An economic evaluation of the randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo (the HI-Light Vitiligo Trial).

BACKGROUND: Economic evidence for vitiligo treatments is absent. OBJECTIVES: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo. METHODS: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months' treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost-utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015. RESULTS: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188-235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151-196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment. CONCLUSIONS: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success.

Randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo: results of the HI-Light Vitiligo Trial.

BACKGROUND: Evidence for the effectiveness of vitiligo treatments is limited. OBJECTIVES: To determine the effectiveness of (i) handheld narrowband UVB (NB-UVB) and (ii) a combination of potent topical corticosteroid (TCS) and NB-UVB, compared with TCS alone, for localized vitiligo. METHODS: A pragmatic, three-arm, placebo-controlled randomized controlled trial (9-month treatment, 12-month follow-up). Adults and children, recruited from secondary care and the community, aged ≥ 5 years and with active vitiligo affecting < 10% of skin, were randomized 1 : 1 : 1 to receive TCS (mometasone furoate 0·1% ointment + dummy NB-UVB), NB-UVB (NB-UVB + placebo TCS) or a combination (TCS + NB-UVB). TCS was applied once daily on alternating weeks; NB-UVB was administered on alternate days in escalating doses, adjusted for erythema. The primary outcome was treatment success at 9 months at a target patch assessed using the participant-reported Vitiligo Noticeability Scale, with multiple imputation for missing data. The trial was registered with number ISRCTN17160087 on 8 January 2015. RESULTS: In total 517 participants were randomized to TCS (n = 173), NB-UVB (n = 169) and combination (n = 175). Primary outcome data were available for 370 (72%) participants. The proportions with target patch treatment success were 17% (TCS), 22% (NB-UVB) and 27% (combination). Combination treatment was superior to TCS: adjusted between-group difference 10·9% (95% confidence interval 1·0%-20·9%; P = 0·032; number needed to treat = 10). NB-UVB alone was not superior to TCS: adjusted between-group difference 5·2% (95% CI - 4·4% to 14·9%; P = 0·29; number needed to treat = 19). Participants using interventions with ≥ 75% expected adherence were more likely to achieve treatment success, but the effects were lost once treatment stopped. Localized grade 3 or 4 erythema was reported in 62 (12%) participants (including three with dummy light). Skin thinning was reported in 13 (2·5%) participants (including one with placebo ointment). CONCLUSIONS: Combination treatment with home-based handheld NB-UVB plus TCS is likely to be superior to TCS alone for treatment of localized vitiligo. Combination treatment was relatively safe and well tolerated but was successful in only around one-quarter of participants.

A randomised feasibility trial comparing needle fasciotomy with limited fasciectomy treatment for Dupuytren's contractures.

PURPOSE: The purpose of this study is to assess the feasibility of conducting a large, multicentre randomised controlled trial (RCT) comparing needle fasciotomy with limited fasciectomy for treatment of Dupuytren's contractures. DESIGN: The design of this study is a parallel, two-arm, multicentre, randomised feasibility trial with embedded QuinteT Recruitment Intervention. PARTICIPANTS: Patients aged 18 years or over who were referred from primary to secondary care for treatment of a hand with Dupuytren's contractures of one or more fingers of more than 30° at the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joints and well-defined cord(s). Patients were excluded if they had undergone previous Dupuytren's contracture surgery on the same hand. METHODS: Potential participants were screened for eligibility. Recruited participants randomised (1:1) to treatment with either needle fasciotomy or limited fasciectomy and followed-up for up to 6 months after treatment. Data on recruitment rates, completion of follow-up, and procedure costs were collected. Four patient reported outcome measures (PROMs) and objective outcome measures were collected before intervention and 6 weeks and 6 months afterwards. RESULTS: One hundred and fifty-three of 267 (57%) primary-care referrals for Dupuytren's contractures met the eligibility criteria for the study. Seventy-one of the 153 (46%) agreed to participate and were randomly allocated to treatment with needle fasciotomy or limited fasciectomy. Sixty-seven of these underwent their allocated treatment, two were crossovers from limited fasciectomy to needle fasciotomy, and two (both allocated limited fasciectomy) received no treatment. Fifty-nine participants (85%) completed 6-month follow-up PROMs. Participants felt the MYMOP, PEM and URAM PROMs allowed them to better describe how their treatment affected their hand function than the DASH PROM. The estimated costs of limited fasciectomy (in an operating theatre) and needle fasciotomy (in a clinic room) were £777 and £111 respectively. CONCLUSION: A large RCT comparing treatment of Dupuytren's contractures by needle fasciotomy and limited fasciectomy is feasible. Data from this study will help determine the number of sites and duration of recruitment required to complete an adequately powered RCT and will assist the selection of PROMs in future studies on the treatment of Dupuytren's contractures. (Level 1 feasibility study). TRIAL REGISTRATION: Trial registered with ISRCTN (registration number: ISRCTN11164292), date assigned - 28/08/2015.

Clinical pharmacokinetic properties of magnesium sulphate in women with pre-eclampsia and eclampsia.

