Medical treatment for early fetal death (less than 24 weeks).

BACKGROUND: In most pregnancies that miscarry, arrest of embryonic or fetal development occurs some time (often weeks) before the miscarriage occurs. Ultrasound examination can reveal abnormal findings during this phase by demonstrating anembryonic pregnancies or embryonic or fetal death. Treatment has traditionally been surgical but medical treatments may be effective, safe, and acceptable, as may be waiting for spontaneous miscarriage. This is an update of a review first published in 2006. OBJECTIVES: To assess, from clinical trials, the effectiveness and safety of different medical treatments for the termination of non-viable pregnancies. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (24 October 2018) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials comparing medical treatment with another treatment (e.g. surgical evacuation), or placebo, or no treatment for early pregnancy failure. Quasi-randomised studies were excluded. Cluster-randomised trials were eligible for inclusion, as were studies reported in abstract form, if sufficient information was available to assess eligibility. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Forty-three studies (4966 women) were included. The main interventions examined were vaginal, sublingual, oral and buccal misoprostol, mifepristone and vaginal gemeprost. These were compared with surgical management, expectant management, placebo, or different types of medical interventions were compared with each other. The review includes a wide variety of different interventions which have been analysed across 23 different comparisons. Many of the comparisons consist of single studies. We limited the grading of the quality of evidence to two main comparisons: vaginal misoprostol versus placebo and vaginal misoprostol versus surgical evacuation of the uterus. Risk of bias varied widely among the included trials. The quality of the evidence varied between the different comparisons, but was mainly found to be very-low or low quality.Vaginal misoprostol versus placeboVaginal misoprostol may hasten miscarriage when compared with placebo: e.g. complete miscarriage (5 trials, 305 women, risk ratio (RR) 4.23, 95% confidence interval (CI) 3.01 to 5.94; low-quality evidence). No trial reported on pelvic infection rate for this comparison. Vaginal misoprostol made little difference to rates of nausea (2 trials, 88 women, RR 1.38, 95% CI 0.43 to 4.40; low-quality evidence), diarrhoea (2 trials, 88 women, RR 2.21, 95% CI 0.35 to 14.06; low-quality evidence) or to whether women were satisfied with the acceptability of the method (1 trial, 32 women, RR 1.17, 95% CI 0.83 to 1.64; low-quality evidence). It is uncertain whether vaginal misoprostol reduces blood loss (haemoglobin difference > 10 g/L) (1 trial, 50 women, RR 1.25, 95% CI 0.38 to 4.12; very-low quality) or pain (opiate use) (1 trial, 84 women, RR 5.00, 95% CI 0.25 to 101.11; very-low quality), because the quality of the evidence for these outcomes was found to be very low.Vaginal misoprostol versus surgical evacuation Vaginal misoprostol may be less effective in accomplishing a complete miscarriage compared to surgical management (6 trials, 943 women, average RR 0.40, 95% CI 0.32 to 0.50; Heterogeneity: Tau² = 0.03, I² = 46%; low-quality evidence) and may be associated with more nausea (1 trial, 154 women, RR 21.85, 95% CI 1.31 to 364.37; low-quality evidence) and diarrhoea (1 trial, 154 women, RR 40.85, 95% CI 2.52 to 662.57; low-quality evidence). There may be little or no difference between vaginal misoprostol and surgical evacuation for pelvic infection (1 trial, 618 women, RR 0.73, 95% CI 0.39 to 1.37; low-quality evidence), blood loss (post-treatment haematocrit (%) (1 trial, 50 women, mean difference (MD) 1.40%, 95% CI -3.51 to 0.71; low-quality evidence), pain relief (1 trial, 154 women, RR 1.42, 95% CI 0.82 to 2.46; low-quality evidence) or women's satisfaction/acceptability of method (1 trial, 45 women, RR 0.67, 95% CI 0.40 to 1.11; low-quality evidence).Other comparisonsBased on findings from a single trial, vaginal misoprostol was more effective at accomplishing complete miscarriage than expectant management (614 women, RR 1.25, 95% CI 1.09 to 1.45). There was little difference between vaginal misoprostol and sublingual misoprostol (5 trials, 513 women, average RR 0.84, 95% CI 0.61 to 1.16; Heterogeneity: Tau² = 0.10, I² = 871%; or between oral and vaginal misoprostol in terms of complete miscarriage at less than 13 weeks (4 trials, 418 women), average RR 0.68, 95% CI 0.45 to 1.03; Heterogeneity: Tau² = 0.13, I² = 90%). However, there was less abdominal pain with vaginal misoprostol in comparison to sublingual (3 trials, 392 women, RR 0.58, 95% CI 0.46 to 0.74). A single study (46 women) found mifepristone to be more effective than placebo: miscarriage complete by day five after treatment (46 women, RR 9.50, 95% CI 2.49 to 36.19). However the quality of this evidence is very low: there is a very serious risk of bias with signs of incomplete data and no proper intention-to-treat analysis in the included study; and serious imprecision with wide confidence intervals. Mifepristone did not appear to further hasten miscarriage when added to a misoprostol regimen (3 trials, 447 women, RR 1.18, 95% CI 0.95 to 1.47). AUTHORS' CONCLUSIONS: Available evidence from randomised trials suggests that medical treatment with vaginal misoprostol may be an acceptable alternative to surgical evacuation or expectant management. In general, side effects of medical treatment were minor, consisting mainly of nausea and diarrhoea. There were no major differences in effectiveness between different routes of administration. Treatment satisfaction was addressed in only a few studies, in which the majority of women were satisfied with the received intervention. Since the quality of evidence is low or very low for several comparisons, mainly because they included only one or two (small) trials; further research is necessary to assess the effectiveness, safety and side effects, optimal route of administration and dose of different medical treatments for early fetal death.

Medical treatments for incomplete miscarriage.

BACKGROUND: Miscarriage occurs in 10% to 15% of pregnancies. The traditional treatment, after miscarriage, has been to perform surgery to remove any remaining placental tissues in the uterus ('evacuation of uterus'). However, medical treatments, or expectant care (no treatment), may also be effective, safe, and acceptable. OBJECTIVES: To assess the effectiveness, safety, and acceptability of any medical treatment for incomplete miscarriage (before 24 weeks). SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (13 May 2016) and reference lists of retrieved papers. SELECTION CRITERIA: We included randomised controlled trials comparing medical treatment with expectant care or surgery, or alternative methods of medical treatment. We excluded quasi-randomised trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion, assessed risk of bias, and carried out data extraction. Data entry was checked. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included 24 studies (5577 women). There were no trials specifically of miscarriage treatment after 13 weeks' gestation.Three trials involving 335 women compared misoprostol treatment (all vaginally administered) with expectant care. There was no difference in complete miscarriage (average risk ratio (RR) 1.23, 95% confidence interval (CI) 0.72 to 2.10; 2 studies, 150 women, random-effects; very low-quality evidence), or in the need for surgical evacuation (average RR 0.62, 95% CI 0.17 to 2.26; 2 studies, 308 women, random-effects; low-quality evidence). There were few data on 'deaths or serious complications'. For unplanned surgical intervention, we did not identify any difference between misoprostol and expectant care (average RR 0.62, 95% CI 0.17 to 2.26; 2 studies, 308 women, random-effects; low-quality evidence).Sixteen trials involving 4044 women addressed the comparison of misoprostol (7 studies used oral administration, 6 studies used vaginal, 2 studies sublingual, 1 study combined vaginal + oral) with surgical evacuation. There was a slightly lower incidence of complete miscarriage with misoprostol (average RR 0.96, 95% CI 0.94 to 0.98; 15 studies, 3862 women, random-effects; very low-quality evidence) but with success rate high for both methods. Overall, there were fewer surgical evacuations with misoprostol (average RR 0.05, 95% CI 0.02 to 0.11; 13 studies, 3070 women, random-effects; very low-quality evidence) but more unplanned procedures (average RR 5.03, 95% CI 2.71 to 9.35; 11 studies, 2690 women, random-effects; low-quality evidence). There were few data on 'deaths or serious complications'. Nausea was more common with misoprostol (average RR 2.50, 95% CI 1.53 to 4.09; 11 studies, 3015 women, random-effects; low-quality evidence). We did not identify any difference in women's satisfaction between misoprostol and surgery (average RR 1.00, 95% CI 0.99 to 1.00; 9 studies, 3349 women, random-effects; moderate-quality evidence). More women had vomiting and diarrhoea with misoprostol compared with surgery (vomiting: average RR 1.97, 95% CI 1.36 to 2.85; 10 studies, 2977 women, random-effects; moderate-quality evidence; diarrhoea: average RR 4.82, 95% CI 1.09 to 21.32; 4 studies, 757 women, random-effects; moderate-quality evidence).Five trials compared different routes of administration, or doses, or both, of misoprostol. There was no clear evidence of one regimen being superior to another. Limited evidence suggests that women generally seem satisfied with their care. Long-term follow-up from one included study identified no difference in subsequent fertility between the three approaches. AUTHORS' CONCLUSIONS: The available evidence suggests that medical treatment, with misoprostol, and expectant care are both acceptable alternatives to routine surgical evacuation given the availability of health service resources to support all three approaches. Further studies, including long-term follow-up, are clearly needed to confirm these findings. There is an urgent need for studies on women who miscarry at more than 13 weeks' gestation.

