematically review the effects of different types and frequency of ultrasound surveillance for women with a twin pregnancy on neonatal, fetal and maternal outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (all searched 11 August 2017), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised and quasi-randomised trials (including those published in abstract form) comparing the effects of described antenatal ultrasound surveillance regimens in twin pregnancies. Trials using a cluster-randomised design would have been eligible for inclusion in this review but none were identified. Trials using a cross-over design are not eligible for inclusion in this review.Different types and frequencies of ultrasound testing (for fetal surveillance and detection of specific problems) compared with each other and also compared with no testing. For example, an intervention might comprise a specific approach to ultrasound examination with dedicated components to detect twin-specific pathology. Different interventions could also include a specific type of surveillance at different intervals or different combinations at the same intervals.In this review we only found one study looking at fetal growth (biometry) and Doppler ultrasounds at 25, 30 and 35 weeks' gestation versus fetal growth alone. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and quality, and extracted data. We checked data for accuracy. MAIN RESULTS: We included one trial of 526 women with a twin pregnancy of two viable twins, with no known morphological abnormality, in this review. The trial compared women receiving fetal growth and Doppler ultrasounds at 25, 30 and 35 weeks' gestation to fetal growth alone. We judged the included study to be at low risk of bias however the risk of performance and detection bias were unclear.The primary outcome was the perinatal mortality rate (after randomisation), for which there was no evidence of a clear difference between the fetal growth + Doppler and the fetal growth alone groups (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.32 to 2.41, low-quality evidence) with similar rates in both groups (seven events in the Dopper + fetal growth group and eight in the fetal growth alone group). No clear differences were seen between the two regimens for the other outcomes in this review: stillbirth (RR 0.67, 95% CI 0.11 to 3.99), neonatal death (RR 1.01, 95% CI 0.29 to 3.46, low-quality evidence), gestational age at birth (weeks) (mean difference 0.10, 95% CI -0.39 to 0.59, moderate-quality evidence), infant requiring ventilation (RR 0.86, 95% CI 0.59 to 1.25), admission to special care or intensive care units (RR 0.96, 95% CI 0.88 to 1.05), caesarean section (any) (RR 1.00, 95% CI 0.81 to 1.23, high-quality evidence), elective caesarean section (RR 1.06, 95% CI 0.77 to 1.47), emergency caesarean section (RR 0.93, 95% CI 0.66 to 1.32), induction of labour (RR 1.10, 95% CI 0.80 to 1.50, moderate-quality evidence) or antenatal hospital admission (RR 0.96, 95% CI 0.80 to 1.15, high-quality evidence). The number of preterm births before 28 weeks' gestation was not reported in the included study. For the mortality-related outcomes, event numbers were small.The included study did not report the majority of our maternal and infant secondary outcomes. Infant outcomes not reported included fetal acidosis, Apgar scores less than 7 at five minutes and preterm birth before 37 and 34 weeks' gestation. The maternal outcomes; length of antenatal hospital stay, timely diagnosis of significant complications, rate of preterm, prelabour rupture of membranes and women's level of satisfaction with their care were not reported. The study did not classify twin pregnancies according to their chorionicity. An awareness of the chorionicity may have improved applicability of this data set.We downgraded outcomes assessed using GRADE for imprecision of effect estimates. AUTHORS' CONCLUSIONS: This review is based on one small study which was underpowered for detection of rare outcomes such as perinatal mortality, stillbirth and neonatal death.There is insufficient evidence from randomised controlled trials to inform best practice for fetal ultrasound surveillance regimens when caring for women with a twin pregnancy. More studies are needed to evaluate the effects of currently used ultrasound surveillance regimens in twin pregnancies. Future research could report on the important maternal and infant outcomes as listed in this review.

Prenatal administration of progestogens for preventing spontaneous preterm birth in women with a multiple pregnancy.

