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1.  Magnesium sulphate at 30 to 34 weeks’ gestational age: neuroprotection trial (MAGENTA) - study protocol 
Background
Magnesium sulphate is currently recommended for neuroprotection of preterm infants for women at risk of preterm birth at less than 30 weeks’ gestation, based on high quality evidence of benefit. However there remains uncertainty as to whether these benefits apply at higher gestational ages.
The aim of this randomised controlled trial is to assess whether giving magnesium sulphate compared with placebo to women immediately prior to preterm birth between 30 and 34 weeks’ gestation reduces the risk of death or cerebral palsy in their children at two years’ corrected age.
Methods/design
Design: Randomised, multicentre, placebo controlled trial.
Inclusion criteria: Women, giving informed consent, at risk of preterm birth between 30 to 34 weeks’ gestation, where birth is planned or definitely expected within 24 hours, with a singleton or twin pregnancy and no contraindications to the use of magnesium sulphate.
Trial entry & randomisation: Eligible women will be randomly allocated to receive either magnesium sulphate or placebo.
Treatment groups: Women in the magnesium sulphate group will be administered 50 ml of a 100 ml infusion bag containing 8 g magnesium sulphate heptahydrate [16 mmol magnesium ions]. Women in the placebo group will be administered 50 ml of a 100 ml infusion bag containing isotonic sodium chloride solution (0.9%). Both treatments will be administered through a dedicated IV infusion line over 30 minutes.
Primary study outcome: Death or cerebral palsy measured in children at two years’ corrected age.
Sample size: 1676 children are required to detect a decrease in the combined outcome of death or cerebral palsy, from 9.6% with placebo to 5.4% with magnesium sulphate (two-sided alpha 0.05, 80% power, 5% loss to follow up, design effect 1.2).
Discussion
Given the magnitude of the protective effect in the systematic review, the ongoing uncertainty about benefits at later gestational ages, the serious health and cost consequences of cerebral palsy for the child, family and society, a trial of magnesium sulphate for women at risk of preterm birth between 30 to 34 weeks’ gestation is both important and relevant for clinical practice globally.
Trial registration
Australian New Zealand Clinical Trials Registry - ACTRN12611000491965
doi:10.1186/1471-2393-13-91
PMCID: PMC3636106  PMID: 23570677
Magnesium sulphate; Neuroprotection; Preterm birth; Randomised controlled trial; Cerebral palsy
2.  Australasian randomised trial to evaluate the role of maternal intramuscular dexamethasone versus betamethasone prior to preterm birth to increase survival free of childhood neurosensory disability (A*STEROID): study protocol 
Background
Both dexamethasone and betamethasone, given to women at risk of preterm birth, substantially improve short-term neonatal health, increase the chance of the baby being discharged home alive, and reduce childhood neurosensory disability, remaining safe into adulthood. However, it is unclear which corticosteroid is of greater benefit to mother and child.
This study aims to determine whether giving dexamethasone to women at risk of preterm birth at less than 34 weeks’ gestation increases the chance of their children surviving free of neurosensory disability at two years’ corrected age, compared with betamethasone.
Methods/Design
Design randomised, multicentre, placebo controlled trial.
Inclusion criteria women at risk of preterm birth at less than 34 weeks’ gestation with a singleton or twin pregnancy and no contraindications to the use of antenatal corticosteroids and who give informed consent.
Trial entry & randomisation at telephone randomisation eligible women will be randomly allocated to either the dexamethasone group or the betamethasone group, allocated a study number and corresponding treatment pack.
Study groups women in the dexamethasone group will be administered two syringes of 12 mg dexamethasone (dexamethasone sodium phosphate) and women in the betamethasone group will be administered two syringes of 11.4 mg betamethasone (Celestone Chronodose). Both study groups consist of intramuscular treatments 24 hours apart.
Primary study outcome death or any neurosensory disability measured in children at two years’ corrected age.
Sample size a sample size of 1449 children is required to detect either a decrease in death or any neurosensory disability from 27.0% to 20.1% with dexamethasone compared with betamethasone, or an increase from 27.0% to 34.5% (two-sided alpha 0.05, 80% power, 5% loss to follow up, design effect 1.2).
Discussion
This study will provide high-level evidence of direct relevance for clinical practice. If one drug clearly results in significantly fewer deaths and fewer disabled children then it should be used consistently in women at risk of preterm birth and would be of great importance to women at risk of preterm birth, their children, health services and communities.
Trial registration
Trial registration number: ACTRN12608000631303
doi:10.1186/1471-2393-13-104
PMCID: PMC3655914  PMID: 23642125
Antenatal corticosteroids; Dexamethasone; Betamethasone; Preterm birth; Randomised controlled trial; Neurosensory disability
3.  Hospitalisation for bed rest for women with a triplet pregnancy: an abandoned randomised controlled trial and meta-analysis 
Background
This abandoned randomised controlled trial assessed the effects of hospitalisation from 24 to 30 weeks gestation for women with a triplet pregnancy on the risk of preterm birth.
Methods
Women with a triplet pregnancy and no other condition necessitating hospital admission were approached for participation in the study, and randomised to either antenatal hospitalisation (hospitalised group), or to routine antenatal care (control group). The randomisation schedule used variable blocks with stratification by parity, and a researcher not involved with clinical care contacted by telephone to determine treatment allocation by opening the next in a series of consecutively numbered, opaque, sealed envelopes. Primary study outcomes were preterm birth (defined as birth less than 37 weeks gestation) and very preterm birth (defined as birth less than 34 weeks gestation), and the development of maternal pregnancy induced hypertension. The trial was ceased prior to achieving the calculated sample size due to difficulties in recruitment. The results of this randomised controlled trial were then combined with the results of another comparing bed rest in women with a triplet pregnancy.
