Landmarks Flashcards
HAPO study Journal Year Aim Type of study Outcomes Results Limitations Strengths
New England Journal of Medicine 2009
Hyperglycaemia and adverse pregnancy outcomes
Looked at risks of adverse outcomes associated with various degrees of maternal glucose intolerance less severe than overt diabetes mellitus
23000 women
Bascially just had to do OGTT
Primary outcomes - all increased risk with increasing glucose at testing
1. Macrosomia
2. C peptide in cord blood (measure of insulin production in fetus)
3. Neonatal hypoglycaemia
4. CS rates
Secondary outcomes also altered
1. Shoulder dystocia and birth injury
2. PET
3. PTB
4. Neonatal jaundice
Gave ADIPS cutoffs of fasting 5.1, 1h 10, 2h 8.5
RR 1.75 of adverse outcome
Limitations: observation study, doesn’t report on confounders such as obesity, gestaiotnal weight gain, previous mode of delivery, previous macrosomia, no cost analysis
Strengths: very large study, heterogenous population
ACHOIS Journal Year Aim Type of study Intervention Outcomes Results Limitations Strengths
NEJM
2005
Does treating GDM improve perinatal outcomes?
RCT
Intervention: dietician, physician, BSL monitoring, +/- insulin vs placebo
blinded if positive for GDM but in placebo arm
Primary outcome
Serious perinatal outcome composite: shoulder dystocia, bone fracture, nerve injury, death, NICU admission, jaundice requiring phototherapy, IOL, CS, maternal anxiety and depression
Secondary outcomes included LGA and macrosomia
Outcome
RR 0.33 primary outcome
Also significant decrease in LGA / macrosomia
Treatment improves outcomes
NNT = 34
Strengths: RCT
Limitiation: wide variety of outcomes in perinatal composite outcome
CLASP trial -Year Journal Aim Type of study Inclusion / exclusion criteria - brief Primary outcomes Results
1994 Lancet Aim: does low dose aspirin reduce risk of PET and IUGR RCT >9000 women Pregnant with risk factors for PET or IUGR or current concern for PET or IUGR Randomised to aspirin or placebo no significnat change in outcomes - Reduced PEt but not significant Reduced PTB but average of 1 day No signifcant change in birthweight No differnece in SB or NND
Cochrane meta-analysis NNT 160 starting <16/40 with those at high risk PET
What was the hypitat study? Year Journal Aim Type of study Inclusion / exclusion criteria - brief Primary outcomes Results
Comparing IOL vs expectant management in women with mild Gest HTN or PET, did it affect serious maternal outcomes?
Lancet 2009
Multicentre open label RCT
Inclusion: singletons, >36/40, no severe PET or other serious comorbidity
Number 377 and 397
intervention: IOL within 24h vs expectant management with close surveillance
Primary outcome: Composite maternal morbidity
- Mortality
- Development of severe PET: eclampsia, HELLP, abruption, pulmonary oedema, VTE, >170/110 AN or PN, major PPH
Results: significant difference, 29% relative risk reduction, OR 0.58, NNT = 8.
No significant difference in mode of delivery or composite neonatal outcome
Offer IOL to women with PET post 3740
MAGPIE Year Journal Aim Type of study Inclusion / exclusion criteria - brief Primary outcomes Results
2002
Lancet
Does MgSO4 prevent adverse outcomes for women with PET and their babies
RCT
9996 women
ITT, blinded, multicentre
MgSO4 loading and maintenance vs placebo
Inclusion: pregnant or delivered within 24h, PET, uncertainty whether should have MgSO4
Primary outcomes: eclampsia, death, matneral morbidity
Results: halved chance of eclampsia, reduction in mortality but not signficiant, SS reduced placental abruption
TRUFFLE
Lancet 2015
Multicentre prospective RCT
500 women
Europe
26-32/40 with FGR (AC <10th with abnormal UAPI), >500g, no delivery plan or fetal anomly, normal DV and normal STV, no karyotype abnormlaity, >18y o
1:1:1 - STV (daily CTG) <3 (26-29), <4 (29-32), Early DV changes (>9th), Lat DV changes (absent or reversed A wave) - twice weekly scans
Safety: STV <2.6 or <3, maternal reason for delivery
Primary outcomes: survival at 2 years without cerebral palsy, neurosensory impairment or Bayley III score <85
Secondary outcomes: death or severe neonatal morbidity
No difference
If take away the deaths in favour of late DV changes
92% survival
2% IUFD
6% NND
ORACLE
Lancet 2001
Kenyon et al
Analysing broad spectrum antibiotic use for women with PPROM <37/40
4800 women
Randomised to erythromycin + placebo vs erythromycin + augmentin vs Augmentin + placebo vs placebo x 2
Primary outcome
- Composite of neonatal death or severe neonatal disease (respiratory or cerebral)
Secondary outcome: lots. Such as number delivered in 48h, number delivered in 7/7, RDS, NEC, birth weight, days in hospital, surfactant use, oxygen use etc. etc.
Results
Both Augmentin and Erythromycin decreased the primary outcome but wasn’t SS
Both Augmentin and Erythromycin significantly decreased number birthed within 48h, and 7/7
Augmentin 4 x risk of NEC
Both decreased chorio, neonatal infection, surfactant use, O2 use, cerebral USS abnormal results
Impression
- Erythromycin decreases composite primary outcome and prolongs gestation
- Avoid Augmentin - NEC x 4 fold.
