Obstetric Landmark trials Flashcards
TRUFFLE Trial
2 neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomised trial
European, multi centre, unblinded randomised study.
P: women with singleton fetuses 26-32 weeks who had very preterm FGR (AC <10th and abnormal UAPI)
503 women
I/C delivery timing based on
- Reduced CTG fatal heart rate STV
- Early DV changes (abnormal PI >95%)
Late DV changes (no A wave)
O: survival without cerebral palsy or neurosensory impairment or a Bayley III developmental score <85 at 2 years of age
Findings:
- No difference in proportion of infants surviving without neuroimpairment between all groups
interpretation: delivery timing based on late changes in DV waveform might produce an improvement in developmental outcomes at 2 years of age
MAGPIE trial
Do women with pre-eclampsia and their babies benefit from magnesium sulphate - the MAGPIE trial: a randomised placebo control trial
RCT, multi country, placebo controlled, 10,100 women
P: PET or delivered <24h) with uncertainty about whether to use MgSO4
I/C: MgSO4 bolus over 10-15 mins then 1g/h or 5g Q4H IM vs placebo
O: eclampsia, death of baby in antenatal woman
Secondary outcomes: composite of serious maternal morbidity (rest arrest, coagulopathy, pulmonary oedema)
Labour/delivery complications
severe PET
Results:
- Significantly less eclampsia with MgSO4 RR 0.42
- No difference in NND
Secondary:
- Sig less severe PET
- Less placental abruption
- More SE in MgSO4
Strengths
- RCT, multi country, large numbers, blinded
- Very few maternal deaths had eclampsia - does MgSO4 protect other organ groups
Limits
- Still underpowered for death outcome
- Nil evidence of use as antihypertensive, tocolytic or interaction with nifedipine
- Variability in route of administration
- Intention to treat analysis - meaning intervention group did not always get MgSO4 - but may be more real world reflection
CLASP trial
A randomised trial of low dose aspirin for the prevention and treatment of preeclampsia among 9364 pregnant women
Aim: to establish if low dose aspirin via inhibition of platelet cyclooxygenase and thromboxane synthesis can prevent PET
RCT - multi centre - placebo controlled 9000 women
P: 12-32 weeks
- prophylactic entry: at risk of PET
- therapeutic entry: signs or sx of PET or growth restriction
I/C: low dose aspirin 60 mg or placebo
O: development of PET
Gestation at delivery
IGUR
stillbirth/NND
death at any time attributed to PET
Results:
- no effect on reducing PET (12% less not significant), IUGR or still birth
- Significantly less preterm delivery - 14% reduction
Strengths
- Randomised, large numbers
Limits
- Low dose of aspirin used - 60 mg impact smaller than other studies
- 80% compliance
- ⅔ started prior to 20 weeks
- If IUGR alone entry - could be due to smoking - 40% reported
- Included both therapeutic and prophylactic
Aspirin reduced PTB in high risk women, no direct reduction in PET/IUGR
ACTORDS Trial
Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial
Aim: can repeat doses of corticosteroids for women at risk of PTB reduce neonatal morbidity without harm
RCT - international (ANZ) - blinded - 982 women
P: <32 weeks at risk to PTB, if >7 days since prior steroid
I/C: repeat dose of 11.4 mg betamethasone IM or saline placebo, repeated weekly until delivery if at ongoing risk of PTB, up to 32/40
O:
- Occurrence and severity of RDS
- Use and duration of oxygen and mechanical ventilation
- Weight, length, HC at birth and hospital DC
Secondary outcomes
- Other neonatal morbidity
- Chorio requiring antibiotics
Results
- Significantly less RDS RR 0.82, NNT 14
- Sig less severe lung disease, NNT 14
- Sig less O2 therapy NNT 15
- No difference in mean weight at birth or DC
Secondary Outcomes
- No difference in chorio, NICU admission
- Sig increase in CS
Strengths
- RCT with good retention rates
- Adds information to safety profile of steroids for maternal and feral
Limits
- no long term follow-up
- Wide range of gestational ages, treatment doses and number of doses
- Meta-analysis after this study did not show reductio in RDS
Repeat doses reduced serious neonatal morbidity up to 32 weeks without increased infection or growth at discharge
ACHOIS TRIAL
Effect of treatment of GDM on pregnancy outcomes (ACHOIS)
Aim: does treatment of GDM reduce the risk of perinatal complications
RCT - multi centre - 1000 women
P: single/twin, 16-30 weeks, + risk factor or +ve polycose and IGT on GTT 24-34 weeks (f <7.8 2 hr 7.8-11)
Primary outcome (6)
- Composite of serious complications (death, birth injury)
- NICU admission
- Jaundice needing phototherapy
- IOL
- CS
- Health status survey
Secondary outcomes
- Birth weight
- GWG
- PIH
Results
- Significantly less composite of serious NN complications RR 0.3
