Obstetrics Flashcards
TRUFFLE
2 year neurodevelopmental and intermediate perinatal outcomes in infants with very preterm fetal growth restriction (TRUFFLE): a randomized trial
The Lancet, March 2015
Aim to establish whether changes in fetal DV could be used as indication instead of CTG short term variation
Multi-centre, unblinded RCT
IUGR (26-32weeks, AC <10% and abnormal UAPI), singleton, EFW >500g
Delivery triggers
- Reduced STV on CTG (<3.5 <29weeks and <4 after) - Early DV changes - >95% - Late DV changes - reversed/absent a wave
Primary outcome - survival without cerebral palsy or neurosensory impairment
542 women
No difference in primary outcome between groups - only 48% delivered on above criteria
77% vs 84% vs 85%
Conclusion - although difference in endpoint is unchanged delivery on late changes may yield better outcomes at 2years
Strengths - RCT, multi-centre, ITT, independent review of data yearly, paeds follow-up were masked
Limitations - large LTFU, resource intensive, need fetal medicine unit so not generalizable to all, computerised CTG, large amount made it past 32weeks or delivered for other reasons (38%)
CLASP
A randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women
The Lancet, 1994
Aim - assess safety of LDA in pregnancy and whether LDA reduces morbidity, fetal and neonatal mortality overall and in those at high risk of IUGR or severe PET
Multicenter double blinded RCT
Participants 12-32weeks, at risk of PET or IUGR (prophylaxis) or have PET or IUGR (therapeutic)
Randomised to 60mg aspirin OD vs placebo
Outcomes - proteinuric PET, estimated pregnancy duration, BW <3%, Perinatal death secondary to PET, HTN, IUGR, maternal or neonatal bleeding from any cause
9364 randomised
12% reduction in PET (not statistically significant)
- Stronger effect if started <20weeks (still not significant)
No significant effect on IUGR, perinatal mortality
Interpretation - Aspirin should not be used routinely for PET/IUGR prevention, May have an effect in prevention if started at <20weeks, May have a stronger effect if high risk of early onset PET
Limitations - PET definition not consistent
Strengths - Good follow-up, good compliance, large cohort,
MAGPIE
Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate?
The Lancet, 2002
Magpie Trial Collaborative group
Aim - ascertain benefit of MgSO4 for women and babies in women with PET
International, double blind, placebo controlled, RCT
Antenatal or <24hr post-partum
PET and uncertainty about whether to use MgSO4
Primary outcomes - eclampsia, death of baby before discharge
Secondary outcomes - serious maternal morbidity, toxicity, side effects, morbidity composite
10,141 women
Reduced eclampsia by 58%, NNT 91 and 63 for severe
No difference in neonatal death
Lower maternal mortality (not statistically significant)
Side effects 24% vs 0.5%, higher abruption in those not on Mg
Conclusion - MgSO4 reduces the risk of eclampsia and likely maternal death
At this dosage, no substantive harmful effects on the mother or child, although a quarter of women will have side effects
Strengths - Intention to treat, multi centre (33), RCT, double-blinded, generalisable to large range of clinical settings, 99.7% follow-up.
Limitations - IV and IM - variable route of administration, side effects may have allowed the allocation to be guessed, eligibility dependent on attending clinicians’ beliefs about MgSO4 - unable to keep an accurate record of those eligible but not recruited
HYPITAT
Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicentre, open label randomised controlled trial
The Lancet, 2009
Koopmans et al
Aim - to establish whether IOL in women with PIH or mild PET beyond 36weeks reduces severe maternal morbidity
Multicentre, open label randomised controlled trial
Singleton cephalic 36+ to 41+0 with PIH or mild PET
765 women randomised to IOL vs expectant monitoring (until 41weeks or earlier IOL if acute concerns)
Primary outcome - composite maternal morbidity
Results IOL associated with less maternal morbidity RR 0.71 - NNT 8, fewer need for IV antihypertensives, fewer CS (not significant). Benefit not seen in women 36-37weeks Expectant - 50% needed IOL Similar rates of NICU admission
Conclusion - IOL should be advised for women with PIH or mild PET from 37weeks, higher benefit achieved in women with unfavorable cervix
Strengths - Multicentre, RCT, design reflects real work practice, biological plausibility (shortens time to delivery to lessen disease progression)
Limitations - Composite outcome, open label subjects to bias, no difference in severe outcomes
ACHOIS
Effect of treatment of gestational diabetes mellitus and pregnancy outcomes
NEJM, 2005
Australian carbohydrate intolerance in pregnancy study group - Crowther et al
Multicentre RCT
1000 women
GDM 24-34weeks and attended ANC 16-30weeks
Treatment vs non treatment of BSLs with GDM
Dietary advice, BSL testing, insulin treatment
Primary outcome - serious perinatal complication (death, shoulder dystocia, boney fracture, nerve palsy), NICU admission, jaundice needing phototherapy, IOL, CS, maternal anxiety, health status.
