The efficacy and fetal-maternal cardiovascular effects of transdermal glyceryl trinitrate in the prophylaxis of pre-eclampsia and its complications: a randomized double-blind placebo-controlled trial. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. A small randomised trial of low-dose aspirin in women at high risk of pre-eclampsia. Reducing stillbirths: interventions during labour. Individualized developmental care for the very low-birth-weight preterm infant. Medical and neurofunctional effects. Randomised comparison of uterine artery Doppler and aspirin (100 mg) with placebo in nulliparous women: the Essai Régional Aspirine Mère-Enfant study (Part 2). Small for gestational age preterm infants: nutritional strategies and quality of growth after discharge. Methyldopa versus no drug treatment in the management of mild pre-eclampsia. Antioxidants in the treatment of severe pre-eclampsia: an explanatory randomised controlled trial. Tailoring systematic reviews to meet critical priorities in maternal health in the intrapartum period. Effect of prenatal ultrasound screening on perinatal outcome. RADIUS Study Group.
Pre-eclampsia continues to be a major cause of maternal and perinatal mortality. A disorder of the nitric oxide system is implicated in the pathogenesis of this condition and preliminary studies have suggested a possible therapeutic role for nitric oxide donors in women with established pre-eclampsia. The aim of this study was to determine whether pre-eclampsia and its complications could be prevented by the long-term use of nitric oxide donors in a group of women identified to be at risk on the basis of abnormal uterine artery Doppler measurements.
                We enrolled 40 healthy normotensive women at high risk of pre-eclampsia selected on the basis of abnormal uterine artery Doppler waveforms at 24-26 weeks of gestation. Women were randomly allocated to receive transdermal glyceryl trinitrate 5 mg-patches or equivalent placebo patches in a double-blind randomized study. The primary outcome measures were pre-eclampsia, fetal growth restriction, preterm delivery or small for gestational age/fetal growth restriction rates. Patches were worn daily from recruitment for 10 weeks or until delivery.
                The primary outcomes were not significantly different in the placebo compared to the glyceryl trinitrate group. However, survival analysis of adverse events with gestation in both groups showed a significantly reduced risk of an adverse event in the glyceryl trinitrate group (p = 0.004), equating to a 73% reduction in hazard. There was no difference in maternal systolic and diastolic blood pressure, mean uterine artery resistance index and fetal umbilical and middle cerebral artery pulsatility indices between the groups.
                Low-dose prophylactic transdermal glyceryl trinitrate commenced late in the second trimester did not reduce the incidence of pre-eclampsia, preterm delivery or fetal growth restriction, but may increase the likelihood of a complication-free pregnancy. Transdermal glyceryl trinitrate (5 mg/day) did not affect maternal cardiovascular, uterine artery or fetal arterial Doppler parameters. Oxidative stress could play a part in pre-eclampsia, and there is some evidence to suggest that vitamin C and vitamin E supplements could reduce the risk of the disorder. Our aim was to investigate the potential benefit of these antioxidants in a cohort of women with a range of clinical risk factors.
                We did a randomised, placebo-controlled trial to which we enrolled 2410 women identified as at increased risk of pre-eclampsia from 25 hospitals. We assigned the women 1000 mg vitamin C and 400 IU vitamin E (RRR alpha tocopherol; n=1199) or matched placebo (n=1205) daily from the second trimester of pregnancy until delivery. Our primary endpoint was pre-eclampsia, and our main secondary endpoints were low birthweight (<2.5 kg) and small size for gestational age (<5th customised birthweight centile). Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN 62368611 .
                Of 2404 patients treated, we analysed 2395 (99.6%). The incidence of pre-eclampsia was similar in treatment placebo groups (15% [n=181] vs 16% [n=187], RR 0.97 [95% CI 0.80-1.17]). More low birthweight babies were born to women who took antioxidants than to controls (28% [n=387] vs 24% [n=335], 1.15 [1.02-1.30]), but small size for gestational age did not differ between groups (21% [n=294] vs 19% [n=259], 1.12 [0.96-1.31]).
