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BACKGROUND: Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with women's quality of life, regardless of the absolute amount of bleeding. It is a very common condition in women of reproductive age, affecting 2 to 5 of every 10 women. Diverse treatments, either medical (hormonal or non‐hormonal) or surgical, are currently available for HMB, with different effectiveness, acceptability, costs and side effects. The best treatment will depend on the woman's age, her intention to become pregnant, the presence of other symptoms, and her personal views and preferences. OBJECTIVES: To identify, systematically assess and summarise all evidence from studies included in Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), using reviews with comparable participants and outcomes; and to present a ranking of the first‐ and second‐line treatments for HMB. METHODS: We searched for published Cochrane Reviews of HMB interventions in the Cochrane Database of Systematic Reviews. The primary outcomes were menstrual bleeding and satisfaction. Secondary outcomes included quality of life, adverse events and the requirement of further treatment. Two review authors independently selected the systematic reviews, extracted data and assessed quality, resolving disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool and evaluated the certainty of the evidence for each outcome using GRADE methods. We grouped the interventions into first‐ and second‐line treatments, considering participant characteristics (desire for future pregnancy, failure of previous treatment, candidacy for surgery). First‐line treatments included medical interventions, and second‐line treatments included both the levonorgestrel‐releasing intrauterine system (LNG‐IUS) and surgical treatments; thus the LNG‐IUS is included in both groups. We developed different networks for first‐ and second‐line treatments. We performed network meta‐analyses of all outcomes, except for quality of life, where we performed pairwise meta‐analyses. We reported the mean rank, the network estimates for mean difference (MD) or odds ratio (OR), with 95% confidence intervals (CIs), and the certainty of evidence (moderate, low or very low certainty). We also analysed different endometrial ablation and resection techniques separately from the main network: transcervical endometrial resection (TCRE) with or without rollerball, other resectoscopic endometrial ablation (REA), microwave non‐resectoscopic endometrial ablation (NREA), hydrothermal ablation NREA, bipolar NREA, balloon NREA and other NREA. MAIN RESULTS: We included nine systematic reviews published in the Cochrane Library up to July 2021. We updated the reviews that were over two years old. In July 2020, we started the overview with no new reviews about the topic. The included medical interventions were: non‐steroidal anti‐inflammatory drugs (NSAIDs), antifibrinolytics (tranexamic acid), combined oral contraceptives (COC), combined vaginal ring (CVR), long‐cycle and luteal oral progestogens, LNG‐IUS, ethamsylate and danazol (included to provide indirect evidence), which were compared to placebo. Surgical interventions were: open (abdominal), minimally invasive (vaginal or laparoscopic) and unspecified (or surgeon's choice of route of) hysterectomy, REA, NREA, unspecified endometrial ablation (EA) and LNG‐IUS. We grouped the interventions as follows. First‐line treatments Evidence from 26 studies with 1770 participants suggests that LNG‐IUS results in a large reduction of menstrual blood loss (MBL; mean rank 2.4, MD −105.71 mL/cycle, 95% CI −201.10 to −10.33; low certainty evidence); antifibrinolytics probably reduce MBL (mean rank 3.7, MD −80.32 mL/cycle, 95% CI −127.67 to −32.98; moderate certainty evidence); long‐cycle progestogen reduces MBL (mean rank 4.1, MD −76.93 mL/cycle, 95% CI −153.82 to −0.05; low certainty evidence), and NSAIDs slightly reduce MBL (mean rank 6.4, MD −40.67 mL/cycle, −84.61 to 3.27; low certainty evidence; reference comparator mean rank 8.9). We are uncertain of the true effect of the remaining interventions and the sensitivity analysis for reduction of MBL, as the evidence was rated as very low certainty. We are uncertain of the true effect of any intervention (very low certainty evidence) on the perception of improvement and satisfaction. Second‐line treatments Bleeding reduction is related to the type of hysterectomy (total or supracervical/subtotal), not the route, so we combined all routes of hysterectomy for bleeding outcomes. We assessed the reduction of MBL without imputed data (11 trials, 1790 participants) and with imputed data (15 trials, 2241 participants). Evidence without imputed data suggests that hysterectomy (mean rank 1.2, OR 25.71, 95% CI 1.50 to 439.96; low certainty evidence) and REA (mean rank 2.8, OR 2.70, 95% CI 1.29 to 5.66; low certainty evidence) result in a large reduction of MBL, and NREA probably results in a large reduction of MBL (mean rank 2.0, OR 3.32, 95% CI 1.53 to 7.23; moderate certainty evidence). Evidence with imputed data suggests hysterectomy results in a large reduction of MBL (mean rank 1.0, OR 14.31, 95% CI 2.99 to 68.56; low certainty evidence), and NREA probably results in a large reduction of MBL (mean rank 2.2, OR 2.87, 95% CI 1.29 to 6.05; moderate certainty evidence). We are uncertain of the true effect for REA (very low certainty evidence). We are uncertain of the effect on amenorrhoea (very low certainty evidence). Evidence from 27 trials with 4284 participants suggests that minimally invasive hysterectomy results in a large increase in satisfaction (mean rank 1.3, OR 7.96, 95% CI 3.33 to 19.03; low certainty evidence), and NREA also increases satisfaction (mean rank 3.6, OR 1.59, 95% CI 1.09 to 2.33; low certainty evidence), but we are uncertain of the true effect of the remaining interventions (very low certainty evidence). AUTHORS' CONCLUSIONS: Evidence suggests LNG‐IUS is the best first‐line treatment for reducing menstrual blood loss (MBL); antifibrinolytics are probably the second best, and long‐cycle progestogens are likely the third best. We cannot make conclusions about the effect of first‐line treatments on perception of improvement and satisfaction, as evidence was rated as very low certainty. For second‐line treatments, evidence suggests hysterectomy is the best treatment for reducing bleeding, followed by REA and NREA. We are uncertain of the effect on amenorrhoea, as evidence was rated as very low certainty. Minimally invasive hysterectomy may result in a large increase in satisfaction, and NREA also increases satisfaction, but we are uncertain of the true effect of the remaining second‐line interventions, as evidence was rated as very low certainty.

Background Preterm infants require high protein intake to achieve adequate growth and development. Although breast milk feeding has many benefits for this population, the protein content is highly variable, and inadequate to support rapid infant growth. This is a 2018 update of a Cochrane Review first published in 1999. Objectives To determine whether protein-supplemented human milk compared with unsupplemented human milk, fed to preterm infants, improves growth, body composition, cardio-metabolic, and neurodevelopmental outcomes, without significant adverse effects. Search methods We used the standard search strategy of Cochrane Neonatal to search CENTRAL, MEDLINE via PubMed, Embase, and CINAHL (February 2018). We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials. Selection criteria Published and unpublished RCTs were eligible if they used random or quasi-random methods to allocate hospitalised preterm infants who were being fed human milk, to additional protein supplementation or no supplementation. Data collection and analysis Two review authors independently abstracted data, assessed risk of bias and the quality of evidence at the outcome level, using GRADE methodology. We performed meta-analyses, using risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data, with their respective 95% confidence intervals (CIs). We used a fixed-effect model and had planned to explore potential causes of heterogeneity via subgroup or sensitivity analyses. Main results We included six RCTs, involving 204 preterm infants. Low-quality evidence showed that protein supplementation of human milk increased in-hospital rates of growth in weight (MD 3.82 g/kg/day, 95% CI 2.94 to 4.7; five RCTs, 101 infants; I² = 73%), length (MD 0.12 cm/wk, 95% CI 0.07 to 0.17; four RCTs, 68 infants; I² = 89%), and head circumference (MD 0.06 cm/wk, 95% CI 0.01 to 0.12; four RCTs, 68 infants; I² = 84%). There was no evidence of a clear difference in rate of growth of skin fold thickness between the supplemented and unsupplemented groups (triceps MD 0.06 mm/wk, 95% CI –0.09 to 0.21; one RCT, 20 infants; or subscapular MD 0.00 mm/wk, 95% CI –0.17 to 0.17; one RCT, 20 infants). Protein supplementation led to longer hospital stays (MD 18.5 days, 95% CI 4.39 to 32.61; one RCT, 20 infants; very low-quality evidence), and higher blood urea nitrogen concentrations compared to the unsupplemented group (MD 0.95 mmol/L, 95% CI 0.81 to 1.09; four RCTs, 81 infants; I² = 56%). Very low-quality evidence did not show that protein supplementation clearly increased the risk of feeding intolerance (RR 2.70, 95% CI 0.13 to 58.24; one RCT, 17 infants), or necrotizing enterocolitis (RR 1.11, 95% CI 0.07 to 17.12; one RCT, 76 infants), or clearly altered serum albumin concentrations (MD 2.5 g/L, 95% CI –5.66 to 10.66; one RCT, 11 infants), compared with the unsupplemented groups. No data were available about the effects of protein supplementation on long-term growth, body mass index, body composition, neurodevelopmental, or cardio-metabolic outcomes. Authors' conclusions Low-quality evidence showed that protein supplementation of human milk, fed to preterm infants, increased short-term growth. However, the small sample sizes, low precision, and very low-quality evidence regarding duration of hospital stay, feeding intolerance, and necrotising enterocolitis precluded any conclusions about these outcomes. There were no data on outcomes after hospital discharge. Our findings may not be generalisable to low-resource settings, as none of the included studies were conducted in these settings. Since protein supplementation of human milk is now usually done as a component of multi-nutrient fortifiers, future studies should compare different amounts of protein in multi-component fortifiers, and be designed to determine the effects on duration of hospital stay and safety, as well as on long-term growth, body composition, cardio-metabolic, and neurodevelopmental outcomes.

This evidence-based review aimed to identify and evaluate current existing evidence relating to the efficacy of dressing materials for spit-thickness skin graft donor site wounds in relation to promoting rapid healing and reducing patient pain. A comprehensive systematic search of the literature between 2006 and 2016 identified 35 publications that were included in the review. Based on the results of the review, it was found that moist wound-healing products have a clear advantage over non-moist products in the reduction of pain and increased healing rates. This review concluded that moist wound-healing products are more effective than non-moist wound-healing products in reducing pain and promoting healing in split-thickness skin graft donor site wounds. A recommendation based on this review is that further research examine the role of secondary dressing usage in donor site wound management, and the consideration of using more than one primary dressing product during the donor site wound-healing process should be undertaken.

Background Child health research in clinical practice is increasing throughout the UK. Nurses and midwives facilitate access to patients, enact research study protocols and have a critical role in parental decisions to enrol children into research studies. Little is known about their perception of this process. Aims & Objectives To explore the views of nurses towards child health research and to identify factors influencing their willingness to facilitate it in practice. Design This study was a descriptive study design. Methods A newly designed questionnaire was completed in 2013 by 105 nurses in 3 neonatal and 2 children's units in 2 discrete acute hospital sites. Results Overwhelming support for clinical research was reported. Participants were motivated to facilitate research in order to improve patient care and contribute to the evidence base; but discouraged by external organisational factors and ethical concerns. Training, education and a dedicated team to support research were considered important. Misconceptions regarding consent and the allocation of treatment were reported. Participants raised particular concerns about trials of Investigational Medicinal Product (IMP). Conclusion Negative views of nurses towards research, combined with a lack of knowledge of research processes, governance and ethics have the potential to threaten the success of clinical research studies. Recommendations for clinical practice Focus on three main areas; staff education, improved communication and the demonstration of managerial commitment to clinical research. This article is protected by copyright. All rights reserved.

