Obstetrics Flashcards
What was the aim of the TRUFFLE trial? (Lancet 2015)
To assess whether changes in the fetal ductus venosus doppler waveform (DV) could be used as indications for delivery instead of CTG short-term variation (STV).
What type of the study was the TRUFFLE trial?
Prospective, European multicentre, unblinded, RCT
What was the inclusion criteria in the TRUFFLE trial?
Singleton fetuses 26-32/40 (assigned by dating scan) with very preterm fetal growth restriction (AC <10th centile and UAPI >95th)
What were the interventions in the TRUFFLE trial?
Delivery of the fetus according to the criteria of the randomisation group
1. CTG STV - delivery if reduced STV (<3.5ms <29/40 and <4.0ms >29/40)
2. DV p95 - delivery with DV >95th centile with forward flowing EDF (early changes)
3. DV no A - delivery with absent or reversed A wave on DV (late changes)
What was the primary outcome of the TRUFFLE trial?
Survival without cerebral palsy or neurosensory impairment at 2 years of age (corrected for prematurity)
or
Bayley III development score of less than 85 at 2 years of age (corrected for prematurity)
What was the secondary outcome of the TRUFFLE trial?
Composite of adverse neonatal outcome
- perinatal mortality or 1 or more of other neonatal morbidities
What were the main findings of the TRUFFLE trial?
- No statistically significant difference in the primary outcome between groups (the proportion of infants surviving without neurodevelopmental impairment).
- Off survivors, more infants in the DV no A group were free of neuroimpairment when compared to those in the CTG STV group, but this was accompanied by a non-significant increase in perinatal and infant mortality.
What was the conclusion of the TRUFFLE trial?
Although the difference in the proportion of infants surviving without neuroimpairment was non-significant at the primary endpoint, timing of delivery based on the study protocol using late changes in the DV waveform might produce an improvement in developmental outcomes at 2 years of age.
TRUFFLE study strengths
High powered/large numbers
Randomised control trial
Those assessing outcomes were blinded to intervention
Low numbers lost to follow-up
TRUFFLE study weaknesses
Randomisation not blinded
11% of women were delivered for maternal reasons (not by the randomised delivery criteria)
11% of women were delivered for fetal distress (not by the randomised delivery criteria)
What was the aim of the MAGPIE trial (Lancet 2002)?
Whether women with PET and their babies benefit from magnesium sulfate
What type of study was the MAGPIE trial?
Large (10,000), multi-centre, multi-country (33), placebo-controlled, double blinded RCT
What was the inclusion criteria for the MAGPIE trial?
Pregnant women or women within 24h postpartum with a diagnosis of PET (BP 140/90 or more and proteinuria of 1+ (30mg/dL) or more) + clinical uncertainty about magnesium sulfate
What was the intervention and comparison in the MAGPIE trial?
Intervention - 4mg loading dose MgSO4 IV bolus over 10-15 minutes, then 1g/hr infusion or 5g q4h IM
Comparison - Placebo (normal saline)
What were the primary outcomes in the MAGPIE trial?
Eclampsia
Stillbirth or neonatal death before discharge from hospital (in women randomised antenatally)
What were the secondary outcomes in the MAGPIE trial?
Composite of serious maternal morbidity
Magnesium sulfate toxicity and side effects
Labour and delivery complications
Neonatal morbidity
Maternal deaths
What were the main results of the MAGPIE trial?
Statistically significant reduction in eclampsia in the MgSO4 group - 0.8% vs 1.9%, RR 0.42, NNT 91
No difference in perinatal mortality (in women randomised prior to birth)
Statistically significant reduction in placental abruption RR 0.67
Non-significant reduction in maternal mortality (0.2% 11 vs 0.4% 20)
No statistically significant difference in severe maternal morbidity, however more side effects reported in MgSO4 group
What is the conclusion of the MAGPIE trial?
MgSO4 significantly reduces the risk of eclampsia by greater than half and probably reduces the risk of maternal death. There does not appear to be substantive harmful effects to mother or baby in the short term
MAGPIE study strengths
Double blinded RCT
High power/large numbers (10,000)
Included 33 countries, so high level of generalisability
Provided a specific dosing regimen
Low level lost to follow-up
MAGPIE study limitations
Underpowered to give statistically significant data on deaths
Variability in route of administration
What was the aim of the CLASP study (Lancet 1994)?
To establish if low dose aspirin can prevent PET and whether it is safe
What type of study was the CLASP study?
Multi-centre, placebo-controlled RCT
What was the inclusion criteria of the CLASP trial?