2, 4, 6: significantly more NICU admission RR 1.13, IOL 1.36, better MMH 50% lower score
3 and 5 no difference in CS or jaundice
Secondary
- Less macrosomia RR 0.5
Strengths:
- RCT
- Pt blinded to dx
Limits
- Nil criteria for routine care - may have varied
- Use of composite outcome given rare individual neonatal events
- nil info on how glycemic control differed between the 2 groups
outcomes measured are not unique to GDM
Treatment of GDM reduces serious perinatal morbidity, better MMH, no difference in CS
PROGESTERONE
Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous PTB in women at increased risk: a randomised placebo controlled double blind study
Aim: evaluate the effect of prophylactic vaginal progesterone to decrease preterm birth rate in high risk women
RCT - double blinded - placebo controlled - 157
P: women with previous PTB, prophylactic cerclage and uterine malformation
I/C: 100 mg of progesterone or placebo administered vaginally daily from 24-34/40
Primary outcomes
- Rate of PTB
- Uterine activity
Results
- Progesterone reduces PTB 50%
- PTB (14% vs 29%)
- PTB <34 weeks (3% vs 19%)
- Uterine activity (24% vs 54%)
Strengths
- double blind so low risk of bias
Most women included were for previous PTB, most common RF
- Clinical relevance good
Limits
- high risk of PTB 21%, possible reflection of studying a high risk population
- Small numbers
- Mechanism of action not understood
- Only started progesterone at 24/4-
prophylactic vaginal progesterone reduced frequency of uterine contractions and rate of preterm delivery for high risk women
MgSO4 for neuroprotection
Magnesium Sulphate for women at risk of preterm birth for neuroprotection of the foetus (Cochrane review 2009)
Aim: effectiveness and safety of MgSO4 for neuroprotection if risk PTB
Cochrane review 2009 - 5 trials, 6145 babies
Inclusion criteria: RCTs of MgSO4 given to women likely to deliver <37 weeks for neuroprotective intent (4) or PET (MAGPIE) - most up to 34 weeks MAGPIE up to 37
Intervention: 4g IV MgSO4
Primary outcomes
- Fetus: death, neurological impairment and disability
- Women: serious adverse effects, stopping Tx
Results
- No overall effect in paediatric mortality RR 1.04
- Sig less cerebral palsy RR 0.68
- Sig less gross motor dysfunction RR 0.61
- Sig increase minor maternal SE
- Sig increase maternal hypotension and tachycardia
Strengths
- level 1 evidence
- Low risk of bias in studies
Limits
- should evaluate outcome later in childhood, only 2 studies followed up to 2 years
- Difference gestational cut off for MgSO4 in different studies
UPDATED 2024
Inclusion criteria: RCTs of women at risk of PTB that assess prenatal MgSO4 for fatal neuroprotection compared with placebo or no treatment. All methods of administration were eligible excluded: studies where the primary aim of tocolysis or eclampsia
Six RCTs 6759 babies all at less than 34/40
Primary outcomes for infants/children up to 2 years
- MgSO4 reduced cerebral palsy RR 0.71
- MgSO4 reduced cerebral plays or death RR 0.87
- MgSO4 probably resulted in little to no difference in death, major neurodevelopment disability or death or major neurodevelopment disability
- At early school age MgSO4 may have results in little to no difference in death; death or cerebral palsy; and death or major neurodevelopment disability
Secondary outcomes for infants/children:
- MgSO4 probably reduced severe IVH and may have resulted in little to no difference in chronic lung disease
Primary outcomes for women
- May have resulted in little or no difference in severe maternal outcomes, however probably increases maternal adverse SE severe enough to stop treatment
PROGESTERONE
Progesterone and the risk of PTB among women with a short cervix 2007
Aim: to assess if progesterone decreased risk of preterm birth with asymptomatic women found to have a short cervix at mid trimester scan
RCT - 5 hospital - 250
Inclusion criteria
- Cx <15 mm in TVUSS 20-25/40. 24,620 women scanned 413 had shot cervix 1.7%
Intervention 200 mg vaginal progesterone nocte or placebo 24+0 - 33+6
Primary outcome - delivery before 34/40
Results
- Sig less PTB <34/40 RR 0.56
- No reduction in mortality, no serious adverse effects
- Not significant for twins
Strengths
- Placebo controlled RCT
Limits
- self-opt in for TVUSS
- would effect be seen with longer cervix e.g. 20 or 25 mm
- Dose used was 200 mg, prev RCT used 100 mg not sure if reduced dose would still be effective
- Short cervix patients accounted for only ⅓ of PTBs
In women with short cervix, progesterone = less early preterm delivery
ARRIVE trial
Labour induction vs expectant management in low-risk nulliparous women
Aim: to assess the perinatal and maternal consequences of IOL at 39 weeks among low risk nulliparous women