First trimester ultrasound tests alone or in combination with first trimester serum tests for Down's syndrome screening.

BACKGROUND: Down's syndrome occurs when a person has three, rather than two copies of chromosome 21; or the specific area of chromosome 21 implicated in causing Down's syndrome. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life.Non-invasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing.Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have. OBJECTIVES: To estimate and compare the accuracy of first trimester ultrasound markers alone, and in combination with first trimester serum tests for the detection of Down's syndrome. SEARCH METHODS: We carried out extensive literature searches including MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), and The Database of Abstracts of Reviews of Effects (the Cochrane Library 2011, Issue 7). We checked reference lists and published review articles for additional potentially relevant studies. SELECTION CRITERIA: Studies evaluating tests of first trimester ultrasound screening, alone or in combination with first trimester serum tests (up to 14 weeks' gestation) for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection. DATA COLLECTION AND ANALYSIS: Data were extracted as test positive/test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS criteria. We used hierarchical summary ROC meta-analytical methods to analyse test performance and compare test accuracy. Analysis of studies allowing direct comparison between tests was undertaken. We investigated the impact of maternal age on test performance in subgroup analyses. MAIN RESULTS: We included 126 studies (152 publications) involving 1,604,040 fetuses (including 8454 Down's syndrome cases). Studies were generally good quality, although differential verification was common with invasive testing of only high-risk pregnancies. Sixty test combinations were evaluated formed from combinations of 11 different ultrasound markers (nuchal translucency (NT), nasal bone, ductus venosus Doppler, maxillary bone length, fetal heart rate, aberrant right subclavian artery, frontomaxillary facial angle, presence of mitral gap, tricuspid regurgitation, tricuspid blood flow and iliac angle 90 degrees); 12 serum tests (inhibin A, alpha-fetoprotein (AFP), free beta human chorionic gonadotrophin (ßhCG), total hCG, pregnancy-associated plasma protein A (PAPP-A), unconjugated oestriol (uE3), disintegrin and metalloprotease 12 (ADAM 12), placental growth factor (PlGF), placental growth hormone (PGH), invasive trophoblast antigen (ITA) (synonymous with hyperglycosylated hCG), growth hormone binding protein (GHBP) and placental protein 13 (PP13)); and maternal age. The most frequently evaluated serum markers in combination with ultrasound markers were PAPP-A and free ßhCG.Comparisons of the 10 most frequently evaluated test strategies showed that a combined NT, PAPP-A, free ßhCG and maternal age test strategy significantly outperformed ultrasound markers alone (with or without maternal age) except nasal bone, detecting about nine out of every 10 Down's syndrome pregnancies at a 5% false positive rate (FPR). In both direct and indirect comparisons, the combined NT, PAPP-A, free ßhCG and maternal age test strategy showed superior diagnostic accuracy to an NT and maternal age test strategy (P < 0.0001). Based on the indirect comparison of all available studies for the two tests, the sensitivity (95% confidence interval) estimated at a 5% FPR for the combined NT, PAPP-A, free ßhCG and maternal age test strategy (69 studies; 1,173,853 fetuses including 6010 with Down's syndrome) was 87% (86 to 89) and for the NT and maternal age test strategy (50 studies; 530,874 fetuses including 2701 Down's syndrome pregnancies) was 71% (66 to 75). Combinations of NT with other ultrasound markers, PAPP-A and free ßhCG were evaluated in one or two studies and showed sensitivities of more than 90% and specificities of more than 95%.High-risk populations (defined before screening was done, mainly due to advanced maternal age of 35 years or more, or previous pregnancies affected with Down's syndrome) showed lower detection rates compared to routine screening populations at a 5% FPR. Women who miscarried in the over 35 group were more likely to have been offered an invasive test to verify a negative screening results, whereas those under 35 were usually not offered invasive testing for a negative screening result. Pregnancy loss in women under 35 therefore leads to under-ascertainment of screening results, potentially missing a proportion of affected pregnancies and affecting test sensitivity. Conversely, for the NT, PAPP-A, free ßhCG and maternal age test strategy, detection rates and false positive rates increased with maternal age in the five studies that provided data separately for the subset of women aged 35 years or more. AUTHORS' CONCLUSIONS: Test strategies that combine ultrasound markers with serum markers, especially PAPP-A and free ßhCG, and maternal age were significantly better than those involving only ultrasound markers (with or without maternal age) except nasal bone. They detect about nine out of 10 Down's affected pregnancies for a fixed 5% FPR. Although the absence of nasal bone appeared to have a high diagnostic accuracy, only five out of 10 affected Down's pregnancies were detected at a 1% FPR.

First and second trimester serum tests with and without first trimester ultrasound tests for Down's syndrome screening.