BACKGROUND: Multiple pregnancy is a strong risk factor for preterm birth, and more than 50% of women with a twin pregnancy will give birth prior to 37 weeks' gestation. Infants born preterm are recognised to be at increased risk of many adverse health outcomes, contributing to more than half of overall perinatal mortality. Progesterone is produced naturally in the body and has a role in maintaining pregnancy, although it is not clear whether administering progestogens to women with multiple pregnancy at high risk of early birth is effective and safe. OBJECTIVES: To assess the benefits and harms of progesterone administration for the prevention of preterm birth in women with a multiple pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (1 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials examining the administration of a progestogen by any route for the prevention of preterm birth in women with multiple pregnancy. We did not include quasi-randomised or cross-over studies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed reports identified by the search for eligibility, extracted data, assessed risk of bias and graded the quality of the evidence. MAIN RESULTS: We included 17 trials, which all compared either vaginal or intramuscular (IM) progesterone with a placebo or no treatment, and involved a total of 4773 women. The risk of bias for the majority of included studies was low, with the exception of four studies that had inadequate blinding, or significant loss to follow-up or both, or were not reported well enough for us to make a judgement. We graded the evidence low to high quality, with downgrading for statistical heterogeneity, design limitations in some of the studies contributing data, and imprecision of the effect estimate. 1 IM progesterone versus no treatment or placeboMore women delivered at less than 34 weeks' gestation in the IM progesterone group compared with placebo (risk ratio (RR) 1.54, 95% confidence interval (CI) 1.06 to 2.26; women = 399; studies = 2; low-quality evidence). Although the incidence of perinatal death in the progesterone group was higher, there was considerable uncertainty around the effect estimate and high heterogeneity between studies (average RR 1.45, 95% CI 0.60 to 3.51; infants = 3089; studies = 6; I2 = 71%; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up.There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (RR 1.05, 95% CI 0.98 to 1.13; women = 2010; studies = 5; high-quality evidence); preterm birth less than 28 weeks (RR 1.08, 95% CI 0.75 to 1.55; women = 1920; studies = 5; moderate-quality evidence); infant birthweight less than 2500 g (RR 0.99, 95% CI 0.90 to 1.08; infants = 4071; studies = 5; I2 = 76%, moderate-quality evidence)). No childhood outcomes were reported in the trials. 2 Vaginal progesterone versus no treatment or placebo by doseThere were no clear group differences in incidence of preterm birth before 34 weeks (average RR 0.83, 95% CI 0.63 to 1.09; women = 1727; studies = 6; I2 = 46%; low-quality evidence). Although fewer births before 34 weeks appeared to occur in the progesterone group, the CIs crossed the line of no effect. Incidence of perinatal death was higher in the progesterone group, although there was considerable uncertainty in the effect estimate and the quality of the evidence was low for this outcome (RR 1.23, 95% CI 0.74 to 2.06; infants = 2287; studies = 3; low-quality evidence). No studies reported maternal mortality or major neurodevelopmental disability at childhood follow-up.There were no clear group differences found in any of the other maternal or infant outcomes (preterm birth less than 37 weeks (average RR 0.97, 95% CI 0.89 to 1.06; women = 1597; studies = 6; moderate-quality evidence); preterm birth less than 28 weeks (RR 1.22, 95% CI 0.68 to 2.21; women = 1569; studies = 4; low-quality evidence); infant birthweight less than 2500 g (RR 0.95, 95% CI 0.88 to 1.03; infants = 3079; studies = 4; I2 = 49%, moderate-quality evidence)). No childhood outcomes were reported in the trials.For secondary outcomes, there were no clear group differences found in any of the other maternal outcomes except for caesarean section, where women who received vaginal progesterone did not have as many caesarean sections as those in the placebo group, although the difference between groups was not large (7%) (RR 0.93, 95% CI 0.88 to 0.98; women = 2143; studies = 6; I2 = 0%). There were no clear group differences found in any of the infant outcomes except for mechanical ventilation, which was required by fewer infants whose mothers had received the vaginal progesterone (RR 0.61, 95% CI 0.48 to 0.77; infants = 3134; studies = 5). AUTHORS' CONCLUSIONS: Overall, for women with a multiple pregnancy, the administration of progesterone (either IM or vaginal) does not appear to be associated with a reduction in risk of preterm birth or improved neonatal outcomes.Future research could focus on a comprehensive individual participant data meta-analysis including all of the available data relating to both IM and vaginal progesterone administration in women with a multiple pregnancy, before considering the need to conduct trials in subgroups of high-risk women (for example, women with a multiple pregnancy and a short cervical length identified on ultrasound).

Elective repeat caesarean section versus induction of labour for women with a previous caesarean birth.