Multi-centre randomised trial - 6000
Inclusion criteria
- First pregnancy
- Live, singleton, cephalic
- No contraindication to vaginal birth
- No maternal or feral conditions warranting IOL before 40+5
Intervention
- IOL at 39+0 - 39+4 or expectant management with IOL by 42/40
Primary outcome
- Composite of perinatal death or severe neonatal complications
Secondary outcomes
- Caesarean delivery
Results
- Sig less CS in IOL group RR 0.84
Induction of labour at 39 weeks in low risk nulliparous women did not result in sig less frequency of composite adverse perinatal outcome but did result in sig lower CS
- Commentary
○ Does not reflect current NZ maternity practice. In USA care is mostly obstetrician led with only 6% midwifery led
○ Different ethnic mix to NZ
○ Different IOL methods used
○ No long term data on neurodevelopmental or metabolic outcomes for babies
○ Self selection bias >15,000 women declined participation in the study - Application to practice
○ Not recommended in NZ to offer IOL in the absence of medical indication
○ Management of IOL for maternal request needs to be individualised
Not valid to suggest IOL’s to avoid CS
STEROIDS
Antenatal betamethasone for women at risk for late preterm delivery 2016
Aim: To assess if betamethasone given to late preterm babies reduced rate of neonatal morbidity
RCT - double blinded - 17 centres - 2831
Inclusion criteria
- singleton 34+0 - 36+5, risk of delivery <37 (risk = 3-8 cm, 75% off, PPROM or IOL or CS >24 hours from randomisation)
Intervention: Betamethasone 11.4 mg or placebo, dose repeated 24 hours later
Primary outcomes
- Composite outcome in first 72 hours of: treatment, SB or NND
Secondary outcomes
- Severe respiratory complications
- RDS, IVH, NEC
- NN hypoglycaemia
- Chorio
Results
- Primary outcome - sig less (treatment only as no death) RR 0.8
- secondary outcomes
- sig less severe respiratory complications
- sig more NN hypoglycaemia
- No difference in chorio, NN sepsis, RDS, CS
Strengths
- RCT, includes with PPROM, IOL preterm and CS
- Indications to Gove steroids clinically relevant to practice
- High F/U rate
Limits
- only 60% patients received randomised medication, as other delivered before second dose given, however all were included in analysis and effect still seen
- Need longer f/up to see if decrease in bronchopulmonary dysplasia has long term benefit
- No data collected on neonatal BSL over time
- study do not allow use of tocolytics
- study suspended halfway to find another med distribution company
- no deaths so can’t assess this
TERM BREECH TRIAL
Planned CS vs. Planned paginal birth for breech presentation at term - a randomised multicentre trial
Aim: to determine the safest way of managing breech delivery
RCT 26 countries 2088
P: live singleton, frank (ext) or complete (fix) breech >37 weeks
I/C: planned CS (38+) vs planned vaginal breech
Primary outcomes
- Perinatal and NN mortality
- Serious NN morbidity (birth trauma, seizure, Apgar <4 at 5 minutes, BE >15)
Secondary Outcomes
- Maternal mortality/serious morbidity (PPH, hysterectomy, infection, PE)
Results
- CS = sig reduction in overall primary outcome
- sig less perinatal mortality RR 0.23 NNT 100
- Sig less perinatal morbidity RR 0.36 NNT 14
- No difference in maternal morbidity or mortality
Strengths
- Large number multicentre randomised
- deliveries in usual manner for the individual units giving real world outcomes
- interim analysis ID large difference = study stopped
- Clearly defined inclusion and exclusion criteria
- Intention to treat analysis
Limits
- Recruitment stopped after interim analysis showed difference in rate of primary outcome
- Protocol violations and varied standard of care
- 2 dead babies included in vaginal analysis - likely dead before randomisation
- 21 deliveries by non-experts in BVD
12 footling or uncertain presentation
- 30% nil USS available - head extension, type of breech, IUGR
- More >4 kg in BVD
- 8/13 deaths likely to have nothing to do with MOD
- 33% only had CEFM
- Analysis via ITT - only 50% of VD group had VD
- difference in countries with high PMR was the same
- Many women recruited in active labour
lower perinatal mortality and serious morbidity in CS but multi-flaw study
TERM PROM
IOL compared to expectant management for PROM at term
Aim: establish if intervention (IOL) vs expectant management for TERM PROM decreases maternal/neonatal risk of infection
RCT - multi-country - 5041
Inclusion criteria: ROM >37 weeks, singleton, cephalic
Intervention: IOL oxytocin vs IOL PGE2 gel vs expectant management for up to 4 days then IOL if complication
Primary outcome: neonatal infection
Secondary outcome
- CS
- Women’s evaluation of treatment
Results:
Primary
- No difference in neonatal infection
Secondary