BACKGROUND: Down's syndrome occurs when a person has three copies of chromosome 21 (or the specific area of chromosome 21 implicated in causing Down's syndrome) rather than two. It is the commonest congenital cause of mental disability. Non-invasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing.  Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal) and false negative screening tests (i.e. a fetus with Down's syndrome will be missed). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have. OBJECTIVES: To estimate and compare the accuracy of first and second trimester serum markers with and without first trimester ultrasound markers for the detection of Down's syndrome in the antenatal period, as combinations of markers. SEARCH METHODS: We conducted a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), the Database of Abstracts of Reviews of Effectiveness (the Cochrane Library 25 August 2011), MEDION (25 August 2011), the Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), the National Research Register (Archived 2007), and Health Services Research Projects in Progress database (25 August 2011). We did not apply a diagnostic test search filter. We did forward citation searching in ISI citation indices, Google Scholar and PubMed 'related articles'. We also searched reference lists of retrieved articles SELECTION CRITERIA: Studies evaluating tests of combining first and second trimester maternal serum markers in women up to 24 weeks of gestation for Down's syndrome, with or without first trimester ultrasound markers, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection. DATA COLLECTION AND ANALYSIS: Data were extracted as test positive/test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS criteria. We used hierarchical summary ROC meta-analytical methods to analyse test performance and compare test accuracy. Analysis of studies allowing direct comparison between tests was undertaken. We investigated the impact of maternal age on test performance in subgroup analyses. MAIN RESULTS: Twenty-two studies (reported in 25 publications) involving 228,615 pregnancies (including 1067 with Down's syndrome) were included. Studies were generally high quality, although differential verification was common with invasive testing of only high risk pregnancies. Ten studies made direct comparisons between tests. Thirty-two different test combinations were evaluated formed from combinations of eight different tests and maternal age; first trimester nuchal translucency (NT) and the serum markers AFP, uE3, total hCG, free ßhCG, Inhibin A, PAPP-A and ADAM 12. We looked at tests combining first and second trimester markers with or without ultrasound as complete tests, and we also examined stepwise and contingent strategies.Meta-analysis of the six most frequently evaluated test combinations showed that a test strategy involving maternal age and a combination of first trimester NT and PAPP-A, and second trimester total hCG, uE3, AFP and Inhibin A significantly outperformed other test combinations that involved only one serum marker or NT in the first trimester, detecting about nine out of every 10 Down's syndrome pregnancies at a 5% false positive rate. However, the evidence was limited in terms of the number of studies evaluating this strategy, and we therefore cannot recommend one single screening strategy. AUTHORS' CONCLUSIONS: Tests involving first trimester ultrasound with first and second trimester serum markers in combination with maternal age are significantly better than those without ultrasound, or those evaluating first trimester ultrasound in combination with second trimester serum markers, without first trimester serum markers. We cannot make recommendations about a specific strategy on the basis of the small number of studies available.

Fetal electrocardiogram (ECG) for fetal monitoring during labour.

BACKGROUND: Hypoxaemia during labour can alter the shape of the fetal electrocardiogram (ECG) waveform, notably the relation of the PR to RR intervals, and elevation or depression of the ST segment. Technical systems have therefore been developed to monitor the fetal ECG during labour as an adjunct to continuous electronic fetal heart rate monitoring with the aim of improving fetal outcome and minimising unnecessary obstetric interference. OBJECTIVES: To compare the effects of analysis of fetal ECG waveforms during labour with alternative methods of fetal monitoring. SEARCH METHODS: The Cochrane Pregnancy and Childbirth Group's Trials Register (latest search 23 September 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials comparing fetal ECG waveform analysis with alternative methods of fetal monitoring during labour. DATA COLLECTION AND ANALYSIS: One review author independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. One review author assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Seven trials (27,403 women) were included: six trials of ST waveform analysis (26,446 women) and one trial of PR interval analysis (957 women). The trials were generally at low risk of bias for most domains and the quality of evidence for ST waveform analysis trials was graded moderate to high. In comparison to continuous electronic fetal heart rate monitoring alone, the use of adjunctive ST waveform analysis made no obvious difference to primary outcomes: births by caesarean section (risk ratio (RR) 1.02, 95% confidence interval (CI) 0.96 to 1.08; six trials, 26,446 women; high quality evidence); the number of babies with severe metabolic acidosis at birth (cord arterial pH less than 7.05 and base deficit greater than 12 mmol/L) (average RR 0.72, 95% CI 0.43 to 1.20; six trials, 25,682 babies; moderate quality evidence); or babies with neonatal encephalopathy (RR 0.61, 95% CI 0.30 to 1.22; six trials, 26,410 babies; high quality evidence). There were, however, on average fewer fetal scalp samples taken during labour (average RR 0.61, 95% CI 0.41 to 0.91; four trials, 9671 babies; high quality evidence) although the findings were heterogeneous and there were no data from the largest trial (from the USA). There were marginally fewer operative vaginal births (RR 0.92, 95% CI 0.86 to 0.99; six trials, 26,446 women); but no obvious difference in the number of babies with low Apgar scores at five minutes or babies requiring neonatal intubation, or babies requiring admission to the special care unit (RR 0.96, 95% CI 0.89 to 1.04, six trials, 26,410 babies; high quality evidence). There was little evidence that monitoring by PR interval analysis conveyed any benefit of any sort. AUTHORS' CONCLUSIONS: The modest benefits of fewer fetal scalp samplings during labour (in settings in which this procedure is performed) and fewer instrumental vaginal births have to be considered against the disadvantages of needing to use an internal scalp electrode, after membrane rupture, for ECG waveform recordings. We found little strong evidence that ST waveform analysis had an effect on the primary outcome measures in this systematic review.There was a lack of evidence showing that PR interval analysis improved any outcomes; and a larger future trial may possibly demonstrate beneficial effects.There is little information about the value of fetal ECG waveform monitoring in preterm fetuses in labour. Information about long-term development of the babies included in the trials would be valuable.

Nutritional advice for improving outcomes in multiple pregnancies.

BACKGROUND: Multiple pregnancies are associated with higher rates of perinatal mortality and morbidity than singleton pregnancies, mainly due to an increased risk of preterm birth. Because fetal outcome is best at a particular range of maternal weight gain, it has been suggested that women with multiple pregnancies should take special diets (particularly high-calorie diets) designed to boost weight gain. However, 'optimal weight gain' in the mother in retrospective studies may merely reflect good growth of her babies and delivery at or near term (both associated with a good outcome) and artificially boosting weight gain by nutritional input may confer no advantage. Indeed, a high-calorie diet may be unpleasant to consume, and could lead to long-term problems of being overweight. It is therefore important to establish if specialised diets are actually of benefit to women with multiple pregnancies and their babies. OBJECTIVES: To assess the effects of specialised diets or nutritional advice for women with multiple pregnancies (two or more fetuses). SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 June 2015). SELECTION CRITERIA: Randomised controlled trials, 'quasi-random' studies, and cluster-randomised trials of women with multiple pregnancies (two or more fetuses) either nulliparous or multiparous and their babies. Cross-over trials and studies reported only as abstracts were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: We identified no trials for inclusion in this review. MAIN RESULTS: A comprehensive search of the Cochrane Pregnancy and Childbirth Group's Trials Register found no potentially eligible trial reports. AUTHORS' CONCLUSIONS: There is no robust evidence from randomised trials to indicate whether specialised diets or nutritional advice for women with multiple pregnancies do more good than harm. There is a clear need to undertake a randomised controlled trial.

First trimester serum tests for Down's syndrome screening.