Aim Falls in infants are a common cause of injury. Compared to older children, infants under age one are likely to have distinctive causation and injury patterns, as they are pre-mobile or have limited independent mobility and falls are more directly the responsibility of the care giver. There is little known about the mechanistic factors, predictors of injury and injury patterns in this age group. Methods We conducted a retrospective review of infants under age one who presented after a fall to a paediatric trauma centre in Sydney, Australia. Circumstances and mechanisms of the fall, injury patterns, burden of investigations and outcomes were analysed. Results Over a 3-year period (2011–2013), 916 infants presented following a fall. One hundred and six (11.6%) were admitted and there was one death. Head injury was the most common reason for admission (85%). While there were severe and critical head injuries (Abbreviated Injury Scale 4–5) these were infrequent (2% of presentations). All admitted cases involved a short distance fall. Patients dropped by others were three times more likely to be admitted than infants presenting following other fall types (95% CI 1.9–4.8). Compared to other mechanisms, patients who fell from furniture had significantly longer hospital stays. Conclusions Fall mechanisms involving infants being dropped by adults, and falls from beds or couches carry the highest clinical burden. These mechanisms should be targets for injury prevention and inform the design of safe equipment and environments for babies.

Background Menorrhagia or heavy menstrual bleeding (HMB) is an excessive blood loss that impairs a woman's quality of life, either physical, emotional, social or material. It is benign and not associated with pregnancy or any other gynaecological or systemic disease. Medical treatments used to reduce excessive menstrual blood loss (MBL) include prostaglandin synthetase inhibitors, antifibrinolytics, oral contraceptive pills, and other hormones. The combined oral contraceptive pill (COCP) is claimed to have a variety of beneficial effects, inducing a regular shedding of a thinner endometrium and inhibiting ovulation, thus having the effect of both treating HMB and providing contraception. More recently, a contraceptive vaginal ring (CVR) has been trialled to investigate whether this treatment can provide similar benefits to COCP while lessening hormonal systemic exposure. This review is an update of a review which originally focused on COCP alone. The scope of the review has been widened to consider other types of delivery of combined hormonal contraceptives for reduction of MBL. Objectives To determine the efficacy of combined hormonal contraceptives (pills, vaginal ring or patch) compared with other medical therapies, placebo, or no therapy in the treatment of HMB. A secondary objective was to compare the COCP with the CVR. Search methods We searched the Gynecology and Fertility Group trials register, MEDLINE, Embase, CENTRAL, CINAHL and PsycINFO (search dates: Oct 1996, May 2002, June 2004, April 2006, June 2009, July 2017 and September 2018) for all randomised controlled trials (RCTs) of COCP and CVR for the treatment of HMB. We also searched trial registers and the reference lists of retrieved studies for additional trials. Selection criteria We included randomised controlled trials (RCTs) of the use of COCP or CVR compared with no treatment, placebo, or other medical therapies for women with HMB and regular menstrual cycles. Data collection and analysis All assessments of trial quality and data extraction were performed unblinded by at least two review authors. Our primary review outcomes were treatment success, menstrual bleeding (assessed objectively, semi-objectively or subjectively), and participant satisfaction with treatment. Secondary outcomes were adverse events, quality of life, and haemoglobin level. Main results We identified eight RCTs involving 805 participants. Two trials comparing COCP with placebo were considered to be moderate quality and the remaining studies were low to very low quality, mainly because of serious risk of bias from lack of blinding and concerns over precision.COCP versus placeboCOCP, with a step-down oestrogen and step-up progestogen regimen, improved response to treatment (return to menstrual 'normality') (OR 22.12, 95% CI 4.40 to 111.12; 2 trials; 363 participants; I2 = 50%; moderate-quality evidence), and lowered MBL (OR 5.15, 95% CI 3.16 to 8.40; 2 trials; 339 participants; I2 = 0%; moderate-quality evidence) when compared to placebo. The results suggested that, if the chance of 'successful' treatment was 3% in women taking placebo, then COCP increased this chance from 12% to 77% in women with unacceptable HMB. Minor adverse events, in particular breast pain, were more common with COCP. No study in this comparison reported semi-objectively assessed MBL or participant satisfaction with treatment.COCP versus other medical treatmentsNon-steroidal anti-inflammatory drugs (NSAIDs)There was insufficient evidence to determine whether the COCP reduced MBL when compared to NSAIDs (mefenamic acid and naproxen). No study in this comparison reported semi-objectively assessed MBL, subjectively assessed MBL, participant satisfaction with treatment or adverse events.Levonorgestrel-releasing intrauterine system (LNG IUS)The LNG IUS was more effective than COCP in reducing MBL (OR 0.21, 95% CI 0.09 to 0.48; 2 trials; 151 participants; I2 = 0%; low-quality evidence) but it was not clear whether satisfaction with treatment or adverse effects varied according to which treatment was used. No study in this comparison reported semi-objectively assessed MBL or subjectively assessed MBL.Contraceptive vaginal ring (CVR) versus other medical treatmentsCOCP COCP was compared with CVR in two trials. There were discrepancies between some of the findings and there was no evidence of a benefit for one treatment compared to the other for response to treatment, MBL or participant satisfaction with treatment. There was a greater likelihood of nausea with COCP. No study in this comparison reported objectively assessed MBL or subjectively assessed MBL.ProgestogensCVR was compared to long course progestogens in one trial. It is possible that CVR increased the odds of satisfaction; but we are uncertain whether CVR improved MBL. The evidence was based on small numbers of participants and was very low quality, so definitive conclusions could not be reached. No study in this comparison reported objectively assessed MBL, subjectively assessed MBL, or adverse events. Authors' conclusions Moderate-quality evidence suggests that the combined oral contraceptive pill over six months reduces HMB in women with unacceptable HMB from 12% to 77% (compared to 3% in women taking placebo). When compared with other medical options for HMB, COCP was less effective than the LNG IUS. Limited evidence suggested that COCP and CVR had similar effects. There was insufficient evidence to determine comparative efficacy of combined hormonal contraceptives with NSAIDs, or long course progestogens.

Background High-quality, evidence-based guidelines can improve the quality of health care and facilitate standardisation of practice within and across healthcare organisations. Limited information is known regarding existing antenatal corticosteroid (ACS) guideline practices within organisations across Australia and New Zealand. Aims To assess existing ACS clinical practice guidelines (CPG). To describe current organisational practice related to the production, implementation and renewal of CPG. Design A cross-sectional survey of hospital practice using an online questionnaire. Methods Clinical Managers at 27 secondary and 25 tertiary maternity hospitals, that contribute data to the Australia and New Zealand Neonatal Network, were approached from May to September 2015 and completed the questionnaire on behalf of their organisation. Results Of the hospitals surveyed, 93% reported having a CPG or protocol. Of these, 89% of CPG included recommendations on a single course of ACS, 37% on the use of repeat course/s and 41% on use prior to elective caesarean section at term. Variation in the recommendations provided existed between countries and depending on the level of neonatal care provided. A guideline development group existed in 85% of hospitals. The preferred tools to facilitate implementation of a CPG include: email with a link to the hospital intranet, education sessions and an opinion leader. Only 28% of respondents reported auditing the use of ACS administration. Conclusions There is significant variation in the recommendations provided by current ACS CPGs. Utilisation of a single ACS CPG reflective of the current available evidence base may limit this variation.

BACKGROUND: Heavy menstrual bleeding (HMB) is a significant health problem in premenopausal women; it can reduce their quality of life and can cause social disruption and physical problems such as iron deficiency anaemia. First‐line treatment has traditionally consisted of medical therapy (hormonal and non‐hormonal), but this is not always successful in reducing menstrual bleeding to acceptable levels. Hysterectomy is a definitive treatment, but it is more costly and carries some risk. Endometrial ablation may be an alternative to hysterectomy that preserves the uterus. Many techniques have been developed to 'ablate' (remove) the lining of the endometrium. First‐generation techniques require visualisation of the uterus with a hysteroscope during the procedure; although it is safe, this procedure requires specific technical skills. Newer techniques for endometrial ablation (second‐ and third‐generation techniques) have been developed that are quicker than previous approaches because they do not require hysteroscopic visualisation during the procedure. OBJECTIVES: To compare the efficacy, safety, and acceptability of endometrial destruction techniques to reduce heavy menstrual bleeding (HMB) in premenopausal women. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, CINAHL, and PsycInfo (from inception to May 2018). We also searched trials registers, other sources of unpublished or grey literature, and reference lists of retrieved studies, and we made contact with experts in the field and with pharmaceutical companies that manufacture ablation devices. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing different endometrial ablation or resection techniques for women reporting HMB without known uterine pathology, other than fibroids outside the uterine cavity and smaller than 3 centimetres, were eligible. Outcomes included improvement in HMB and in quality of life, patient satisfaction, operative outcomes, complications, and the need for further surgery, including hysterectomy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trials for risk of bias, and extracted data. We contacted study authors for clarification of methods or for additional data. We assessed adverse events only if they were separately measured in the included trials. We undertook comparisons with individual techniques as well as an overall comparison of first‐ and second‐generation ablation methods. MAIN RESULTS: We included in this update 28 studies (4287 women) with sample sizes ranging from 20 to 372. Most studies had low risk of bias for randomisation, attrition, and selective reporting. Less than half of these studies had adequate allocation concealment, and most were unblinded. Using GRADE, we determined that the quality of evidence ranged from moderate to very low. We downgraded evidence for risk of bias, imprecision, and inconsistency. Overall comparison of second‐generation versus first‐generation (i.e. gold standard hysteroscopic ablative) techniques revealed no evidence of differences in amenorrhoea at 1 year and 2 to 5 years' follow‐up (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.78 to 1.27; 12 studies; 2145 women; I² = 77%; and RR 1.16, 95% CI 0.78 to 1.72; 672 women; 4 studies; I² = 80%; very low‐quality evidence) and showed subjective improvement at 1 year follow‐up based on a Pictorial Blood Assessment Chart (PBAC) (< 75 or acceptable improvement) (RR 1.03, 95% CI 0.98 to 1.09; 5 studies; 1282 women; I² = 0%; and RR 1.12, 95% CI 0.97 to 1.28; 236 women; 1 study; low‐quality evidence). Study results showed no difference in patient satisfaction between second‐ and first‐generation techniques at 1 year follow‐up (RR 1.01, 95% CI 0.98 to 1.04; 11 studies; 1750 women; I² = 36%; low‐quality evidence) nor at 2 to 5 years' follow‐up (RR 1.02, 95% CI 0.93 to 1.13; 672 women; 4 studies; I² = 81%). Compared with first‐generation techniques, second‐generation endometrial ablation techniques were associated with shorter operating times (mean difference (MD) ‐13.52 minutes, 95% CI ‐16.90 to ‐10.13; 9 studies; 1822 women; low‐quality evidence) and more often were performed under local rather than general anaesthesia (RR 2.8, 95% CI 1.8 to 4.4; 6 studies; 1434 women; low‐quality evidence). We are uncertain whether perforation rates differed between second‐ and first‐generation techniques (RR 0.32, 95% CI 0.10 to 1.01; 1885 women; 8 studies; I² = 0%). Trials reported little or no difference between second‐ and first‐generation techniques in requirement for additional surgery (ablation or hysterectomy) at 1 year follow‐up (RR 0.72, 95% CI 0.41 to 1.26; 6 studies: 935 women; low‐quality evidence). At 5 years, results showed probably little or no difference between groups in the requirement for hysterectomy (RR 0.85, 95% CI 0.59 to 1.22; 4 studies; 758 women; moderate‐quality evidence). AUTHORS' CONCLUSIONS: Approaches to endometrial ablation have evolved from first‐generation techniques to newer second‐ and third‐generation approaches. Current evidence suggests that compared to first‐generation techniques (endometrial laser ablation, transcervical resection of the endometrium, rollerball endometrial ablation), second‐generation approaches (thermal balloon endometrial ablation, microwave endometrial ablation, hydrothermal ablation, bipolar radiofrequency endometrial ablation, endometrial cryotherapy) are of equivalent efficacy for heavy menstrual bleeding, with comparable rates of amenorrhoea and improvement on the PBAC. Second‐generation techniques are associated with shorter operating times and are performed more often under local rather than general anaesthesia. It is uncertain whether perforation rates differed between second‐ and first‐generation techniques. Evidence was insufficient to show which second‐generation approaches were superior to others and to reveal the efficacy and safety of third‐generation approaches versus first‐ and second‐generation techniques.