- No difference in CS rates
IOL vs expectant oxytocin
- Less chorioamnionitis
- Quicker labour
- Intervention viewed more positively by mums
Strengths
- RCT, Multicentre
Limits
- need large study to detect reduction in perinatal mortality
- did not control for parity, cervical ripeness, or use of oxytocin in expectant group
- Did not look at expectant management for shorter time e.g. 24/48h
- Expectant group had more VE - could influence choiro result
PROL IOL with oxytocin doe not reduce neonatal infection or CS Arte but less chorio
ORACLE I trial
Broad-spectrum antibiotics for PPROM: the ORACLE I randomised trial 2001
Aim: to assess best antibiotics for PPROM
RCT - Large 4826 - Multi-centre - double blind - placebo
Inclusion criteria: PPROM <37, no infection, unclear if should give abx
Intervention: erythromycin 250 mg vs augmentin 325 mg vs both vs placebo PO QID 10/7 or until delivery
Primary outcomes
- Composite neonatal outcomes
– death
– chronic lung disease
– major cerebral abnormality on USS before DC
Results
Erythromycin group
- Less primary composite outcomes but non-significant, nut was significant in singletons (11% vs 14%)
- Sig less major cerebral USS
- Sig prolongation of pregnancy to 48 hours
- Sig less surfactant use
- Sig less oxygen use >28d
- Sit less positive blood culture (singleton only)
Augmentin and augmentin + erythromycin
- prolonged pregnancy but still significant NEC
- No difference in composite outcomes
Strengths
- RCT with large numbers, clinical relevance
- Risk of bias low
- Possible implications for future with reduced lung and cerebral inflammation and neutrophils to dec risk of chronic lung disease and childhood neuromotor and cognitive function
- strict exclusion criteria
Limits
- low doses compared to usual practice
- UK pop not generalisable to all
Erythromycin for PPROM associated with a range of health benefits for neonates and reduced composite outcome in singletons. Augmentin cannot be recommended as associated with NEC
7 year follow-up of ORACLE I trial
Childhood outcomes after prescription of antibiotics of the pregnant woman with PPROM: 7 year follow-up of the ORACLE I trial
Lancet 2008
Aim: to assess if any long term benefits existed for different antibiotics used for PPROM in ORACLE I
Follow-up cohort study - 7 year follow-up of RCT with study questionnaire
Inclusion criteria: children previously enrolled in ORACLE I study and living in UK
Intervention
- 7 year follow-up of RCT with study questionnaires
- 4378 children, 3298 (75%) whose outcome is known, 72% completed questionnaire
Primary outcomes
- Presence and level of any functional assessment (vision, hearing, speech, ambulation, dexterity, emotion, cognition)
Results
- No difference in functional impairment, behavioural difficulties, developmental cognitive milestones, developmental issues, diabetes - with any regime of antibiotics
- Some evidence of reduction in respiratory problems in erythromycin group
- increase in total bowel problems in augmentin group
strengths
- High follow-up response rate from questionnaires
- Using national test scores so standardised way of assessing child cognition
Limits
- some aspects reliant on parents filling out questionnaire, maybe underreporting or inaccuracy, which might reduce power
- Disadvantaged groups over represented in non-responders
no evidence of long term sustained benefit in child at 7 years
HYPITAT trial
IOL vs expectant monitoring for gestational HTN or mild PET after 36 weeks - HYPITAT - a multi-centre, open label randomised control trial. Lancet 2009
Aim: to determine the best management of mild PET/PIH from 36 weeks
RCT - multi-centre - 756
inclusion criteria
- 36-41 weeks, singleton, cephalic
- PIH - 2x DBP >95 6h apart
- Mild PET - DBP >90 with proteinuria 2x 6 hrs apart
- No IUGR or previous CS/medical issues/severe PET/GDM/ess HTN
Intervention
- IOL with 24 hours vs expectant monitoring (BP, MSU, CTG)
Primary outcome
- composite measure of poor maternal outcome: mortality, morbidity (eclampsia, HELLP, VTE, abruption, Pulmonary oedema)
Secondary outcomes
- MOD
- Neonatal mortality/morbidity
Results
- Primary: IOL =
– less composite poor maternal outcome RR 0.71 NNT 8
– Less progression to severe disease
– Less anti-hypertensive use
- secondary: IOL =
– no difference in CS rate or NN outcomes
strengths
- Mutlicentre RCT
Limits
- Active approach to mild disease - this group generally have good outcomes
- unblinded
- one country - population may not give generalisable results
IOL associated with improved maternal outcome for mild PIH/PET >37/40
Only women 36-37 weeks or cx 2 cm or more dilated might benefit from expectant management
when results stratified IOL significantly better in 38-39 weeks 0.63 and 40-41 weeks 0.46