BACKGROUND: Down's syndrome occurs when a person has three, rather than two copies of chromosome 21; or the specific area of chromosome 21 implicated in causing Down's syndrome. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life.Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. However, no test can predict the severity of problems a person with Down's syndrome will have. OBJECTIVES: The aim of this review was to estimate and compare the accuracy of first trimester serum markers for the detection of Down's syndrome in the antenatal period, both as individual markers and as combinations of markers. Accuracy is described by the proportion of fetuses with Down's syndrome detected by screening before birth (sensitivity or detection rate) and the proportion of women with a low risk (normal) screening test result who subsequently had a baby unaffected by Down's syndrome (specificity). SEARCH METHODS: We conducted a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 25 August 2011), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (Archived 2007), Health Services Research Projects in Progress database (25 August 2011). We did forward citation searching ISI citation indices, Google Scholar and PubMed 'related articles'. We did not apply a diagnostic test search filter. We also searched reference lists and published review articles.   SELECTION CRITERIA: We included studies in which all women from a given population had one or more index test(s) compared to a reference standard (either chromosomal verification or macroscopic postnatal inspection). Both consecutive series and diagnostic case-control study designs were included. Randomised trials where individuals were randomised to different screening strategies and all verified using a reference standard were also eligible for inclusion. Studies in which test strategies were compared head-to-head either in the same women, or between randomised groups were identified for inclusion in separate comparisons of test strategies. We excluded studies if they included less than five Down's syndrome cases, or more than 20% of participants were not followed up. DATA COLLECTION AND ANALYSIS: We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC meta-analytical methods or random-effects logistic regression methods to analyse test performance and compare test accuracy as appropriate. Analyses of studies allowing direct and indirect comparisons between tests were undertaken. MAIN RESULTS: We included 56 studies (reported in 68 publications) involving 204,759 pregnancies (including 2113 with Down's syndrome). Studies were generally of good quality, although differential verification was common with invasive testing of only high-risk pregnancies. We evaluated 78 test combinations formed from combinations of 18 different tests, with or without maternal age; ADAM12 (a disintegrin and metalloprotease), AFP (alpha-fetoprotein), inhibin, PAPP-A (pregnancy-associated plasma protein A, ITA (invasive trophoblast antigen), free ßhCG (beta human chorionic gonadotrophin), PlGF (placental growth factor), SP1 (Schwangerschafts protein 1), total hCG, progesterone, uE3 (unconjugated oestriol), GHBP (growth hormone binding protein), PGH (placental growth hormone), hyperglycosylated hCG, ProMBP (proform of eosinophil major basic protein), hPL (human placental lactogen), (free αhCG, and free ßhCG to AFP ratio. Direct comparisons between two or more tests were made in 27 studies.Meta-analysis of the nine best performing or frequently evaluated test combinations showed that a test strategy involving maternal age and a double marker combination of PAPP-A and free ßhCG significantly outperformed the individual markers (with or without maternal age) detecting about seven out of every 10 Down's syndrome pregnancies at a 5% false positive rate (FPR). Limited evidence suggested that marker combinations involving PAPP-A may be more sensitive than those without PAPP-A. AUTHORS' CONCLUSIONS: Tests involving two markers in combination with maternal age, specifically PAPP-A, free ßhCG and maternal age are significantly better than those involving single markers with and without age. They detect seven out of 10 Down's affected pregnancies for a fixed 5% FPR. The addition of further markers (triple tests) has not been shown to be statistically superior; the studies included are small with limited power to detect a difference.The screening blood tests themselves have no adverse effects for the woman, over and above the risks of a routine blood test. However some women who have a 'high risk' screening test result, and are given amniocentesis or chorionic villus sampling (CVS) have a risk of miscarrying a baby unaffected by Down's. Parents will need to weigh up this risk when deciding whether or not to have an amniocentesis or CVS following a 'high risk' screening test result.

Urine tests for Down's syndrome screening.

BACKGROUND: Down's syndrome occurs when a person has three copies of chromosome 21, or the specific area of chromosome 21 implicated in causing Down's syndrome, rather than two. It is the commonest congenital cause of mental disability and also leads to numerous metabolic and structural problems. It can be life-threatening, or lead to considerable ill health, although some individuals have only mild problems and can lead relatively normal lives. Having a baby with Down's syndrome is likely to have a significant impact on family life. The risk of a Down's syndrome affected pregnancy increases with advancing maternal age.Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing. Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive and false negative screening tests (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have. OBJECTIVES: To estimate and compare the accuracy of first and second trimester urine markers for the detection of Down's syndrome. SEARCH METHODS: We carried out a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), EMBASE (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2011, Issue 7), MEDION (25 August 2011), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), The National Research Register (archived 2007), Health Services Research Projects in Progress database (25 August 2011). We studied reference lists and published review articles. SELECTION CRITERIA: Studies evaluating tests of maternal urine in women up to 24 weeks of gestation for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection. DATA COLLECTION AND ANALYSIS: We extracted data as test positive or test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS (Quality Assessment of Diagnostic Accuracy Studies) criteria. We used hierarchical summary ROC (receiver operating characteristic) meta-analytical methods to analyse test performance and compare test accuracy. We performed analysis of studies allowing direct comparison between tests. We investigated the impact of maternal age on test performance in subgroup analyses. MAIN RESULTS: We included 19 studies involving 18,013 pregnancies (including 527 with Down's syndrome). Studies were generally of high quality, although differential verification was common with invasive testing of only high-risk pregnancies. Twenty-four test combinations were evaluated formed from combinations of the following seven different markers with and without maternal age: AFP (alpha-fetoprotein), ITA (invasive trophoblast antigen), ß-core fragment, free ßhCG (beta human chorionic gonadotrophin), total hCG, oestriol, gonadotropin peptide and various marker ratios. The strategies evaluated included three double tests and seven single tests in combination with maternal age, and one triple test, two double tests and 11 single tests without maternal age. Twelve of the 19 studies only evaluated the performance of a single test strategy while the remaining seven evaluated at least two test strategies. Two marker combinations were evaluated in more than four studies; second trimester ß-core fragment (six studies), and second trimester ß-core fragment with maternal age (five studies).In direct test comparisons, for a 5% false positive rate (FPR), the diagnostic accuracy of the double marker second trimester ß-core fragment and oestriol with maternal age test combination was significantly better (ratio of diagnostic odds ratio (RDOR): 2.2 (95% confidence interval (CI) 1.1 to 4.5), P = 0.02) (summary sensitivity of 73% (CI 57 to 85) at a cut-point of 5% FPR) than that of the single marker test strategy of second trimester ß-core fragment and maternal age (summary sensitivity of 56% (CI 45 to 66) at a cut-point of 5% FPR), but was not significantly better (RDOR: 1.5 (0.8 to 2.8), P = 0.21) than that of the second trimester ß-core fragment to oestriol ratio and maternal age test strategy (summary sensitivity of 71% (CI 51 to 86) at a cut-point of 5% FPR). AUTHORS' CONCLUSIONS: Tests involving second trimester ß-core fragment and oestriol with maternal age are significantly more sensitive than the single marker second trimester ß-core fragment and maternal age, however, there were few studies. There is a paucity of evidence available to support the use of urine testing for Down's syndrome screening in clinical practice where alternatives are available.

Betamimetics for inhibiting preterm labour.

BACKGROUND: Preterm birth is a major contributor to perinatal mortality and morbidity worldwide. Tocolytic agents are drugs used to inhibit uterine contractions. Betamimetics are tocolytic agents that have been widely used, especially in resource-poor countries. OBJECTIVES: To assess the effects of betamimetics given to women with preterm labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2013) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials of betamimetics, administered by any route or any dose, in the treatment of women in preterm labour where betamimetics were compared with other betamimetics, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias and extracted the data independently. MAIN RESULTS: Twenty-eight trials were assessed as eligible for inclusion in the review, but eight did not report any outcome data relevant to the review. Results are based on the 20 trials that contributed data.Twelve trials, involving 1367 women, compared betamimetics with placebo. Betamimetics decreased the number of women in preterm labour giving birth within 48 hours (average risk ratio (RR) 0.68, 95% confidence interval (CI) 0.53 to 0.88, 10 trials, 1209 women). There was a decrease in the number of births within seven days (average RR 0.80; 95% CI 0.65 to 0.98, five trials, 911 women) but there was no evidence of a reduction in preterm birth (before 37 weeks' gestation) (RR 0.95; 95% CI 0.88 to 1.03, 10 trials, 1212 women). No benefit was demonstrated for betamimetics for perinatal death (RR 0.84; 95% CI 0.46 to 1.55, 11 trials, 1332 infants), or neonatal death (RR 0.90; 95% CI 0.27 to 3.00, six trials, 1174 infants). No significant effect was demonstrated for respiratory distress syndrome (RR 0.87; 95% CI 0.71 to 1.08, eight trials, 1239 infants). A few trials reported on cerebral palsy, infant death and necrotising enterocolitis; no significant differences between groups were identified for any of these outcomes. Betamimetics were significantly associated with the following outcomes: withdrawal from treatment due to adverse effects; maternal chest pain; dyspnoea; palpitation; tremor; headaches; hypokalaemia; hyperglycaemia; nausea or vomiting; nasal stuffiness; and fetal tachycardia.Nine trials compared different types of betamimetics. Other betamimetics were compared with ritodrine in five trials (n = 948). Other comparisons were examined in single trials: hexoprenaline compared with salbutamol (n = 140), slow versus moderate release salbutamol (n = 52) and salbutamol compared with terbutaline (n = 200). Trials were small, varied, and of insufficient quality to delineate any consistent patterns of effect. AUTHORS' CONCLUSIONS: Betamimetics help to delay birth, which may give time to allow women to be transferred to tertiary care or to complete a course of antenatal corticosteroids. However, multiple adverse effects must be considered. The data are too few to support the use of any particular betamimetic.