Prophylactic entry: Women 12-32/40 at risk of PET (prev PET/IUGR, chronic HTN, renal disease, risk factors such as AMA, FHx, multiples)
Therapeutic entry: Women 12-32/40 with signs or symptoms of PET or IUGR in current pregnancy
What was the intervention and comparison in the CLASP study?
Intervention - 60mg/day aspirin
Comparison - placebo tablet
What was the primary outcomes of the CLASP trial?
Development of PET
Gestation at birth
LBW <3rd centile
Perinatal mortality
What were the main findings of the CLASP trial?
Statistically insignificant reduction in PET (12%)
No statistically significant reduction in perinatal mortality or LBW
Statistically significant reduction in preterm delivery <37/40 - 14%
What were the conclusions of the CLASP trial?
Findings do not support routine low dose aspirin in all women with PET/IUGR risk factors, however may be justified in women thought to be at high risk of PET severe enough to cause preterm birth
CLASP trial strengths
RCT
Double blinded
Large numbers (9300)
Multi-country (16)
CLASP trial weaknesses
60mg/day aspirin used (lower dose than most other studies)
Only 80% compliance
Only 2/3 commenced aspirin before 20 weeks gestation
What was the aim of the ACTORDS study (Lancet 2006)?
To establish whether repeat prenatal corticosteroids given to women at risk of preterm birth can reduce neonatal morbidity without harm
What type of study was ACTORDS?
International (Aus/NZ) double blinded, placebo controlled RCT
What was the ACTORDS inclusion criteria?
<32/40 who had received corticosteroids 7 or more days previously and deemed at continued risk of preterm birth
What was the intervention and comparison in the ACTORDS trial?
Intervention - Single dose IM 11.4mg Betamethasone
Comparison - Single dose IM normal saline placebo
What were the primary outcomes of the ACTORDS trial?
Occurrence and severity of RDS
Use and duration of oxygen and mechanical ventilation
Weight, length, HC at birth and hospital discharge
What were the secondary outcomes of the ACTORDS trial?
Clinical chorioamnionitis requiring intrapartum antibiotics
Maternal postpartum pyrexia 38 degrees +
Maternal side effects
Other measures of neonatal morbidity
What were the main findings of the ACTORDS trial?
Statistically significant reduction in RDS in the steroid group - 33 vs 41%, RR 0.82, NNT 14
Statistically significant less severe lung disease in the RDS group - 12 vs 20%, RR 0.6, NNT 14
Statistically significant less oxygen and mechanical ventilation
No difference in mean weight, length and HC at birth and discharge
No difference in secondary outcomes (chorio, other neonatal morbidity)
More women in steroid group had CS
What was the conclusion of the ACTORDS trial?
Repeat doses of corticosteroids reduced short term neonatal morbidity up to 32 weeks gestation without an increase in infection or negative impacts on fetal growth
ACTORDS trial strengths
Large numbers (1000)
Low loss to follow-up
Double blinded
RCT
ACTORDS trial limitations
No long term follow-up data
Significant heterogeneity - wide range of gestational ages
A meta-analysis after this study did not show a reduction in RDS
What is the aim of the ACHOIS trial (NEJM 2005)?
To determine whether treatment of GDM reduces the risk of perinatal complications
What sort of study was the ACHOIS trial?
Multi-centre, randomised control trial
What was the inclusion criteria of the ACHOIS trial?
Singleton/twin pregnancy 16-30/40 + one or more risk factors for GDM or positive polycose test
AND
Had impaired glucose tolerance on OGTT at 24-34/40
<7.8 1h, 7.8-11 2h)
What was the intervention and comparison in the ACHOIS trial?
Intervention - dietary advice, glucose monitoring +/- insulin
Comparison - routine care (not advised of insulin resistance)
What were the primary outcomes of the ACHOIS trial?
Fetal
- Composite of serious complications (death, SD, fracture, nerve palsy)
- Admission to NNU
- Jaundice requiring phototherapy
Maternal
- Need for IOL
- Need for CS
- Health status on survey
What was one important secondary outcome of the ACHOIS trial?
Birth weight
What were the main findings of the ACHOIS study?
- Statistically significant decrease serious neonatal complications in the treatment group - 1 vs 4%, RR 0.33, NNT 34
-Statistically significant increase in NNU admission (RR 1.13), IOL (RR 1.36) - Statistically significant improvement in maternal mental health
- Statistically significant reduction in macrosomia (RR 0.47)
- No difference in CS, jaundice, shoulder dystocia
What was the main conclusion of the ACHOIS study?