Results
Seven women with a triplet pregnancy were recruited to the trial, with three randomised to the hospitalisation group, and four to the control group. There were no statistically significant differences between the two groups for the primary outcomes birth before 37 weeks (3/3 hospitalisation group versus 4/4 control group; relative risk (RR) not estimable), birth before 34 weeks (3/3 hospitalisation group versus 2/4 control group; RR 2.00 95% Confidence Intervals (CI) 0.75–5.33) and pregnancy induced hypertension (1/3 hospitalisation group versus 1/4 control group; RR 1.33 95%CI 0.13–13.74).
When the results of this trial were incorporated into a meta-analysis with the previous randomised controlled trial assessing hospitalisation and bed rest for women with a triplet pregnancy, (total sample size 26 women and 78 infants), there were no statistically significant differences identified between the two groups.
Conclusion
The results of this trial and meta-analysis suggest no benefit of routine hospitalisation and bed rest for women with a triplet pregnancy to reduce the risk of preterm birth. The adoption or continuation of a policy of routine hospitalisation and bed rest for women with an uncomplicated triplet pregnancy cannot be recommended.
doi:10.1186/1471-2393-5-8
PMCID: PMC1084350  PMID: 15804370
4.  Antenatal lifestyle advice for women who are overweight or obese: LIMIT randomised trial 
Objective To determine the effect of antenatal dietary and lifestyle interventions on health outcomes in overweight and obese pregnant women.
Design Multicentre randomised trial. We utilised a central telephone randomisation server, with computer generated schedule, balanced variable blocks, and stratification for parity, body mass index (BMI) category, and hospital.
Setting Three public maternity hospitals across South Australia.
Participants 2212 women with a singleton pregnancy, between 10+0 and 20+0 weeks’ gestation, and BMI ≥25.
Interventions 1108 women were randomised to a comprehensive dietary and lifestyle intervention delivered by research staff; 1104 were randomised to standard care and received pregnancy care according to local guidelines, which did not include such information.
Main outcome measures Incidence of infants born large for gestational age (birth weight ≥90th centile for gestation and sex). Prespecified secondary outcomes included birth weight >4000 g, hypertension, pre-eclampsia, and gestational diabetes. Analyses used intention to treat principles.
Results 2152 women and 2142 liveborn infants were included in the analyses. The risk of the infant being large for gestational age was not significantly different in the two groups (lifestyle advice 203/1075 (19%) v standard care 224/1067 (21%); adjusted relative risk 0.90, 95% confidence interval 0.77 to 1.07; P=0.24). Infants born to women after lifestyle advice were significantly less likely to have birth weight above 4000 g (lifestyle advice 164/1075 (15%) v standard care 201/1067 (19%); 0.82, 0.68 to 0.99; number needed to treat (NNT) 28, 15 to 263; P=0.04). There were no differences in maternal pregnancy and birth outcomes between the two treatment groups.
Conclusions For women who were overweight or obese, the antenatal lifestyle advice used in this study did not reduce the risk delivering a baby weighing above the 90th centile for gestational age and sex or improve maternal pregnancy and birth outcomes.
Trial registration Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).
doi:10.1136/bmj.g1285
PMCID: PMC3919179  PMID: 24513442
5.  A Randomized Trial of Planned Cesarean or Vaginal Delivery for Twin Pregnancy 
The New England journal of medicine  2013;369(14):1295-1305.
BACKGROUND
Twin birth is associated with a higher risk of adverse perinatal outcomes than singleton birth. It is unclear whether planned cesarean section results in a lower risk of adverse outcomes than planned vaginal delivery in twin pregnancy.
METHODS
We randomly assigned women between 32 weeks 0 days and 38 weeks 6 days of gestation with twin pregnancy and with the first twin in the cephalic presentation to planned cesarean section or planned vaginal delivery with cesarean only if indicated. Elective delivery was planned between 37 weeks 5 days and 38 weeks 6 days of gestation. The primary outcome was a composite of fetal or neonatal death or serious neonatal morbidity, with the fetus or infant as the unit of analysis for the statistical comparison.
RESULTS
A total of 1398 women (2795 fetuses) were randomly assigned to planned cesarean delivery and 1406 women (2812 fetuses) to planned vaginal delivery. The rate of cesarean delivery was 90.7% in the planned-cesarean-delivery group and 43.8% in the planned-vaginal-delivery group. Women in the planned-cesarean-delivery group delivered earlier than did those in the planned-vaginal-delivery group (mean number of days from randomization to delivery, 12.4 vs. 13.3; P = 0.04). There was no significant difference in the composite primary outcome between the planned-cesarean-delivery group and the planned-vaginal-delivery group (2.2% and 1.9%, respectively; odds ratio with planned cesarean delivery, 1.16; 95% confidence interval, 0.77 to 1.74; P = 0.49).
CONCLUSIONS
In twin pregnancy between 32 weeks 0 days and 38 weeks 6 days of gestation, with the first twin in the cephalic presentation, planned cesarean delivery did not significantly decrease or increase the risk of fetal or neonatal death or serious neonatal morbidity, as compared with planned vaginal delivery. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00187369; Current Controlled Trials number, ISRCTN74420086.)
doi:10.1056/NEJMoa1214939
PMCID: PMC3954096  PMID: 24088091 CAMSID: cams3905
6.  Exposure to repeat doses of antenatal glucocorticoids is associated with altered cardiovascular status after birth 
Objective
To determine if exposure to more than one course of antenatal glucocorticoids is associated with changes in infant blood pressure and myocardial wall thickness in the first month after birth.
Design
Prospective cohort study.
Setting
Tertiary neonatal intensive care unit.
Participants
Mothers who were eligible for but declined to enter a randomised trial of repeated doses of antenatal glucocorticoids (ACTORDS)—that is, who had a singleton, twin, or triplet pregnancy at <32 weeks gestation, had received an initial course of glucocorticoids seven or more days previously, and were considered to be at continued risk of preterm birth.
Main outcome measures
Blood pressure daily for the first week then weekly until 4 weeks of age. End diastolic interventricular septal and left ventricular posterior wall (EDIVS and EDLVPW) thickness at 48–72 hours after birth.