Interventions for the treatment of twin-twin transfusion syndrome.

BACKGROUND: Twin-twin transfusion syndrome, a condition affecting monochorionic twin pregnancies, is associated with a high risk of perinatal mortality and morbidity. A number of treatments have been introduced to treat the condition but it is unclear which intervention improves maternal and fetal outcome. OBJECTIVES: The objective of this review was to evaluate the impact of treatment modalities in twin-twin transfusion syndrome. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013). SELECTION CRITERIA: Randomised and quasi-randomised studies of amnioreduction versus laser coagulation, septostomy versus laser coagulation or septostomy versus amnioreduction. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three studies (253 women and 506 babies) were included. All three trials were judged to be of moderate quality. One study compared amnioreduction with septostomy (71 women), whilst the other two studies compared amnioreduction with endoscopic laser coagulation (182 women). Not all trials provided outcome data that could be included in all meta-analyses. Amnioreduction compared with laser coagulation Although there was no difference in overall death between amnioreduction and laser coagulation (average risk ratio (RR) 0.87; 95% confidence interval (CI) 0.55 to 1.38 adjusted for clustering, two trials) or death of at least one infant per pregnancy (RR 0.91; 95% CI 0.75 to 1.09, two trials), or death of both infants per pregnancy (average RR 0.76; 95% 0.27 to 2.10, two trials), more babies were alive without neurological abnormality at the age of six years in the laser group than in the amnioreduction groups (RR 1.57; 95% CI 1.05 to 2.34 adjusted for clustering, one trial). There were no significant differences in the babies alive at six years with major neurological abnormality treated by laser coagulation or amnioreduction (RR 0.97; 95% CI 0.34 to 2.77 adjusted for clustering, one trial). Outcomes for death in this 2013 update are different from the previous 2008 update, where improvements in perinatal death and death of both infants per pregnancy were shown in the laser intervention arm. The NIHCD trial included in this update exerts an opposite direction of effects to the Eurofetus study, which was previously the only included laser study, hence the difference in outcome. Amnioreduction compared with septostomy There are no differences in overall death (RR 0.83; 95% CI 0.47 to 1.47, adjusted for clustering, one trial), death of at least one infant per pregnancy (RR 0.80; 95% CI 0.48 to 1.35, one trial), or death of both infants per pregnancy (RR 0.90; 95% CI 0.37 to 2.22, one trial) or gestational age at birth (RR 1.20; 95% CI -0.81 to 3.21, one trial) between amnioreduction and septostomy. AUTHORS' CONCLUSIONS: Endoscopic laser coagulation of anastomotic vessels should continue to be considered in the treatment of all stages of twin-twin transfusion syndrome to improve neurodevelopmental outcomes.Further research targeted towards assessing the effect of treatment on milder (Quintero stage 1 and 2) and more severe (Quintero stage 4) forms of twin-twin transfusion syndrome is required. Studies should aim to assess long-term outcomes of survivors.

Fetal electrocardiogram (ECG) for fetal monitoring during labour.

BACKGROUND: Hypoxaemia during labour can alter the shape of the fetal electrocardiogram (ECG) waveform, notably the relation of the PR to RR intervals, and elevation or depression of the ST segment. Technical systems have therefore been developed to monitor the fetal ECG during labour as an adjunct to continuous electronic fetal heart rate monitoring with the aim of improving fetal outcome and minimising unnecessary obstetric interference. OBJECTIVES: To compare the effects of analysis of fetal ECG waveforms during labour with alternative methods of fetal monitoring. SEARCH METHODS: The Cochrane Pregnancy and Childbirth Group's Trials Register (latest search 12 February 2013). SELECTION CRITERIA: Randomised trials comparing fetal ECG waveform analysis with alternative methods of fetal monitoring during labour. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were performed by one review author, without blinding. MAIN RESULTS: Six trials (16,295 women) were included: five trials of ST waveform analysis (15,338 women) and one trial of PR interval analysis (957 women). In comparison to continuous electronic fetal heart rate monitoring alone, the use of adjunctive ST waveform analysis made no significant difference to primary outcomes: births by caesarean section (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.91 to 1.08), the number of babies with severe metabolic acidosis at birth (cord arterial pH less than 7.05 and base deficit greater than 12 mmol/L) (RR 0.78, 95% CI 0.44 to 1.37, data from 14,574 babies), or babies with neonatal encephalopathy (RR 0.54, 95% CI 0.24 to 1.25). There were, however, on average fewer fetal scalp samples taken during labour (RR 0.61, 95% CI 0.41 to 0.91) although the findings were heterogeneous; there were fewer operative vaginal deliveries (RR 0.89, 95% CI 0.81 to 0.98) and admissions to special care unit (RR 0.89, 95% CI 0.81 to 0.99); there was no statistically significant difference in the number of babies with low Apgar scores at five minutes or babies requiring neonatal intubation. There was little evidence that monitoring by PR interval analysis conveyed any benefit. AUTHORS' CONCLUSIONS: These findings provide some modest support for the use of fetal ST waveform analysis when a decision has been made to undertake continuous electronic fetal heart rate monitoring during labour. However, the advantages need to be considered along with the disadvantages of needing to use an internal scalp electrode, after membrane rupture, for ECG waveform recordings.

Antibiotics for preterm rupture of membranes.