Outcomes - Composite serious neonatal outcome lower in intervention group - 1% vs 4%, NNT 34. Intervention group had more NICU admissions 71%vs 61% (but no increase in secondary outcomes such as hypoglycaemia requiring IV etc), higher IOL 39% vs 29%, better post-partum health survey results. No difference in CS or phototherapy. Less macrosomia 10% vs 21%.
Conclusion - Treatment of mild GDM for glycaemic control reduces the rate of serious perinatal complications without increasing the rate of caesarean section. May also improve woman’s health-related quality of life.
Strengths - Multicentre RCT
Limitations - those in routine treatment not informed of GDM result when WHO guidelines of diagnosis changed during study, routine care likely varied, outcomes all rare neonatal outcomes, not powered individually just for composite, outcomes not unique to GDM, IOL not blinded
HAPO
Hyperglycaemia and adverse pregnancy outcomes
NEJM, 2008
HAPO study cooperative research group
Observational study, blinded to BSL result
Aim - to assess whether maternal hyperglycaemia below the threshold for overt diabetes diagnosis was associated with adverse pregnancy outcomes
25,505 women
75g OGTT, stratified into 7 groups depending on levels
<5.8 fasting, <11.1 2hours
Primary outcomes - LGA >90%, primary CS, neonatal low BSL, cord blood C-peptide >90%
Secondary outcomes - delivery <37weeks, shoulder dystocia or birth injury, NICU, hyperbilirubinaemia, PET
Results - higher primary outcome with higher BSL category, higher birthweight, higher cord C-peptide level.
Secondary outcome higher too.
Conclusion - maternal BSL levels (below those for DM diagnosis at the time) have a linear association with adverse pregnancy outcomes (higher birthweight.
-> Gave ADIPS cutoffs of fasting 5.1, 1h 10, 2h 8.5 (RR 1.75 of APO)
Strengths - results generalisable as large and heterogenous population, multi-centre, double blinded, OGTT validated at single lab, adds weighting to ACHOIS study findings, biological plausibility - maternal hyperglycaemia -> fetal hyperglycaemia -> exaggerated response to insulin.
Limitations - no data on nutritional status, BMI or weight gain (confounders), mode of delivery influenced by prev GDM, BMI, prev macrosomia, participation ~50%. Statistically underpowered for rare severe outcomes (e.g. perinatal deaths, threshold effect not established, no cost analysis,
Fonesca
Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study
Fonesca et al
American Journal of Obstetrics and Gynaecology, 2003
Aim - Evaluate the effect of prophylactic vaginal progesterone in decreasing preterm birth rate in a high risk population
RCT, double-blind
142 pregnancies
High risk singleton pregnancies - prev sPTB, prev prophylactic cerclage, uterine malformation
Progesterone 100mg PV vs placebo nocte 24-34weeks
Primary outcome - PTB <37weeks
PTB <37weeks 13.8% vs 28.5% p=0.03
PTB <34weeks 2.8% vs 18.5% p=0.002
Conclusion - Prophylactic vaginal progesterone reduced the frequency of uterine contractions and the rate of preterm delivery in women at high risk for prematurity. Beta-mimetics had higher effect in progesterone group.
Strengths - Double blinded, RCT
Limitations - Single centre, small difference in GA in average gestation of PTB, small sample size, neonatal morbidity/mortality not covered, closer care may reduce PTB in placebo group too. Didn’t analyse PPROM.
Fonesca 2
Progesterone and the risk of preterm birth among women with a short cervix
NEJM, 2007
Fonesca et al
Aim - to assess whether progesterone pessaries reduced the risk of spontaneous preterm labour before 34weeks in asymptomatic women with demonstrated cervical shortening on mid-trimester screening assessment
Multicentre, double blinded RCT
413 women randomised (24,620 scanned of 29,000 screened)
Singleton or twins, undergoing routine USS 20-25weeks
Included if cervix = 15mm
Uterogestan 200mg PV vs placebo 24-33+6weeks
Primary outcome: sPTB <34weeks
Results - 34% vs 19% sPTB (SS)
Conlcusion - benefits at-risk women, uncertai dose-response.