Results
Thirty seven women were enrolled and delivered 50 infants. Thirty mothers (39 infants) were exposed to one course of glucocorticoids, and seven mothers (11 infants) to more than one course. Blood pressures were higher in the first week after birth in infants exposed to multiple courses of glucocorticoids, and in infants with a latency between last exposure and delivery of less than seven days. Systolic blood pressure on day 1 was >2SD above published normal ranges in 67% of babies exposed to multiple courses and 24% of babies exposed to a single course of glucocorticoids (p  =  0.04). There was no difference between groups in thickness of the EDIVS or EDLVPW. However, 44/50 (88%) babies had EDIVS and 49/50 (98%) babies had EDLVPW thickness >2 SD above the expected mean for birth weight and gestation. EDIVS but not EDLVPW thickness increased with increasing latency (mean 0.02 mm/day, p  =  0.03).
Conclusion
Future randomised trials should assess the long term effects of exposure to antenatal glucocorticoids, particularly multiple courses, on the cardiovascular status of the infant.
doi:10.1136/adc.2004.065300
PMCID: PMC2672653  PMID: 16174665
corticosteroids; premature; blood pressure; cardiac hypertrophy
7.  Effects on birth weight and perinatal mortality of maternal dietary supplements in rural Gambia: 5 year randomised controlled trial . 
BMJ : British Medical Journal  1997;315(7111):786-790.
OBJECTIVE: To test the efficacy in terms of birth weight and infant survival of a diet supplement programme in pregnant African women through a primary healthcare system. DESIGN: 5 year controlled trial of all pregnant women in 28 villages randomised to daily supplementation with high energy groundnut biscuits (4.3 MJ/day) for about 20 weeks before delivery (intervention) or after delivery (control). SETTING: Rural Gambia. SUBJECTS: Chronically undernourished women (twin bearers excluded), yielding 2047 singleton live births and 35 stillbirths. MAIN OUTCOME MEASURES: Birth weight; prevalence of low birth weight (< 2500 g); head circumference; birth length; gestational age; prevalence of stillbirths; neonatal and postneonatal mortality. RESULTS: Supplementation increased weight gain in pregnancy and significantly increased birth weight, particularly during the nutritionally debilitating hungry season (June to October). Weight gain increased by 201 g (P < 0.001) in the hungry season, by 94 g (P < 0.01) in the harvest season (November to May), and by 136 g (P < 0.001) over the whole year. The odds ratio for low birthweight babies in supplemented women was 0.61 (95% confidence interval 0.47 to 0.79, P < 0.001). Head circumference was significantly increased (P < 0.01), but by only 3.1 mm. Birth length and duration of gestation were not affected. Supplementation significantly reduced perinatal mortality: the odds ratio was 0.47 (0.23 to 0.99, P < 0.05) for stillbirths and 0.54 (0.35 to 0.85, P < 0.01) for all deaths in first week of life. Mortality after 7 days was unaffected. CONCLUSION: Prenatal dietary supplementation reduced retardation in intrauterine growth when effectively targeted at genuinely at-risk mothers. This was associated with a substantial reduction in the prevalence of stillbirths and in early neonatal mortality. The intervention can be successfully delivered through a primary healthcare system.
PMCID: PMC2127544  PMID: 9345173
8.  Induction of labour versus expectant monitoring in women with pregnancy induced hypertension or mild preeclampsia at term: the HYPITAT trial 
Background
Hypertensive disorders, i.e. pregnancy induced hypertension and preeclampsia, complicate 10 to15% of all pregnancies at term and are a major cause of maternal and perinatal morbidity and mortality. The only causal treatment is delivery. In case of preterm pregnancies conservative management is advocated if the risks for mother and child remain acceptable. In contrast, there is no consensus on how to manage mild hypertensive disease in pregnancies at term. Induction of labour might prevent maternal and neonatal complications at the expense of increased instrumental vaginal delivery rates and caesarean section rates.
Methods/Design
Women with a pregnancy complicated by pregnancy induced hypertension or mild preeclampsia at a gestational age between 36+0 and 41+0 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant management for spontaneous delivery. The primary outcome of this study is severe maternal morbidity, which can be complicated by maternal mortality in rare cases. Secondary outcome measures are neonatal mortality and morbidity, caesarean and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be by intention to treat. In total, 720 pregnant women have to be randomised to show a reduction in severe maternal complications of hypertensive disease from 12 to 6%.
Discussion
This trial will provide evidence as to whether or not induction of labour in women with pregnancy induced hypertension or mild preeclampsia (nearly) at term is an effective treatment to prevent severe maternal complications.
Trial Registration
The protocol is registered in the clinical trial register number ISRCTN08132825.
doi:10.1186/1471-2393-7-14
PMCID: PMC1950708  PMID: 17662114
9.  Birth after caesarean study – planned vaginal birth or planned elective repeat caesarean for women at term with a single previous caesarean birth: protocol for a patient preference study and randomised trial 
Background
For women who have a caesarean section in their preceding pregnancy, two care policies for birth are considered standard: planned vaginal birth and planned elective repeat caesarean. Currently available information about the benefits and harms of both forms of care are derived from retrospective and prospective cohort studies. There have been no randomised trials, and recognising the deficiencies in the literature, there have been calls for methodologically rigorous studies to assess maternal and infant health outcomes associated with both care policies.
The aims of our study are to assess in women with a previous caesarean birth, who are eligible in the subsequent pregnancy for a vaginal birth, whether a policy of planned vaginal birth after caesarean compared with a policy of planned repeat caesarean affects the risk of serious complications for the woman and her infant.
Methods/Design
Design: Multicentred patient preference study and a randomised clinical trial.
Inclusion Criteria: Women with a single prior caesarean presenting in their next pregnancy with a single, live fetus in cephalic presentation, who have reached 37 weeks gestation, and who do not have a contraindication to a planned VBAC.
Trial Entry & Randomisation: Eligible women will be given an information sheet during pregnancy, and will be recruited to the study from 37 weeks gestation after an obstetrician has confirmed eligibility for a planned vaginal birth. Written informed consent will be obtained. Women who consent to the patient preference study will be allocated their preference for either planned VBAC or planned, elective repeat caesarean. Women who consent to the randomised trial will be randomly allocated to either the planned vaginal birth after caesarean or planned elective repeat caesarean group.
