landmark trials Flashcards
What is the primary research question of the TRUFFLE study?
Assess whether changes in fetal ductus venosus (DV) doppler waveform changes could be used instead of short-term variation (STV) to trigger delivery in pregnancies with diagnosis of fetal growth restriction.
What was the study design of the TRUFFLE trial?
Prospective, multicentre, unblinded, randomised trial.
What were the inclusion criteria for the TRUFFLE study?
- Singleton pregnancies
- 26-32 weeks of gestation
- Diagnosis of fetal growth restriction (FGR)
- AC < 10th centile
- High umbilical artery doppler PI > 95th centile regardless of EDF pattern.
What were the exclusion criteria for the TRUFFLE study?
- EFW <500g at inclusion
- Abnormal DV A wave or PI at inclusion
- Decreased STV at inclusion
- Fetal structural or karyotype abnormality.
What were the primary and secondary outcomes of the TRUFFLE study?
Primary: survival without neurodevelopmental impairment at 2 years. Secondary: median age of delivery, mean birth weight.
What conclusion was drawn from the TRUFFLE study regarding delivery timing?
The study supports waiting for late DV changes for delivery <32 weeks.
What was the main finding of the CLASP trial regarding low-dose aspirin?
Low-dose aspirin may be justified in women at high risk of early-onset pre-eclampsia.
What was the primary outcome measured in the CLASP trial?
Development of proteinuric pre-eclampsia (PET).
What was the result of the ACTORDS trial concerning repeat prenatal corticosteroids?
Fewer babies exposed to repeat corticosteroids had respiratory distress syndrome.
What was the intervention used in the ACTORDS study?
Repeat IM betamethasone 11.4mg, administered weekly until 32 weeks gestation or until delivery.
What was the primary outcome of the study on prophylactic administration of progesterone?
Preterm delivery before 37 weeks.
What significant result was found regarding preterm delivery rates in the progesterone study?
Reduced rates of preterm delivery in the progesterone group (13.8%) compared to placebo (28.5%).
What was the primary research question of the ACHOIS study?
Effect of treatment of gestational diabetes mellitus on pregnancy outcomes.
What were the inclusion criteria for the ACHOIS study?
- Singleton or twin pregnancy between 16 to 30 weeks
- Attended antenatal clinics at collaborating hospital.
- One or more risk factors for GDM on selective screening.
What was the intervention used in the ACHOIS study?
Individualised dietary advice, blood glucose monitoring, and insulin therapy.
What was the outcome measured regarding neonatal complications in the ACHOIS study?
Composite serious perinatal complications including death, shoulder dystocia, and nerve palsy.
What was a key limitation noted in the TRUFFLE study?
Limited to tertiary centres with specialist MFM able to undertake arterial and venous doppler assessments regularly.
True or False: In the CLASP trial, there was a statistically significant reduction in the development of proteinuric PET with aspirin.
False.
Fill in the blank: The ACTORDS trial found that repeat prenatal corticosteroids reduced the incidence of _______.
[neonatal respiratory distress syndrome].
What was the mean birth weight reported in the primary outcomes of the TRUFFLE study?
1019g.
What was a noted criticism of the ACHOIS study regarding its population?
Women with more severe glucose impairment were excluded.
What are composite serious perinatal complications?
Death, shoulder dystocia, bone fracture, and nerve palsy
These complications are assessed using a standardized checklist during birth.
What was the primary outcome comparing the intervention group to the routine-care group?
Lower rates of serious perinatal outcomes (1% vs 4%; P=0.01, NNT 34)
NNT stands for Number Needed to Treat.
What was the percentage of neonatal nursery admission for the intervention group compared to the routine-care group?
61% in the intervention group vs 71% in the routine-care group (adjusted P=0.01)
Indicates a significant difference in nursery admission rates.
Was there a significant difference in jaundice requiring phototherapy between the two groups?
No significant difference (P = 0.72)
This suggests similar rates of jaundice in both groups.
What was the increase in induction of labour rates in the intervention group?