Treatment of gestation diabetes reduces serious perinatal morbidity and may improve maternal mental health
ACHOIS study strengths
RCT
Large numbers (1000)
ACHOIS study weaknesses
No criteria for “routine care”
Possibility for confounding factors
What was the aim of the AJOG 2003 Progesterone Trial - Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: A randomised placebo-controlled double-blind study
To evaluate the effect of prophylactic vaginal progesterone in decreasing preterm birth rate in a high risk population
What is the inclusion criteria for the AJOG 2003 Progesterone PTB trial?
Pregnant women at high risk for preterm delivery - at least one prior spontaneous PTB, prophylactic cervical cerclage and uterine malformation.
What was the intervention and comparison in the AJOG 2003 Progesterone PTB trial?
Intervention - 100mg progesterone suppository PV OD from 24-34/40
Comparison - identical placebo control
What were the primary outcomes of the AJOG 2003 Progesterone PTB trial?
Preterm birth
Uterine contractions
What were the main results of the AJOG 2003 Progesterone PTB trial?
Statistically significant reduction in preterm birth <37/40 in the progesterone group - 13.8% vs 28.5% (50% reduction)
Statistically significant reduction in preterm birth <34/40 in the progesterone group - 2.8% vs 18.6% (73% reduction)
Uterine contractions more frequently found in the placebo group that the progesterone group - 54.3% vs 23.6%
What was the conclusion of the 2003 AJOG Progesterone PTB trial?
Prophylactic progesterone reduced the frequency of uterine contractions and the rate of preterm delivery in women at high risk for prematurity
2003 AJOG Progesterone PTB trial - strengths
Double blinded
2003 AJOG Progesterone PTB trial - weaknesses
Low numbers (142 women), 32 total preterm births
Mechanism of action not well understood
Only commenced progesterone at 24/40
What was the aim of the 2009 Cochrane study: Magnesium sulfate for women at risk of PTB for neuroprotection of the fetus?
To assess the effects of MgSO4 as a neuroprotective agent when given to women considered at risk of preterm birth
What type of study was the 2009 Cochrane MgSO4 for Neuroprotection?
Cochrane systematic review of 5 RCTs
What was the inclusion criteria for the 2009 Cochrane MgSO4 for neuroprotection study?
RCTs of MgSO4 in women likely to give birth <37/40.
- 4x studies were for neuroprotective effect <34/40
- 1x study (MAGPIE) was for PET (<37/40)
What were the primary outcomes of the 2009 Cochrane MgSO4 for neuroprotection study?
Fetal/infant/child
- Perinatal mortality
- Major neurological disability
- Paediatric mortality + major neurological disability
Maternal
- Serious adverse cardio/resp outcome
- Adverse effects severe enough to stop treatment
What were the secondary outcomes of the 2009 Cochrane MgSO4 for neuroprotection study?
Other neonatal serious morbidity
Childhood growth and educational achievements
Other maternal morbidity
Use of health services
What were the main findings of the 2009 Cochrane MgSO4 for neuroprotection study?
Statistically significant reduction in cerebral palsy 3% vs 5%, RR 0.68, NNT 63
Statistically significant reduction in gross motor dysfunction RR 0.61
No difference in paediatric mortality or other neurological outcomes
Higher rates of maternal side effects in MgSO4 group
2009 Cochrane MgSO4 for neuroprotection study - strengths
Level 1 evidence
- Low chance of bias
Large overall numbers (6000)
2009 Cochrane MgSO4 for neuroprotection study - weaknesses
Did not evaluate long term outcomes beyond 2 years of life (and only 2 studies evaluated to up to 2 years of life)
What was the conclusion of the 2009 Cochrane MgSO4 for neuroprotection study?
The neuroprotective role for antenatal MgSO4 given to women at risk of PTB is now established.
What was the aim of the 2007 NEJM study - Progesterone and the risk of PTB among women with a short cervix?
To evaluate the effect of vaginal progesterone on the incidence of spontaneous early preterm delivery in asymptomatic women found at routine mid-trimester screening to have a short cervix
What type of study was the 2007 NEJM progesterone for short cervix study?
Multicentre (5), double blinded, RCT
What was the inclusion criteria of the 2007 NEJM progesterone for short cervix study?
Asymptomatic singleton/twin pregnancies 20-25/40 with cervical length <15mm on midtrimester TVUSS
What were the intervention and comparison in the 2007 NEJM progesterone for short cervix study?