BACKGROUND: When a woman has had a previous caesarean birth and requires induction of labour for a subsequent pregnancy, two options are available for her care: an elective repeat caesarean and planned induction of labour. Although risks and benefits are associated with both elective repeat caesarean birth and planned induction of labour, current sources of information are limited to non-randomised cohort studies, and studies designed in this way have significant potential for bias. Consequently, any conclusions based on results of these studies are limited in their reliability and should be interpreted with caution. OBJECTIVES: To assess, using the best available evidence, the benefits and harms of a policy of planned elective repeat caesarean section versus a policy of induction of labour for women with a previous caesarean birth who require induction of labour for a subsequent pregnancy. Primary outcomes include success of induction of labour, need for caesarean section, maternal and neonatal mortality, and maternal and neonatal morbidity. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Trials Register (31 May 2017) and planned to search reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials with reported data on comparison of outcomes in mothers and babies between women who planned an elective repeat caesarean section and women who planned induction of labour when a previous birth was performed by caesarean. Cluster trials and quasi-randomised trials were also eligible for inclusion. We would consider trials published only as abstracts if they provided enough information to meet review inclusion criteria. DATA COLLECTION AND ANALYSIS: We performed no data extraction. For future updates, if randomised controlled trials are identified, two review authors will independently assess trials for inclusion and risk of bias, and will extract data and check extracted data for accuracy. Review authors will assess the quality of the evidence using the GRADE approach. MAIN RESULTS: Review authors identified no randomised controlled trials. AUTHORS' CONCLUSIONS: Both planned elective repeat caesarean section and planned induction of labour for women with a prior caesarean birth are associated with benefits and harms. Evidence for these care practices has been drawn from non-randomised studies, which are associated with potential bias. Therefore, any results and conclusions presented must be interpreted with caution. Randomised controlled trials are required to provide the most reliable evidence regarding the benefits and harms of both planned elective repeat caesarean section and planned induction of labour for women with a previous caesarean birth.

Approaches for optimising intravenous iron dosing in pregnancy: a retrospective cohort study.

BACKGROUND: Intravenous iron is commonly utilised in pregnancy when treatment with oral is not tolerated or where rapid replenishment of iron stores is required. AIMS: To examine the relationship between doses of intravenous iron administered during pregnancy according to different maternal bodyweight measures and subsequent treatment response. METHODS: Retrospective cohort study of pregnant women with confirmed iron deficiency anaemia who received intravenous iron polymaltose at a tertiary teaching hospital in Australia from 1 January 2014 to 31 January 2016. Diagnosis of anaemia and/or iron deficiency, infusion dosage characteristics and haematological parameters were collected from paper-based case notes and electronic records. The dose of intravenous iron administered was examined relative to maternal total bodyweight (TBW), ideal bodyweight (IBW) (equation = 45.5 kg + 0.9 kg/cm for each cm over 152 cm) and adjusted bodyweight (equation = IBW + [0.4 × (TBW - IBW)]). RESULTS: A total of 122 pregnancies was identified where women had confirmed iron deficiency anaemia and received a single infusion of intravenous iron polymaltose. Dose-response relationships were evident between change in haemoglobin from treatment until delivery and intravenous iron dose according to adjusted bodyweight (adjusted beta coefficient 0.70 (95% CI 0.24-1.15)) and pre-pregnancy total bodyweight (adjusted beta coefficient 0.83 (95% CI 0.36-1.29)), but not ideal bodyweight (adjusted beta coefficient 0.37 (95% CI -0.04-0.78)). Calculating iron deficit using adjusted bodyweight most closely matched that based on a physiological estimate of iron deficit according to weight-based total blood volume. CONCLUSION: Optimal treatment outcomes in pregnant women requiring intravenous iron may be reached by dosing according to adjusted pre-pregnancy bodyweight rather than ideal bodyweight.

Trends in receipt of single and repeat courses of antenatal corticosteroid administration among preterm and term births: A retrospective cohort study.

AIM: To investigate trends in receipt and timing of antenatal corticosteroid (ACS) administration over a ten-year interval. METHODS: Retrospective cohort study of all live births from 2006 to 2015 occurring at a tertiary level teaching hospital in Adelaide, Australia. We analysed temporal trends in the receipt of single courses and repeat doses of ACSs, according to administration timing prior to birth. The main outcome measures were receipt of a single course of ACS and whether administration was 'Optimal' (≥24 h to

Sealing procedures for preterm prelabour rupture of membranes.