39% in the intervention group vs 29% in the routine-care group (P< 0.001)
This indicates a significant increase in induction rates.
What were the perinatal death rates in the intervention group compared to the routine care group?
No perinatal deaths in the intervention group; 5 in the routine care group (3 stillbirths and 2 neonatal deaths)
Highlights the safety of the intervention.
What was the impact of the intervention on birth weights?
Lower mean birth weights in the intervention group compared to the routine-care group (P<0.001)
This is associated with earlier deliveries due to higher induction rates.
What percentage of women received insulin in the intervention group?
20% (100 women) in the intervention group vs 3% (17 women) in the routine care group
Reflects the management of gestational diabetes in the study.
What was the conclusion regarding the treatment of GDM?
Dietary advice, blood glucose monitoring, and insulin therapy reduce serious perinatal complications without increasing CS rates
Emphasizes effective management strategies for gestational diabetes.
What was a notable criticism of the study design?
Women were not informed of their diagnosis of gestational diabetes during the study
Raises ethical concerns regarding informed consent.
What is the role of magnesium sulphate in preterm birth?
Used as a neuroprotective agent for fetuses at risk of preterm birth
Aimed at preventing neurological impairments in newborns.
What were the primary outcomes of magnesium sulphate treatment?
No difference in paediatric mortality; reduced risk of cerebral palsy and gross motor dysfunction
Highlights the benefits of magnesium sulphate for neurological outcomes.
What was the NNT to benefit one baby from magnesium sulphate treatment?
63 (95% confidence interval 43 to 155)
Indicates the number of women needed to treat to prevent one case of cerebral palsy.
What were the inclusion criteria for the MAGPIE trial?
Women with preeclampsia not yet given birth or <24h postpartum with specific blood pressure and proteinuria criteria
Ensures that the study population met necessary health conditions.
What was the primary outcome of the MAGPIE trial?
Eclampsia prevention and neonatal death before discharge
Focused on maternal and neonatal health outcomes.
What is the effect of progesterone on preterm birth risk?
Reduces rates of spontaneous delivery <34 weeks
Proven effective for women with a short cervix.
What was the primary outcome of the ARRIVE trial?
Lower risk of composite outcome of perinatal death or severe neonatal complications with elective induction at 39 weeks
Indicates potential benefits of early induction in low-risk pregnancies.
What was the sample size of participants in the ARRIVE trial?
6106 participants (3062 intervention, 3044 comparator)
Reflects the scale of the trial.
What is singleton gestation?
A single fetus developing during pregnancy.
What is the eligibility criterion for twin gestation reduced to singleton?
Reduction must occur before 14 weeks 0 days project gestational age.
What is the gestational age range for randomization in the study?
Between 38 weeks 0 days and 38 weeks 6 days inclusive.
What type of presentation is required for eligibility?
Vertex presentation.
What is an exclusion criterion related to ultrasound timing?
Project gestational age at date of first ultrasound is > 20 weeks 6 days.
What is the maximum gestational age for induction of labour in this study?
Prior to 40 weeks 5 days.
Name a maternal medical condition that excludes participation.
Any diabetes mellitus.
What is the primary outcome of the study?
Composite of perinatal death or severe neonatal complications.
List two severe neonatal complications included in the primary outcome.
- Need for respiratory support within 72 hours after birth
- Hypoxic–ischemic encephalopathy
How is fetal growth restriction defined in this study?
EFW < 10th percentile.
What was the result regarding the primary composite perinatal outcome?
No statistically significant difference in the induction group.
What was the reduction in caesarean delivery in the induction group?
Decreased from 22.2% to 18.6%; RR, 0.84.
What is a criticism regarding the primary outcome’s statistical significance?
Not statistically significant.
What intervention was studied for women at risk for late pre-term delivery?
Antenatal betamethasone.
What was the primary neonatal outcome measured in the betamethasone study?
Neonatal composite outcome for respiratory support by 72 hours.
What was the result of betamethasone administration on neonatal outcomes?
Decreased need for substantial respiratory support.
What increased risk was noted in the betamethasone group?