BACKGROUND: Premature birth carries substantial neonatal morbidity and mortality. Subclinical infection is associated with preterm rupture of membranes (PROM). Prophylactic maternal antibiotic therapy might lessen infectious morbidity and delay labour, but could suppress labour without treating underlying infection. OBJECTIVES: To evaluate the immediate and long-term effects of administering antibiotics to women with PROM before 37 weeks, on maternal infectious morbidity, neonatal morbidity and mortality, and longer-term childhood development. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2013). SELECTION CRITERIA: Randomised controlled trials comparing antibiotic administration with placebo that reported clinically relevant outcomes were included as were trials of different antibiotics. Trials in which no placebo was used were included for the outcome of perinatal death alone. DATA COLLECTION AND ANALYSIS: We extracted data from each report without blinding of either the results or the treatments that women received. We sought unpublished data from a number of authors. MAIN RESULTS: We included 22 trials, involving 6872 women and babies.The use of antibiotics following PROM is associated with statistically significant reductions in chorioamnionitis (average risk ratio (RR) 0.66, 95% confidence interval (CI) 0.46 to 0.96, and a reduction in the numbers of babies born within 48 hours (average RR 0.71, 95% CI 0.58 to 0.87) and seven days of randomisation (average RR 0.79, 95% CI 0.71 to 0.89). The following markers of neonatal morbidity were reduced: neonatal infection (RR 0.67, 95% CI 0.52 to 0.85), use of surfactant (RR 0.83, 95% CI 0.72 to 0.96), oxygen therapy (RR 0.88, 95% CI 0.81 to 0.96), and abnormal cerebral ultrasound scan prior to discharge from hospital (RR 0.81, 95% CI 0.68 to 0.98). Co-amoxiclav was associated with an increased risk of neonatal necrotising enterocolitis (RR 4.72, 95% CI 1.57 to 14.23).One study evaluated the children's health at seven years of age (ORACLE Children Study) and found antibiotics seemed to have little effect on the health of children. AUTHORS' CONCLUSIONS: Routine prescription of antibiotics for women with preterm rupture of the membranes is associated with prolongation of pregnancy and improvements in a number of short-term neonatal morbidities, but no significant reduction in perinatal mortality. Despite lack of evidence of longer-term benefit in childhood, the advantages on short-term morbidities are such that we would recommend antibiotics are routinely prescribed. The antibiotic of choice is not clear but co-amoxiclav should be avoided in women due to increased risk of neonatal necrotising enterocolitis.

Medical treatments for incomplete miscarriage.

BACKGROUND: Miscarriage occurs in 10% to 15% of pregnancies. The traditional treatment, after miscarriage, has been to perform surgery to remove any remaining placental tissues in the uterus ('evacuation of uterus'). However, medical treatments, or expectant care (no treatment), may also be effective, safe and acceptable. OBJECTIVES: To assess the effectiveness, safety and acceptability of any medical treatment for incomplete miscarriage (before 24 weeks). SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2012) and reference lists of retrieved papers. SELECTION CRITERIA: Randomised controlled trials comparing medical treatment with expectant care or surgery or alternative methods of medical treatment. Quasi-randomised trials were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. Data entry was checked. MAIN RESULTS: Twenty studies (4208 women) were included. There were no trials specifically of miscarriage treatment after 13 weeks' gestation.Three trials involving 335 women compared misoprostol treatment (all vaginally administered) with expectant care. There was no statistically significant difference in complete miscarriage (average risk ratio (RR) 1.23, 95% confidence interval (CI) 0.72 to 2.10; two studies, 150 women, random-effects), or in the need for surgical evacuation (average RR 0.62, 95% CI 0.17 to 2.26; two studies, 308 women, random-effects). There were few data on 'deaths or serious complications'.Twelve studies involving 2894 women addressed the comparison of misoprostol (six studies used oral administration, four studies used vaginal, one study sub-lingual, one study combined vaginal + oral) with surgical evacuation. There was a slightly lower incidence of complete miscarriage with misoprostol (average RR 0.97, 95% CI 0.95 to 0.99, 11 studies, 2493 women, random-effects) but with success rate high for both methods. Overall, there were fewer surgical evacuations with misoprostol (average RR 0.06, 95% CI 0.02 to 0.13; 11 studies, 2654 women, random-effects) but more unplanned procedures (average RR 5.82, 95% CI 2.93 to 11.56; nine studies, 2274 women, random-effects). There were few data on 'deaths or serious complications'. Nausea was more common with misoprostol (average RR 2.41, 95% CI 1.44 to 4.03; nine studies, 2179 women, random-effects).Five trials compared different routes of administration and/or doses of misoprostol. There was no clear evidence of one regimen being superior to another. Limited evidence suggests that women generally seem satisfied with their care. Long-term follow-up from one included study identified no difference in subsequent fertility between the three approaches. AUTHORS' CONCLUSIONS: The available evidence suggests that medical treatment, with misoprostol, and expectant care are both acceptable alternatives to routine surgical evacuation given the availability of health service resources to support all three approaches. Women experiencing miscarriage at less than 13 weeks should be offered an informed choice. Future studies should include long-term follow-up.

Biochemical tests of placental function for assessment in pregnancy.

BACKGROUND: Biochemical tests of placental or feto-placental function were widely used in the 1960s and 1970s in high-risk pregnancies to try to predict, and thus try to avoid, adverse fetal outcome. OBJECTIVES: To assess the effects of performing biochemical tests of placental function in high-risk, low-risk, or unselected pregnancies. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (10 May 2012). SELECTION CRITERIA: Controlled trials (randomized or 'quasi-randomized') that compare the use of biochemical tests of placental function in pregnancy with non-use. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted by the review author. MAIN RESULTS: A single eligible trial of poor quality was identified. It involved 622 women with high-risk pregnancies who had had plasma (o)estriol estimations. Women were allocated to have their (o)estriol results revealed or concealed on the basis of hospital record number (with attendant risk of selection bias). There were no obvious differences in perinatal mortality (relative risk (RR) 0.88, 95% confidence interval (CI) 0.36 to 2.13) or planned delivery (RR 0.97, 95% CI 0.81 to 1.15) between the two groups. AUTHORS' CONCLUSIONS: The available trial data do not support the use of (o)estriol estimation in high-risk pregnancies. The single small trial available does not have the power to exclude a beneficial effect but this is probably of historical interest since biochemical testing has been superseded by biophysical testing in antepartum fetal assessment.

Fetal electrocardiogram (ECG) for fetal monitoring during labour.

BACKGROUND: Hypoxaemia during labour can alter the shape of the fetal electrocardiogram (ECG) waveform, notably the relation of the PR to RR intervals, and elevation or depression of the ST segment. Technical systems have therefore been developed to monitor the fetal ECG during labour as an adjunct to continuous electronic fetal heart rate monitoring with the aim of improving fetal outcome and minimising unnecessary obstetric interference. OBJECTIVES: To compare the effects of analysis of fetal ECG waveforms during labour with alternative methods of fetal monitoring. SEARCH METHODS: The Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2012). SELECTION CRITERIA: Randomised trials comparing fetal ECG waveform analysis with alternative methods of fetal monitoring during labour. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were performed by one review author, without blinding. MAIN RESULTS: Six trials (16,295 women) were included: five trials of ST waveform analysis (15,338 women) and one trial of PR interval analysis (957 women). In comparison to continuous electronic fetal heart rate monitoring alone, the use of adjunctive ST waveform analysis made no significant difference to primary outcomes: births by caesarean section (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.91 to 1.08), the number of babies with severe metabolic acidosis at birth (cord arterial pH less than 7.05 and base deficit greater than 12 mmol/L) (RR 0.78, 95% CI 0.44 to 1.37, data from 14,574 babies), or babies with neonatal encephalopathy (RR 0.54, 95% CI 0.24 to 1.25). There were, however, on average fewer fetal scalp samples taken during labour (RR 0.61, 95% CI 0.41 to 0.91) although the findings were heterogeneous; there were fewer operative vaginal deliveries (RR 0.90, 95% CI 0.81 to 0.98) and admissions to special care unit (RR 0.89, 95% CI 0.81 to 0.99); there was no statistically significant difference in the number of babies with low Apgar scores at five minutes or babies requiring neonatal intubation. There was little evidence that monitoring by PR interval analysis conveyed any benefit. AUTHORS' CONCLUSIONS: These findings provide some modest support for the use of fetal ST waveform analysis when a decision has been made to undertake continuous electronic fetal heart rate monitoring during labour. However, the advantages need to be considered along with the disadvantages of needing to use an internal scalp electrode, after membrane rupture, for ECG waveform recordings.

Non-opioid drugs for pain management in labour.