BACKGROUND: The pharmacokinetic basis of magnesium sulphate (MgSO4 ) dosing regimens for eclampsia prophylaxis and treatment is not clearly established. OBJECTIVES: To review available data on clinical pharmacokinetic properties of MgSO4 when used for women with pre-eclampsia and/or eclampsia. SEARCH STRATEGY: MEDLINE, EMBASE, CINAHL, POPLINE, Global Health Library and reference lists of eligible studies. SELECTION CRITERIA: All study types investigating pharmacokinetic properties of MgSO4 in women with pre-eclampsia and/or eclampsia. DATA COLLECTION AND ANALYSIS: Two authors extracted data on basic pharmacokinetic parameters reflecting the different aspects of absorption, bioavailability, distribution and excretion of MgSO4 according to identified dosing regimens. MAIN RESULTS: Twenty-eight studies investigating pharmacokinetic properties of 17 MgSO4 regimens met our inclusion criteria. Most women (91.5%) in the studies had pre-eclampsia. Baseline serum magnesium concentrations were consistently <1 mmol/l across studies. Intravenous loading dose between 4 and 6 g was associated with a doubling of this baseline concentration half an hour after injection. Maintenance infusion of 1 g/hour consistently produced concentrations well below 2 mmol/l, whereas maintenance infusion at 2 g/hour and the Pritchard intramuscular regimen had higher but inconsistent probability of producing concentrations between 2 and 3 mmol/l. Volume of distribution of magnesium varied (13.65-49.00 l) but the plasma clearance was fairly similar (4.28-5.00 l/hour) across populations. CONCLUSION: The profiles of Zuspan and Pritchard regimens indicate that the minimum effective serum magnesium concentration for eclampsia prophylaxis is lower than the generally accepted level. Exposure-response studies to identify effective alternative dosing regimens should target concentrations achievable by these standard regimens. TWEETABLE ABSTRACT: Minimum effective serum magnesium concentration for eclampsia prophylaxis is lower than the generally accepted therapeutic level.

The ethical issues regarding consent to clinical trials with pre-term or sick neonates: a systematic review (framework synthesis) of the empirical research.

BACKGROUND: Conducting clinical trials with pre-term or sick infants is important if care for this population is to be underpinned by sound evidence. Yet approaching parents at this difficult time raises challenges for the obtaining of valid informed consent to such research. This study asked: what light does the empirical literature cast on an ethically defensible approach to the obtaining of informed consent in perinatal clinical trials? METHODS: A systematic search identified 49 studies. Analysis began by applying philosophical frameworks which were then refined in light of the concepts emerging from empirical studies to present a coherent picture of a broad literature. RESULTS: Between them, studies addressed the attitudes of both parents and clinicians concerning consent in neonatal trials; the validity of the consent process in the neonatal research context; and different possible methods of obtaining consent. CONCLUSIONS: Despite a variety of opinions among parents and clinicians there is a strongly and widely held view that it is important that parents do give or decline consent for neonatal participation in trials. However, none of the range of existing consent processes reviewed by the research is satisfactory. A significant gap is evaluation of the widespread practice of emergency 'assent', in which parents assent or refuse their baby's participation as best they can during the emergency and later give full consent to ongoing participation and follow-up. Emergency assent has not been evaluated for its acceptability, how such a process would deal with bad outcomes such as neonatal death between assent and consent, or the extent to which late parental refusal might bias results. This review of a large number of empirical papers, while not making fundamental changes, has refined and developed the conceptual framework from philosophy for examining informed consent in this context.

Innovation in immediate neonatal care: development of the Bedside Assessment, Stabilisation and Initial Cardiorespiratory Support (BASICS) trolley.

OBJECTIVE: Babies receive oxygen through their umbilical cord while in the uterus and for a few minutes after birth. Currently, if the baby is not breathing well at birth, the cord is cut so as to transfer the newborn to a resuscitation unit. We sought to develop a mobile resuscitation trolley on which newly born babies can be resuscitated while still receiving oxygenated blood and the 'placental transfusion' through the umbilical cord. This would also prevent separation of the mother and baby in the first minutes after birth. DESIGN: Multidisciplinary iterative product development. SETTING: Clinical Engineering Department of a University Teaching Hospital. METHODS: Following an initial design meeting, a series of prototypes were developed. At each stage, the prototype was reviewed by a team of experts in the laboratory and in the hospital delivery suite to determine ease of use and fitness for purpose. A commercial company was identified to collaborate on the trolley's development and secure marking with the Conformité Européenne mark, allowing the trolley to be introduced into clinical practice. RESULTS: The trolley is a small mobile resuscitation unit based on the concept of an overbed hospital table. It can be manoeuvred to within 50 cm of the mother's pelvis so that the umbilical cord can remain intact during resuscitation, irrespective of whether the baby is born naturally, by instrumental delivery or by caesarean section. Warmth for the newborn comes from a heated mattress and the trolley has the facility to provide suction, oxygen and air. CONCLUSIONS: This is the first mobile resuscitation device designed specifically to facilitate newborn resuscitation at the bedside and with an intact cord. The next step is to assess its safety, its acceptability to clinicians and parents, and to determine whether it allows resuscitation with an intact cord.