Increased risk of neonatal hypoglycaemia.
What type of trial was the Term Breech Trial?
International multicentre randomised control trial.
What was the primary outcome of the Term Breech Trial?
Perinatal or neonatal mortality at <28 days of age.
What was the conclusion regarding planned caesarean section versus vaginal birth?
Planned caesarean section is better than planned vaginal birth for term breech presentation.
What is the significance of the NNT in the Term Breech Trial results?
NNT 14 for significantly lower risk of perinatal/neonatal morbidity.
What was a major criticism of the Term Breech Trial?
Standard of care was not consistent.
What was the research question of the TERMPROM study?
Is IOL in women with PROM at term preferable to waiting for spontaneous labour?
What does PROM stand for?
Prelabour rupture of membranes.
What was the study design for the TERMPROM trial?
International multicentre randomised control trial.
What is the research question of the study conducted by Hannah et al?
Is IOL in women with PROM at term preferable to waiting for spontaneous labour if there is no evidence of fetal or maternal compromise.
What was the study design of the trial conducted by Hannah et al?
International, multicentre randomised control trial.
What were the inclusion criteria for the study by Hannah et al?
- ROM > 37 weeks
- Singleton
- Cephalic
What were the exclusion criteria for the study by Hannah et al?
- Active labour
- Previous failed IOL
- Contraindication to IOL
- Meconium-stained liquor
- Chorioamnionitis
What was the intervention in the study by Hannah et al?
Immediate IOL with subgroups IV oxytocin or PV prostaglandin.
What was the comparator in the study by Hannah et al?
Expectant management for up to 4 days.
What were the primary outcomes measured in the study by Hannah et al?
Definite or probable neonatal infection.
How was definite neonatal infection defined in the study by Hannah et al?
Presence of clinical signs of infection and > 1 of the following: positive blood culture, CSF, urine, tracheal aspirate or lung tissue, positive gram stain of CSF, CXR compatible with pneumonia or histologic dx of pneumonia.
What was the conclusion of the study by Hannah et al?
For term PROM, IOL with oxytocin or prostaglandin E2 and expectant management result in similar rates of neonatal infection and caesarean section.
What was the main criticism of the study by Hannah et al?
Women with GBS were not managed differently from those without GBS.
What is the research question of the ORACLE I study?
Does initiating antibiotics in PPROM have benefits for the neonate?
What was the primary outcome measured in the ORACLE I study?
Composite of neonatal death, chronic lung disease, major cerebral abnormality on USS before discharge from hospital.
What were the secondary outcomes of the ORACLE I study?
- Delivery <48hrs or 7 days
- Mode of delivery
- Gestation at birth
- BW <2500g or <1500g
- Admission to NICU
- Requirement for ventilation, RDS
- Positive blood cultures
- NEC
What were the results regarding erythromycin in the ORACLE I study?
Erythromycin alone was associated with decreased primary outcomes vs placebo.
What was the conclusion of the ORACLE I study?
In singleton pregnancies, erythromycin decreases neonatal death, chronic lung disease, and major cerebral abnormality on USS.
What was the research question of the 7-year follow-up of the ORACLE I trial?
Does initiating antibiotics in preterm labour with intact membranes have benefits for the neonate?
What were the primary outcomes measured in the 7-year follow-up of the ORACLE I trial?
Presence of any level of functional impairment from mark III MAHS system.
What was the conclusion of the 7-year follow-up of the ORACLE I trial?
The prescription of antibiotics for women with preterm rupture of the membranes seems to have little effect on the health of children at 7 years of age.
What is the research question of the ORACLE II study?
Does initiating antibiotics in preterm labour with intact membranes have benefits for the neonate?
What were the results regarding the use of antibiotics in the ORACLE II study?
No evidence that use of any antibiotic regimen prolonged pregnancy or influenced mode of delivery.
What was the conclusion of the ORACLE II study?
Antibiotics should not be routinely prescribed to women in spontaneous preterm labour without clinical evidence of infection or PPROM.
What is the research question of the 7-year follow-up of the ORACLE II trial?