                Concomitant supplementation with vitamin C and vitamin E does not prevent pre-eclampsia in women at risk, but does increase the rate of babies born with a low birthweight. As such, use of these high-dose antioxidants is not justified in pregnancy. To determine if aspirin (ASA) therapy reduces the incidence of pre-eclampsia in women at high risk of this condition.
                Randomised clinical trial. We recruited pregnant women with gestational age at randomisation <14 weeks, who satisfied the following criteria: chronic hypertension, history of severe pre-eclampsia or eclampsia or intrauterine growth retardation (IUGR) or intrauterine foetal death. Nineteen women in the no-treatment group and 16 in the ASA group were successfully followed up.
                The mean birthweight was higher in the ASA group than in the no-treatment group (2790 g (S.D. 340 g) versus 2616 g (S.D. 779 g)), but the difference was not statistically significant. We found no statistically significant differences between the groups in the proportion of infants with birthweight below 2500 g (13.3% versus 29.4%) and the number of cases with pregnancy-induced hypertension (PIH)/pre-eclampsia (31.3% versus 36.8%).
                These limited data give some support to the potential favourable effect of early treatment with ASA in pregnant women at risk of PIH and IUGR. Approximately one million stillbirths occur annually during labour; most of these stillbirths occur in low and middle-income countries and are associated with absent, inadequate, or delayed obstetric care. The low proportion of intrapartum stillbirths in high-income countries suggests that intrapartum stillbirths are largely preventable with quality intrapartum care, including prompt recognition and management of intrapartum complications. The evidence for impact of intrapartum interventions on stillbirth and perinatal mortality outcomes has not yet been systematically examined.
                We undertook a systematic review of the published literature, searching PubMed and the Cochrane Library, of trials and reviews (N = 230) that reported stillbirth or perinatal mortality outcomes for eight interventions delivered during labour. Where eligible randomised controlled trials had been published after the most recent Cochrane review on any given intervention, we incorporated these new trial findings into a new meta-analysis with the Cochrane included studies.
                We found a paucity of studies reporting statistically significant evidence of impact on perinatal mortality, especially on stillbirths. Available evidence suggests that operative delivery, especially Caesarean section, contributes to decreased stillbirth rates. Induction of labour rather than expectant management in post-term pregnancies showed strong evidence of impact, though there was not enough evidence to suggest superior safety for the fetus of any given drug or drugs for induction of labour. Planned Caesarean section for term breech presentation has been shown in a large randomised trial to reduce stillbirths, but the feasibility and consequences of implementing this intervention routinely in low-/middle-income countries add caveats to recommending its use. Magnesium sulphate for pre-eclampsia and eclampsia is effective in preventing eclamptic seizures, but studies have not demonstrated impact on perinatal mortality. There was limited evidence of impact for maternal hyperoxygenation, and concerns remain about maternal safety. Transcervical amnioinfusion for meconium staining appears promising for low/middle income-country application according to the findings of many small studies, but a large randomised trial of the intervention had no significant impact on perinatal mortality, suggesting that further studies are needed.
                Although the global appeal to prioritise access to emergency obstetric care, especially vacuum extraction and Caesarean section, rests largely on observational and population-based data, these interventions are clearly life-saving in many cases of fetal compromise. Safe, comprehensive essential and emergency obstetric care is particularly needed, and can make the greatest impact on stillbirth rates, in low-resource settings. Other advanced interventions such as amnioinfusion and hyperoxygenation may reduce perinatal mortality, but concerns about safety and effectiveness require further study before they can be routinely included in programs. To investigate the effectiveness of individualized developmental care in reducing medical and neurodevelopmental sequelae for very low-birth-weight infants.
                Randomized controlled trial.
                Newborn intensive care unit.