Measuring parents' experiences and satisfaction with care during very preterm birth: a questionnaire development study.

OBJECTIVE: To develop a questionnaire to assess parents' experiences and satisfaction with care during very preterm birth. DESIGN: Questionnaire development. SETTING: Parents whose babies had been cared for at five tertiary neonatal units in England. POPULATION: A total of 145 women who gave birth before 32 weeks of gestation, and 85 of their partners. METHODS: A 30-item questionnaire was developed on the basis of qualitative interviews with parents of very preterm babies, a literature review and discussion with relevant experts. The questionnaire was posted to a second group of parents, and its reliability and validity were explored. MAIN OUTCOME MEASURES: The Preterm Birth Experience and Satisfaction Scale (P-BESS) was correlated with two global questions measuring satisfaction with care during the birth. Internal consistency was measured using Cronbach's α. RESULTS: Parents of 458 babies were invited to take part and 147 (32%) responded. Two women and 22 partners were excluded or ineligible, leaving 145 women and 85 partners. Factor analysis produced three clear dimensions: Staff professionalism and empathy, Information and explanations, and Confidence in staff. The total scale and three subscales showed high reliability. Strong positive correlations were found between the questionnaire scales and the two global questions, indicating convergent validity. For women whose partners were present at the birth, a fourth factor was identified 'Partner Involvement'. CONCLUSIONS: The P-BESS appears to be a valid measure of satisfaction with care during very preterm birth.

Parents' experiences and satisfaction with care during the birth of their very preterm baby: a qualitative study.

OBJECTIVE: To assess parents' experiences and satisfaction with care during very preterm birth and to identify domains associated with positive and negative experiences of care. DESIGN: Qualitative study using semi-structured interviews. SETTING: Three neonatal units in tertiary care hospitals in South-East England. POPULATION: Thirty-two mothers and seven fathers who had a baby born before 32 weeks of gestation and spoke English well. METHODS: Semi-structured interviews were conducted. Results were analysed using thematic analysis. MAIN OUTCOME MEASURES: Participants' experiences and satisfaction with care during the birth of their preterm baby. RESULTS: Overall, 80% of participants were extremely satisfied with the care during the birth of their preterm baby, seven were generally satisfied but felt some things could be improved and one was dissatisfied. Four key determinants of experiences of care were identified: staff professionalism, which included information and explanation, being calm in a crisis, appearing confident and in control, and conversely not listening to the woman; staff empathy, which included caring and emotional support, and encouragement and reassurance; involvement of the father; and birth environment. CONCLUSIONS: Although the determinants of experiences of care are generally consistent with previous research on term births, unique factors to preterm birth were identified. These were the importance of the staff appearing calm during the birth, and the staff portraying confidence and taking control during the birth. Women valued being listened to, and both they and their partners valued staff helping fathers to feel involved during the birth.

Measuring placental transfusion for term births: weighing babies with cord intact.

OBJECTIVE: To estimate the volume and duration of placental transfusion at term. DESIGN: Prospective observational study. SETTING: Maternity unit in Bradford, UK. POPULATION: Twenty-six term births. METHODS: Babies were weighed with umbilical cord intact using digital scales that record an average weight every 2 seconds. Placental transfusion was calculated from the change in weight between birth and either cord clamping or when weighing stopped. Start and end weights were estimated using both a B-spline and inspection of graphs. Weight was converted to volume, 1 ml of blood weighing 1.05 g. MAIN OUTCOME MEASURES: Volume and duration of placental transfusion. RESULTS: Twenty-six babies were weighed. Start weights were difficult to determine because of artefacts in the data as the baby was placed on the scales and wrapped. The mean difference in weight was 116 g [95% confidence interval (CI), 72-160 g] using the B-spline and 87 g (95% CI, 64-110 g) using inspection. Converting this to the mean volume of placental transfusion gave 110 ml (95% CI, 69-152 ml) and 83 ml (95% CI, 61-106 ml), respectively. Placental transfusion was usually complete by 2 minutes, but sometimes continued for up to 5 minutes. Based on the B-spline, placental transfusion contributed 32 ml (95% CI, 30-33 ml) per kilogram of birth weight to blood volume, but 24 ml (95% CI, 19-32 ml) based on inspection. This equates to 40% (95% CI, 37-42%) and 30% (24-40%), respectively, of total potential blood volume. CONCLUSION: Inspection of the graphs probably underestimates placental transfusion. For term infants, placental transfusion contributes between one-third and one-quarter of total potential blood volume at birth.

Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling.