Treatment Groups: Women in the planned vaginal birth group will await spontaneous onset of labour whilst appropriate. Women in the elective repeat caesarean group will have this scheduled for between 38 and 40 weeks.
Primary Study Outcome: Serious adverse infant outcome (death or serious morbidity).
Sample Size: 2314 women in the patient preference study to show a difference in adverse neonatal outcome from 1.6% to 3.6% (p = 0.05, 80% power).
Clinical Trial Registration
ISCTRN5397431
doi:10.1186/1471-2393-7-17
PMCID: PMC1988834  PMID: 17697343
10.  Birth order, gestational age, and risk of delivery related perinatal death in twins: retrospective cohort study 
BMJ : British Medical Journal  2002;325(7371):1004.
Objective
To determine whether twins born second are at increased risk of perinatal death because of complications during labour and delivery.
Design
Retrospective cohort study.
Setting
Scotland, 1992 and 1997.
Participants
All twin births at or after 24 weeks' gestation, excluding twin pairs in which either twin died before labour or delivery or died during or after labour and delivery because of congenital abnormality, non-immune hydrops, or twin to twin transfusion syndrome.
Main outcome measure
Delivery related perinatal deaths (deaths during labour or the neonatal period).
Results
Overall, delivery related perinatal deaths were recorded for 23 first twins only and 23 second twins only of 1438 twin pairs born before 36 weeks (preterm) by means other than planned caesarean section (P>0.99). No deaths of first twins and nine deaths of second twins (P=0.004) were recorded among the 2436 twin pairs born at or after 36 weeks (term). Discordance between first and second twins differed significantly in preterm and term births (P=0.007). Seven of nine deaths of second twins at term were due to anoxia during the birth (2.9 (95% confidence interval 1.2 to 5.9) per 1000); five of these deaths were associated with mechanical problems with the second delivery following vaginal delivery of the first twin. No deaths were recorded among 454 second twins delivered at term by planned caesarean section.
Conclusions
Second twins born at term are at higher risk than first twins of death due to complications of delivery. Previous studies may not have shown an increased risk because of inadequate categorisation of deaths, lack of statistical power, inappropriate analyses, and pooling of data about preterm births and term births.
What is already known on this topicIt is difficult to assess the wellbeing of second twins during labourDeliveries of second twins are at increased risk of mechanical problems, such as cord prolapse and malpresentation, after vaginal delivery of first twinsIncreased risks of perinatal death in second twins have not been shown, but the methods of these studies were flawedWhat this study addsSecond twins delivered at term are at increased risk of delivery related perinatal deathsIntrapartum anoxia caused 75% of these deaths in second twins, and most of these resulted from mechanical problems after vaginal delivery of first twinsPlanned caesarean section of twins at term may prevent perinatal deaths
PMCID: PMC131015  PMID: 12411358
11.  A complex intervention to improve pregnancy outcome in obese women; the UPBEAT randomised controlled trial 
Background
Despite the widespread recognition that obesity in pregnant women is associated with adverse outcomes for mother and child, there is no intervention proven to reduce the risk of these complications. The primary aim of this randomised controlled trial is to assess in obese pregnant women, whether a complex behavioural intervention, based on changing diet (to foods with a lower glycemic index) and physical activity, will reduce the risk of gestational diabetes (GDM) and delivery of a large for gestational age (LGA) infant. A secondary aim is to determine whether the intervention lowers the long term risk of obesity in the offspring.
Methods/Design
Multicentre randomised controlled trial comparing a behavioural intervention designed to improve glycemic control with standard antenatal care in obese pregnant women.
Inclusion criteria; women with a BMI ≥30 kg/m2 and a singleton pregnancy between 15+0 weeks and 18+6 weeks’ gestation. Exclusion criteria; pre-defined, pre-existing diseases and multiple pregnancy. Randomisation is on-line by a computer generated programme and is minimised by BMI category, maternal age, ethnicity, parity and centre. Intervention; this is delivered by a health trainer over 8 sessions. Based on control theory, with elements of social cognitive theory, the intervention is designed to improve maternal glycemic control. Women randomised to the control arm receive standard antenatal care until delivery according to local guidelines. All women have a 75 g oral glucose tolerance test at 27+0- 28+6 weeks’ gestation.
Primary outcome; Maternal: diagnosis of GDM, according to the International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria. Neonatal; infant LGA defined as >90th customised birth weight centile.
Sample size; 1546 women to provide 80% power to detect a 25% reduction in the incidence of GDM and a 30% reduction in infants large for gestational age.
Discussion
All aspects of this protocol have been evaluated in a pilot randomised controlled trial, with subsequent optimisation of the intervention. The findings of this trial will inform whether lifestyle mediated improvement of glycemic control in obese pregnant women can minimise the risk of pregnancy complications.
Trial registration
Current controlled trials; ISRCTN89971375.
doi:10.1186/1471-2393-14-74
PMCID: PMC3938821  PMID: 24533897
Study protocol; Pregnancy; Obesity; Complex intervention; Randomised controlled trial; Glycemic index; Physical activity; Gestational diabetes; Large for gestational age
12.  Birth order of twins and risk of perinatal death related to delivery in England, Northern Ireland, and Wales, 1994-2003: retrospective cohort study 
BMJ : British Medical Journal  2007;334(7593):576.
Objective To determine the effect of birth order on the risk of perinatal death in twin pregnancies.
Design Retrospective cohort study.
Setting England, Northern Ireland, and Wales, 1994-2003.
Participants 1377 twin pregnancies with one intrapartum stillbirth or neonatal death from causes other than congenital abnormality and one surviving infant.
Main outcome measures The risk of perinatal death in the first and second twin estimated with conditional logistic regression.