                Thirty-eight singleton preterm infants, free of known congenital abnormalities, weighing less than 1250 g, born before 30 weeks' gestation, mechanically ventilated within 3 hours of delivery and for more than 24 hours in the first 48 hours, randomly assigned to a control or an experimental group.
                Caregiving by nurses specifically trained in individualized developmental care; observation and documentation of the infants' behavior within 12 hours of admission, and subsequently every 10th day; developmental care recommendations and ongoing clinical support for the nurses and parents based on regular observation of the infant by developmental specialists; and the availability of special caregiving accessories.
                Medical outcome, including average daily weight gain; number of days the infant required mechanical ventilation, oxygen, gavage tube feeding, and hospitalization; severity of retinopathy of prematurity, bronchopulmonary dysplasia, pneumothorax, and intraventricular hemorrhage; pediatric complications; age at discharge; and hospital charges. Neurodevelopmental outcome, including Assessment of Preterm Infants' Behavior scale and quantified electroencephalography (2 weeks after due date); and Bayley Scales of Infant Development and Kangaroo Box Paradigm (9 months after due date).
                The infants in the experimental group had a significantly shorter duration of mechanical ventilation and supplemental oxygen support; earlier oral feeding; reduced incidence of intraventricular hemorrhage, pneumothorax, and severe bronchopulmonary dysplasia; improved daily weight gain; shorter hospital stays; younger ages at hospital discharge; and reduced hospital charges compared with the infants in the control group. At 2 weeks after their due dates, these infants also showed improved autonomic regulation, motor system functioning, self-regulatory abilities, and visual evoked potential measures; and at 9 months, they had improved Bayley Mental and Psychomotor Developmental Index scores, as well as Kangaroo Box Paradigm scores.
                Very low-birth-weight preterm infants may benefit from individualized developmental care in the neonatal intensive care unit in terms of medical and neurodevelopmental outcome. To assess the effectiveness of a pre-eclampsia prevention strategy based on routine uterine artery Doppler flow velocity waveform examination during the second trimester of pregnancy, followed by a prescription for 100 mg aspirin in the case of abnormal Doppler findings.
                Multicentre randomised controlled trial.
                Eleven centres in the north of France and one in Belgium.
                One thousand and eight hundred and fifty-three nulliparous women recruited between 14 and 20 weeks of gestation.
                Randomisation either to undergo a uterine Doppler examination between 22 and 24 week of gestation or to take a placebo. Women with abnormal Doppler waveforms received 100 mg of aspirin daily from Doppler examination through 36 weeks.
                Pre-eclampsia was defined as hypertension (> or = 140 and/or 90 mmHg) associated with proteinuria (> or = 0.5 g/L).
                One thousand two hundred and fifty-three women (67%) were randomised into the systematic Doppler group and 617 (33%) into the placebo group. Of the 1175 patients in the Doppler group who underwent this examination, 239 (20.3%) had abnormal uterine artery Doppler and received a prescription for aspirin. Despite the aspirin prescription, the frequency of pre-eclampsia did not differ between the systematic Doppler group and the placebo group (28 of 1237 [2.3%] vs 9 of 616 [1.5%]; RR = 1.55, 95% CI 0.7-3.3). Furthermore, the groups did not differ in the frequency of children who were very small for their gestational age (< or =3rd centile) or for perinatal deaths. Compared with patients with normal Doppler findings, those with abnormal Doppler were at high risk of pre-eclampsia (RR = 5.5, 95% CI 2.5-12.2) and of giving birth to a small-for-gestational-age child (RR = 3.6, 95% CI 1.6-8.1).