This is a protocol for a Cochrane Review (Overview). The objectives are as follows:. To identify, systematically assess and summarise all evidence from Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), through a network meta-analysis. To compare the efficacy, satisfaction and safety of different treatments available for HMB (that have been assessed in Cochrane Reviews), performing direct and indirect comparisons through a network meta-analysis.

Background Preterm infants are born with low glycogen stores and require higher glucose intake to match fetal accretion rates. In spite of the myriad benefits of breast milk for preterm infants, it may not adequately meet the needs of these rapidly growing infants. Supplementing human milk with carbohydrates may help. However, there is a paucity of data on assessment of benefits or harms of carbohydrate supplementation of human milk to promote growth in preterm infants. This is a 2018 update of a Cochrane Review first published in 1999. Objectives To determine whether human milk supplemented with carbohydrate compared with unsupplemented human milk fed to preterm infants improves growth, body composition, and cardio-metabolic and neurodevelopmental outcomes without significant adverse effects. Search methods We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), MEDLINE via PubMed (1966 to 21 February 2018), Embase (1980 to 21 February 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 21 February 2018). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. Selection criteria Published and unpublished controlled trials were eligible if they used random or quasi-random methods to allocate preterm infants in hospital fed human milk to supplementation or no supplementation with additional carbohydrate. Data collection and analysis Two review authors independently abstracted data and assessed trial quality and the quality of evidence at the outcome level using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method. We planned to perform meta-analyses using risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, with their respective 95% confidence intervals (CIs). We planned to use a fixed-effect model and to explore potential causes of heterogeneity via sensitivity analyses. We contacted study authors for additional information. Main results One unblinded, quasi-randomised controlled trial (RCT) assessing effects of carbohydrate supplementation of human milk in the form of a prebiotic in 75 preterm infants was eligible for inclusion in this review. We identified two publications of the same trial, which reported different methods regarding blinding and randomisation. Study authors confirmed that these publications pertain to the same trial, but they have not yet clarified which method is correct. We were unable to reproduce analyses from the data presented. At 30 days of age, the mean weight of preterm infants in the trial was greater in the prebiotic carbohydrate-supplemented group than in the unsupplemented group (MD 160.4 grams, 95% CI 12.4 to 308.4 grams; one RCT, N = 75; very low-quality evidence). We found no evidence of a clear difference in risk of feeding intolerance (RR 0.64, 95% CI 0.36 to 1.15; one RCT, N = 75 infants; very low-quality evidence) or necrotising enterocolitis (NEC) (RR 0.2, 95% CI 0.02 to 1.3; one RCT, N = 75 infants; very low-quality evidence) between the prebiotic-supplemented group and the unsupplemented group. Duration of hospital stay was shorter in the prebiotic group than in the control group at a median (range) of 16 (9 to 45) days (95% CI 15.34 to 24.09) and 25 (11 to 80) days (95% CI 25.52 to 34.39), respectively. No other data were available for assessing effects of carbohydrate supplementation on short- and long-term growth, body mass index, body composition, and neurodevelopmental or cardio-metabolic outcomes. Authors' conclusions We found insufficient evidence on the short- and long-term effects of carbohydrate supplementation of human milk in preterm infants. The only trial included in this review presented very low-quality evidence, and study authors provided uncertain information about study methods and analysis. The evidence may be limited in its applicability because researchers included a small sample of preterm infants from a single centre. However, the outcomes assessed are common to all preterm infants, and this trial demonstrates the feasibility of prebiotic carbohydrate supplementation in upper-middle-income countries. Future trials should assess the safety and efficacy of different types and concentrations of carbohydrate supplementation for preterm infants fed human milk. Although prebiotic carbohydrate supplementation in preterm infants is currently a topic of active research, we do not envisage that further trials of digestible carbohydrates will be conducted, as this is currently done as a component of multi-nutrient human milk fortification. Hence we do not plan to publish any further updates of this review.

Background: Pelvic organ prolapse (POP) is common in women and is frequently associated with stress urinary incontinence (SUI). In many cases however, SUI is present only with the prolapse reduced (occult SUI) or may develop after surgical treatment for prolapse (de novo SUI). Objectives: To determine the impact on postoperative bladder function of surgery for symptomatic pelvic organ prolapse with or without concomitant or delayed two-stage continence procedures to treat or prevent stress urinary incontinence. Search methods: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE-In-Process, ClinicalTrials.gov, WHO ICTRP, handsearching journals and conference proceedings (searched 11 November 2017) and reference lists of relevant articles. We also contacted researchers in the field. Selection criteria: Randomised controlled trials (RCTs) including surgical operations for POP with or without continence procedures in continent or incontinent women. Our primary outcome was subjective postoperative SUI. Secondary outcomes included recurrent POP on examination, overactive bladder (OAB) symptoms, and voiding dysfunction. Data collection and analysis: We used standard methodological procedures as expected by Cochrane. Main results: We included 19 RCTs (2717 women). The quality of the evidence ranged from low to moderate. The main limitations were risk of bias (especially blinding of outcome assessors), indirectness and imprecision associated with low event rates and small samples. POP surgery in women with SUI Vaginal repair with vs without concomitant mid-urethral sling (MUS) A concomitant MUS probably improves postoperative rates of subjective SUI, as the evaluated clinical effect appears large (risk ratio (RR) 0.30, 95% confidence interval (CI) 0.19 to 0.48; 319 participants, two studies; I2 = 28%; moderate-quality evidence), and probably decreases the need for further continence surgery (RR 0.04, 95% CI 0.00 to 0.74; 134 participants, one study; moderate-quality evidence). This suggests that if the risk of SUI with POP surgery alone is 39%, the risk with an MUS is between 8% and 19%. Rates of recurrent POP on examination, OAB, and voiding dysfunction were not reported. Vaginal repair with concomitant vs delayed MUS Evidence suggested little or no difference between groups in reporting postoperative SUI (RR 0.41, 95% CI 0.12 to 1.37; 140 participants, one study; moderate-quality evidence). Rates of recurrent POP on examination, OAB, and voiding dysfunction and the need for further surgery were not reported. Abdominal sacrocolpopexy with vs without Burch colposuspension An additional Burch colposuspension probably has little or no effect on postoperative SUI at one year (RR 1.38, 95% CI 0.74 to 2.60; 47 participants, one study; moderate-quality evidence), OAB symptoms (RR 0.85, 95% CI 0.61 to 1.18; 33 participants, one study; moderate-quality evidence), or voiding dysfunction (RR 0.96, 95% CI 0.06 to 14.43; 47 participants, one study; moderate-quality evidence). Rates of recurrent POP and the need for further surgery were not reported. POP surgery in women with occult SUI Vaginal repair with vs without concomitant MUS MUS probably improves rates of subjective postoperative SUI (RR 0.38, 95% CI 0.26 to 0.55; 369 participants, five studies; I2 = 44%; moderate-quality evidence). This suggests that if the risk with surgery alone is 34%, the risk with a concomitant MUS is between 10% and 22%. Evidence suggests little or no difference between groups in rates of recurrent POP (RR 0.86, 95% CI 0.34 to 2.19; 50 participants, one study; moderate-quality evidence), OAB symptoms (RR 0.75, 95% CI 0.52 to 1.07; 43 participants, one study; low-quality evidence), or voiding dysfunction (RR 1.00, 95% CI 0.15 to 6.55; 50 participants, one study; low-quality evidence). The need for further surgery was not reported. POP surgery in continent women Vaginal repair with vs without concomitant MUS Researchers provided no conclusive evidence of a difference between groups in rates of subjective postoperative SUI (RR 0.69, 95% CI 0.47 to 1.00; 220 participants, one study; moderate-quality evidence). This suggests that if the risk with surgery alone is 40%, the risk with a concomitant MUS is between 19% and 40%. Rates of recurrent POP, OAB, and voiding dysfunction and the need for further surgery were not reported. Abdominal sacrocolpopexy with vs without Burch colposuspension We are uncertain whether there is a difference between groups in rates of subjective postoperative SUI (RR 1.31, 95% CI 0.19 to 9.01; 379 participants, two studies; I2 = 90%; low-quality evidence), as RCTs produced results in different directions with a very wide confidence interval. We are also uncertain whether there is a difference between groups in rates of voiding dysfunction (RR 8.49, 95% CI 0.48 to 151.59; 66 participants, one study; low-quality evidence) or recurrent POP (RR 0.98, 95% CI 0.74 to 1.30; 250 participants, one study; moderate-quality evidence. No study reported OAB symptoms and need for further surgery. Vaginal repair with armed anterior vaginal mesh repair vs anterior native tissue Anterior armed mesh repair may slightly increase postoperative de novo SUI (RR 1.58, 95% CI 1.05 to 2.37; 905 participants, seven studies; I2 = 0%; low-quality evidence) but may decrease recurrent POP (RR 0.29, 95% CI 0.22 to 0.38; 848 participants, five studies; I2 = 0%; low-quality evidence). There may be little or no difference in rates of voiding dysfunction (RR 1.65, 95% CI 0.22 to 12.10; 125 participants, two studies; I2 = 0%; low-quality evidence). Rates of OAB and the need for further surgery were not reported. Adverse events were infrequently reported in all studies; cost was not studied in any trial. Authors' conclusions: In women with POP and SUI (symptomatic or occult), a concurrent MUS probably reduces postoperative SUI and should be discussed in counselling. It might be feasible to postpone the MUS and perform a delayed (two-stage) continence procedure, if required. Although an abdominal continence procedure (Burch colposuspension) during abdominal POP surgery in continent women reduced de novo SUI rates in one underpowered trial, another RCT reported conflicting results. Adding an MUS during vaginal POP repair might reduce postoperative development of SUI. An anterior native tissue repair might be better than use of transobturator mesh for preventing postoperative SUI; however, prolapse recurrence is more common with native tissue repair.

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. Effective Lifestyle versus usual care Lifestyle 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). Promising No evidence for any outcome for any comparison could be classified to this category. Ineffective or possibly harmful Lifestyle versus usual care Lifestyle 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 control Exercise 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 therapy Insulin 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 interventions Insulin versus oral therapy For 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). Inconclusive Lifestyle versus usual care The 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 control The 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 therapy The 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 diet The 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 insulin The 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 possible No 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.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the safety and effectiveness of probiotics in treating pregnant women with gestational diabetes mellitus (GDM) on maternal and infant outcomes.

Objectives To explore and deepen understanding of factors influencing driving exposure for older drivers. Design Cross-sectional. Setting Baseline data on function and driving exposure from 1 week of driving were evaluated. Participants A convenience sample of 380 drivers aged 75 and older, residing in northwest Sydney, was recruited. Participants were required to be the primary drivers of their own vehicle. Measurements Driver function was evaluated using the DriveSafe and DriveAware clinic-based assessments to measure visual attention to the driving environment and awareness of driving ability. Demographic information was obtained through interview. An in-vehicle monitoring device with data logger and GPS receiver, was used to measure driving exposure in 362 of 380 participants' vehicles. Driving exposure outcomes were total distance driven, furthest distance traveled from home, and average trip length. Factors influencing these exposure outcomes were analyzed using generalized linear regression. Results Drivers typically drove 100 km in local and surrounding areas during the week. Function was predictive of all driving exposure outcomes. Drivers with lower levels of function drove fewer kilometers and took shorter trips closer to home. Age, health status, and personal circumstance (e.g., rural residence) also influenced exposure, but sex did not. Conclusion Using objective measures, this study provides evidence that function, age, health status, and personal circumstance influence driving exposure of older drivers. Understanding how older people use driving to preserve their independence is important for exploring safe driving strategies for older people.