Intervention - 200mcg utrogestan PV nocte from 24/40 to 33+6/40
Comparison - identical placebo
What was the primary outcome of the 2007 NEJM progesterone for short cervix study?
Spontaneous PTB <34/40
What were the secondary outcomes of the 2007 NEJM progesterone for short cervix study?
Birth weight
Perinatal mortality
Major neonatal adverse outcomes before discharge
Need for NICU care
What were the main findings of the 2007 NEJM progesterone for short cervix study?
Statistically significant less PTB <34/40 in progesterone group - 19% vs 34%, RR 0.56 (not statistically significant in twins)
Non-significant reduction in neonatal mortality
No serious adverse effects
What was the conclusion of the 2007 NEJM progesterone for short cervix study?
In women with a short cervix, treatment with progesterone reduces the rates of spontaneous PTB
2007 NEJM progesterone for short cervix study - strengths
Placebo controlled RCT
Double blinded
Low risk of bias
Large numbers (25000 screened, 413 included)
2007 NEJM progesterone for short cervix study - weaknesses
Self opt-in for TVUSS (82% of eligible population)
No data on effect on longer cervix i.e. 16-25mm
What was the aim of the 2018 NEJM ARRIVE trial?
To test the hypothesis that elective IOL at 39/40 results in less perinatal death or severe neonatal complications than expectant management in low-risk nulliparous women
What type of study was the 2018 NEJM ARRIVE trial?
Multi-centre USA RCT
What was the ARRIVE trial inclusion criteria?
Low risk nulliparous women who were 34+0-38+6 with a live cephalic singleton and no contraindication to vaginal birth
What were the intervention and comparison in the ARRIVE trial?
Intervention - IOL 39+0-39+4
Comparison - no elective delivery <40+5 and delivery initiated no later than 42+2
What were the primary outcomes of the ARRIVE trial?
Composite of perinatal death or severe neonatal complications
Caesarean section
What were the secondary outcomes of the ARRIVE trial?
Neonatal - other neonatal complications, birth weight, hospital stay etc.
Maternal - perinatal morbidity, instrumental birth etc
What were the main findings of the ARRIVE trial?
No statistically significant difference in composite perinatal death/severe neonatal outcome - RR 0.8 (CI 0.64-1.0 - contains null), however suggestive of no adverse perinatal outcome
Statistically significant reduction in CS rates - 18.6% vs 22.2%, RR 0.84
Statistically significant reduction in development of maternal hypertensive disorders RR 0.64
What was the conclusion of the ARRIVE trial?
IOL at 39/40 in low risk nulliparous women resulted in a lower frequency of CS delivery and likely associated with no adverse perinatal outcome
ARRIVE trial - strengths
RCT
Large numbers (6000)
Objective outcomes
ARRIVE trial - weaknesses
Does not reflect current NZ maternity practice (largely midwifery led)
Different ethnic mix than Aus/NZ
IOL methods not specified
No long term data
Selection bias - 16,000 women declined to participate
What was the aim of the Antenatal Betamethasone for Women at Risk of Later Preterm Delivery (ALPS) trial NEJM 2016?
To assess whether AN betamethasone in women likely to deliver in the later preterm period would decrease respiratory and other neonatal complications
What was the ALPS study type?
Multi-centre (17 USA), double-blinded, placebo-controlled RCT
What was the ALPS inclusion criteria?
Women with a singleton pregnancy 34+0-36+5 at high risk of delivery in the late preterm period (up to 36+6)
What were the ALPS trial intervention and comparison?
Intervention - course of 2x IM injections of 12mg betamethasone 24h apart
Comparison - matching placebo
What was the ALPS trial primary outcome?
Composite end point for the need for respiratory support within 72h of birth
What were the ALPS trial secondary outcomes?
Neonatal morbidity - Severe respiratory complications, hypothermia, hypoglycaemia, feeding difficulty, IVH, sepsis, NEC etc.
Maternal chorio, endometritis, delivery before steroids completed, length of hospitalisation
What were the main findings of the ALPS trial?
Statistically significant reduction in the need for respiratory support within 72h in steroid group - 11.6% vs 14.4%, RR 0.80, NNT 35
Statistically significant reduction in severe respiratory complications in the steroid group - 7.9% vs 12.1%, RR 0.66, NNT 25
but…
Statistically significant increased rate of neonatal hypoglycaemia in the steroid group - 24% vs 15%, RR 1.6
ALPS trial - strengths
RCT
Double blinding
Clear enrollment criteria
Large numbers (2800)
Small numbers lost to follow-up
ALPS trial - weaknesses
Looked at short term outcomes only
?applicable to Aus/NZ population
ALPS trial conclusion?