                Despite its sensitivity in screening for pre-eclampsia, routine uterine Doppler in the second trimester cannot be recommended for nulliparous patients. Infants born preterm are at high risk for poor growth achievement. Small for gestational age (SGA (birth weight below the 10th percentile) preterm infants are even more prone to develop postnatal growth retardation in the early neonatal period, as they do not have a large storage of protein/energy. Both SGA and appropriate for gestational age (AGA: birth weight between the 10th and 90th percentiles) infants show persistent postnatal growth failure after discharge. Although the available data clearly demonstrate that preterm infants, especially if born SGA, exhibit postnatal growth retardation at the time of hospital discharge, the importance of the nutritional post discharge management has not been sufficiently taken into account. We have recently conducted a randomized controlled trial to assess whether infants born SGA may benefit from an enriched post discharge formula. This study suggests that the growth pattern in SGA preterm infants is not affected by the consumption of an enriched post discharge formula. The ponderal and linear growth of these infants does not accelerate to achieve early catch up growth. However, as far as the quality of growth is concerned, the fat mass accretion after term decelerates, so that an increase of fat free mass accretion takes place. Future research effort should be directed toward longer follow up and personalized nutrition management. To evaluate the efficacy of methyldopa in the treatment of mild pre-eclampsia, to prevent its progress and to investigate its effect on the pregnancy outcomes.
                Randomised clinical trial.
                Wad Medani Hospital in the central Sudan.
                Seventy primigravidae with single, alive baby of 28-36 weeks gestational age suffering from true mild pre-eclampsia were enrolled. The patients were randomised in two groups, treatment group who received methyldopa 750-4000 mg/day (n=34) and a control group who received no treatment (n=36). All the (treatment and control) patients were drug followed as in-patients till the delivery, seen with their babies on the days 7, 42 after the delivery.
                The outcomes examined were, rise of the diastolic blood pressure to 110 mm Hg or more, occurrence of imminent eclampsia or the eclampsia, if the maturity could be achieved, occurrence of intrauterine growth retardation, abruptio placentae, mode of delivery, birth weight, placental weight, perinatal death, Apgar score and referral of the babies to the pediatrician.
                Three out of 34 (8.8%) of the treatment group had a rise in the diastolic blood pressure of 110 mm Hg, 18/36 (50%) of the control had a rise in the diastolic blood pressure of 110 mmHg (p < 0.05). Three out of thirty four (8.8%) of the treatment group developed imminent eclampsia, while 10/36 (27.8) of the control group developed imminent eclampsia (p < 0.05). The maturity was achieved in 82.3% and 88.8% of the treatment and the control, respectively (p > 0.05). There were ten (14.2%) perinatal deaths, four of them in the treatment group, while six in the control (p > 0.05). There was no difference regarding birth weight, occurrence of intrauterine growth retardation, placental weight, mode of delivery, Apgar score, referral of the babies to the paediatrician. No patient developed eclampsia or abruptio placenta; there was no maternal death in both groups.
                Methyldopa can prevent the progress of the mild pre-eclampsia to severe pre-eclampsia, without affecting the maturity, birthweight or the neonatal outcomes. To determine whether antioxidant therapy alters the disease process in severe early onset pre-eclampsia, in support of the hypothesis that increased lipid peroxides and reactive oxygen species production-play an important role in the pathogenesis of the disease.
                Randomised, double-blind, placebo controlled trial.
                Two tertiary care, referral hospitals in Johannesburg, South Africa.
                Women with severe pre-eclampsia diagnosed between 24 and 32 weeks of gestation.
                Combined antioxidant treatment with vitamin E (800 IU/day), vitamin C (1000 mg/day), and allopurinol (200 mg/day).
                Primary outcomes: 1. prolongation of pregnancy and 2, biochemical assessment of lipid peroxides and antioxidants. Secondary outcomes: data on maternal complications, side effects of treatment, infant outcomes and regular assessment of haematologic and renal parameters.