Background Respiratory morbidity including respiratory distress syndrome (RDS) is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. While researching the effects of the steroid dexamethasone on premature parturition in fetal sheep in 1969, Liggins found that there was some inflation of the lungs of lambs born at gestations at which the lungs would be expected to be airless. Liggins and Howie published the first randomised controlled trial in humans in 1972 and many others followed. Objectives To assess the effects of administering a course of corticosteroids to the mother prior to anticipated preterm birth on fetal and neonatal morbidity and mortality, maternal mortality and morbidity, and on the child in later life. Search methods We searched Cochrane Pregnancy and Childbirth's Trials Register (17 February 2016) and reference lists of retrieved studies. Selection criteria We considered all randomised controlled comparisons of antenatal corticosteroid administration (betamethasone, dexamethasone, or hydrocortisone) with placebo, or with no treatment, given to women with a singleton or multiple pregnancy, prior to anticipated preterm delivery (elective, or following spontaneous labour), regardless of other co-morbidity, for inclusion in this review. Most women in this review received a single course of steroids; however, nine of the included trials allowed for women to have weekly repeats. Data collection and analysis Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. The quality of the evidence was assessed using the GRADE approach. Main results This update includes 30 studies (7774 women and 8158 infants). Most studies are of low or unclear risk for most bias domains. An assessment of high risk usually meant a trial had potential for performance bias due to lack of blinding. Two trials had low risks of bias for all risk of bias domains. Treatment with antenatal corticosteroids (compared with placebo or no treatment) is associated with a reduction in the most serious adverse outcomes related to prematurity, including: perinatal death (average risk ratio (RR) 0.72, 95% confidence interval (CI) 0.58 to 0.89; participants = 6729; studies = 15; Tau² = 0.05, I² = 34%; moderate-quality); neonatal death (RR 0.69, 95% CI 0.59 to 0.81; participants = 7188; studies = 22), RDS (average RR 0.66, 95% CI 0.56 to 0.77; participants = 7764; studies = 28; Tau² = 0.06, I² = 48%; moderate-quality); moderate/severe RDS (average RR 0.59, 95% CI 0.38 to 0.91; participants = 1686; studies = 6; Tau² = 0.14, I² = 52%); intraventricular haemorrhage (IVH) (average RR 0.55, 95% CI 0.40 to 0.76; participants = 6093; studies = 16; Tau² = 0.10, I² = 33%; moderate-quality), necrotising enterocolitis (RR 0.50, 95% CI 0.32 to 0.78; participants = 4702; studies = 10); need for mechanical ventilation (RR 0.68, 95% CI 0.56 to 0.84; participants = 1368; studies = 9); and systemic infections in the first 48 hours of life (RR 0.60, 95% CI 0.41 to 0.88; participants = 1753; studies = 8). There was no obvious benefit for: chronic lung disease (average RR 0.86, 95% CI 0.42 to 1.79; participants = 818; studies = 6; Tau² = 0.38 I² = 65%); mean birthweight (g) (MD -18.47, 95% CI -40.83 to 3.90; participants = 6182; studies = 16; moderate-quality); death in childhood (RR 0.68, 95% CI 0.36 to 1.27; participants = 1010; studies = 4); neurodevelopment delay in childhood (RR 0.64, 95% CI 0.14 to 2.98; participants = 82; studies = 1); or death into adulthood (RR 1.00, 95% CI 0.56 to 1.81; participants = 988; studies = 1). Treatment with antenatal corticosteroids does not increase the risk of chorioamnionitis (RR 0.83, 95% CI 0.66 to 1.06; participants = 5546; studies = 15; moderate-quality evidence) or endometritis (RR 1.20, 95% CI 0.87 to 1.63; participants = 4030; studies = 10; Tau² = 0.11, I² = 28%; moderate-quality). No increased risk in maternal death was observed. However, the data on maternal death is based on data from a single trial with two deaths; four other trials reporting maternal death had zero events (participants = 3392; studies = 5; moderate-quality). There is no definitive evidence to suggest that antenatal corticosteroids work differently in any pre-specified subgroups (singleton versus multiple pregnancy; membrane status; presence of hypertension) or for different study protocols (type of corticosteroid; single course or weekly repeats). GRADE outcomes were downgraded to moderate-quality. Downgrading decisions (for perinatal death, RDS, IVH, and mean birthweight) were due to limitations in study design or concerns regarding precision (chorioamnionitis, endometritis). Maternal death was downgraded for imprecision due to few events. Authors' conclusions Evidence from this update supports the continued use of a single course of antenatal corticosteroids to accelerate fetal lung maturation in women at risk of preterm birth. A single course of antenatal corticosteroids could be considered routine for preterm delivery. It is important to note that most of the evidence comes from high income countries and hospital settings; therefore, the results may not be applicable to low-resource settings with high rates of infections. There is little need for further trials of a single course of antenatal corticosteroids versus placebo in singleton pregnancies in higher income countries and hospital settings. However, data are sparse in lower income settings. There are also few data regarding risks and benefits of antenatal corticosteroids in multiple pregnancies and other high-risk obstetric groups. Further information is also required concerning the optimal dose-to-delivery interval, and the optimal corticosteroid to use. We encourage authors of previous studies to provide further information, which may answer any remaining questions about the use of antenatal corticosteroids in such pregnancies without the need for further randomised controlled trials. Individual patient data meta-analysis from published trials is likely to answer some of the evidence gaps. Follow-up studies into childhood and adulthood, particularly in the late preterm gestation and repeat courses groups, are needed. We have not examined the possible harmful effects of antenatal corticosteroids in low-resource settings in this review. It would be particularly relevant to explore this finding in adequately powered prospective trials.

Background Preterm infants are born with low skeletal stores of calcium and phosphorus. Preterm human milk provides insufficient calcium and phosphorus to meet the estimated needs of preterm infants for adequate growth. Supplementation of human milk with calcium and phosphorus may improve growth and development of preterm infants. Objectives To determine whether addition of calcium and phosphorus supplements to human milk leads to improved growth and bone metabolism of preterm infants without significant adverse effects. Search methods We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3), MEDLINE via PubMed (1966 to 14 April 2016), Embase (1980 to 14 April 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 14 April 2016). We also searched clinical trials databases (11 May 2016) and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. Selection criteria Randomised and quasi-randomised trials comparing supplementation of human milk with calcium and/or phosphorus versus no supplementation in hospitalised preterm infants were eligible for inclusion in this review. Data collection and analysis Two review authors (JB, JW) independently extracted data and assessed trial quality using standard methods of the Cochrane Neonatal Review Group. We reported dichotomous data as risk ratios (RRs) and continuous data as mean differences (MDs) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. Main results This is an update of a 2001 review that identified no eligible trials. One trial including 40 infants met the inclusion criteria for this review. Using GRADE criteria, we judged the quality of the evidence as low owing to risk of bias (inadequate reporting of methods of randomisation, allocation concealment and/or blinding) and imprecision (wide confidence intervals and data from a single small trial). We found no evidence of a difference between calcium and phosphorus supplementation versus no supplementation for neonatal growth outcomes (weight, length, head circumference) at any time point reported (two, four or six weeks postnatal age). At six weeks postnatal age, supplementation with calcium/phosphorus was associated with a decrease in serum alkaline phosphatase concentration (MD -56.85 IU/L, 95% CI -101.27 to -12.43; one randomised controlled trial (RCT); n = 40 infants). Investigators provided no data on growth at 12 to 18 months, neonatal fractures, feed intolerance, breastfeeding or any of the prespecified childhood outcomes for this review (fractures, growth, neurodevelopmental outcomes). Authors' conclusions We identified one small trial including only 40 infants that compared supplementation of human milk with calcium and phosphorus versus no supplementation in hospitalised preterm infants. We judged the evidence to be of low quality and found no evidence of differences between groups for clinically important outcomes including growth and fractures. Although serum alkaline phosphatase concentration was reduced in the group receiving supplementation at six weeks postnatal age, this difference is unlikely to be of clinical significance. We conclude that evidence is insufficient to determine whether benefit or harm ensues when human milk is supplemented with calcium and/or phosphorus for the hospitalised preterm infant. We see no advantage of conducting further trials of this intervention because with the advent of multi-component human milk fortifier, supplementation of human milk with calcium and/or phosphorus alone is no longer common practice. Future trials should consider assessing effects of multi-component fortifiers with different mineral compositions on clinically important outcomes during the neonatal period and in later childhood.

Background Subfertility due to anovulation is a common problem in women. First-line oral treatment is with antioestrogens such as clomiphene citrate, but resistance may be apparent with clomiphene. Alternative and adjunctive treatments have been used including tamoxifen, dexamethasone, and bromocriptine. The effectiveness of these is to be determined. Objectives To determine the relative effectiveness of antioestrogen agents including clomiphene alone or in combination with other medical therapies in women with subfertility associated with anovulation, possibly caused by polycystic ovarian syndrome. Search methods We conducted a search of the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, and CINAHL (all from inception to August 2016) to identify relevant randomised controlled trials (RCTs). We searched the United Kingdom National Institute for Clinical Excellence (NICE) guidelines and the references of relevant reviews and RCTs. We also searched the clinical trial registries for ongoing trials (inception until August 2016). Selection criteria We considered RCTs comparing oral antioestrogen agents for ovulation induction (alone or in conjunction with medical therapies) in anovulatory subfertility. We excluded insulin-sensitising agents, aromatase inhibitors, and hyperprolactinaemic infertility. Data collection and analysis Two review authors independently performed data extraction and quality assessment. The primary outcome was live birth; secondary outcomes were pregnancy, ovulation, miscarriage, multiple pregnancy, ovarian hyperstimulation syndrome, and adverse effects. Main results This is a substantive update of a previous review. We identified an additional 13 studies in the 2016 update. The review now includes 28 RCTs (3377 women) and five RCTs awaiting classification. Five of the 28 included trials reported live birth/ongoing pregnancy. Secondary outcomes were poorly reported. The quality of the evidence ranged from low to very low. The primary reasons for downgrading the evidence were imprecision and risk of bias associated with poor reporting. Antioestrogen versus placebo Live birth rate, miscarriage rate, multiple pregnancy rate, and ovarian hyperstimulation syndrome (OHSS) No data were reported for these outcomes. Clinical pregnancy rate Clomiphene citrate was associated with an increased chance of a clinical pregnancy compared with placebo, though the size of the benefit was very uncertain (odds ratio (OR) 5.91, 95% confidence interval (CI) 1.77 to 19.68; 3 studies; 133 women; low-quality evidence). If the chance of a clinical pregnancy was 5% in the placebo group, then between 8% and 50% of women would have a clinical pregnancy in the clomiphene group. Clomiphene citrate versus tamoxifen Live birth rate There was no clear evidence of a difference in the chance of a live birth between the clomiphene citrate and tamoxifen groups (OR 1.24, 95% CI 0.59 to 2.62; 2 studies; 195 women; low-quality evidence). If 20% of women in the tamoxifen group had a live birth, then between 13% and 40% of women in the clomiphene citrate group would have a live birth. Miscarriage rate There was no clear evidence of a difference in the chance of a miscarriage between the clomiphene citrate and tamoxifen groups (OR 1.81, 95% CI 0.80 to 4.12; 4 studies; 653 women; low-quality evidence). If 3% of women in the tamoxifen group had a miscarriage, then between 2% and 10% in the clomiphene citrate group would have a miscarriage. Clinical pregnancy rate There was no clear evidence of a difference in the chance of a clinical pregnancy between the clomiphene citrate and tamoxifen groups (OR 1.30, 95% CI 0.92 to 1.85; 5 studies; 757 women; I2 = 69%; low-quality evidence). If 22% of women in the tamoxifen group had a clinical pregnancy, then between 21% and 35% in the clomiphene citrate group would have a clinical pregnancy. Multiple pregnancy rate There was insufficient evidence of a difference in the chance of a multiple pregnancy between the clomiphene citrate group (OR 2.34, 95% CI 0.34 to 16.04; 3 studies; 567 women; very low-quality evidence). If 0% of women in the tamoxifen group had a multiple pregnancy, then between 0% and 0.5% of women in the clomiphene group would have a multiple pregnancy. OHSS There were no instances of OHSS in either the clomiphene citrate or the tamoxifen group reported from three studies. Clomiphene citrate with tamoxifen versus tamoxifen alone Clinical pregnancy rate There was insufficient evidence to determine whether there was a difference between groups (OR 3.32, 95% CI 0.12 to 91.60; 1 study; 20 women; very low-quality evidence). No data were reported for the other outcomes. Other comparisons of interest Limited evidence suggested that compared with a gonadotropin, clomiphene citrate was associated with a reduced chance of a pregnancy, ongoing pregnancy, or live birth, with no clear evidence of a difference in multiple pregnancy rates. The comparison of clomiphene citrate plus medical adjunct versus clomiphene alone was limited by the number of trials reporting the comparison and poor reporting of clinical outcomes relevant to this systematic review and by the number of adjuncts reported (ketoconazole, bromocriptine, dexamethasone, combined oral contraceptive, human chorionic gonadotropin, hormone supplementation). The addition of dexamethasone or combined oral contraceptive suggested a possible benefit in pregnancy outcomes, but findings were very uncertain and further research is required to confirm this. There was limited evidence suggesting that a 10-day regimen of clomiphene citrate improves pregnancy outcomes compared with a 5-day regimen. Data for early versus late regimens of clomiphene citrate were insufficient to be able to make a judgement on differences for pregnancy outcomes. Authors' conclusions We found evidence suggesting that clomiphene citrate improves the chance of a clinical pregnancy compared with placebo, but may reduce the chance of live birth or ongoing pregnancy when compared with a gonadotropin. Due to low event rates, we advise caution interpreting these data. The comparison of clomiphene citrate plus medical adjunctive versus clomiphene alone was limited by the number of trials reporting the comparison. The evidence was very low quality and no firm conclusions could be drawn, but very limited evidence suggested a benefit from adjunctive dexamethasone or combined oral contraceptives. Low-quality evidence suggested that a 10-day regimen of clomiphene citrate improves pregnancy rates compared with a 5-day regimen, but further research is required.