BACKGROUND: Labour is a normal physiological process, but is usually associated with pain and discomfort. Numerous methods are used to relieve labour pain. These include pharmacological (e.g. epidural, opioids, inhaled analgesia) and non-pharmacological (e.g. hypnosis, acupuncture) methods of pain management. Non-opioid drugs are a pharmacological method used to control mild to moderate pain. OBJECTIVES: To summarise the evidence regarding the effects and safety of the use of non-opioid drugs to relieve pain in labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (15 February 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) using non-opioid drugs (non-steroidal anti-inflammatory drugs (NSAIDs); paracetamol; antispasmodics; sedatives and antihistamines) in comparison with placebo or standard care; different forms of non-opioid drugs (e.g. sedatives versus antihistamines); or different interventions (e.g. non-opioids versus opioids) for women in labour. Quasi-RCTs and trials using a cross-over design were not included. Cluster-randomised RCTs were eligible for inclusion but none were identified for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed for inclusion all studies identified by the search strategy, carried out data extraction and assessed risk of bias. We resolved any disagreement through discussion with a third author. Data were checked for accuracy. MAIN RESULTS: Nineteen studies randomising a total of 2863 women were included in this review. There were three main comparison groups: 15 studies compared non-opioid drugs with placebo or no treatment (2133 women); three studies compared non-opioid drugs with opioids (563 women); and three studies compared one type of non-opioid drug with a different type or dose of non-opioid drug (590 women). Some of the studies included three or more groups and so have been put in more than one comparison. Overall, there was little difference between groups for most of the comparisons. Any differences observed for outcomes were mainly limited to one or two studies. Non-opioid drugs (sedatives) were found to offer better pain relief (mean difference (MD) -22.00; 95% confidence interval (CI) -35.86 to -8.14, one trial, 50 women), better satisfaction with pain relief (sedatives and antihistamines) (risk ratio (RR) 1.59; 95% CI 1.15 to 2.21, two trials, 204 women; RR 1.80; 95% CI 1.16 to 2.79, one trial, 223 women) and better satisfaction with the childbirth experience (RR 2.16; 95% CI 1.34 to 3.47, one trial, 40 women) when compared with placebo or no treatment. However, women having non-opioid drugs (NSAIDs or antihistamines) were less likely to be satisfied with pain relief compared with women having opioids (RR 0.50; 95% CI 0.27 to 0.94, one trial, 76 women; RR 0.73; 95% CI 0.54 to 0.98, one trial, 223 women). Women receiving the antihistamine hydroxyzine were more likely to express satisfaction with pain relief compared with the antihistamine promethazine (RR 1.21; 95% CI 1.02 to 1.43, one trial, 289 women). Women receiving sedatives were more likely to express satisfaction with pain relief compared with antihistamines (RR 1.52; 95% CI 1.06 to 2.17, one study, 157 women). The majority of studies were conducted over 30 years ago. The studies were at unclear risk of bias for most of the quality domains.Opioids appear to be superior to non-opioids in satisfaction with pain relief, while non-opioids appear to be superior to placebo for pain relief and satisfaction with the childbirth experience. There were little data and no evidence of a significant difference for any of the comparisons of non-opioids for safety outcomes.  AUTHORS' CONCLUSIONS: Overall, the findings of this review demonstrated insufficient evidence to support a role for non-opioid drugs on their own to manage pain during labour.

Caesarean section for non-medical reasons at term.

BACKGROUND: Caesarean section rates are progressively rising in many parts of the world. One suggested reason is increasing requests by women for caesarean section in the absence of clear medical indications, such as placenta praevia, HIV infection, contracted pelvis and, arguably, breech presentation or previous caesarean section. The reported benefits of planned caesarean section include greater safety for the baby, less pelvic floor trauma for the mother, avoidance of labour pain and convenience. The potential disadvantages, from observational studies, include increased risk of major morbidity or mortality for the mother, adverse psychological sequelae, and problems in subsequent pregnancies, including uterine scar rupture and a greater risk of stillbirth and neonatal morbidity. The differences in neonatal physiology following vaginal and caesarean births are thought to have implications for the infant, with caesarean section potentially increasing the risk of compromised health in both the short and the long term. An unbiased assessment of advantages and disadvantages would assist discussion of what has become a contentious issue in modern obstetrics. OBJECTIVES: To assess, from randomised trials, the effects on perinatal and maternal morbidity and mortality, and on maternal psychological morbidity, of planned caesarean delivery versus planned vaginal birth in women with no clear clinical indication for caesarean section. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2012) and reference lists of relevant studies. SELECTION CRITERIA: All comparisons of intention to perform caesarean section and intention for women to give birth vaginally; random allocation to treatment and control groups; adequate allocation concealment; women at term with single fetuses with cephalic presentations and no clear medical indication for caesarean section. DATA COLLECTION AND ANALYSIS: We identified no studies that met the inclusion criteria. MAIN RESULTS: There were no included trials. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials, upon which to base any practice recommendations regarding planned caesarean section for non-medical reasons at term. In the absence of trial data, there is an urgent need for a systematic review of observational studies and a synthesis of qualitative data to better assess the short- and long-term effects of caesarean section and vaginal birth.

Second trimester serum tests for Down's Syndrome screening.

BACKGROUND: Down's syndrome occurs when a person has three copies of chromosome 21 - or the specific area of chromosome 21 implicated in causing Down's syndrome - rather than two. It is the commonest congenital cause of mental retardation. Noninvasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing.   OBJECTIVES: To estimate and compare the accuracy of second trimester serum markers for the detection of Down's syndrome. SEARCH METHODS: We carried out a sensitive and comprehensive literature search of MEDLINE (1980 to May 2007), EMBASE (1980 to 18 May 2007), BIOSIS via EDINA (1985 to 18 May 2007), CINAHL via OVID (1982 to 18 May 2007), The Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2007, Issue 1), MEDION (May 2007), The Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (May 2007), The National Research Register (May 2007), Health Services Research Projects in Progress database (May 2007). We studied reference lists and published review articles.   SELECTION CRITERIA: Studies evaluating tests of maternal serum in women at 14-24 weeks of gestation for Down's syndrome, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection. DATA COLLECTION AND ANALYSIS: Data were extracted as test positive/test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS criteria. We used hierarchical summary ROC meta-analytical methods to analyse test performance and compare test accuracy. Analysis of studies allowing direct comparison between tests was undertaken. We investigated the impact of maternal age on test performance in subgroup analyses. MAIN RESULTS: Fifty-nine studies involving 341,261 pregnancies (including 1,994 with Down's syndrome) were included. Studies were generally high quality, although differential verification was common with invasive testing of only high-risk pregnancies. Seventeen studies made direct comparisons between tests. Fifty-four test combinations were evaluated formed from combinations of 12 different tests and maternal age; alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free beta human chorionic gonadotrophin (ßhCG), free alpha human chorionic gonadotrophin (αhCG), Inhibin A, SP2, CA125, troponin, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PGF) and proform of eosinophil major basic protein (ProMBP).Meta-analysis of 12 best performing or frequently evaluated test combinations showed double and triple tests (involving AFP, uE3, total hCG, free ßhCG) significantly outperform individual markers, detecting six to seven out of every 10 Down's syndrome pregnancies at a 5% false positive rate. Tests additionally involving inhibin performed best (eight out of every 10 Down's syndrome pregnancies) but were not shown to be significantly better than standard triple tests in direct comparisons. Significantly lower sensitivity occurred in women over the age of 35 years. Women who miscarried in the over 35 group were more likely to have been offered an invasive test to verify a negative screening results, whereas those under 35 were usually not offered invasive testing for a negative screening result. Pregnancy loss in women under 35 therefore leads to under ascertainment of screening results, potentially missing a proportion of affected pregnancies and affecting the accuracy of the sensitivity. AUTHORS' CONCLUSIONS: Tests involving two or more markers in combination with maternal age are significantly more sensitive than those involving one marker. The value of combining four or more tests or including inhibin have not been proven to show statistically significant improvement. Further study is required to investigate reduced test performance in women aged over 35 and the impact of differential pregnancy loss on study findings.