Antenatal betamethasone in women at risk of late preterm delivery significantly decreased the rate of respiratory complications in newborns, but increased the rate of neonatal hypoglycaemia
What was the aim of the Planned caesarean section vs planned vaginal birth for breech presentation at term trial? (Term Breech Trial - Lancet 2000)
To determine whether planned caesarean section was safer than planned vaginal birth for selected fetuses in breech presentation at term
What sort of study was the Term Breech Trial?
Multi-centre (121), multi-country (26), RCT
What was the inclusion criteria in the Term Breech Trial?
Singleton live frank (extended) or complete (flexed) breech presentation at >/= 37/40
What was the intervention and comparison in the Term Breech Trial?
Intervention - planned CS at 38+/40
Comparison - planned spontaneous vaginal birth unless indication for IOL or CS developed.
What were the primary outcomes of the Term breech trial?
Perinatal mortality <28d
Serious neonatal morbidity e.g birth trauma, seizures <24h, Apgar <4 at 5min etc
What was the secondary outcome of the Term Breech trial?
Maternal mortality or serious maternal morbidity within 6 weeks postpartum e.g.PPH, hysterectomy, infection, PE
What were the main findings of the Term Breech trial?
Statistically significant reduction in perinatal mortality in CS group 0.3% vs 1.3%, RR 0.23, NNT 100
- RR 0.07, NNT 7 in countries with low perinatal mortality rate
Statistically significant reduction in perinatal morbidity in CS group 1.4% vs 3.8%, RR 0.36, NNT 14 (not significant in high perinatal mortality rate countries)
No difference in maternal mortality or morbidity
Term Breech Trial - Strengths
Multi-country - generalisability
RCT
Large numbers (2000)
Deliveries in usual manner for the individual units giving real world outcomes
Clearly defined inclusion and exclusion criteria
Decision to treat analysis
Term Breech Trial - Weaknesses
Recruitment stopped after interim analysis showed differing rate in primary outcome
9% protocol violations and varied standard of care
2 babies included in the vaginal analysis likely dead prior to randomisation
21 breech vaginal births performed by non-experts
12 vaginal breechs were footling or uncertain presentation
30% of vaginal breech births had no USS available
More LGA babies in vaginal breech group
8/13 deaths unlikely due to mode of birth
Intention to treat analysis mean only 50% of vaginal birth group actually had a vaginal birth
What was the aim of the Induction of labour compared with expectant management for prelabor rupture of membranes at term study (TERM PROM trial NEJM 1996)?
To determine if IOL for women with term PROM is better than awaiting spontaneous labour and whether oxytocin or vaginal prostin was preferable IOL method.
What type of study was the TERM PROM trial?
Multi-centre (72), multi-country (6), RCT
What was the interventions and comparisons in the TERM PROM trial?
Interventions:
- Immediate oxytocin IOL
- Immediate Prostin IOL
Comparisons:
- Expectant management with oxytocin IOL at 4 days or if complications
- Expectant management with Prostin IOL at 4 days or if complications
What was the inclusion criteria in the TERM PROM trial?
Rupture of membranes >/= 37/40 live cephalic singleton
What was the primary and secondary outcomes in the TERM PROM trial?
Primary - Neonatal infection
Secondary - CS, other measures of maternal/fetal/neonatal health, women’s evaluation of care
What were the main findings of the TERM PROM trial?
No statistically significant difference in neonatal infection and CS rates in all groups.
Clinical chorioamnionitis and postpartum fever less likely to occur in oxytocin IOL group than in expectant oxytocin group - 4% vs 8.6%
Quicker labour with oxytocin vs prostaglandins
Intervention viewed more positively in women
TERM PROM trial - Strengths
RCT
Multi-country - generalisable
Large numbers (5000)
TERM PROM trial - Weaknesses
Need larger study to detect effect on perinatal mortality (4 deaths total)
Did not control for parity, cervical ripeness, oxytocin augmentation in labour
Did not look at shorter expectant management time i.e. 24-48h
Expectant management group had more VEs - ?explains chorio result
What was the conclusion of the TERM PROM study?
IOL for PROM with oxytocin does not reduce neonatal infection or CS rate, but does reduce chorioamnionitis rates
What type of study was the Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial? (Lancet 2001)
Multicentre (161), double-blinded, placebo-controlled RCT
What was the aim of the ORACLE I trial?
To more definitively determine whether antibiotics for PPROM benefit the neonate.