Limitations - not powered to detect secndary outcomes, relies on USS assessment (skill)
Strengths - mulitcemtre RCT, blinded, good adherence, high uptake of screen.
TERM PROM
Induction of labour compared with expectant management for prelabour rupture of the membranes at term. TERMPROM Study Group
NEJM 1996
Aim - determine whether IOL is preferable to expectant management in prelabour ROM at term
Multicentre, RCT, unblinded
5041 women
Single, cephalic, ROM >37weeks
IOL immediate with IV oxytocin vs IOL with PV prostaglandin gel vs expectant (IOL after 4 days vs PG)
Primary outcome - neonatal infection (definite or probable)
Secondary outcome - CS, women’s evaluation of treatment
Results - no difference in neonatal infection or CS
Less chorio in oxy IOL compared to expectant.
Intervention viewed more positively
Conclusion - All methods are reasonable options as no impact on neonatal infection or CS. Oxytocin IOL reduces risk of maternal infection, women view IOL as preferable to expectant management
Strengths - large RCT, international multicentre, intention to treat, comparison of IOL methods, neonatal infection data reviewers blinded.
Limitations - mothers not blinded, did not exclude lethal congenital anomaly, larger study needed to assess impact on perinatal mortality, no stratification by IOL interval (24 vs 48 vs 72h etc), no stratification by higher parity (0 vs 1+ only)
PPROMT
Immediate delivery compared with expectant management after preterm pre-labour rupture of membranes close to term (PPROMT trial): a randomised controlled trial
The Lancet, 2016
Morris, Roberts, Bowen et al
Immediate delivery vs expectant management with pre-term pre-labour rupture of membranes.
Multi-centre RCT
1839 assigned
Inclusion: >16years, singleton pregnancy, PPROM, 34-36+6
*can enter at 34+0 if PPROM earlier
Exclusion: established labour, chorioamnionitis, meconium
Primary outcome - neonatal sepsis
Secondary infant outcomes - composite, RDS, mechanical ventilation, NICU duration
Secondary maternal outcomes - Haemorrhage, intrapartum fever, postpartum antibiotics, mode of delivery
Results - no difference in neonatal sepsis. Immediate delivery: Higher CS, RDS, mechanical ventilation, longer NICU stay . Expectant: Higher APH, maternal ABx use
Conclusion - expectant management better as avoids prematurity complications, lower CS rate, no higher neonatal sepsis rate. Maternal observation is required due to higher risk of APH and infection.
Strengths - RCT, multi centre, assessors blinded
Limitations - 9 year study period
ORACLE I
Broad-spectrum antibiotics for preterm, pre-labour rupture of fetal membranes: the ORACLE 1 randomised trial
Lancet, March 2001
S J Kenyon, D J Taylor, W Tarnow-Mordi
Aim - to resolve the issue of whether effects of antibiotics on neonatal outcomes are variable or whether they are the consequence of biases associated with smaller studies and test whether beneficial effects reported are related to antibiotic type
Multicentre, double blinded RCT
4826 women randomised
- Co-amoxiclav + erythromycin
- Co-amoxiclav
- Erythromycin
- Placebo
Primary outcome - composite (neonatal death before DC, chronic lung disease, major cerebral abnormality on USS before DC)
Large number of secondary outcomes - time to delivery, mode of delivery, maternal ABx, birthweight, NICU admission, ventilation, RDS, surfactant, positive blood culture, NEC,
Non-significant reduction in composites both groups (not for combined vs placebo). Erythromycin assoc with prolonged gestation, less surfactant, less O2 dependence 28days, less major cerebral abnormalities on DC, less positive blood cultures.
Conclusion - Erythromycin longer latency compared to placebo, stronger effect on singletons.