Background Embryo transfer (ET) was traditionally performed two days after oocyte retrieval; however, developments in culture media have allowed embryos to be maintained in culture for longer periods. Delaying transfer from Day two to Day three would allow for further development of the embryo and might have a positive effect on pregnancy outcomes. Objectives To determine if there are any differences in live birth and pregnancy rates when embryo transfer is performed on day three after oocyte retrieval, compared with day two, in infertile couples undergoing treatment with in vitro fertilisation (IVF), including intracytoplasmic sperm injection (ICSI). Search methods We searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) from the inception of the databases to 26th April 2016. We also searched ClinicalTrials.gov and the WHO portal for ongoing trials plus citation lists of relevant publications, review articles and included studies, as well as abstracts of appropriate scientific meetings. Selection criteria Randomised controlled trials that compared Day 3 versus Day 2 embryo transfer after oocyte retrieval during an IVF or ICSI treatment cycle in infertile couples. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. The primary outcome measures were live birth rate and ongoing pregnancy rate. Main results We included 15 studies. Fourteen studies reported data per woman (2894 women) and one study reported data per cycle (969 cycles). The quality of the evidence using the GRADE approach ranged from moderate quality to very low quality. The main reasons for downgrading evidence were poor methodological reporting, selective reporting, inconsistency and imprecision. Live birth per woman - Overall, there was no evidence of a difference in live birth rate between Day three and Day two embryo transfer (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.89 to 1.23; three studies, n = 1200 women; I2 = 63%; very low quality evidence). The data suggest that if 32% of women who underwent a Day two embryo transfer had a live birth, then between 28% to 39% of women undergoing a Day three embryo transfer would have a live birth. Ongoing pregnancy per woman - There was no evidence of a difference between Day three and Day two embryo transfer for ongoing pregnancy (RR 0.98, 95% CI 0.85 to 1.12; six studies, n = 1740 women; I2 = 52%; very low quality of evidence). The data suggest that if 33% of women undergoing a Day two embryo transfer had an ongoing pregnancy then between 28% to 37% of women undergoing a Day three embryo transfer would have an ongoing pregnancy. Clinical pregnancy per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the chance of a clinical pregnancy (RR 1.08, 95% CI 0.98 to 1.19; 12 studies, n = 2461, I2 = 51%; very low quality evidence). The data suggest that if 39% of women undergoing Day two embryo transfer had a clinical pregnancy, then between 38% to 46% of women undergoing a Day three embryo transfer would have a clinical pregnancy. Multiple pregnancy per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the risk of a multiple pregnancy (RR 1.12, 95% CI 0.86 to 1.44; eight studies, n = 1837; I2 = 0%; moderate quality evidence). The data suggest that if 11% of women undergoing Day two embryo transfer had a multiple pregnancy, then between 9% to 15% of women undergoing a Day three embryo transfer would have a multiple pregnancy. Miscarriage rate per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the risk of miscarriage (RR 1.16, 95% CI 0.84 to 1.60; nine studies, n = 2153 women, I2 = 26%; moderate quality evidence). The data suggest that if 6% of women undergoing Day two embryo transfer had a miscarriage, then between 5% to 10% of women undergoing a Day three embryo transfer would have a miscarriage. Ectopic pregnancy rate per woman - There was no evidence of a difference between Day three and Day two embryo transfer for the risk of ectopic pregnancy (RR 0.99, 95% CI 0.29 to 3.40; six studies, n = 1531 women, I2 = 0%; low quality evidence). The data suggest that if 0.7% of women undergoing Day two embryo transfer have an ectopic pregnancy, then between 0.2% to 2% of women undergoing Day three embryo transfer would have an ectopic pregnancy. Subgroup analysis for pregnancy outcomes did not identify any differential effect between IVF and ICSI. None of the included studies prespecified complication rate (e.g. OHSS), fetal abnormality or women's evaluation of the procedure as outcomes in their studies. Authors' conclusions Twelve of 15 studies contributed data that could be included in meta-analyses. The quality of the evidence ranged from moderate to very low. Only three of the 15 studies reported data for live birth, although the data for ongoing pregnancy and clinical pregnancy are consistent with the live birth data, suggesting no difference between Day three and Day two embryo transfer for these outcomes. There was no evidence of a difference identified between Day three and Day two embryo transfer for multiple pregnancy, miscarriage or ectopic pregnancy per woman randomised. No data were reported for complication rate, fetal abnormality or woman's evaluation of the procedure. The current evidence has not identified any evidence of differences in pregnancy outcomes between Day two and Day three embryo transfers. Any further studies comparing these timings of embryo transfer are unlikely to alter the findings and we suggest that this review no longer be updated.

Background Apical vaginal prolapse is a descent of the uterus or vaginal vault (post-hysterectomy). Various surgical treatments are available and there are no guidelines to recommend which is the best. Objectives To evaluate the safety and efficacy of any surgical intervention compared to another intervention for the management of apical vaginal prolapse. Search methods We searched the Cochrane Incontinence Group's Specialised Register of controlled trials, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched July 2015) and ClinicalTrials.gov (searched January 2016). Selection criteria We included randomised controlled trials (RCTs). Data collection and analysis We used Cochrane methods. Our primary outcomes were awareness of prolapse, repeat surgery and recurrent prolapse (any site). Main results We included 30 RCTs (3414 women) comparing surgical procedures for apical vaginal prolapse. Evidence quality ranged from low to moderate. Limitations included imprecision, poor methodological reporting and inconsistency. Vaginal procedures versus sacral colpopexy (six RCTs, n = 583; one to four-year review). Awareness of prolapse was more common after vaginal procedures (risk ratio (RR) 2.11, 95% confidence interval (CI) 1.06 to 4.21, 3 RCTs, n = 277, I2 = 0%, moderate-quality evidence). If 7% of women are aware of prolapse after sacral colpopexy, 14% (7% to 27%) are likely to be aware after vaginal procedures. Repeat surgery for prolapse was more common after vaginal procedures (RR 2.28, 95% CI 1.20 to 4.32; 4 RCTs, n = 383, I2 = 0%, moderate-quality evidence). The confidence interval suggests that if 4% of women require repeat prolapse surgery after sacral colpopexy, between 5% and 18% would require it after vaginal procedures. We found no conclusive evidence that vaginal procedures increaserepeat surgery for stress urinary incontinence (SUI) (RR 1.87, 95% CI 0.72 to 4.86; 4 RCTs, n = 395; I2 = 0%, moderate-quality evidence). If 3% of women require repeat surgery for SUI after sacral colpopexy, between 2% and 16% are likely to do so after vaginal procedures. Recurrent prolapse is probably more common after vaginal procedures (RR 1.89, 95% CI 1.33 to 2.70; 4 RCTs, n = 390; I2 = 41%, moderate-quality evidence). If 23% of women have recurrent prolapse after sacral colpopexy, about 41% (31% to 63%) are likely to do so after vaginal procedures. The effect of vaginal procedures on bladder injury was uncertain (RR 0.57, 95% CI 0.14 to 2.36; 5 RCTs, n = 511; I2 = 0%, moderate-quality evidence). SUI was more common after vaginal procedures (RR 1.86, 95% CI 1.17 to 2.94; 3 RCTs, n = 263; I2 = 0%, moderate-quality evidence). Dyspareunia was also more common after vaginal procedures (RR 2.53, 95% CI 1.17 to 5.50; 3 RCTs, n = 106, I2 = 43%, low-quality evidence). Vaginal surgery with mesh versus without mesh (6 RCTs, n = 598, 1-3 year review). Awareness of prolapse - There may be little or no difference between the groups for this outcome (RR 1.08 95% CI 0.35 to 3.30 1 RCT n = 54, low quality evidence). The confidence interval was wide suggesting that if 18% of women are aware of prolapse after surgery without mesh, between 6% and 59% will be aware of prolapse after surgery with mesh. Repeat surgery for prolapse - There may be little or no difference between the groups for this outcome (RR 0.69, 95% CI 0.30 to 1.60; 5 RCTs, n = 497; I2 = 9%, low-quality evidence). If 4% of women require repeat surgery for prolapse after surgery without mesh, 1% to 7% are likely to do so after surgery with mesh. We found no conclusive evidence that surgery with mesh increases repeat surgery for SUI (RR 4.91, 95% CI 0.86 to 27.94; 2 RCTs, n = 220; I2 = 0%, low-quality evidence). The confidence interval was wide suggesting that if 2% of women require repeat surgery for SUI after vaginal colpopexy without mesh, 2% to 53% are likely to do so after surgery with mesh. We found no clear evidence that surgery with mesh decreases recurrent prolapse (RR 0.36, 95% CI 0.09 to 1.40; 3 RCTs n = 269; I2 = 91%, low-quality evidence). The confidence interval was very wide and there was serious inconsistency between the studies. Other outcomes There is probably little or no difference between the groups in rates of SUI (de novo) (RR 1.37, 95% CI 0.94 to 1.99; 4 RCTs, n = 295; I2 = 0%, moderate-quality evidence) or dyspareunia (RR 1.21, 95% CI 0.55 to 2.66; 5 RCTs, n = 501; I2 = 0% moderate-quality evidence). We are uncertain whether there is any difference for bladder injury (RR 3.00, 95% CI 0.91 to 9.89; 4 RCTs, n = 445; I2 = 0%; very low-quality evidence). Vaginal hysterectomy versus alternatives for uterine prolapse (six studies, n = 667) No clear conclusions could be reached from the available evidence, though one RCT found that awareness of prolapse was less likely after hysterectomy than after abdominal sacrohysteropexy (RR 0.38, 955 CI 0.15 to 0.98, n = 84, moderate-quality evidence). Other comparisons There was no evidence of a difference for any of our primary review outcomes between different types of vaginal native tissue repair (two RCTs), comparisons of graft materials for vaginal support (two RCTs), different routes for sacral colpopexy (four RCTs), or between sacral colpopexy with and without continence surgery (four RCTs). Authors' conclusions Sacral colpopexy is associated with lower risk of awareness of prolapse, recurrent prolapse on examination, repeat surgery for prolapse, postoperative SUI and dyspareunia than a variety of vaginal interventions. The limited evidence does not support use of transvaginal mesh compared to native tissue repair for apical vaginal prolapse. Most of the evaluated transvaginal meshes are no longer available and new lighter meshes currently lack evidence of safety The evidence was inconclusive when comparing access routes for sacral colpopexy. No clear conclusion can be reached from the available data comparing uterine preserving surgery versus vaginal hysterectomy for uterine prolapse.