To determine the best antibiotic choice.
What was the inclusion criteria in ORACLE I?
PPROM <37/40, no evidence of infection and unclear need for abx.
What were the interventions in ORACLE I?
Interventions:
- Erythromycin 250mg + placebo
- Co-amoxyclav 325mg + placebo
- Erythromycin + co-amoxyclav
- Double placebo
All PO QID x 10/7
What were the primary outcomes in ORACLE I?
Fetal/neonatal - Composite primary outcome of perinatal mortality or major adverse outcome prior to discharge (i.e. chronic lung disease) or major cerebral abnormality on USS
*lots of difference secondary outcomes
What were the main findings of ORACLE I?
Significantly significant decrease in primary outcomes in singletons (not twins) in the erythromycin only group- 11 vs 14%, with significantly less major cerebral anomalies 3 vs 5%
Significantly more prolongation of pregnancy to 48h in erythromycin group
Both co-amoxyclav groups had prolonged pregnancy, but significantly increased rates or NEC 4 vs 2.5%
What were the conclusions of the ORACLE I trial?
Erythromycin for PPROM associated with a range of health benefits for the neonate. Co-amoxiclav can not be routinely recommended due to association with NEC.
ORACLE I - strengths
Multi-centre RCT with large numbers (4800)
- Low risk of bias
Provided specific antibiotic and dosing regimen
ORACLE I - weaknesses
No long term data, but has follow-up trial
UK population - not generalisable to all
What was the aim of the ORACLE I 7y follow-up trial?
To determine the long-term effects on children of the antibiotic regimens/placebo given during the ORACLE I trial
What type of study was the Childhood outcomes after prescription of antibiotics to pregnant women with PPROM - a 7y follow-up of teh ORACLE I trial?
Cohort study
What was the inclusion criteria for the ORACLE I 7y follow-up study?
Children of mothers previously enrolled in ORACLE I trial living in the UK
How was information collected for the ORACLE I 7y follow-up study?
Parent-completion postal questionnaire
What was the primary outcome in the ORACLE I 7y follow-up study?
Functional impairment (mild/mod/severe - vision, hearing, speech, ambulation, dexterity, emotion, cognition)
What were the main findings of the ORACLE I 7y follow-up study?
No difference in functional impairment, behavioural difficulties, developmental cognitive milestones, diabetes in any group.
Some evidence of reduction in respiratory problems in erythromycin group
Increase in total bowel problems in co-amoxyclav group
ORACLE I 7y follow-up study conclusion?
The prescription of antibiotics for women with PPROM seems to have little effect on the health of children at 7 years of age
ORACLE I 7y follow-up study - strengths
75% follow-up and high response rate
Used standardised questionaire to determine functional impairment
ORACLE I 7y follow-up study - weaknesses
Risk of bias from parents underreporting or inaccurately reporting responses
Disadvantaged groups over represented in non-responders
What was the aim of the HYPITAT study?
To assess whether IOL in women with GHTN or mild PET reduces poor maternal outcome compared with expectant monitoring
What sort of study was the Induction of labour vs expectant monitoring for gestational HTN or mild PET after 36/40 (HYPITAT Lancet 2009)?
Multi-centre (38), unblinded RCT
What was the inclusion criteria in the HYPITAT study?
Singleton cephalic 36+0 - 41+0 with GHTN (2x DBP >95 6h apart) or mild PET (2x DBP >90 6h apart + proteinuria)
Excluded severe HTN > 170/110 and other complications
What was the intervention and comparison in the HYPITAT study?
Intervention - IOL within 24h of randomisation (Bishops score >6 - AROM +/- synto, Bishops score 6 or less - cervical ripening)
Comparison - expectant management (BP, urinalysis, CTGs, USS) until spontaneous labour - IOL if severe range BPs or other complicating features
What were the primary outcomes of the HYPITAT trial?
Composite measure of poor maternal outcome
- mortality, morbidity (HELLP, eclampsia, pulm. oedema, VTE, abruption)
- progression to severe disease
- major PPH >1000mL
What were the secondary outcomes of the HYPITAT trial?
Mode of birth
Neonatal mortality
Neonatal morbidity
What were the main findings of the HYPITAT trial?
Significantly significant less composite poor maternal outcome in IOL group - 31% vs 44%, RR 0.71, NNT 8
Less progression to severe disease and less antihypertensive use in IOL group.
No difference in CS rates or neonatal outcomes.
What was the conclusion of the HYPITAT trial?
IOL associated with improved maternal outcomes in women with GHTN or mild PET, and should be advised for these women beyond 37 weeks.