BACKGROUND: Preterm prelabour rupture of the membranes (PPROM) complicates approximately 2% of pregnancies and can be either spontaneous or iatrogenic in nature. Complications of PPROM include prematurity, chorioamnionitis, neonatal sepsis, limb position defects, respiratory distress syndrome, pulmonary hypoplasia chronic lung disease, periventricular leukomalacia and intraventricular haemorrhage.A number of different sealing techniques have been employed which aim to restore a physical barrier against infection and encourage the re-accumulation of amniotic fluid. Routine use of sealants is currently not recommended due to a lack of sufficient evidence to support the safety and effectiveness of such interventions. OBJECTIVES: To assess the effects of sealing techniques following PPROM against each other, or versus standard care (including no sealant), on maternal and neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 May 2016) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing different techniques for sealing preterm prelabour ruptured membranes. Cluster-randomised trials and trials using a cross-over design were not eligible for inclusion in this review. We planned to include abstracts when sufficient information was provided. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed trial quality. Two review authors independently extracted data. Data were checked for accuracy. MAIN RESULTS: We included two studies (involving 141 women - with data from 124 women). We considered both studies as being at high risk of bias. Meta-analysis was not possible because the included studies examined different interventions (both in comparison with standard care) and reported on few, but different, outcomes. One study compared cervical adapter (mechanical sealing), and the other study examined an immunological membrane sealant. Neither of the included studies reported on this review's primary outcome of interest - perinatal mortality. Similarly, data were not reported for the majority of this review's secondary infant and maternal outcomes. Cervical adapter (mechanical sealing) versus standard care (one study, data from 35 participants)No data were reported for this review's primary outcome - perinatal mortality. Data were reported for few of this review's infant or maternal secondary outcomes.There was no clear difference between the mechanical sealing group and the standard care control in relation to the incidence of neonatal sepsis (risk ratio (RR) 1.19, 95% confidence interval (CI) 0.28 to 5.09 (very low-quality evidence)) or chorioamnionitis (RR 1.19, 95% CI 0.28 to 5.09 (very low-quality evidence)). Oral immunological membrane sealant versus standard care (one study, data from 94 participants)No data were available for perinatal mortality (this review's primary outcome) or for the majority of this review's infant and maternal secondary outcomes. Compared to standard care, the immunological membrane sealant was associated with a reduction in preterm birth less than 37 weeks (RR 0.48, 95% CI 0.34 to 0.68 (very low-quality evidence)) and a reduction in neonatal death (RR 0.38, 95% CI 0.19 to 0.75 (very low-quality evidence)). However, there was no clear difference between groups in terms of neonatal sepsis (RR 0.64, 95% CI 0.28 to 1.46 (very low-quality evidence)) or respiratory distress syndrome (RR 0.64, 95% CI 0.28 to 1.46 (very low-quality evidence)). AUTHORS' CONCLUSIONS: There is insufficient evidence to evaluate sealing procedures for PPROM. There were no data relating to this review's primary outcome (perinatal mortality) and the majority of our infant and maternal secondary outcomes were not reported in the two included studies.There was limited evidence to suggest that an immunological membrane sealant was associated with a reduction in preterm birth at less than 37 weeks and neonatal death, but these results should be interpreted with caution as this is based on one small study, with a high risk of bias, and the intervention has not been tested in other studies.Although midtrimester PPROM is not a rare occurrence, there are only a small amount of published data addressing the benefits and risks of sealing procedures. Most of these studies are retrospective and cohort based and could therefore not be included in our data-analysis.This review highlights the paucity of prospective randomised trials in this area. Current evidence provides limited information both on effectiveness and safety for the interventions described. Given the paucity of high-quality data, we recommend that future research efforts focus on the conduct of randomised trials assessing the effect of promising interventions that have been only evaluated to date in cohort studies (e.g. amniopatch). Future trials should address outcomes including perinatal mortality, preterm birth, neonatal death, respiratory distress syndrome, neonatal sepsis and developmental delay. They should also evaluate maternal outcomes including sepsis, mode of delivery, length of hospital stay and emotional well-being.