OBJECTIVES: To investigate the accuracy of predictive tests for pre-eclampsia and the effectiveness of preventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies (test-intervention combinations) to predict and prevent pre-eclampsia. DATA SOURCES: Major electronic databases were searched to January 2005 at least. REVIEW METHODS: Systematic reviews were carried out for test accuracy and effectiveness. Quality assessment was carried out using standard tools. For test accuracy, meta-analyses used a bivariate approach. Effectiveness reviews were conducted under the auspices of the Cochrane Pregnancy and Childbirth Group and used standard Cochrane review methods. The economic evaluation was from an NHS perspective and used a decision tree model. RESULTS: For the 27 tests reviewed, the quality of included studies was generally poor. Some tests appeared to have high specificity, but at the expense of compromised sensitivity. Tests that reached specificities above 90% were body mass index greater than 34, alpha-foetoprotein and uterine artery Doppler (bilateral notching). The only Doppler test with a sensitivity of over 60% was resistance index and combinations of indices. A few tests not commonly found in routine practice, such as kallikreinuria and SDS-PAGE proteinuria, seemed to offer the promise of high sensitivity, without compromising specificity, but these would require further investigation. For the 16 effectiveness reviews, the quality of included studies was variable. The largest review was of antiplatelet agents, primarily low-dose aspirin, and included 51 trials (36,500 women). This was the only review where the intervention was shown to prevent both pre-eclampsia and its consequences for the baby. Calcium supplementation also reduced the risk of pre-eclampsia, but with some uncertainty about the impact on outcomes for the baby. The only other intervention associated with a reduction in RR of pre-eclampsia was rest at home, with or without a nutritional supplement, for women with normal blood pressure. However, this review included just two small trials and its results should be interpreted with caution. The cost of most of the tests was modest, ranging from 5 pounds for blood tests such as serum uric acid to approximately 20 pounds for Doppler tests. Similarly, the cost of most interventions was also modest. In contrast, the best estimate of additional average cost associated with an average case of pre-eclampsia was high at approximately 9000 pounds. The results of the modelling revealed that prior testing with the test accuracy sensitivities and specificities identified appeared to offer little as a way of improving cost-effectiveness. Based on the evidence reviewed, none of the tests appeared sufficiently accurate to be clinically useful and the results of the model favoured no-test/treat-all strategies. Rest at home without any initial testing appeared to be the most cost-effective 'test-treatment' combination. Calcium supplementation to all women, without any initial testing, appeared to be the second most cost-effective. The economic model provided little support that any form of Doppler test has sufficiently high sensitivity and specificity to be cost-effective for the early identification of pre-eclampsia. It also suggested that the pattern of cost-effectiveness was no different in high-risk mothers than the low-risk mothers considered in the base case. CONCLUSIONS: The tests evaluated are not sufficiently accurate, in our opinion, to suggest their routine use in clinical practice. Calcium and antiplatelet agents, primarily low-dose aspirin, were the interventions shown to prevent pre-eclampsia. The most cost-effective approach to reducing pre-eclampsia is likely to be the provision of an effective, affordable and safe intervention applied to all mothers without prior testing to assess levels of risk. It is probably premature to suggest the implementation of a treat-all intervention strategy at present, however the feasibility and acceptability of this to women could be explored. Rigorous evaluation is needed of tests with modest cost whose initial assessments suggest that they may have high levels of both sensitivity and specificity. Similarly, there is a need for high-quality, adequately powered randomised controlled trials to investigate whether interventions such as advice to rest are indeed effective in reducing pre-eclampsia. In future, an economic model should be developed that considers not just pre-eclampsia, but other related outcomes, particularly those relevant to the infant such as perinatal death, preterm birth and small for gestational age. Such a modelling project should make provision for primary data collection on the safety of interventions and their associated costs.

Antioxidants for preventing pre-eclampsia.

BACKGROUND: Oxidative stress has been proposed as a key factor involved in the development of pre-eclampsia. Supplementing women with antioxidants during pregnancy may help to counteract oxidative stress and thereby prevent or delay the onset of pre-eclampsia. OBJECTIVES: To determine the effectiveness and safety of any antioxidant supplementation during pregnancy and the risk of developing pre-eclampsia and its related complications. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (May 2007), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 3), MEDLINE (1950 to October 2007) and Current Contents (1998 to August 2004). SELECTION CRITERIA: All randomised trials comparing one or more antioxidants with either placebo or no antioxidants during pregnancy for the prevention of pre-eclampsia, and trials comparing one or more antioxidants with another, or with other interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and trial quality and extracted data. MAIN RESULTS: Ten trials, involving 6533 women, were included in this review, five trials were rated high quality. For the majority of trials, the antioxidant assessed was combined vitamin C and E therapy. There was no significant difference between antioxidant and control groups for the relative risk (RR) of pre-eclampsia (RR 0.73, 95% confidence intervals (CI) 0.51 to 1.06; nine trials, 5446 women) or any other primary outcome: severe pre-eclampsia (RR 1.25, 95% CI 0.89 to 1.76; two trials, 2495 women), preterm birth (before 37 weeks) (RR 1.10, 95% CI 0.99 to 1.22; five trials, 5198 women), small-for-gestational-age infants (RR 0.83, 95% CI 0.62 to 1.11; five trials, 5271 babies) or any baby death (RR 1.12, 95% CI 0.81 to 1.53; four trials, 5144 babies). Women allocated antioxidants were more likely to self-report abdominal pain late in pregnancy (RR 1.61, 95% CI 1.11 to 2.34; one trial, 1745 women), require antihypertensive therapy (RR 1.77, 95% CI 1.22 to 2.57; two trials, 4272 women) and require an antenatal hospital admission for hypertension (RR 1.54, 95% CI 1.00 to 2.39; one trial, 1877 women). However, for the latter two outcomes, this was not clearly reflected in an increase in any other hypertensive complications. AUTHORS' CONCLUSIONS: Evidence from this review does not support routine antioxidant supplementation during pregnancy to reduce the risk of pre-eclampsia and other serious complications in pregnancy.