HYPITAT strengths
Multi-centre RCT
Large numbers (700)
HYPITAT weaknesses
Single country (Netherlands) - ?generalisable
Unblinded
Half of the women in expectant management ended up with IOL
What type of study was the PPROMT trial?
Multi-centre, multi-country (11), unblinded RCT
What was the aim of the Immediate delivery compared with expectant management after PPROM close to term (PPROMT) (2016 Lancet)?
To establish whether immediate birth in singletons with ROM close to term reduces neonatal infection without increasing other morbidity
What was the inclusion criteria in the PPROMT trial?
Singleton pregnancies in women >16y with prelabour ROM 34+0-36+6 without signs of infection
What was the intervention and comparison in the PPROMT trial?
Intervention - immediate IOL
Comparison - expectant management
What was the primary outcome in the PPROMT trial?
Neonatal sepsis
What were the secondary outcomes in the PPROMT trial?
Composite neonatal morbidity and mortality e.g. RDS, ventilation, NICU stay, perinatal death
Maternal:
- APH
- Intrapartum fever
- PN abx
- Mode of birth
What were the main findings of PRROMT?
No significant difference in neonatal sepsis (even if GBS +ve) *note that follow-up study found benefit with immediate delivery if GBS positive
No significant difference in composite neonatal outcome
BUT
- Significant increase in RDS (8 vs 5%, RR 1.6), mechanical ventilation (RR 1.4), NICU stay and CS (RR 1.4) in IOL group
Statistically signicant increase in APH (RR 0.6), maternal fever (RR 0.4) and longer hospital stay in expectant management group
What was the conclusion of the PRROMT trial?
In the absence of overt signs of infection or fetal compromise, a policy of expectant management with appropriate surveillance of maternal and fetal wellbeing should be followed in pregnant women who present with PROM close to term
PPROMT - strengths
RCT
Large numbers (1800)
Multi-country - generalisable
Low level lost to follow-up
PPROMT - weaknesses
Unblinded
No protocol for monitoring in expectant management
What type of study was the WOMAN trial (Lancet 2017)?
Multi-country double-blinded placebo-controlled RCT
What was the aim of the Effect of early TXA administration on mortality, hysterectomy, and other morbidities in women with PPH ‘WOMAN’ trial (Lancet 2017)?
To assess the effects of early TXA on death, hysterectomy and other relevant outcomes in women with PPH
What was the inclusion criteria for the WOMAN trial?
16y+ with PPH after CS (1000mL) or NVB (500mL) or clinical diagnosis
What were the intervention and comparison in the WOMANtrial?
Intervention - 1g TXA slow infusion (second dose if bleeding continued after 30min or restarted within 24h)
Comparison - Matching placebo
What was the primary outcome of the WOMAN trial?
Composite of maternal death from all causes or hysterectomy within 42d of randomisation
What were the secondary outcomes in the WOMAN trial?
Maternal mortality due to bleeding
Other maternal morbidity e.g. VTE, laparotomy, sepsis
What were the main findings of the WOMAN trial?
No significant difference primary outcome (all cause death/hysterectomy).
Statistically significant reduction in death from bleeding in the TXA group if given within 3h of birth (1.2% vs 1.7%, RR 0.69)
Statistically significant reduction in laparotomy in TXA group (0.8 vs 1.3%, RR 0.64)
No difference in adverse outcomes e.g. VTE
What was the conclusion of the WOMAN trial?
TXA reduces death from bleeding in women with PPH with no adverse effects. Should be given ASAP after bleeding onset.
WOMAN trial strengths
Very large numbers (20,000)
Multi-country (21) - more generalisable
Multi-centre (193)
Double-blinded - low chance of bias
Low loss to follow-up
WOMAN trial - weaknesses
- Funded by drug company (conflict of interest)
- Did not study PO TXA
What was the aim of the Antenatal betamethasone and incidence of neonatal respiratory distress after ELCS: pragmatic randomised trial (BMJ 2005)? ASTECS
To test whether steroids reduce respiratory distress in babies born by ELCS at term
What type of study was the ASTECS study?
Multicentre (10), unblinded RCT
What was the inclusion criteria for the ASTECS trial?
Intervention - 2x IM doses of 12mg betamethasone 24h apart, within 48h before ELCS
Comparison - treatment as usual
What were the primary and secondary outcomes of the ASTECS trial?
Primary - Admission to NNU with respiratory distress
Secondary - severity of respiratory distress and level of care neded
What were the main results of the ASTECS trial?