Pain management for women in labour: an overview of systematic reviews.

BACKGROUND: The pain that women experience during labour is affected by multiple physiological and psychosocial factors and its intensity can vary greatly.  Most women in labour require pain relief. Pain management strategies include non-pharmacological interventions (that aim to help women cope with pain in labour) and pharmacological interventions (that aim to relieve the pain of labour). OBJECTIVES: To summarise the evidence from Cochrane systematic reviews on the efficacy and safety of non-pharmacological and pharmacological interventions to manage pain in labour. We considered findings from non-Cochrane systematic reviews if there was no relevant Cochrane review. METHODS: We searched the Cochrane Database of Systematic Reviews (The Cochrane Library 2011, Issue 5), The Cochrane Database of Abstracts of Reviews of Effects (The Cochrane Library 2011, Issue 2 of 4), MEDLINE (1966 to 31 May 2011) and EMBASE (1974 to 31 May 2011) to identify all relevant systematic reviews of randomised controlled trials of pain management in labour. Each of the contributing Cochrane reviews (nine new, six updated) followed a generic protocol with 13 common primary efficacy and safety outcomes. Each Cochrane review included comparisons with placebo, standard care or with a different intervention according to a predefined hierarchy of interventions. Two review authors extracted data and assessed methodological quality, and data were checked by a third author. This overview is a narrative summary of the results obtained from individual reviews. MAIN RESULTS: We identified 15 Cochrane reviews (255 included trials) and three non-Cochrane reviews (55 included trials) for inclusion within this overview. For all interventions, with available data, results are presented as comparisons of: 1. Intervention versus placebo or standard care; 2. Different forms of the same intervention (e.g. one opioid versus another opioid); 3. One type of intervention versus a different type of intervention (e.g. TENS versus opioid). Not all reviews included results for all comparisons. Most reviews compared the intervention with placebo or standard care, but with the exception of opioids and epidural analgesia, there were few direct comparisons between different forms of the same intervention, and even fewer comparisons between different interventions. Based on these three comparisons, we have categorised interventions into: " What works" ,"What may work", and "Insufficient evidence to make a judgement".WHAT WORKSEvidence suggests that epidural, combined spinal epidural (CSE) and inhaled analgesia effectively manage pain in labour, but may give rise to adverse effects. Epidural, and inhaled analgesia effectively relieve pain when compared with placebo or a different type of intervention (epidural versus opioids). Combined-spinal epidurals relieve pain more quickly than traditional or low dose epidurals. Women receiving inhaled analgesia were more likely to experience vomiting, nausea and dizziness.When compared with placebo or opioids, women receiving epidural analgesia had more instrumental vaginal births and caesarean sections for fetal distress, although there was no difference in the rates of caesarean section overall. Women receiving epidural analgesia were more likely to experience hypotension, motor blockade, fever or urinary retention. Less urinary retention was observed in women receiving CSE than in women receiving traditional epidurals. More women receiving CSE than low-dose epidural experienced pruritus.  WHAT MAY WORKThere is some evidence to suggest that immersion in water, relaxation, acupuncture, massage and local anaesthetic nerve blocks or non-opioid drugs may improve management of labour pain, with few adverse effects.  Evidence was mainly limited to single trials. These interventions relieved pain and improved satisfaction with pain relief (immersion, relaxation, acupuncture, local anaesthetic nerve blocks, non-opioids) and childbirth experience (immersion, relaxation, non-opioids) when compared with placebo or standard care. Relaxation was associated with fewer assisted vaginal births and acupuncture was associated with fewer assisted vaginal births and caesarean sections.INSUFFICIENT EVIDENCEThere is insufficient evidence to make judgements on whether or not hypnosis, biofeedback, sterile water injection, aromatherapy, TENS, or parenteral opioids are more effective than placebo or other interventions for pain management in labour. In comparison with other opioids more women receiving pethidine experienced adverse effects including drowsiness and nausea.  AUTHORS' CONCLUSIONS: Most methods of non-pharmacological pain management are non-invasive and appear to be safe for mother and baby, however, their efficacy is unclear, due to limited high quality evidence. In many reviews, only one or two trials provided outcome data for analysis and the overall methodological quality of the trials was low. High quality trials are needed.There is more evidence to support the efficacy of pharmacological methods, but these have more adverse effects. Thus, epidural analgesia provides effective pain relief but at the cost of increased instrumental vaginal birth.It remains important to tailor methods used to each woman's wishes, needs and circumstances, such as anticipated duration of labour, the infant's condition, and any augmentation or induction of labour.A major challenge in compiling this overview, and the individual systematic reviews on which it is based, has been the variation in use of different process and outcome measures in different trials, particularly assessment of pain and its relief, and effects on the neonate after birth. This made it difficult to pool results from otherwise similar studies, and to derive conclusions from the totality of evidence. Other important outcomes have simply not been assessed in trials; thus, despite concerns for 30 years or more about the effects of maternal opioid administration during labour on subsequent neonatal behaviour and its influence on breastfeeding, only two out of 57 trials of opioids reported breastfeeding as an outcome. We therefore strongly recommend that the outcome measures, agreed through wide consultation for this project, are used in all future trials of methods of pain management.

Post-neonatal mortality, morbidity, and developmental outcome after ultrasound-dated preterm birth in rural Malawi: a community-based cohort study.

BACKGROUND: Preterm birth is considered to be associated with an estimated 27% of neonatal deaths, the majority in resource-poor countries where rates of prematurity are high. There is no information on medium term outcomes after accurately determined preterm birth in such settings. METHODS AND FINDINGS: This community-based stratified cohort study conducted between May-December 2006 in Southern Malawi followed up 840 post-neonatal infants born to mothers who had received antenatal antibiotic prophylaxis/placebo in an attempt to reduce rates of preterm birth (APPLe trial ISRCTN84023116). Gestational age at delivery was based on ultrasound measurement of fetal bi-parietal diameter in early-mid pregnancy. 247 infants born before 37 wk gestation and 593 term infants were assessed at 12, 18, or 24 months. We assessed survival (death), morbidity (reported by carer, admissions, out-patient attendance), growth (weight and height), and development (Ten Question Questionnaire [TQQ] and Malawi Developmental Assessment Tool [MDAT]). Preterm infants were at significantly greater risk of death (hazard ratio 1.79, 95% CI 1.09-2.95). Surviving preterm infants were more likely to be underweight (weight-for-age z score; p<0.001) or wasted (weight-for-length z score; p<0.01) with no effect of gestational age at delivery. Preterm infants more often screened positively for disability on the Ten Question Questionnaire (p = 0.002). They also had higher rates of developmental delay on the MDAT at 18 months (p = 0.009), with gestational age at delivery (p = 0.01) increasing this likelihood. Morbidity-visits to a health centre (93%) and admissions to hospital (22%)-was similar for both groups. CONCLUSIONS: During the first 2 years of life, infants who are born preterm in resource poor countries, continue to be at a disadvantage in terms of mortality, growth, and development. In addition to interventions in the immediate neonatal period, a refocus on early childhood is needed to improve outcomes for infants born preterm in low-income settings.