Techniques for assisting difficult delivery at caesarean section.

BACKGROUND: Caesarean section involves making an incision in the woman's abdomen and cutting through the uterine muscle. The baby is then delivered through that incision. Difficult caesarean birth may result in injury for the infant or complications for the mother. Methods to assist with delivery include vacuum or forceps extraction or manual delivery utilising fundal pressure. Medication that relaxes the uterus (tocolytic medication) may facilitate the birth of the baby at caesarean section. Delivery of the impacted head after prolonged obstructed labour can be associated with significant maternal and neonatal complication; to facilitate delivery of the head the surgeon may utilise either reverse breech extraction or head pushing. OBJECTIVES: To compare the use of tocolysis (routine or selective use) with no use of tocolysis or placebo and to compare different extraction methods at the time of caesarean section for outcomes of infant birth trauma, maternal complications (particularly postpartum haemorrhage requiring blood transfusion), and long-term measures of infant and childhood morbidity. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All published, unpublished, and ongoing randomised controlled trials comparing the use of tocolytic agents (routine or selective) at caesarean section versus no use of tocolytic or placebo at caesarean section to facilitate the birth of the baby. Use of instrument versus manual delivery to facilitate birth of the baby. Reverse breech extraction versus head pushing to facilitate delivery of the deeply impacted fetal head. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Seven randomised controlled trials, involving 582 women undergoing caesarean section were included in this review. The risk of bias of included trials was variable, with some trials not adequately describing allocation or randomisation.Three comparisons were included. 1. Tocolysis versus no tocolysisA single randomised trial involving 97 women was identified and included in the review. Birth trauma was not reported. There were no cases of any maternal side-effect reported in either the nitroglycerin or the placebo group. No other maternal and infant health outcomes were reported. 2. Reverse breech extraction versus head push for the deeply impacted head at full dilation at caesarean section Four randomised trials involving 357 women were identified and included in the review. The primary outcome of birth trauma was reported by three trials and there was no difference between reverse breech extraction and head push for this rare outcome (three studies, 239 women, risk ratio (RR) 1.55, 95% confidence interval (CI) 0.42 to 5.73). Secondary outcomes including endometritis rate (three studies, 285 women, average RR 0.52, 95% CI 0.26 to 1.05, Tau I² = 0.22, I² = 56%), extension of uterine incision (four studies, 357 women, average RR 0.23, 95% CI 0.13 to 0.40), mean blood loss (three studies, 298 women, mean difference (MD) -294.92, 95% CI -493.25 to -96.59; I² = 98%) and neonatal intensive care unit (NICU)/special care nursery (SCN) admission (two studies, 226 babies, average RR 0.53, 95% CI 0.23 to 1.22, Tau I² = 0.27, I² = 74%) were decreased with reverse breech extraction. No differences were observed between groups for many of the other secondary outcomes reported (blood loss > 500 mL; blood transfusion; wound infection; mean hospital stay; average Apgar score).There was significant heterogeneity between the trials for the outcomes mean blood loss, operative time and mean hospital stay, making comparison difficult. However the operation duration was significantly shorter for reverse breech extraction, which may correspond with ease of delivery and therefore, the amount of tissue trauma and therefore, significantly less blood loss. Given the heterogeneity, we cannot define the amount of difference in blood loss, operative time or hospital stay however. 3. Instrument (vacuum or forceps) versus manual extraction at elective caesarean section Two randomised trials involving 128 women were identified and included in the review. Only one trial reported maternal and infant health outcomes as prespecified in this review. This trial reported birth trauma as an outcome but there were no instances of birth trauma in either comparison group. There were no differences found in mean fall in haemoglobin (Hb) between groups (one study, 44 women, MD 0.03, 95% CI -0.53 to 0.59), or in uterine incision extension (one study, 44 women, RR 0.70, 95% CI 0.13 to 3.73). AUTHORS' CONCLUSIONS: There is currently insufficient information available from randomised trials to support or refute the routine or selective use of tocolytic agents or instrument to facilitate infant birth at the time of difficult caesarean section. There is limited evidence that reverse breech extraction may improve maternal and fetal outcomes, though there was no difference in primary outcome of infant birth trauma. Further randomised controlled trials are needed to answer these questions.