Co-amoxiclauv prolongs gestation but assoc with 4x NEC
Strengths - large multi centre RCT, blinded, intention to treat, low LTFU, erythromycin cheap and widely available, suitable for penicillin allergies
Limitations - 11 unblindings included in analysis, no data on patient obstetric Hx, uncertain impacts on longterm respiratory and neurological outcomes
ORACLE 1 -7year F/up
Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of membranes: 7-year follow-up to the ORACLE I trial
The Lancet 2008
Kenyon et al
Aim - Determine whether perinatal use of erythromycin and/or co-amoxiclauv for women with PROM in ORACLE I resulted in differences in functional and educational ability in childhood
Multicentre
3298 followed up (75%)
Primary outcome - any level of functional impairment form mark III MAHS classification
No difference between groups of any antibiotic
Conclusion - no evidence of substantial long term difference at 7 years following ABx for PPROM despite beneficial initial findings on neonatal outcomes
Strengths - still blinded to allocation, used validated and standardised reporting tools, 75% follow-up rate, no difference in reporting between groups
Limitations - proxy information from parents, potential for under-reporting, postal questionnaires limit follow-up, disadvantaged groups over-represented in non-responders
ACTORDS
Neonatal Respiratory Distress Syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial
Lancet, 2006
Crowther et al
RCT, blinded placebo
Establish if repeat prenatal corticosteroids given to women at risk of preterm birth can reduce neonatal morbidity without harm
982 women
<32weeks, at risk of PTB, 7+days after last dose
Singleton, twins, triplet
Betamethasone vs saline placebo
Weekly until delivery or 32weeks if remained at risk of PTB
Primary outcome - occurrence and severity of neonatal RDS, mechanical ventilation, weight/length/HC at birth and d/c.
Secondary outcome - chorio, fevers
Results - RDS 33% vs 41% 0.82 (NNT 14), less severe lung disease, less O2, shorter duration of mechanical ventilation, no difference in weight/length/HC at birth or discharge.
Steroid group: Significantly higher CS birth and more minor maternal side-effects
No difference in NICU admission and duration, IVH, NEC, Chorio.
Conclusion - Repeat doses of antenatal corticosteroids reduces morbidity, no short term harm. 2year follow-up: no benefit, possible higher rate of attention seeking behaviour. 6-8year follow-up: no benefit, no harm.
Strengths - RCT, multi-centre, ITT, provided with safety profile information, follow-up 2y 6-8y,
Limitations - Only studies up to 32weeks, included wide range of gestations and numbers of courses
ASTECS
Antenatal betamethasone and incidence of neonatal respiratory distress after elective caesarean section: pragmatic randomised trial
BMJ 2005
Stutchfield et al
Multi centre pragmatic randomised trial
998 participants
Elective CS from 37weeks
Betamethasone 12mg IM x2 doses 24hours apart 48hours pre CS vs routine care
Primary outcome - admission to special care unit for treatment of respiratory distress
Secondary outcome - severity of respiratory distress and measures required to treat
Results - steroid group 24 vs 11 admissions (p=0.02). Overall 2.4% vs 5%. Less TTN in steroid group. Effect reduced with increasing gestation 5% difference 37weeks vs 1% difference 39weeks.
Conclusion - antenatal corticosteroids prior to ElCS after 37weeks reduces admission for RDS and TTN, benefits do not remain after 39weeks. Defer elective CS until 39weeks where possible.
Strengths - randomised, pragmatic (in real world scenario), multicentre, ITT analysis, biological plausibility exists, generalisable
Limitations - allocation not stratified by gestation or centre, not blinded, no placebo, did not measure fetal hypoglycaemia
ALPS
Antenatal Betamethasone for Women at Risk for Late Preterm Delivery
NEJM 2016
Gyamfi-Bannerman et al
Multicentre RCT
To assess if betamethasone given to late preterm babies reduced rate of neonatal morbidity
2832 women
34+0 to 36+5, high probability of late preterm delivery
Excluded if had prev steroids
12mg betamethasone IM x2 vs placebo
Primary outcome - neonatal composite first 72h (CPAP or high flow nasal cannula >2h, FiO2 >0.3 for 4hours, ECMO, mechanical ventilation, stillbirth, NND 72h)
Results - primary outcome 11.6% vs 14.4% (OR 0.8 NNT 35), less severe resp composite, less TTN, higher neonatal hyperglycaemia RR 1.6
Conclusion - Antenatal corticosteroids for women expected to deliver late preterm causes significantly less respiratory complications. Does increases the chances of neonatal hyperglycaemia but no other neonatal or maternal complications
Limtiations - only 60% got both doses - results not analysed separately, challenging to predict PTB, no further neonatal BSL data, no longterm follow-up
Strengths - Multicentre, RCT, ITT, consistent findings with ASTECS, adequately powered, steroid indications clinically relevant to practice