Does initiating antibiotics in preterm labour with intact membranes have benefits for the neonate?
What were the primary outcomes measured in the 7-year follow-up of the ORACLE II trial?
Presence of any level of functional impairment from mark III MAHS system.
What was the conclusion of the 7-year follow-up of the ORACLE II trial?
Erythromycin for women in spontaneous preterm labour with intact membranes was associated with an increase in functional impairment among their children at 7 years of age.
What is the research question of the HYPITAT study?
To compare the outcomes of induction of labour and expectant monitoring in pregnant women with gestational hypertension or mild preeclampsia between 36- and 41-weeks’ gestation.
What was the study design of the HYPITAT study?
Multicentre, parallel, open label randomised controlled trial.
What was the number of patients involved in the HYPITAT study?
756 women.
What were the inclusion criteria for the HYPITAT study?
Women with gestational hypertension or mild preeclampsia between 36- and 41-weeks’ gestation.
What was the primary research question of the study on induction of labour and expectant monitoring?
To compare the outcomes of induction of labour and expectant monitoring in pregnant women with gestational hypertension or mild preeclampsia between 36- and 41-weeks’ gestation.
What type of study design was used in the trial comparing induction of labour and expectant monitoring?
Multicentre, parallel, open label randomised controlled trial.
During which years was the study on induction of labour conducted?
2005 - 2008.
How many patients were involved in the trial comparing induction of labour and expectant monitoring?
756 patients.
What were the inclusion criteria for the study on induction of labour?
- Singleton pregnancy
- Cephalic presentation
- Gestational age of between 36 and 41 weeks at enrolment
- Gestational hypertension or mild pre-eclampsia.
How was gestational hypertension defined in the study?
Diastolic blood pressure of 95mm Hg or higher measured on two occasions at least 6 hours apart.
What is mild pre-eclampsia defined as in the study?
Diastolic blood pressure of 90 mm Hg or higher measured on two occasions at least 6 hours apart, combined with proteinuria.
What were the exclusion criteria for the study on induction of labour?
- Severe gestational hypertension or pre-eclampsia
- Use of IV hypertensives or pre-existing hypertension
- HELLP syndrome
- Oliguria of less than 500 mL per 24 h
- Medical conditions such as pre-existing diabetes requiring insulin
- Previous caesarean section
- Fetal anomalies.
What was the primary outcome of the study comparing induction of labour and expectant monitoring?
Composite of maternal mortality, maternal morbidity, progression to severe hypertension or proteinuria, and major postpartum hemorrhage.
What was the result regarding maternal outcomes in the induction of labour group?
Decreased poor maternal outcome (31% vs 44% RR risk 0·71, 95% CI 0·59–0·86, p<0·0001).
What conclusion was drawn from the study on induction of labour for women with mild hypertensive disease?
Induction of labour is associated with improved maternal outcome and should be advised for women with mild hypertensive disease beyond 37 weeks’ gestation.
What was the primary question of the PPROMT trial?
Does a policy of inducing labour reduce neonatal infection without increasing other morbidity?
What was the study design of the PPROMT trial?
Randomised controlled trial using a central telephone service.
How many patients were included in the PPROMT trial?
1839 patients.
What were the inclusion criteria for the PPROMT trial?
- Ruptured membranes prior to the onset of labour between 34+0 and 36+6 weeks
- No clinical signs of infection.
What were the primary outcomes of the PPROMT trial?
Definite or probable neonatal infection.
What was concluded from the PPROMT trial regarding management of PPROM?
In the absence of overt signs of infection or fetal compromise, expectant management with appropriate surveillance should be followed.
What was the main research question in the WOMAN trial?
Does early administration of tranexamic acid affect death, hysterectomy, and other morbidities in women with postpartum hemorrhage?
What study design was used in the WOMAN trial?
International, multicentre, randomised double-blind, placebo-controlled trial.
What was the primary outcome measured in the WOMAN trial?
Composite outcome: death from all causes or hysterectomy within 42 days of randomisation.
What was the result regarding the risk of death due to bleeding in the WOMAN trial?