Results There was no association between birth order and the risk of death overall (odds ratio 1.0, 95% confidence interval 0.9 to 1.1). However, there was a highly significant interaction with gestational age (P<0.001). There was no association between birth order and the risk of death among infants born before 36 weeks' gestation but there was an increased risk of death among second twins born at term (2.3, 1.7 to 3.2, P<0.001), which was stronger for deaths caused by intrapartum anoxia or trauma (3.4, 2.2 to 5.3). Among term births, there was a trend (P=0.1) towards a greater risk of the second twin dying from anoxia among those delivered vaginally (4.1, 1.8 to 9.5) compared with those delivered by caesarean section (1.8, 0.9 to 3.6).
Conclusions In this cohort, compared with first twins, second twins born at term were at increased risk of perinatal death related to delivery. Vaginally delivered second twins had a fourfold risk of death caused by intrapartum anoxia.
doi:10.1136/bmj.39118.483819.55
PMCID: PMC1828292  PMID: 17337456
13.  Progesterone for the prevention of preterm birth in women with multiple pregnancies: the AMPHIA trial 
Background
15% of multiple pregnancies ends in a preterm delivery, which can lead to mortality and severe long term neonatal morbidity. At present, no generally accepted strategy for the prevention of preterm birth in multiple pregnancies exists. Prophylactic administration of 17-alpha hydroxyprogesterone caproate (17OHPC) has proven to be effective in the prevention of preterm birth in women with singleton pregnancies with a previous preterm delivery. At present, there are no data on the effectiveness of progesterone in the prevention of preterm birth in multiple pregnancies.
Methods/Design
We aim to investigate the hypothesis that 17OHPC will reduce the incidence of the composite neonatal morbidity of neonates by reducing the early preterm birth rate in multiple pregnancies. Women with a multiple pregnancy at a gestational age between 15 and 20 weeks of gestation will be entered in a placebo-controlled, double blinded randomised study comparing weekly 250 mg 17OHPC intramuscular injections from 16–20 weeks up to 36 weeks of gestation versus placebo. At study entry, cervical length will be measured. The primary outcome is composite bad neonatal condition (perinatal death or severe morbidity). Secondary outcome measures are time to delivery, preterm birth rate before 32 and 37 weeks, days of admission in neonatal intensive care unit, maternal morbidity, maternal admission days for preterm labour and costs. We need to include 660 women to indicate a reduction in bad neonatal outcome from 15% to 8%. Analysis will be by intention to treat. We will also analyse whether the treatment effect is dependent on cervical length.
Discussion
This trial will provide evidence as to whether or not 17OHPC-treatment is an effective means of preventing bad neonatal outcome due to preterm birth in multiple pregnancies.
Trial registration
Current Controlled Trials ISRCTN40512715
doi:10.1186/1471-2393-7-7
PMCID: PMC1914085  PMID: 17578562
14.  Limiting weight gain in overweight and obese women during pregnancy to improve health outcomes: the LIMIT randomised controlled trial 
Background
Obesity is a significant global health problem, with the proportion of women entering pregnancy with a body mass index greater than or equal to 25 kg/m2 approaching 50%. Obesity during pregnancy is associated with a well-recognised increased risk of adverse health outcomes both for the woman and her infant, however there is more limited information available regarding effective interventions to improve health outcomes.
The aims of this randomised controlled trial are to assess whether the implementation of a package of dietary and lifestyle advice to overweight and obese women during pregnancy to limit gestational weight gain is effective in improving maternal, fetal and infant health outcomes.
Methods/Design
Design: Multicentred randomised, controlled trial.
Inclusion Criteria: Women with a singleton, live gestation between 10+0-20+0 weeks who are obese or overweight (defined as body mass index greater than or equal to 25 kg/m2), at the first antenatal visit.
Trial Entry & Randomisation: Eligible, consenting women will be randomised between 10+0 and 20+0 weeks gestation using a central telephone randomisation service, and randomisation schedule prepared by non-clinical research staff with balanced variable blocks. Stratification will be according to maternal BMI at trial entry, parity, and centre where planned to give birth.
Treatment Schedules: Women randomised to the Dietary and Lifestyle Advice Group will receive a series of inputs from research assistants and research dietician to limit gestational weight gain, and will include a combination of dietary, exercise and behavioural strategies.
Women randomised to the Standard Care Group will continue to receive their pregnancy care according to local hospital guidelines, which does not currently include routine provision of dietary, lifestyle and behavioural advice.
Outcome assessors will be blinded to the allocated treatment group.
Primary Study Outcome: infant large for gestational age (defined as infant birth weight ≥ 90th centile for gestational age).
Sample Size: 2,180 women to detect a 30% reduction in large for gestational age infants from 14.40% (p = 0.05, 80% power, two-tailed).
Discussion
This is a protocol for a randomised trial. The findings will contribute to the development of evidence based clinical practice guidelines.
Trial Registration
Australian and New Zealand Clinical Trials Registry ACTRN12607000161426
doi:10.1186/1471-2393-11-79
PMCID: PMC3219553  PMID: 22026403
15.  Treatment of trichomoniasis in pregnancy in sub-Saharan Africa does not appear to be associated with low birth weight or preterm birth 
Objectives
To determine whether treatment of trichomoniasis increases the risk of prematurity.
Design
Sub-analysis of a randomised trial.
Setting
We analysed data from HPTN 024, a randomised trial of antenatal and intrapartum antibiotics to reduce chorioamnionitis-related perinatal HIV transmission.
Subjects
Pregnant women from four sites in Africa.
Outcome measures
Gestational age at the time of delivery or mean birth weight.
Results
Of 2 428 women-infant pairs included, 428 (18%) had trichomoniasis at enrolment. There were no differences in infant age or birth weight between women with or without trichomoniasis. By randomisation group, there were no differences in gestational age at birth or birth weight. Of the 428 women diagnosed with trichomoniasis, 365 (83%) received antibiotics and 63 (15%) did not. In analysis of actual use of antibiotics, women with trichomoniasis who received no treatment were more likely to deliver a preterm infant when the symphysis-fundal height was used to estimate gestational age (36% v. 23%; p=0.03), but not when the Ballard score was used (16% v. 21%; p=0.41). There were no differences in mean birth weight between groups.