WITHDRAWN: Antiplatelet agents for preventing and treating pre-eclampsia.

BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a platelet-derived vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, and low dose aspirin in particular, might prevent or delay the development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents when given to women at risk of developing pre-eclampsia, and to those with established pre-eclampsia. SEARCH STRATEGY: This review drew on the search strategy developed for the Pregnancy and Childbirth Group as a whole. The Cochrane Controlled Trials Register was also searched, The Cochrane Library 1999 Issue 1, Embase was searched from 1994-1999 and hand searches were performed of the congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent during pregnancy. Quasi random study designs were excluded. Participants were pregnant women considered to be at risk of developing pre-eclampsia, and those with pre-eclampsia before delivery. Women treated postpartum were excluded. Interventions were any comparisons of an antiplatelet agent (such as low dose aspirin or dipyridamole) with either placebo or no antiplatelet agent. DATA COLLECTION AND ANALYSIS: Assessment of trials for inclusion in the review and extraction of data was performed independently and unblinded by two reviewers. Data were entered into the Review Manager software and double checked. MAIN RESULTS: Forty two trials involving over 32,000 women were included in this review, with 30,563 women in the prevention trials. There is a 15% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents [32 trials with 29,331 women; relative risk (RR) 0.85, 95% confidence interval (0.78, 0.92); Number needed to treat (NNT) 89, (59, 167)]. This reduction is regardless of risk status at trial entry or whether a placebo was used, and irrespective of the dose of aspirin or gestation at randomisation.Twenty three trials (28,268 women) reported preterm delivery. There is a small (8%) reduction in the risk of delivery before 37 completed weeks [RR 0.92, (0.88, 0.97); NNT 72 (44, 200)]. Baby deaths were reported in 30 trials (30,093 women). Overall there is a 14% reduction in baby deaths in the antiplatelet group [RR 0.86, (0.75, 0.98); NNT 250 (125, >10000)]. Small for gestational age babies were reported in 25 trials (20,349 women), with no overall difference between the groups, RR 0.92, (0.84, 1.01). There were no significant differences between treatment and control groups in any other measures of outcome. Five trials compared antiplatelet agents with placebo or no antiplatelet agent for the treatment of pre-eclampsia. There are insufficient data for any firm conclusions about the possible effects of these agents when used for treatment of pre-eclampsia. AUTHORS' CONCLUSIONS: Antiplatelet agents, in this review largely low dose aspirin, have small-moderate benefits when used for prevention of pre-eclampsia. Further information is required to assess which women are most likely to benefit, when treatment should be started, and at what dose.

Dietary calcium supplementation for prevention of pre-eclampsia and related problems: a systematic review and commentary.

BACKGROUND: Calcium supplementation during pregnancy may reduce the risk of hypertensive disorders of pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Central Register of Controlled Trials (March 2006). SELECTION CRITERIA: Randomised trials comparing at least 1 g of calcium daily during pregnancy with placebo. Eligibility and trial quality were assessed. DATA COLLECTION AND ANALYSIS: Data were extracted and analysed using Review Manager software. MAIN RESULTS: Twelve studies (15,528 women) were included, all of good quality. Most women were at low risk and had low dietary calcium. High blood pressure was reduced with calcium supplementation rather than placebo (11 trials, 14,946 women: relative risk [RR] random effects model 0.70; 95% CI 0.57-0.86), as was pre-eclampsia (12 trials, 15,206 women: RR 0.48; 95% CI 0.33-0.69). The effect was greatest for women at high risk (five trials, 587 women: RR 0.22; 95% CI 0.12-0.42) and for those with low baseline calcium intake (seven trials, 10,154 women: RR 0.36; 95% CI 0.18-0.70). There was heterogeneity, with less effect in the larger trials. The composite outcome maternal death or serious morbidity was reduced (four trials, 9732 women: RR 0.80; 95% CI 0.65-0.97). The syndrome of haemolysis, elevated liver enzymes and low platelets was increased (two trials, 12,901 women: RR 2.67; 95% CI 1.05-6.82). There was no overall effect on the risk of preterm birth or stillbirth or death before discharge from hospital. CONCLUSIONS: Calcium supplementation appears to reduce the risk of pre-eclampsia and to reduce the rare occurrence of the composite outcome 'maternal death or serious morbidity'. There were no other clear benefits or harms. COMMENTARY: We present the hypothesis that adequate dietary calcium before and in early pregnancy may be needed to prevent the underlying pathology responsible for pre-eclampsia. We suggest that the research agenda be redirected towards calcium supplementation at a community level.