                The proportion of women delivered within 14 days in the antioxidant group was 52% (14/27) compared with 76% (22/29) in the placebo group (relative risk 0.68, 95% confidence interval 0.45-1.04). One woman in each group had eclampsia. Eleven women (42%) in the antioxidant and 16 (59%) in the placebo group required two antihypertensives for blood pressure control. Trial medications were well tolerated with few side effects. Lipid peroxide levels were not significantly altered in the antioxidant and placebo groups. Serum uric acid levels decreased and vitamin E levels increased significantly.
                The results of this explanatory randomised trial do not encourage the routine use of antioxidants against pre-eclampsia. However, further research with modified strategies such as earlier initiation of therapy or different combinations seem worthwhile. Health care practitioners and researchers commonly call for greater reliance on evidence as a means to achieve improvement in quality of care. Systematic reviews provide a means to accelerate the use of evidence-based clinical interventions and public health practices. The extent to which these time- and resource-intensive systematic reviews currently address critical maternal health priorities in the intrapartum period is unclear. This analysis summarises key maternal health and research priorities, maps these priorities to existing reviews, identifies gaps in the literature that can be addressed with systematic reviews, and highlights key methodological concerns in conducting systematic reviews. The analysis draws on published data on maternal morbidities and an overview of 108 systematic reviews in Medline in the past 5 years using the MeSH terms 'Delivery, Obstetric,' to draw the links between health priorities, research priorities, existing evidence and missing evidence. Key causes of morbidity during labour and delivery in the United States include haemorrhage, pre-eclampsia and eclampsia, obstetric trauma and infection. Analyses of maternal morbidity and mortality suggest that key concerns include racial and ethnic disparities in health outcomes and the prevention of adverse events. Systematic reviews, however, generally tend to focus on the reduction of harms associated with interventions, are frequently limited to randomised designs, and do not address issues of health disparities. The results suggest that advances in evidence-based care in maternal health require that systematic reviews address issues of prevention of adverse events, include a larger variety of study designs when necessary and pay closer attention to health disparities. Many clinicians advocate routine ultrasound screening during pregnancy to detect congenital anomalies, multiple-gestation pregnancies, fetal growth disorders, placental abnormalities, and errors in the estimation of gestational age. However, it is not known whether the detection of these conditions through screening leads to interventions that improve perinatal outcome.
                We conducted a randomized trial involving 15,151 pregnant women at low risk for perinatal problems to determine whether ultrasound screening decreased the frequency of adverse perinatal outcomes. The women randomly assigned to the ultrasound-screening group underwent one sonographic examination at 15 to 22 weeks of gestation and another at 31 to 35 weeks. The women in the control group underwent ultrasonography only for medical indications, as identified by their physicians. Adverse perinatal outcome was defined as fetal death, neonatal death, or neonatal morbidity such as intraventricular hemorrhage.
                The mean numbers of sonograms obtained per woman in the ultrasound-screening and control groups were 2.2 and 0.6, respectively. The rate of adverse perinatal outcome was 5.0 percent among the infants of the women in the ultrasound-screening group and 4.9 percent among the infants of the women in the control group (relative risk, 1.0; 95 percent confidence interval, 0.9 to 1.2; P = 0.85). The rates of preterm delivery and the distribution of birth weights were nearly identical in the two groups. The ultrasonographic detection of congenital anomalies had no effect on perinatal outcome. There were no significant differences between the groups in perinatal outcome in the subgroups of women with post-date pregnancies, multiple-gestation pregnancies, or infants who were small for gestational age.
                Screening ultrasonography did not improve perinatal outcome as compared with the selective use of ultrasonography on the basis of clinician judgment.
The review identified no significant differences for the primary outcomes perinatal mortality, preterm birth less than 34 weeks' gestation, and childhood neurodevelopmental handicap, although the number of studies and participants was small. While treatment with heparin appears promising with a reduction in pre-eclampsia, eclampsia, and infant birthweight less than the 10th centile for gestational age, the number of studies and participants included was small, and to date important information about serious adverse infant and long-term childhood outcomes is unavailable. Further research is required.
[Note: The 14 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]