Significantly significant reduction in admission to NNU with respiratory distress in the steroid group - RR 0.46.
No statistically significant difference between rates of TTN and RDS diagnoses
What was the conclusion of the ASTECS trial?
Antenatal betamethasone and delaying delivery until 39/40 both reduce admissions to NNU after ELCS at term
ASTECS - strengths
Multicentre RCT
Large numbers (1000)
ASTECS - weaknesses
Unblinded
Not placebo controlled
What was the aim of the randomised trial of planned caesarean or vaginal delivery for twin pregnancy trial (NEJM 2013)?
To compare the risk of perinatal death or serious morbidity with ELCS and vaginal birth for twin pregnancies 32+0 to 38+6 if leading twin cephalic
What type of study was the Twin Birth Study 2013 NEJM?
Multi-centre (106), Multi-country (25), RCT
What was the inclusion criteria in the Twin Birth Trial?
Twin pregnancy (DCDA or MCDA) 32+0 to 38+6, leading cephalic, both twins EFW 1500-4000g on USS within 7d before randomisation
What were the interventions in the Twin Birth Trial?
Planned caesarean section
Planned vaginal birth
What were the primary and secondary outcomes of the Twin birth Trial?
Primary - Composite outcome of neonatal mortality or serious morbidity (birth injury, Apgar <4 at 5min, seizures etc)
Secondary outcomes
- Composite outcome of maternal mortality or serious morbidity
What were the main findings of the Twin Birth Trial?
No significant difference in all outcomes - neonatal or maternal death or serious morbidity
Twin Birth Trial - strengths
RCT
Multi-country - generalisable
Multi-centre
Large numbers (1398)
Low level lost to follow-up
Twin Birth Trial - weaknesses
Only generalisable to units where experienced obstetrician available for birth and access to EMCS
What was the inclusion criteria of the HAPO study?
18y+ without pre-existing diabetes, ART, HIV/Hepatitis, uncertain dates, multiples or non-english speaking
+ OGTT 24-32/40 with fasting <5.8mmol/L and 2h <11.1mmol/L
What was the exposure in the HAPO study?
Categories of glycaemic index on OGTT
What were the primary outcomes of the HAPO study?
Birthweight > 90th (LGA)
Primary caesarean section
Neonatal hypoglycaemia
Cord blood C peptide >90th centile
What were the secondary outcomes of the HAPO study?
PTB <37/40
SD or birth injury
NICU admission
Jaundice
PET
What were the main findings in the HAPO study?
There is an increasing risk of all primary outcomes (LGA, primary CS, neonatal hypoglycaemia, cord blood C peptide >90th) with increasing glucose category
- Strongest association with LGA and C peptide
Increase in all secondary outcomes (PTB <37/40, SD/birth injury, NICU admission, jaundice, PET) with increasing glucose category
What was the conclusion of the HAPO study?
Increasing glucose intolerance is associated with increasing risk of LGA, CS, cord C peptide, neonatal hypoglycaemia and other adverse outcomes
HAPO study - strengths
Large numbers (23,000)
International study - generalisable
Researchers were blinded to the OGTT result
HAPO study - weaknesses
Not an RCT - increased risk of confounding
Not powered to assess perinatal death
No information on BMI or gestational weight gain
What were the primary and secondary outcomes of the Twin birth Trial?
Primary - Composite outcome of neonatal mortality or serious morbidity (birth injury, Apgar <4 at 5min, seizures etc)
Secondary outcomes
- Composite outcome of maternal mortality or serious morbidity
Twin Birth Trial conclusion
In MCDA/DCDA twin pregnancies with leading twin cephalic, planned delivery via CS did not significantly decrease or increase the risk of fetal or maternal death or serious morbidity
What was the aim of the Hyperglycaemia and Adverse Pregnancy Outcomes (NEJM 2008) study?
To clarify the risks of adverse outcomes associated with various degrees of maternal glucose intolerance less severe than that in overt diabetes mellitus
What type of study was the HAPO study?
International observational study
What were the primary and secondary outcomes of the Twin birth Trial?
Primary - Composite outcome of neonatal mortality or serious morbidity (birth injury, Apgar <4 at 5min, seizures etc)
Secondary outcomes
- Composite outcome of maternal mortality or serious morbidity
What were the primary and secondary outcomes of the Twin birth Trial?
Primary - Composite outcome of neonatal mortality or serious morbidity (birth injury, Apgar <4 at 5min, seizures etc)
Secondary outcomes
- Composite outcome of maternal mortality or serious morbidity