Antiplatelet agents for preventing pre-eclampsia and its complications.

BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, low-dose aspirin in particular, might prevent or delay development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents for women at risk of developing pre-eclampsia. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 1), EMBASE (1994 to November 2005) and handsearched congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent were included. Quasi-random studies were excluded. Participants were pregnant women at risk of developing pre-eclampsia. Interventions were any comparisons of an antiplatelet agent (such as low-dose aspirin or dipyridamole) with either placebo or no antiplatelet. DATA COLLECTION AND ANALYSIS: Two authors assessed trials for inclusion and extracted data independently. MAIN RESULTS: Fifty-nine trials (37,560 women) are included. There is a 17% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents ((46 trials, 32,891 women, relative risk (RR) 0.83, 95% confidence interval (CI) 0.77 to 0.89), number needed to treat (NNT) 72 (52, 119)). Although there is no statistical difference in RR based on maternal risk, there is a significant increase in the absolute risk reduction of pre-eclampsia for high risk (risk difference (RD) -5.2% (-7.5, -2.9), NNT 19 (13, 34)) compared with moderate risk women (RD -0.84 (-1.37, -0.3), NNT 119 (73, 333)). Antiplatelets were associated with an 8% reduction in the relative risk of preterm birth (29 trials, 31,151 women, RR 0.92, 95% CI 0.88 to 0.97); NNT 72 (52, 119)), a 14% reduction in fetal or neonatal deaths (40 trials, 33,098 women, RR 0.86, 95% CI 0.76 to 0.98); NNT 243 (131, 1,666) and a 10% reduction in small-for-gestational age babies (36 trials, 23,638 women, RR 0.90, 95% CI0.83 to 0.98). There were no statistically significant differences between treatment and control groups for any other outcomes. AUTHORS' CONCLUSIONS: Antiplatelet agents, largely low-dose aspirin, have moderate benefits when used for prevention of pre-eclampsia and its consequences. Further information is required to assess which women are most likely to benefit, when treatment is best started, and at what dose.

Nitric oxide for preventing pre-eclampsia and its complications.

BACKGROUND: Pre-eclampsia, a multisystem disorder of pregnancy characterised by high blood pressure and protein in the urine, is associated with endothelial dysfunction. Nitric oxide mediates many functions of the endothelium, including vasodilatation and inhibition of platelet aggregation. Pre-eclampsia may be associated with nitric oxide deficiency, but the evidence to support this suggestion is contradictory. Nevertheless, it has been hypothesised that agents which increase nitric oxide may prevent pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of nitric oxide donors and precursors for preventing pre-eclampsia and its complications. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (November 2006), CENTRAL (The Cochrane Library 2006, Issue 3), and EMBASE (2002 to December 2004). SELECTION CRITERIA: Studies were included if they were randomised trials evaluating nitric oxide donors or precursors for preventing pre-eclampsia and its complications. DATA COLLECTION AND ANALYSIS: Both review authors independently assessed studies for inclusion. Data were extracted and double checked for accuracy. MAIN RESULTS: Six trials (310 women) were included. Four were of good quality and two were of uncertain quality. Four trials (170 women) compared nitric oxide donors (glyceryl trinitrate) or precursors (L-arginine) with either placebo or no intervention. There are insufficient data for reliable conclusions about the effects on pre-eclampsia (four trials, 170 women; relative risk (RR) 0.83, 95% confidence interval (CI) 0.49 to 1.41) or its complications. One trial (36 women) compared a nitric oxide donor with nifedipine, and another (76 women) compared it with antiplatelet agents. Both were too small for reliable conclusions about possible differential effects. Glyceryl trinitrate was associated with an increased risk of headache (two trials, 56 women; RR 6.85, 95% CI 1.42 to 33.04), and of stopping treatment (two trials, 56 women; RR 4.02, 95% CI 1.15 to 14.09) compared to placebo. However, the increase for both outcomes was due to an extreme result in one small trial (7/7 versus 0/9 for both outcomes). AUTHORS' CONCLUSIONS: There is insufficient evidence to draw reliable conclusions about whether nitric oxide donors and precursors prevent pre-eclampsia or its complications.

Antihypertensive drug therapy for mild to moderate hypertension during pregnancy.