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. Effective Lifestyle versus usual care Lifestyle 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). Promising No evidence for any outcome for any comparison could be classified to this category. Ineffective or possibly harmful Lifestyle versus usual care Lifestyle 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 control Exercise 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 therapy Insulin 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 interventions Insulin versus oral therapy For 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). Inconclusive Lifestyle versus usual care The 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 control The 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 therapy The 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 diet The 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 insulin The 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 possible No 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.

BACKGROUND: Neonatal hypoglycaemia, a common condition, can be associated with brain injury. It is frequently managed by providing infants with an alternative source of glucose, often given enterally with milk‐feeding or intravenously with dextrose solution, which may decrease breastfeeding success. Intravenous dextrose also often requires that mother and baby are cared for in separate environments. Oral dextrose gel is simple and inexpensive, and can be administered directly to the buccal mucosa for rapid correction of hypoglycaemia, in association with continued breastfeeding and maternal care. This is an update of a previous review published in 2016. OBJECTIVES: To assess the effectiveness of oral dextrose gel in correcting hypoglycaemia in newborn infants from birth to discharge home and reducing long‐term neurodevelopmental impairment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase from database inception to October 2021. We also searched international clinical trials networks, the reference lists of included trials, and relevant systematic reviews identified in the search. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi‐RCTs comparing oral dextrose gel versus placebo, no treatment, or other therapies for the treatment of neonatal hypoglycaemia in newborn infants from birth to discharge home. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study quality and extracted data; they did not assess publications for which they were study authors. We contacted investigators to obtain additional information. We used fixed‐effect models and the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included two studies conducted in high‐income countries, involving 312 late preterm and at‐risk term infants and comparing oral dextrose gel (40% concentration) to placebo gel. One study was at low risk of bias, and the other (an abstract) was at unclear to high risk of bias. Oral dextrose gel compared with placebo gel probably increases correction of hypoglycaemic events (rate ratio 1.08, 95% confidence interval (CI) 0.98 to 1.20; rate difference 66 more per 1000, 95% CI 17 fewer to 166 more; 1 study; 237 infants; moderate‐certainty evidence), and may result in a slight reduction in the risk of major neurological disability at age two years or older, but the evidence is uncertain (risk ratio (RR) 0.46, 95% CI 0.09 to 2.47; risk difference (RD) 24 fewer per 1000, 95% CI 41 fewer to 66 more; 1 study, 185 children; low‐certainty evidence). The evidence is very uncertain about the effect of oral dextrose gel compared with placebo gel or no gel on the need for intravenous treatment for hypoglycaemia (RR 0.78, 95% CI 0.46 to 1.32; RD 37 fewer per 1000, 95% CI 91 fewer to 54 more; 2 studies, 312 infants; very low‐certainty evidence). Investigators in one study of 237 infants reported no adverse events (e.g. choking or vomiting at the time of administration) in the oral dextrose gel or placebo gel group (low‐certainty evidence). Oral dextrose gel compared with placebo gel probably reduces the incidence of separation from the mother for treatment of hypoglycaemia (RR 0.54, 95% CI 0.31 to 0.93; RD 116 fewer per 1000, 95% CI 174 fewer to 18 fewer; 1 study, 237 infants; moderate‐certainty evidence), and increases the likelihood of exclusive breastfeeding after discharge (RR 1.10, 95% CI 1.01 to 1.18; RD 87 more per 1000, 95% CI 9 more to 157 more; 1 study, 237 infants; moderate‐certainty evidence). AUTHORS' CONCLUSIONS: Oral dextrose gel (specifically 40% dextrose concentration) used to treat hypoglycaemia in newborn infants (specifically at‐risk late preterm and term infants) probably increases correction of hypoglycaemic events, and may result in a slight reduction in the risk of major neurological disability at age two years or older. Oral dextrose gel treatment probably reduces the incidence of separation from the mother for treatment and increases the likelihood of exclusive breastfeeding after discharge. No adverse events have been reported. Oral dextrose gel is probably an effective and safe first‐line treatment for infants with neonatal hypoglycaemia in high‐income settings. More evidence is needed about the effects of oral dextrose gel treatment on later neurological disability and the need for other treatments for hypoglycaemia. Future studies should be conducted in low‐and middle‐income settings, in extremely and moderately preterm infants, and compare oral dextrose gel with other therapies such as intravenous dextrose. There are two ongoing studies that may alter the conclusions of this review when published.

Purpose: The movement to the doctor of nursing practice (DNP) is progressing rapidly with new programs emerging and curricular documents being developed. We argue that the implementation of the DNP is a good move for nursing, provided that we use the opportunity to reconceptualize the core of advanced practice nursing, especially nurse practitioner (NP) practice. Data sources: Theory and research articles from nursing focused on advanced practice nursing, NPs, and doctoral education. Conclusions: The foundation of NP education is currently based essentially on borrowed or shared content in assessment, pharmacology, and pathophysiology. We argue that the heart and soul of nursing is in health promotion, both in healthy persons and in those dealing with chronic illness. Current master’s programs do not prepare NPs to assume high-level practice focused on health promotion and disease management using the latest theoretical developments in health behavior change, behavioral sciences, exercise physiology, nutrition, and medical anthropology. Although these are touched upon in most NP programs, they do not represent the core science of NP education and need to be a critical part of any DNP program. Implications for practice: Ultimately, our vision is for NP care to be consistently “different,” yet just as essential as physician care, leading to positive outcomes in health promotion and disease management.

Background Gestational diabetes mellitus (GDM) is associated with short- and long-term complications for the mother and her infant. Women who are unable to maintain their blood glucose concentration within pre-specified treatment targets with diet and lifestyle interventions will require anti-diabetic pharmacological therapies. This review explores the safety and effectiveness of insulin compared with oral anti-diabetic pharmacological therapies, non-pharmacological interventions and insulin regimens. Objectives To evaluate the effects of insulin in treating women with gestational diabetes. Search methods We searched Pregnancy and Childbirth's Trials Register (1 May 2017), ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (1 May 2017) and reference lists of retrieved studies. Selection criteria We included randomised controlled trials (including those published in abstract form) comparing: a) insulin with an oral anti-diabetic pharmacological therapy; b) with a non-pharmacological intervention; c) different insulin analogues; d) different insulin regimens for treating women with diagnosed with GDM. We excluded quasi-randomised and trials including women with pre-existing type 1 or type 2 diabetes. Cross-over trials were not eligible for inclusion. Data collection and analysis Two review authors independently assessed study eligibility, risk of bias, and extracted data. Data were checked for accuracy. Main results We included 53 relevant studies (103 publications), reporting data for 7381 women. Forty-six of these studies reported data for 6435 infants but our analyses were based on fewer number of studies/participants. Overall, the risk of bias was unclear; 40 of the 53 included trials were not blinded. Overall, the quality of the evidence ranged from moderate to very low quality. The primary reasons for downgrading evidence were imprecision, risk of bias and inconsistency. We report the results for our maternal and infant GRADE outcomes for the main comparison. Insulin versus oral anti-diabetic pharmacological therapy For the mother, insulin was associated with an increased risk for hypertensive disorders of pregnancy (not defined) compared to oral anti-diabetic pharmacological therapy (risk ratio (RR) 1.89, 95% confidence interval (CI) 1.14 to 3.12; four studies, 1214 women; moderate-quality evidence). There was no clear evidence of a difference between those who had been treated with insulin and those who had been treated with an oral anti-diabetic pharmacological therapy for the risk of pre-eclampsia (RR 1.14, 95% CI 0.86 to 1.52; 10 studies, 2060 women; moderate-quality evidence); the risk of birth by caesarean section (RR 1.03, 95% CI 0.93 to 1.14; 17 studies, 1988 women; moderate-quality evidence); or the risk of developing type 2 diabetes (metformin only) (RR 1.39, 95% CI 0.80 to 2.44; two studies, 754 women; moderate-quality evidence). The risk of undergoing induction of labour for those treated with insulin compared with oral anti-diabetic pharmacological therapy may possibly be increased, although the evidence was not clear (average RR 1.30, 95% CI 0.96 to 1.75; three studies, 348 women; I² = 32%; moderate-quality of evidence). There was no clear evidence of difference in postnatal weight retention between women treated with insulin and those treated with oral anti-diabetic pharmacological therapy (metformin) at six to eight weeks postpartum (MD -1.60 kg, 95% CI -6.34 to 3.14; one study, 167 women; low-quality evidence) or one year postpartum (MD -3.70, 95% CI -8.50 to 1.10; one study, 176 women; low-quality evidence). The outcomes of perineal trauma/tearing or postnatal depression were not reported in the included studies. For the infant, there was no evidence of a clear difference between those whose mothers had been treated with insulin and those treated with oral anti-diabetic pharmacological therapies for the risk of being born large-for-gestational age (average RR 1.01, 95% CI 0.76 to 1.35; 13 studies, 2352 infants; moderate-quality evidence); the risk of perinatal (fetal and neonatal death) mortality (RR 0.85; 95% CI 0.29 to 2.49; 10 studies, 1463 infants; low-quality evidence);, for the risk of death or serious morbidity composite (RR 1.03, 95% CI 0.84 to 1.26; two studies, 760 infants; moderate-quality evidence); the risk of neonatal hypoglycaemia (average RR 1.14, 95% CI 0.85 to 1.52; 24 studies, 3892 infants; low-quality evidence); neonatal adiposity at birth (% fat mass) (mean difference (MD) 1.6%, 95% CI -3.77 to 0.57; one study, 82 infants; moderate-quality evidence); neonatal adiposity at birth (skinfold sum/mm) (MD 0.8 mm, 95% CI -2.33 to 0.73; random-effects; one study, 82 infants; very low-quality evidence); or childhood adiposity (total percentage fat mass) (MD 0.5%; 95% CI -0.49 to 1.49; one study, 318 children; low-quality evidence). Low-quality evidence also found no clear differences between groups for rates of neurosensory disabilities in later childhood: hearing impairment (RR 0.31, 95% CI 0.01 to 7.49; one study, 93 children), visual impairment (RR 0.31, 95% CI 0.03 to 2.90; one study, 93 children), or any mild developmental delay (RR 1.07, 95% CI 0.33 to 3.44; one study, 93 children). Later infant mortality, and childhood diabetes were not reported as outcomes in the included studies. We also looked at comparisons for regular human insulin versus other insulin analogues, insulin versus diet/standard care, insulin versus exercise and comparisons of insulin regimens, however there was insufficient evidence to determine any differences for many of the key health outcomes. Please refer to the main results for more information about these comparisons. Authors' conclusions The main comparison in this review is insulin versus oral anti-diabetic pharmacological therapies. Insulin and oral anti-diabetic pharmacological therapies have similar effects on key health outcomes. The quality of the evidence ranged from very low to moderate, with downgrading decisions due to imprecision, risk of bias and inconsistency. For the other comparisons of this review (insulin compared with non-pharmacological interventions, different insulin analogies or different insulin regimens), there is insufficient volume of high-quality evidence to determine differences for key health outcomes. Long-term maternal and neonatal outcomes were poorly reported for all comparisons. The evidence suggests that there are minimal harms associated with the effects of treatment with either insulin or oral anti-diabetic pharmacological therapies. The choice to use one or the other may be down to physician or maternal preference, availability or severity of GDM. Further research is needed to explore optimal insulin regimens. Further research could aim to report data for standardised GDM outcomes.