Conclusions
In pregnant women in sub-Saharan Africa, most of whom were HIV-infected, neither trichomoniasis nor its treatment appears to influence the risk of preterm birth or a low-birth-weight infant.
PMCID: PMC3090676  PMID: 20429491
16.  Protocol for a randomised controlled trial of treatment of asymptomatic candidiasis for the prevention of preterm birth [ACTRN12610000607077] 
Background
Prevention of preterm birth remains one of the most important challenges in maternity care. We propose a randomised trial with: a simple Candida testing protocol that can be easily incorporated into usual antenatal care; a simple, well accepted, treatment intervention; and assessment of outcomes from validated, routinely-collected, computerised databases.
Methods/Design
Using a prospective, randomised, open-label, blinded-endpoint (PROBE) study design, we aim to evaluate whether treating women with asymptomatic vaginal candidiasis early in pregnancy is effective in preventing spontaneous preterm birth. Pregnant women presenting for antenatal care <20 weeks gestation with singleton pregnancies are eligible for inclusion. The intervention is a 6-day course of clotrimazole vaginal pessaries (100 mg) and the primary outcome is spontaneous preterm birth <37 weeks gestation.
The study protocol draws on the usual antenatal care schedule, has been pilot-tested and the intervention involves only a minor modification of current practice. Women who agree to participate will self-collect a vaginal swab and those who are culture positive for Candida will be randomised (central, telephone) to open-label treatment or usual care (screening result is not revealed, no treatment, routine antenatal care). Outcomes will be obtained from population databases.
A sample size of 3,208 women with Candida colonisation (1,604 per arm) is required to detect a 40% reduction in the spontaneous preterm birth rate among women with asymptomatic candidiasis from 5.0% in the control group to 3.0% in women treated with clotrimazole (significance 0.05, power 0.8). Analyses will be by intention to treat.
Discussion
For our hypothesis, a placebo-controlled trial had major disadvantages: a placebo arm would not represent current clinical practice; knowledge of vaginal colonisation with Candida may change participants' behaviour; and a placebo with an alcohol preservative may have an independent affect on vaginal flora. These disadvantages can be overcome by the PROBE study design.
This trial will provide definitive evidence on whether screening for and treating asymptomatic candidiasis in pregnancy significantly reduces the rate of spontaneous preterm birth. If it can be demonstrated that treating asymptomatic candidiasis reduces preterm births this will change current practice and would directly impact the management of every pregnant woman.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12610000607077
doi:10.1186/1471-2393-11-19
PMCID: PMC3061957  PMID: 21396091
17.  Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials 
Background
Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death.
Methods/design
We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups.
Discussion
Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups.
doi:10.1186/1471-2393-12-13
PMCID: PMC3315727  PMID: 22420582
18.  Prenatal diagnosis of conjoined twins: four cases in a prenatal center 
Objective
To assess the findings in conjoined twins diagnosed prenatally.
Material and Methods
Between January 2002 and June 2009, we reviewed the database and medical records of 857 twin pregnancies, including 140 monochorionic twins. Nineteen monochorionic-monoamniotic twin pregnancies were detected, four of which were complicated by conjoined twins.
Results
Of these 4 cases, 2 were complicated by thoracopagus and one had thoraco-omphalopagus; these three cases underwent termination at 16, 11, and 19 weeks gestation, respectively. The last case was diagnosed as a pygopagus tetrapus parasitic twin at 28 weeks gestation. The family decided to continue the pregnancy, and achieved a successful outcome with elective surgery postpartum.
Conclusion
Conjoined twins are an uncommon and complex complication of monozygotic gestations, which is associated with high perinatal mortality. The early prenatal diagnosis of conjoined twins allows improved counseling about the management options, including maintenance of pregnancy with surgery after delivery or termination of pregnancy.
doi:10.5152/jtgga.2010.32
PMCID: PMC3939146  PMID: 24591931
Conjoined twins; prenatal diagnosis
19.  Maternal and neonatal outcome in pregnancies with no risk factors. 
Between November 1979 and April 1984, 790 consecutive pregnant women who considered themselves as having a "normal" pregnancy were followed in private practice from 9 weeks' gestation until 6 weeks post partum. The women had no pre-existing disease or problem classified as a risk to the pregnancy at the time of their first visit, had a singleton pregnancy and gave birth at Notre-Dame Hospital, Montreal. Maternal complications occurred during the course of pregnancy in 181 women (23%). Complications were mostly related to obstetric conditions (10%), such as preterm labour, intrauterine growth retardation (IUGR) and antepartum hemorrhage, or to medical conditions (12%), the most prevalent of which was hypertension (77% of medical conditions). Neonatal complications occurred in 183 infants (23%). The corrected perinatal death rate was 2.5 per 1000. Prematurity, IUGR and dysmaturity/postmaturity accounted for nearly half of the complications. Hyperbilirubinemia occurred in 7% of the cases. Among women without any maternal complications during pregnancy, the frequency rate of neonatal complications was 19%, compared with 23% among the entire group of 790 women. Our results suggest that the absence of maternal complications does not protect the infant from a neonatal complication. Further refinement is needed to identify markers of obstetric, medical and neonatal complications in pregnancies with no risk factors.
PMCID: PMC1267309  PMID: 3651944
20.  The IDEAL study: investigation of dietary advice and lifestyle for women with borderline gestational diabetes: a randomised controlled trial - study protocol 
Background
The Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS) showed that treatment of pregnant women with mild gestational diabetes mellitus is beneficial for both women and their infants. It is still uncertain whether there are benefits of similar treatment for women with borderline gestational diabetes.
This trial aims to assess whether dietary and lifestyle advice and treatment given to pregnant women who screen for borderline gestational diabetes reduces neonatal complications and maternal morbidities.
Methods/design
Design: Multicentre, randomised controlled trial.
Inclusion criteria: Women between 240 and 346 weeks gestation with a singleton pregnancy, a positive oral glucose challenge test (venous plasma glucose ≥7.8 mmol/L) and a normal oral 75 gram glucose tolerance test (fasting venous plasma glucose <5.5 mmol/L and a 2 hour glucose <7.8 mmol/L) with written, informed consent.