BACKGROUND: Mild to moderate hypertension during pregnancy is common. Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby improve outcome. OBJECTIVES: To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 3), MEDLINE (1966 to November 2005), LILACS (1984 to November 2005) and EMBASE (1974 to November 2005). SELECTION CRITERIA: All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy defined, whenever possible, as systolic blood pressure 140 to 169 mmHg and diastolic blood pressure 90 to 109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. MAIN RESULTS: Forty-six trials (4282 women) were included. Twenty-eight trials compared an antihypertensive drug with placebo/no antihypertensive drug (3200 women). There is a halving in the risk of developing severe hypertension associated with the use of antihypertensive drug(s) (19 trials, 2409 women; relative risk (RR) 0.50; 95% confidence interval (CI) 0.41 to 0.61; risk difference (RD) -0.10 (-0.12 to -0.07); number needed to treat (NNT) 10 (8 to 13)) but little evidence of a difference in the risk of pre-eclampsia (22 trials, 2702 women; RR 0.97; 95% CI 0.83 to 1.13). Similarly, there is no clear effect on the risk of the baby dying (26 trials, 3081 women; RR 0.73; 95% CI 0.50 to 1.08), preterm birth (14 trials, 1992 women; RR 1.02; 95 % CI 0.89 to 1.16), or small-for-gestational-age babies (19 trials, 2437 women; RR 1.04; 95 % CI 0.84 to 1.27). There were no clear differences in any other outcomes. Nineteen trials (1282 women) compared one antihypertensive drug with another. Beta blockers seem better than methyldopa for reducing the risk of severe hypertension (10 trials, 539 women, RR 0.75 (95 % CI 0.59 to 0.94); RD -0.08 (-0.14 to 0.02); NNT 12 (6 to 275)). There is no clear difference between any of the alternative drugs in the risk of developing proteinuria/pre-eclampsia. Other outcomes were only reported by a small proportion of studies, and there were no clear differences. AUTHORS' CONCLUSIONS: It remains unclear whether antihypertensive drug therapy for mild to moderate hypertension during pregnancy is worthwhile.

Progesterone for preventing pre-eclampsia and its complications.

BACKGROUND: In the past, progesterone has been advocated for prevention of pre-eclampsia and its complications. Although progestogens are not used for this purpose in current clinical practice, it remains relevant to assess the evidence on their possible benefits and harms. OBJECTIVES: To assess the effects of progesterone during pregnancy on the risk of developing pre-eclampsia and its complications. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 2), and EMBASE (1974 to August 2005). SELECTION CRITERIA: Randomised trials evaluating progesterone or any other progestogen during pregnancy for prevention of pre-eclampsia and its complications were included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and extracted data. MAIN RESULTS: Two trials of uncertain quality were included (296 women). These trials compared progesterone injections with no progesterone. There was insufficient evidence to demonstrate any clear differences between the two groups on the risk of pre-eclampsia (one trial, 128 women; relative risk (RR) 0.21, 95% confidence interval (CI) 0.03 to 1.77), death of the baby (two trials, 296 women; RR 0.72, 95% CI 0.21 to 2.51), preterm birth (one trial, 168 women; RR 1.10, 95% CI 0.33 to 3.66), small-for-gestational-age babies (one trial, 168 women; RR 0.83, 95% CI 0.19 to 3.57) or major congenital defects (one trial, 168 women; RR 1.65, 95% CI 0.28 to 9.62). There were no reported cases of masculinisation of female babies (one trial, 128 women). Long-term follow up for the children has been reported in one trial, but the data are excluded from the review as 54% were lost to follow up at one year and 80% at 16 years. AUTHORS' CONCLUSIONS: There is insufficient evidence for reliable conclusions about the effects of progesterone for preventing pre-eclampsia and its complications. Therefore, progesterone should not be used for this purpose in clinical practice at present. Unless new and plausible hypotheses emerge for the role of progesterone in development of pre-eclampsia, further trials of progesterone are unlikely to be a priority.

Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems.

BACKGROUND: Pre-eclampsia and eclampsia are common causes of serious morbidity and death. Calcium supplementation may reduce the risk of pre-eclampsia through a number of mechanisms, and may help to prevent preterm labour. OBJECTIVES: To assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child outcomes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (February 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2005, Issue 4), and contacted study authors. SELECTION CRITERIA: Randomised trials comparing at least one gram daily of calcium during pregnancy with placebo. DATA COLLECTION AND ANALYSIS: We assessed eligibility and trial quality, extracted and double-entered data. MAIN RESULTS: Twelve studies of good quality were included. The risk of high blood pressure was reduced with calcium supplementation rather than placebo (11 trials, 14,946 women: relative risk (RR) 0.70, 95% confidence interval (CI) 0.57 to 0.86). There was also a reduction in the risk of pre-eclampsia associated with calcium supplementation (12 trials, 15,206 women: RR 0.48, 95% CI 0.33 to 0.69). The effect was greatest for high-risk women (5 trials, 587 women: RR 0.22, 95% CI 0.12 to 0.42), and those with low baseline calcium intake (7 trials, 10,154 women: RR 0.36, 95% CI 0.18 to 0.70). The composite outcome maternal death or serious morbidity was reduced (4 trials, 9732 women; RR 0.80, 0.65 to 0.97). Almost all the women in these trials were low risk and had a low calcium diet. Maternal deaths were reported in only one trial. One death occurred in the calcium group and six in the placebo group, a difference which was not statistically significant (RR 0.17, 95% CI 0.02 to 1.39). There was no overall effect on the risk of preterm birth (10 trials, 14,751 women: RR 0.81, 95% CI 0.64 to 1.03), or stillbirth or death before discharge from hospital (10 trials 15,141 babies; RR 0.89, 95% CI 0.73 to 1.09).Blood pressure in childhood has been assessed in one study: childhood systolic blood pressure greater than 95th percentile was reduced (514 children: RR 0.59, 95% CI 0.39 to 0.91). AUTHORS' CONCLUSIONS: Calcium supplementation appears to almost halve the risk of pre-eclampsia, and to reduce the rare occurrence of the composite outcome 'death or serious morbidity'. There were no other clear benefits, or harms.