Advanced prostate cancer is frequently accompanied by the development of metastasis to bone. In the past, prostate cancer bone metastases were characterized as being osteoblastic (i.e., increasing bone density) based on radiographs. However, emerging evidence suggests that development of prostate cancer bone metastases requires osteoclastic activity in addition to osteoblastic activity. The complexities of how prostate tumor cells influence bone remodeling are just beginning to be elucidated. Prostate cancer cells produce a variety of pro-osteoblastic factors that promote bone mineralization. For example, both bone morphogenetic proteins and endothelin-1 have well recognized pro-osteoblastic activities and are produced by prostate cancer cells. In addition to factors that enhance bone mineralization prostate cancer cells produced factors that promote osteoclast activity. Perhaps the most critical pro-osteoclastogenic factor produced by prostate cancer cells is receptor activator of NFkappaB ligand (RANKL), which has been shown to be required for the development of osteoclasts. Blocking RANKL results in inhibiting prostate cancer-induced osteoclastogenesis and inhibits development and progression of prostate tumor growth in bone. These findings suggest that targeting osteoclast activity may be of therapeutic benefit. However, it remains to be defined how prostate cancer cells synchronize the combination of osteoclastic and osteoblastic activity. We propose that as the bone microenvironment is changed by the developing cancer, this in turn influences the prostate cancer cells' balance between pro-osteoclastic and pro-osteoblastic activity. Accordingly, the determination of how the prostate cancer cells and bone microenvironment crosstalk are important to elucidate how prostate cancer cells modulate bone remodeling.

Background Magnesium sulphate has been used in some settings as a tocolytic agent to inhibit uterine activity in women in preterm labour with the aim of preventing preterm birth. Objectives To assess the effects of magnesium sulphate therapy given to women in threatened preterm labour with the aim of preventing preterm birth and its sequelae. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (last searched 31 January 2014). Selection criteria Randomised controlled trials of magnesium sulphate as the only tocolytic, administered by any route, compared with either placebo, no treatment or alternative tocolytic therapy (not magnesium sulphate) to women considered to be in preterm labour. Data collection and analysis At least two review authors assessed trial eligibility and risk of bias and undertook data extraction independently. Main results The 37 included trials (total of 3571 women and over 3600 babies) were generally of moderate to high risk of bias. Antenatal magnesium sulphate was compared with either placebo, no treatment, or a range of alternative tocolytic agents. For the primary outcome of giving birth within 48 hours after trial entry, no significant differences were seen between women who received magnesium sulphate and women who did not (whether placebo/no alternative tocolytic drug, betamimetics, calcium channel blockers, cox inhibitors, prostaglandin inhibitors, or human chorionic gonadotropin) (19 trials, 1913 women). Similarly for the primary outcome of serious infant outcome, there were no significant differences between the infants exposed to magnesium sulphate and those not (whether placebo/no alternative tocolytic drug, betamimetics, calcium channel blockers, cox inhibitors, prostaglandin inhibitors, human chorionic gonadotropin or various tocolytic drugs) (18 trials; 2187 babies). No trials reported the outcome of extremely preterm birth. In the seven trials that reported serious maternal outcomes, no events were recorded. In the group treated with magnesium sulphate compared with women receiving antenatal placebo or no alternative tocolytic drug, a borderline increased risk of total death (fetal, neonatal, infant) was seen (risk ratio (RR) 4.56, 95% confidence interval (CI) 1.00 to 20.86; two trials, 257 babies); none of the comparisons between magnesium sulphate and other classes of tocolytic drugs showed differences for this outcome (10 trials, 991 babies). The outcomes of neonatal and/or infant deaths and of fetal deaths did not show differences between magnesium sulphate and no magnesium sulphate, whether compared with placebo/no alternative tocolytic drug, or any specific class of tocolytic drug. For most of the other secondary outcomes, there were no significant differences between magnesium sulphate and the control groups for risk of preterm birth (except for a significantly lower risk with magnesium sulphate when compared with barbiturates in one trial of 65 women), gestational age at birth, interval between trial entry and birth, other neonatal morbidities, or neurodevelopmental outcomes. Duration of neonatal intensive care unit stay was significantly increased in the magnesium sulphate group compared with the calcium channel blocker group, but not when compared with cox inhibitors or prostaglandin inhibitors. No maternal deaths were reported in the four trials reporting this outcome. Significant differences between magnesium sulphate and controls were not seen for maternal adverse events severe enough to stop treatment, except for a significant benefit of magnesium sulphate compared with betamimetics in a single trial. Authors' conclusions Magnesium sulphate is ineffective at delaying birth or preventing preterm birth, has no apparent advantages for a range of neonatal and maternal outcomes as a tocolytic agent and its use for this indication may be associated with an increased risk of total fetal, neonatal or infant mortality (in contrast to its use in appropriate groups of women for maternal, fetal, neonatal and infant neuroprotection where beneficial effects have been demonstrated).

BACKGROUND: Thyroid disease is the second most common endocrine disorder affecting women of reproductive age. Subclinical hypothyroidism is diagnosed by an elevated thyroid‐stimulating hormone concentration with a normal concentration of free thyroxine hormone. Autoimmune thyroid disease (ATD) is diagnosed by the presence of thyroid autoantibodies, regardless of thyroid hormone levels. Thyroxine may be a useful treatment for subfertile women with these two specific types of thyroid disease for improving pregnancy outcomes during assisted reproduction. OBJECTIVES: To evaluate the efficacy and harms of levothyroxine replacement in subfertile women with subclinical hypothyroidism or with normal thyroid function and thyroid autoimmunity (euthyroid autoimmune thyroid disease, or euthyroid ATD) undergoing assisted reproduction. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and two trials registers together with reference checking and contact with study authors and experts in the field to identify studies. We searched for all published and unpublished randomised controlled trials (RCTs) comparing thyroxine with no treatment or placebo, without language restrictions, from inception to 8 April 2019, and in consultation with the Cochrane CGF Information Specialist. SELECTION CRITERIA: We included women undergoing assisted reproduction treatment, meaning both in vitro fertilisation and intracytoplasmic sperm injection, with a history of subfertility and with subclinical hypothyroidism or with euthyroid ATD. We excluded women with a previously known clinical hypothyroidism or already taking thyroxine or tri‐iodothyronine. RCTs compared thyroxine (levothyroxine) with either placebo or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary review outcomes were live birth and adverse events of thyroxine; our secondary outcomes were clinical pregnancy, multiple pregnancy and miscarriage. MAIN RESULTS: The review included four studies with 820 women. The included studies were of overall low risk of bias. Using GRADE methodology, we assessed the quality of evidence for the primary outcomes of this review to be very low‐ to low‐quality evidence. Evidence was downgraded for imprecision as it was based on single, small trials with wide confidence intervals (CI). We were able to include data from three of the four included studies. In one study of women with both subclinical hypothyroidism and positive or negative anti‐TPO antibodies (autoimmune disease), the evidence suggested that thyroxine replacement may have improved live birth rate (RR 2.13, 95% CI 1.07 to 4.21; 1 RCT, n = 64; low‐quality evidence) and it may have led to similar miscarriage rates (RR 0.11, 95% CI 0.01 to 1.98; 1 RCT, n = 64; low‐quality evidence). The evidence suggested that women with both subclinical hypothyroidism and positive or negative anti‐TPO antibodies would have a 25% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 27% and 100%. In women with normal thyroid function and thyroid autoimmunity (euthyroid ATD), treatment with thyroxine replacement compared with placebo or no treatment may have led to similar live birth rates (risk ratio (RR) 1.04, 95% CI 0.83 to 1.29; 2 RCTs, number of participants (n) = 686; I(2) = 46%; low‐quality evidence) and miscarriage rates (RR 0.83, 95% CI 0.47 to 1.46, 2 RCTs, n = 686, I(2) = 0%; low‐quality evidence). The evidence suggested that women with normal thyroid function and thyroid autoimmunity would have a 31% chance of a live birth with placebo or no treatment, and that the chance of a live birth in these women using thyroxine would be between 26% and 40%. Adverse events were rarely reported. One RCT reported 0/32 in the thyroxine replacement group and 1/32 preterm births in the control group in women diagnosed with subclinical hypothyroidism and positive or negative anti‐TPO antibodies. One RCT reported 21/300 preterm births in the thyroxine replacement group and 19/300 preterm births in the control group in women diagnosed with positive anti‐TPO antibodies. None of the RCTs reported on other maternal pregnancy complications, foetal complications or adverse effects of thyroxine. AUTHORS' CONCLUSIONS: We could draw no clear conclusions in this systematic review due to the very low to low quality of the evidence reported.

A series of complexes incorporating the epoxy–imidazole adduct of phenyl glycidyl ether with 2-ethyl-4-methylimidazole (PGE-EMI), has been prepared with the acetato and chloro transition metal salts of Mn, Co, Ni, Cu, Zn, and Ag. These complexes have been characterized using spectroscopic methods (IR, UV-Vis, 1H- and 13C-NMR, where appropriate) and their thermal stabilities have been determined using elevated temperature NMR techniques. These high-temperature NMR results indicated that the chloro complexes studied (of Mn2+, Co2+, Ni2+, Cu2+, and Zn2+) exist in equilibrium (i.e., they dissociate reversibly in a solution of dimethylsulphoxide, DMSO, at elevated temperatures), while the corresponding acetato complexes dissociate irreversibly. For the silver complexes, thermogravimetric analysis (TGA) was used to monitor the dissociation, showing that the weight loss recorded was consistent with the dissociation of the metal salt to liberate the PGE–imidazole ligand. The thermal stabilities of the metal complexes were influenced by changing both the transition metal (e.g., from Mn to Zn) and varying the anion (e.g., from acetate to chloride). From 1H-NMR analysis, a decrease of ca. 10°C was observed in the thermal dissociation of the acetato complexes when compared with the chloro complexes, showing that the series of PGE-EMI complexes with acetate anions is less thermally stable than the corresponding chlorides. This finding suggests that these PGE-EMI complexes may be modified to accommodate their use in a variety of different curing schedules when used to cure epoxy resins. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 75: 201–217, 2000

Background Surgical ovarian wedge resection was the first established treatment for women with anovulatory polycystic ovary syndrome (PCOS) but was largely abandoned both due to the risk of postsurgical adhesions and the introduction of medical ovulation induction. However, women with PCOS who are treated with medical ovulation induction, with drugs such as gonadotrophins, often have an over-production of follicles which may result in ovarian hyperstimulation syndrome and multiple pregnancies. Moreover, gonadotrophins, though effective, are costly and time-consuming and their use requires intensive monitoring. Surgical therapy with laparoscopic ovarian 'drilling' (LOD) may avoid or reduce the need for medical ovulation induction, or may facilitate its usefulness. The procedure can be done on an outpatient basis with less trauma and fewer postoperative adhesions than with traditional surgical approaches. Many uncontrolled observational studies have claimed that ovarian drilling is followed, at least temporarily, by a high rate of spontaneous ovulation and conception, or that subsequent medical ovulation induction becomes easier. Objectives To determine the effectiveness and safety of laparoscopic ovarian drilling compared with ovulation induction for subfertile women with clomiphene-resistant PCOS. Search methods We used the search strategy of the Menstrual Disorders and Subfertility Group (MDSG) to search the MDSG Trials Register, CENTRAL, MEDLINE, EMBASE, CINAHL and PsycINFO. The keywords included polycystic ovary syndrome, laparoscopic ovarian drilling, electrocautery and diathermy. Searches were conducted in September 2011, and a further search of the MDSG Trials Register was made on 14 May 2012. Selection criteria We included randomised controlled trials of subfertile women with clomiphene-resistant PCOS who undertook laparoscopic ovarian drilling in order to induce ovulation. Data collection and analysis This is an update of a previously updated review. There were nine RCTs in the previous version; an additional 16 trials were added in the current (2012) update. All trials were assessed for quality. The primary outcomes were live birth and multiple pregnancy. The secondary outcomes were rate of miscarriage, ovulation and pregnancy rates, ovarian hyperstimulation syndrome (OHSS), quality of life and cost. Main results Nine trials, including 1210 women, reported on the primary outcome of live birth rate per couple. Live births were reported in 34% of women in the LOD groups and 38% in other medical treatment groups. There were five different comparisons with LOD and there was no evidence of a difference in live births when compared with clomiphene citrate + tamoxifen (OR 0.81; 95% CI 0.42 to 1.53; P = 0.51, 1 trial, n = 150), gonadotrophins (OR 0.97; 95% CI 0.59 to 1.59; P = 0.89, I(2) = 0%, 2 trials, n = 318), aromatase inhibitors (OR 0.84; 95% CI 0.54 to 1.31; P = 0.44, I(2) = 0%, 2 trials, n = 407) or clomiphene citrate (OR 1.21; 95%CI 0.64 to 2.32; 1 trial, n=176, P= 0.05). There was evidence of significantly fewer live births following LOD compared with clomiphene citrate + metformin (OR 0.44; 95% CI 0.24 to 0.82; P = 0.01, I(2) = 78%, 2 trials, n = 159); the high heterogeneity in this subgroup could not be explained by population differences or differences in quality of the trials.Thirteen trials reported on multiple pregnancies (n= 1305 women). There were no cases of multiple pregnancies in either group for clomiphene citrate or aromatase inhibitors compared with LOD. The rate of multiple pregnancies was significantly lower in the LOD group compared with trials using gonadotrophins (OR 0.13; 95% CI 0.03 to 0.52; P=0.004, I(2) = 0%, 5 trials, n = 166). Authors' conclusions There was no evidence of a significant difference in rates of clinical pregnancy, live birth or miscarriage in women with clomiphene-resistant PCOS undergoing LOD compared to other medical treatments. The reduction in multiple pregnancy rates in women undergoing LOD makes this option attractive. However, there are ongoing concerns about the long-term effects of LOD on ovarian function.