Trial entry and randomisation: Women with an abnormal oral glucose tolerance test (fasting venous plasma glucose ≥5.5 mmol/L or 2 hour glucose ≥7.8 mmol/L) will not be eligible and will be offered treatment for gestational diabetes, consistent with recommendations based on results of the ACHOIS trial. Eligible women will be randomised into either the ‘Routine Care Group’ or the ‘Intervention Group’.
Study groups: Women in the ‘Routine Care Group’ will receive routine obstetric care reflecting current clinical practice in Australian hospitals. Women in the ‘Intervention Group’ will receive obstetric care, which will include dietary and lifestyle advice, monitoring of blood glucose and further medical treatment for hyperglycaemia as appropriate.
Primary study outcome: Incidence of large for gestational age infants.
Sample size: A sample size of 682 women will be sufficient to show a 50% reduction in the risk of large for gestational age infants (alpha 0.05 two-tailed, 80% power, 4% loss to follow up) from 14% to 7% with dietary and lifestyle advice and treatment.
Discussion
A conclusive trial outcome will provide reliable evidence of relevance for the care of women with borderline glucose intolerance in pregnancy and their infants.
Trial registration
Australian New Zealand Clinical Trials Registry - ACTRN12607000174482
doi:10.1186/1471-2393-12-106
PMCID: PMC3506505  PMID: 23046499
Borderline gestational diabetes; Gestational diabetes mellitus; Randomised controlled trial; Diet; Lifestyle; Large for gestational age
21.  Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies 
BMJ : British Medical Journal  2004;328(7434):261.
Objective To compare the perinatal outcome of singleton and twin pregnancies between natural and assisted conceptions.
Design Systematic review of controlled studies published 1985-2002.
Studies reviewed 25 studies were included of which 17 had matched and 8 had non-matched controls.
Main outcome measures Very preterm birth, preterm birth, very low birth weight, low birth weight, small for gestational age, caesarean section, admission to neonatal intensive care unit, and perinatal mortality.
Results For singletons, studies with matched controls indicated a relative risk of 3.27 (95% confidence interval 2.03 to 5.28) for very preterm (< 32 weeks) and 2.04 (1.80 to 2.32) for preterm (< 37 weeks) birth in pregnancies after assisted conception. Relative risks were 3.00 (2.07 to 4.36) for very low birth weight (< 1500 g), 1.70 (1.50 to 1.92) for low birth weight (< 2500 g), 1.40 (1.15 to 1.71) for small for gestational age, 1.54 (1.44 to 1.66) for caesarean section, 1.27 (1.16 to 1.40) for admission to a neonatal intensive care unit, and 1.68 (1.11 to 2.55) for perinatal mortality. Results of the non-matched studies were similar. In matched studies of twin gestations, relative risks were 0.95 (0.78 to 1.15) for very preterm birth, 1.07 (1.02 to 1.13) for preterm birth, 0.89 (0.74 to 1.07) for very low birth weight, 1.03 (0.99 to 1.08) for low birth weight, 1.27 (0.97 to 1.65) for small for gestational age, 1.21 (1.11 to 1.32) for caesarean section, 1.05 (1.01 to 1.09) for admission to a neonatal intensive care unit, and 0.58 (0.44 to 0.77) for perinatal mortality. The non-matched studies mostly showed similar trends.
Conclusions Singleton pregnancies from assisted reproduction have a significantly worse perinatal outcome than non-assisted singleton pregnancies, but this is less so for twin pregnancies. In twin pregnancies, perinatal mortality is about 40% lower after assisted compared with natural conception.
doi:10.1136/bmj.37957.560278.EE
PMCID: PMC324454  PMID: 14742347
22.  Long-Term Neurodevelopmental Outcome of Monochorionic and Matched Dichorionic Twins 
PLoS ONE  2009;4(8):e6815.
Background
Monochorionic (MC) twins are at increased risk for perinatal mortality and serious morbidity due to the presence of placental vascular anastomoses. Cerebral injury can be secondary to haemodynamic and hematological disorders during pregnancy (especially twin-to-twin transfusion syndrome (TTTS) or intrauterine co-twin death) or from postnatal injury associated with prematurity and low birth weight, common complications in twin pregnancies. We investigated neurodevelopmental outcome in MC and dichorionic (DC) twins at the age of two years.
Methods
This was a prospective cohort study. Cerebral palsy (CP) was studied in 182 MC infants and 189 DC infants matched for weight and age at delivery, gender, ethnicity of the mother and study center. After losses to follow-up, 282 of the 366 infants without CP were available to be tested with the Griffiths Mental Developmental Scales at 22 months corrected age, all born between January 2005 and January 2006 in nine perinatal centers in The Netherlands. Due to phenotypic (un)alikeness in mono-or dizygosity, the principal investigator was not blinded to chorionic status; perinatal outcome, with exception of co-twin death, was not known to the examiner.
Findings
Four out of 182 MC infants had CP (2.2%) - two of the four CP-cases were due to complications specific to MC twin pregnancies (TTTS and co-twin death) and the other two cases of CP were the result of cystic PVL after preterm birth - compared to one sibling of a DC twin (0.5%; OR 4.2, 95% CI 0.5–38.2) of unknown origin. Follow-up rate of neurodevelopmental outcome by Griffith's test was 76%. The majority of 2-year-old twins had normal developmental status. There were no significant differences between MC and DC twins. One MC infant (0.7%) had a developmental delay compared to 6 DC infants (4.2%; OR 0.2, 95% 0.0–1.4). Birth weight discordancy did not influence long-term outcome, though the smaller twin had slightly lower developmental scores than its larger co-twin.