Drugs for treatment of very high blood pressure during pregnancy.

BACKGROUND: Very high blood pressure during pregnancy poses a serious threat to women and their babies. Antihypertensive drugs lower blood pressure. Their comparative effects on other substantive outcomes, however, is uncertain. OBJECTIVES: To compare different antihypertensive drugs for very high blood pressure during pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (28 February 2006) and CENTRAL (The Cochrane Library 2006, Issue 2). SELECTION CRITERIA: Studies were randomised trials. Participants were women with severe hypertension during pregnancy. Interventions were comparisons of one antihypertensive drug with another. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. MAIN RESULTS: Twenty-four trials (2949 women) with 12 comparisons were included. Women allocated calcium channel blockers rather than hydralazine were less likely to have persistent high blood (five trials, 263 women; 6% versus 18%; relative risk (RR) 0.33, 95% confidence interval (CI) 0.15 to 0.70). Ketanserin was associated with more persistent high blood pressure than hydralazine (four trials, 200 women; 27% versus 6%; RR 4.79, 95% CI 1.95 to 11.73), but fewer side-effects (three trials, 120 women; RR 0.32, 95% CI 0.19 to 0.53) and a lower risk of HELLP (Haemolysis, Elevated Liver enzymes and Lowered Platelets) syndrome (one trial, 44 women, RR 0.20, 95% CI 0.05 to 0.81). Labetalol was associated with a higher risk of hypotension (one trial 90 women; RR 0.06, 95% CI 0.00 to 0.99) and caesarean section (RR 0.43, 95% CI 0.18 to 1.02) than diazoxide. Data were insufficient for reliable conclusions about other outcomes. The risk of persistent high blood pressure was greater for nimodipine compared to magnesium sulphate (two trials 1683 women; 47% versus 65%; RR 0.84, 95% CI 0.76 to 0.93). Nimodipine was also associated with a higher risk of eclampsia (RR 2.24, 95% CI 1.06 to 4.73) and respiratory difficulties (RR 0.28, 95% CI 0.08 to 0.99), but fewer side-effects (RR 0.68, 95% CI 0.54 to 0.86) and less postpartum haemorrhage (RR 0.41, 95% CI 0.18 to 0.92) than magnesium sulphate. Stillbirths and neonatal deaths were not reported. There are insufficient data for reliable conclusions about the comparative effects of any other drugs. AUTHORS' CONCLUSIONS: Until better evidence is available, the choice of antihypertensive should depend on the clinician's experience and familiarity with a particular drug, and on what is known about adverse effects. Exceptions are diazoxide, ketanserin, nimodipine and magnesium sulphate, which are probably best avoided.

Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction.

BACKGROUND: Population studies have shown that higher intakes of marine foods during pregnancy are associated with longer gestations, higher infant birthweights and a low incidence of pre-eclampsia. It is suggested that the fatty acids of marine foods may be the underlying cause of these associations. OBJECTIVES: To estimate the effects of marine oil, and other prostaglandin precursor, supplementation during pregnancy on the risk of pre-eclampsia, preterm birth, low birthweight and small-for-gestational age. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (December 2005), The Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 2) and MEDLINE (1966 to April 2005). SELECTION CRITERIA: All randomised trials comparing oral marine oil, or other prostaglandin precursor, supplementation during pregnancy with either placebo or no treatment. Trials were excluded if their aim was to treat women with established pre-eclampsia or suspected intrauterine growth restriction. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, data extraction and trial quality. MAIN RESULTS: Six trials, involving 2783 women, are included in this review. Three of these were rated as high quality, including the largest trial with 1477 women. Women allocated a marine oil supplement had a mean gestation that was 2.6 days longer than women allocated to placebo or no treatment (weighted mean difference (WMD), 2.55 days, 95% confidence interval (CI) 1.03 to 4.07 days; 3 trials, 1621 women). This was not reflected in a clear difference between the two groups in the relative risk (RR) of birth before 37 completed weeks, although women allocated marine oil did have a lower risk of giving birth before 34 completed weeks' gestation (RR 0.69, 95% CI 0.49 to 0.99; 2 trials, 860 women). Birthweight was slightly greater in infants born to women in the marine oil group compared with control (WMD 47 g, 95% CI 1 g to 93 g; 3 trials, 2440 women). However, there were no overall differences between the groups in the proportion of low birthweight or small-for-gestational age babies. There was no clear difference in the relative risk of pre-eclampsia between the two groups. AUTHORS' CONCLUSIONS: There is not enough evidence to support the routine use of marine oil, or other prostaglandin precursor, supplements during pregnancy to reduce the risk of pre-eclampsia, preterm birth, low birthweight or small-for-gestational age.