Background The effectiveness of clomiphene citrate is demonstrated in the treatment of subfertility associated with oligo-ovulation. Clomiphene citrate acts as a central estrogen receptor blocker, which results in increased production and secretion of follicle stimulating hormone (FSH). The physiologic effects and clinical benefits in ovulatory women with unexplained subfertility are less clear. The drug is associated with the side effect of increased risk of multiple pregnancy and a suggestion of potentially increased ovarian cancer risks. In light of these concerns, defining the effectiveness of clomiphene citrate for ovulatory women with unexplained subfertility is extremely important. Objectives To determine the effectiveness of clomiphene citrate in improving pregnancy outcomes when given to women with unexplained subfertility in a dose range of 50 to 250 mg for up to ten days. The primary outcome was live births. Search strategy We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials (searched October 31, 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 3), MEDLINE (1966 to October 2006), EMBASE (1980 to October 2006) and reference lists of articles. Selection criteria Randomised controlled trials were included. Quasi-randomised, cross-over designs where data before cross over could not be obtained and cohort studies were excluded. Data collection and analysis Thirteen potentially relevant trials were identified of which five were included in this review. All trials were assessed for quality in terms of method of randomisation, completeness of follow up, presence or absence of cross over and co-intervention, and allocation concealment. Main results There was no evidence that clomiphene citrate was more effective than no treatment or placebo. The odds ratios for clinical pregnancy per patient was 2.40 with a 95% confidence interval (CI) (CI 0.70 to 8.19;P=0.16) for clomiphene citrate with IUI; 0.99 (CI 0.61 to 1.60; P=0.96) without intrauterine insemination (IUI) and 1.66 (CI 0.56 to 4.80; P=0.35) without IUI and using human chorionic gonadotropin (hCG). It should be noted that the heterogeneity between studies ranged from 33.5% to 57.6% using the I2 statistic. Authors' conclusions There does not appear to be any clinical benefit to the use of clomiphene citrate for unexplained fertility although the lack of homogeneity among the studies should be noted. When making this treatment choice, potential side effects should be discussed. These include the increased risk of multiple pregnancy, minor symptoms and the concern that use for more that 12 cycles has been associated with an increased risk of ovarian cancer. Given the extensive use of clomiphene citrate in ovulatory women and recent concerns associated with its long-term use, a definitive trial with adequate power is warranted to establish effectiveness in women with unexplained subfertility.

Background Endometriosis is the presence of endometrial glands or stroma in sites other than the uterine cavity and appears to be an oestrogen-dependent condition. This dependency has prompted the therapeutic use of ovulation suppression agents in an effort to improve subsequent fertility. Objectives To assess the effectiveness of ovulation suppression agents, including danazol, progestins and oral contraceptives, in the treatment of endometriosis-associated subfertility in improving pregnancy outcomes including live births. Search methods We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of trials (February 2009), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2009), MEDLINE (1966 to February 2009), EMBASE (1980 to February 2009), and reference lists of articles. Selection criteria Randomised trials comparing an ovulation suppression agent with placebo or no treatment, a suppressive agent with danazol, or a gonadotropin-releasing hormone analogue (GnRHa) with oral contraception in women with endometriosis. Data collection and analysis Two review authors independently extracted data and assessed quality. We contacted study authors for additional information. Main results Twenty-five trials were included. Only two studies reported live births. The odds ratios (OR) for pregnancy following ovulation suppression versus placebo or no treatment was 0.97 (95% confidence interval (CI) 0.68 to 1.34, P = 0.8) for all women randomised, and 1.02 (95% CI 0.70 to 1.52, P = 0.82) for subfertile couples only despite the use of a variety of suppression agents. There was no evidence of benefit from the treatment. The common OR for pregnancy following all agents versus danazol was 1.38 (95% CI 1.05 to 1.82, P = 0.02) for all women randomised, and 1.37 (95% CI 0.94 to 1.99, P = 0.10) for subfertile couples only. When GnRHa and danazol were directly compared, the OR was 1.45 (95% CI 1.08 to 1.95, P = 0.01) for all women randomised, and 1.63 (95% CI 1.12 to 2.37, P = 0.01) for subfertile couples only, in favour of GnRHa. No effect was observed for GnRHa compared with oral contraception (OR 0.93, 95% CI 0.41 to 2.12, P = 0.86 for all women randomised; OR 0.83, 95% CI 0.34 to 2.05, P = 0.69 for subfertile couples only). Authors' conclusions There is no evidence of benefit in the use of ovulation suppression in subfertile women with endometriosis who wish to conceive.

Background Dysmenorrhoea (occurrence of painful menstrual cramps of uterine origin) is a common gynaecological condition. The character of pain from musculoskeletal dysfunction can be very similar to gynaecological pain by presenting cyclicly and being altered by hormonal changes associated with menstruation. Medical treatment for dysmenorrhoea usually comprises anti-inflammatory drugs, oral contraceptives, or surgical intervention. Spinal manipulation is a non-medical intervention. It has been suggested that manipulation of the vertebrae may increase spinal mobility thus improving pelvic blood supply and facilitating pain relief. Objectives To determine the safety and efficacy of spinal manipulative interventions for the treatment of dysmenorrhoea when compared to each other, placebo, no treatment, or other medical treatment. Search methods In this update we searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (May 2009), CENTRAL (to second quarter, 2009), MEDLINE (1966 to May 2009), EMBASE (1980 to May 2009), CINAHL (1982 to May 2009), and PsycINFO (1806 to May 2009). Citation lists of review articles and included trials were examined. Selection criteria Any randomised controlled trials (RCTs) including spinal manipulative interventions (for example chiropractic, osteopathy, or manipulative physiotherapy) versus each other, placebo, no treatment, or another medical treatment were considered. Exclusion criteria were mild or infrequent dysmenorrhoea or dysmenorrhoea from an intrauterine device (IUD). Data collection and analysis Two trials of high velocity, low amplitude (HVLA) manipulation and one trial of the Toftness technique were included. Quality assessment and data extraction were performed independently by two review authors. No data were suitable for meta-analysis. Data were therefore reported as descriptive data. The outcome measures were pain relief or pain intensity and adverse effects. Main results Results from HVLA manipulation suggested that the technique was no more effective than sham manipulation for the treatment of dysmenorrhoea. One small trial indicated a difference in favour of HVLA manipulation however the one trial with an adequate sample size found no difference between HVLA and sham manipulation. There was no difference in adverse effects. The Toftness technique appeared more effective than sham treatment in one small trial but no conclusions could be made due to the size and other methodological limitations of the trial. Authors' conclusions There is no evidence to suggest that spinal manipulation is effective in the treatment of dysmenorrhoea. In the one trial reporting on adverse effects there was no greater risk of such events with spinal compared with sham manipulation.

Summary Most haemophiliacs treated with non-virally inactivated concentrates have been infected with the hepatitis C virus (HCV). 19/21 (90%) patients with HCV antibody were found to have HCV RNA in their serum and in 16 of these it was also detected in peripheral blood mononuclear cells (PBMC). We used specific primers to detect the negative (replicative) strand of this single positively stranded virus. The negative strand was detected in the serum or PBMC of 16 patients indicating active replication outside the liver. The detection of replicating HCV RNA in the cells of HIV negative haemophiliacs could explain at least some of the immunological abnormalities previously reported in these patients and attributed to clotting factor concentrates.

Dysmenorrhoea is the occurrence of painful menstrual cramps of the uterus. Medical therapy for dysmenorrhoea commonly consists of nonsteroidal anti-inflammatory drugs or the oral contraceptive pill both of which work by reducing myometrial (uterine muscle) activity. However, these treatments are accompanied by a number of side effects, making an effective non-pharmacological method of treating dysmenorrhoea of potential value. Transcutaneous electrical nerve stimulation (TENS) is a treatment that has been shown to be effective for pain relief in a variety of conditions. Electrodes are placed on the skin and electric current applied at different pulse rates (frequencies) and intensities is used to stimulate these areas so as to provide pain relief. In dysmenorrhoea. TENS is thought to work by alteration of the body's ability to receive or perceive pain signals rather than by having a direct effect on the uterine contractions. Acupuncture may also be indicated as a useful, non-pharmacological method for treating dysmenorrhoea. Acupuncture is thought to excite receptors or nerve fibres which, through a complicated interaction with mediators such as serotonin and endorphins, blocks pain impulses. Acupuncture typically involves penetration of the skin by fine, solid metallic needles, which are manipulated manually or by electrical stimulation.To determine the effectiveness of high and low frequency transcutaneous electrical nerve stimulation and acupuncture when compared to each other, placebo, no treatment, or medical treatment for primary dysmenorrhoea.Electronic searches of the Cochrane Menstrual Disorders and Subfertility Group Register of controlled trials, CCTR (Cochrane Library Issue 3, 2001), MEDLINE, EMBASE, CINAHL, Bio extracts, PsycLIT and SPORTDiscus were performed in August 2001 to identify relevant randomised controlled trials (RCTs). The Cochrane Complementary Medicine Field's Register of controlled trials (CISCOM) was also searched. Attempts were also made to identify trials from the UK National Research Register, the Clinical Trial Register and the citation lists of review articles and included trials. In most cases, the first or corresponding author of each included trial was contacted for additional information.The inclusion criteria were randomised controlled trials of transcutaneous electrical nerve stimulation and acupuncture that compared these treatments to each other, placebo, no treatment, or medical treatment for primary dysmenorrhoea. Exclusion criteria were: mild, infrequent or secondary dysmenorrhoea and dysmenorrhoea associated with an IUD.Nine RCTs were identified that fulfilled the inclusion criteria for this review, seven involving TENS, one acupuncture, and one both treatments. Quality assessment and data extraction were performed independently by two reviewers. Meta analysis was performed using odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Data unsuitable for meta-analysis was reported as descriptive data and was also included for discussion. The outcome measures were pain relief (dichotomous, visual analogue scales, descriptive), adverse effects, use of analgesics additional to treatment and absence from work or school.Overall high frequency TENS was shown to be more effective for pain relief than placebo TENS. Low frequency TENS was found to be no more effective in reducing pain than placebo TENS. There were conflicting results regarding whether high frequency TENS is more effective than low frequency TENS. One small trial showed acupuncture to be significantly more effective for pain relief than both placebo acupuncture and two no treatment control groups.High frequency TENS was found to be effective for the treatment of dysmenorrhoea by a number of small trials. The minor adverse effects reported in one trial requires further investigation. There is insufficient evidence to determine the effectiveness of low frequency TENS in reducing dysmenorrhoea. There is also insufficient evidence to determine the effectiveness of acupuncture in reducing dysmenorrhoea, however a single small but methodologically sound trial of acupuncture suggests benefit for this modality.