Risk of death due to bleeding was significantly reduced in patients that received TXA within 3 hours of PPH.
What conclusion was made regarding tranexamic acid in the WOMAN trial?
Tranexamic acid reduces death due to bleeding with no adverse effects.
What was the research question of the antenatal betamethasone study?
Do steroids reduce respiratory distress in babies born by elective caesarean section at term?
What was the primary outcome of the antenatal betamethasone study?
Admission to special care baby unit with respiratory distress.
What was concluded regarding antenatal betamethasone in the study?
Antenatal betamethasone reduces admissions to special care baby units with respiratory distress after elective caesarean section.
What was the primary research question of the twin pregnancy delivery study?
Whether planned caesarean section results in a lower risk of adverse outcomes than planned vaginal delivery in twin pregnancy.
What were the inclusion criteria for the twin pregnancy delivery study?
- Twin pregnancy
- Between 32 weeks 0 days and 38 weeks 6 days of gestation
- First twin in cephalic presentation.
What was the primary outcome of the twin pregnancy delivery study?
A composite of fetal or neonatal mortality or serious neonatal morbidity.
What was the result of the twin pregnancy delivery study regarding the planned delivery methods?
No significant difference in the composite primary outcome between planned caesarean and vaginal delivery.
What is the primary outcome measured in the study regarding planned caesarean delivery versus planned vaginal delivery?
Composite of mortality or serious neonatal morbidity
Includes birth trauma of infant, intracerebral haemorrhage or IVH, APGAR <4 at 5min, intubation, confirmed septicemia, NEC.
What were the primary outcome percentages for the planned-caesarean-delivery group and the planned-vaginal-delivery group?
2.2% for planned caesarean delivery and 1.9% for planned vaginal delivery
OR, 1.16; 95% confidence interval, 0.77 to 1.74; P=0.49.
What was the secondary outcome measured for maternal health in the study?
Composite of maternal death or serious maternal morbidity before 28 days
Includes death, PPH >1.5L, blood transfusion, laparotomy, damage to bladder/bowel/ureter, confirmed sepsis, wound infection requiring readmission or breakdown.
What was the percentage of caesarean delivery in the planned-caesarean-delivery group?
90.7%
What was the percentage of caesarean delivery in the planned-vaginal-delivery group?
43.8%
What was the conclusion regarding the benefits of planned caesarean section compared to planned vaginal delivery for twins?
No benefits of planned caesarean section if the first twin was in cephalic presentation.
What limitation was noted regarding subgroup analysis in the study?
Not powered for subgroup analysis, particularly MCDA twins.
What was the research question of the HAPO study?
Is maternal hyperglycaemia less severe than in diabetes mellitus associated with increased risks of adverse pregnancy outcomes?
What was the study design of the HAPO study?
Multicentre, blinded observational study.
How many patients participated in the HAPO study?
28,562 agreed to participate.
What were the inclusion criteria for the HAPO study?
Singleton pregnancy, age >18 years with certain gestational age.
What was the primary outcome of the HAPO study?
Birth weight >90%, primary caesarean delivery, clinical neonatal hypoglycaemia, cord-blood serum C peptide level >90%.
What were some secondary outcomes measured in the HAPO study?
Premature delivery, shoulder dystocia, birth injury, need for NICU, hyper-bilirubinaemia, pre-eclampsia.
What were the findings regarding associations with birth weight >90% in the HAPO study?
Strong associations that increased across increasing glycaemia categories.
What decision was made based on the results of the HAPO study regarding GDM diagnostic criteria?
To alter the diagnostic criteria of GDM based on RR of 1.75.
What confounders were noted as potential influences on outcomes in the HAPO study?
Previous GDM, maternal BMI, previous macrosomia.
True or False: The observational design of the HAPO study can conclusively establish that maternal glycaemia is causally related to adverse outcomes.
False
What was the rate of blinding in the HAPO study?
54%
What challenge was noted regarding the translation of HAPO study findings into clinical practice?
Lack of clear thresholds for risk and unequal clinical importance of primary outcomes.