Conclusions
There were no significant differences in occurrence of cerebral palsy as well as neurodevelopmental outcome between MC and DC twins. Outcome of MC twins seems favourable in the absence of TTTS or co-twin death.
doi:10.1371/journal.pone.0006815
PMCID: PMC2728837  PMID: 19714240
23.  Use of antenatal corticosteroids prior to preterm birth in four South East Asian countries within the SEA-ORCHID project 
Background
There is strong evidence supporting the use of antenatal corticosteroids in women at risk of preterm birth to promote fetal lung maturation and reduce neonatal mortality and morbidity. This audit aimed to assess the use of antenatal corticosteroids prior to preterm birth in the nine hospitals in four South East Asian countries participating in the South East Asia Optimising Reproductive Health in Developing Countries (SEA-ORCHID) Project.
Method
We reviewed the medical records of 9550 women (9665 infants including 111 twins and two triplets) admitted to the labour wards of nine hospitals in four South East Asian countries during 2005. For women who gave birth before 34 weeks gestation we collected information on women's demographic and pregnancy background, the type, dose and use of corticosteroids, and key birth and infant outcomes.
Results
Administration of antenatal corticosteroids to women who gave birth before 34 weeks gestation varied widely between countries (9% to 73%) and also between hospitals within countries (0% to 86%). Antenatal corticosteroids were most commonly given when women were between 28 and 34 weeks gestation (80%). Overall 6% of women received repeat doses of corticosteroids. Dexamethasone was the only type of antenatal corticosteroid used.
Women receiving antenatal corticosteroids compared with those not given antenatal corticosteroids were less likely to have had a previous pregnancy and to be booked for birth at the hospital and almost three times as likely to have a current multiple pregnancy. Exposed women were less likely to be induced and almost twice as likely to have a caesarean section, a primary postpartum haemorrhage and postpartum pyrexia.
Infants exposed to antenatal corticosteroids compared with infants not exposed were less likely to die. Live born exposed infants were less likely to have Apgar scores of < 7 at five minutes and less likely to have any lung disease.
Conclusion
In this survey the use of antenatal corticosteroids prior to preterm birth varied between countries and hospitals. Evaluation of the enablers and barriers to the uptake of this effective antenatal intervention at individual hospitals is needed.
doi:10.1186/1471-2393-8-47
PMCID: PMC2596081  PMID: 18925968
24.  Risk Factors for Preterm Birth in an International Prospective Cohort of Nulliparous Women 
PLoS ONE  2012;7(7):e39154.
Objectives
To identify risk factors for spontaneous preterm birth (birth <37 weeks gestation) with intact membranes (SPTB-IM) and SPTB after prelabour rupture of the membranes (SPTB-PPROM) for nulliparous pregnant women.
Design
Prospective international multicentre cohort.
Participants
3234 healthy nulliparous women with a singleton pregnancy, follow up was complete in 3184 of participants (98.5%).
Results
Of the 3184 women, 156 (4.9%) had their pregnancy complicated by SPTB; 96 (3.0%) and 60 (1.9%) in the SPTB-IM and SPTB-PPROM categories, respectively. Independent risk factors for SPTB-IM were shorter cervical length, abnormal uterine Doppler flow, use of marijuana pre-pregnancy, lack of overall feeling of well being, being of Caucasian ethnicity, having a mother with diabetes and/or a history of preeclampsia, and a family history of low birth weight babies. Independent risk factors for SPTB-PPROM were shorter cervical length, short stature, participant’s not being the first born in the family, longer time to conceive, not waking up at night, hormonal fertility treatment (excluding clomiphene), mild hypertension, family history of recurrent gestational diabetes, and maternal family history of any miscarriage (risk reduction). Low BMI (<20) nearly doubled the risk for SPTB-PPROM (odds ratio 2.64; 95% CI 1.07–6.51). The area under the receiver operating characteristics curve (AUC), after internal validation, was 0.69 for SPTB-IM and 0.79 for SPTB-PPROM.
Conclusion
The ability to predict PTB in healthy nulliparous women using clinical characteristics is modest. The dissimilarity of risk factors for SPTB-IM compared with SPTB-PPROM indicates different pathophysiological pathways underlie these distinct phenotypes.
Trial Registration
ACTR.org.au ACTRN12607000551493
doi:10.1371/journal.pone.0039154
PMCID: PMC3398037  PMID: 22815699
25.  The Early External Cephalic Version (ECV) 2 Trial: an international multicentre randomised controlled trial of timing of ECV for breech pregnancies 
Bjog  2011;118(5):564-577.
Objective
To investigate whether initiating external cephalic version (ECV) earlier in pregnancy might increase the rate of successful ECV procedures, and be more effective in decreasing the rate of non-cephalic presentation at birth and of caesarean section.
Design
An unblinded multicentred randomised controlled trial.
Setting
A total of 1543 women were randomised from 68 centres in 21 countries.
Population
Women with a singleton breech fetus at a gestational age of 330/7 weeks (231 days) to 356/7 weeks (251 days) of gestation were included.
Methods
Participants were randomly assigned to having a first ECV procedure between the gestational ages of 340/7 (238 days) and 356/7 weeks of gestation (early ECV group) or at or after 370/7 (259 days) weeks of gestation (delayed ECV group).
Main outcome measures
The primary outcome was the rate of caesarean section; the secondary outcome was the rate of preterm birth.
Results
Fewer fetuses were in a non-cephalic presentation at birth in the early ECV group (314/765 [41.1%] versus 377/768 [49.1%] in the delayed ECV group; relative risk [RR] 0.84, 95% CI 0.75, 0.94, P = 0.002). There were no differences in rates of caesarean section (398/765 [52.0%] versus 430/768 [56.0%]; RR 0.93, 95% CI 0.85, 1.02, P = 0.12) or in risk of preterm birth (50/765 [6.5%] versus 34/768 [4.4%]; RR 1.48, 95% CI 0.97, 2.26, P = 0.07) between groups.
Conclusion
External cephalic version at 34–35 weeks versus 37 or more weeks of gestation increases the likelihood of cephalic presentation at birth but does not reduce the rate of caesarean section and may increase the rate of preterm birth.
doi:10.1111/j.1471-0528.2010.02837.x
PMCID: PMC3085121  PMID: 21291506
Breech pregnancy; caesarean section; external cephalic version; fetal version; randomised controlled trial

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