Limitations
- No data collected on past obstetric history, other fetal or maternal disease
Earliest gestaion not specified
uncertain long term imapcts
Strengths
- LArge multicentre RCT blinded trial
Not many lost to FU
Erythromycin cheap and widely available
ORACLE 2
Lancet 2008
Kenyon et al
7y FU from ORACLE trial to assess any long term benefit or adverse outcomes
75% response rate, retrospective cohort trial
Primary outcome: presence of functional impairment from a validated questionaire. Asked questions concerning hospital admissions, respiratory symptoms, neurobehavioural questions, medical conditions, convulsions
No change in primary outcome for any of the groups
No difference in death, neurobehavioural outcomes, CNS / developmental issues, diabetes, bowel issues
Strengths
- Large cohort
- Good response rate
- Validated standardised quesitonairre used
No difference in response rate between groups
Limitations
- Recall questionaire from parents. Relies on parents understanding of childrens medical conditions
- Under-represented were those from lower socioeconomic class
PPROMT
Lancet 2016
Morris
RCT, blinded to assessors, ITT
1800 women
9 year study period
Included if PPROM 34-36+6
(included into study if ROM prior to 34/40 and made it to 34/40_
Randomised 1:1 to immediate management vs expectant and IOL after 37-38/40
Primary outcome: neonatal sepsis: no difference
Secondary outcome
- Neonatal morbidity: increased RDS in immediate, increased NICU stay in immediate, increased CS in immediate
- Maternal morbidity. Decreased fever in immediate, decreased hospital stay in immediate
Interpretation: expectant better to reduce prematurity complications
Limitation: 9 yr study design, women not blinded, hospital polices differed
Strengths: RCT, multi centre, assessors blinded
FONESCA 2003
AJOG 2003
RCT, placebo controlled, double blinded
Tertiary medical centre in Brazil, high rate of PTB
High risk singletons included if at least one spontaneous PTB, previous prophylactic cerclage and therefore inferred incompetent cervix, uterine malformation
100mg PV suppository between 24-34/40
Swabs at entry and UA monitoring each week
ONLY 157 women
Primary outcome: PTB <37/40 or PTL
Half the rate of PTB - significant
Tocolysis worked better for progesterone group by >twice - delayed PTB rate <37/40
Small sample size
Very high preterm birth rate
Women had extensive follow up
Women had vaginal infections treated
FONESCA 2 2007
NEJM 2007
Multicentre, double blinded, RCT
Aim: does progesterone pessaries reduce risk of PTB pre 34/40 in asymptomatic women with demonstrated cervical shortening on mid-trimester screening
Singleton or twin pregnancies, with routine anatomy scan TVUSS cervical screening showing length <15mm
Exclusions: major fetal anomaly, painful contractions, SROM, cerclage
Progesterone PV vs placebo 24 - 33+6
Outcome spontaneous PTB <34/40
Secondary outcomes: neontal morbidity and LBW
Screened 25,000 women and entered 250 women
Outcome: OR 0.56 of PTB <34/40, significant
Progesterone protective against neonatal morbidiyt but not statistically significant
no significant difference in twins but only 26 pregnancies included
Limitations: no comment on IOL if SROM, insufficiently powered to detect secondary outcomes, relies on USS assessment
Strengths: blinded, RCT, no loss to follow up, good treatemnt adherence
ACTORDs
Lancet 2006 RCT
Use of repeated doses of corticosteroids for women at risk of PTB, and neonatal outcomes
NZ and Australia
Crowther et al
1000 women
Placebo or steroids
Women who had received 2 doses of corticosteroids >7/7 prior and are still at risk of PTB, without any contraindication
Rescue dose given weekly until 32/40 or birth if considered still at risk
Primary outcomes: RDS, intubation, oxygen use, weight at hospital discahrge
Secondary outcomes: chorio, neonatal morbidity
Reduction in RDS
Reduction in severe lung disease and no lung disease
No other differences
Safe to give - no short term harm
(FU 2y: NEJM 2007, crowther et al. possible difference in attention problems, otherwise nil differences between groups
STEROIDS - Landmark
2016 NEJM
Gyami-bannerman et al
Aim: assess whether steroids should be given to women who are at risk of late preterm birth to reduce neonatal morbidity
2800 women
RCT, blinded, placebo controlled
Steroids x 2 doses, vs placebo
Inclusion crtieria: 34 - 36+5, high risk of preterm birth e.g. contracting, 3cm dilated or 75% effaced and membranes intact, or SROM etc
Excluded if imminent delivery, already had steroids, chorio, non reassuring fetal status
Primary outcome: need for respiratory within 72h or death
Secondary outcome: lots. Basically any kind of neonatal or maternal morbidity
Primary outcome OR 0.8. Significantly less respiratory compromise
Secondary outcomes: only one which was significant was neonatal hypoglycaemia RR 1.6
Limitations: significant number of woman only got one dose
No tocolysis
No documentation of neonatal hypoglycaemia numbers over time
BEnefits
Large multicentre RCT, blinded, placebo controlled
Consistent with ASTECs
ASTECS
- Antenatal Steroids for term elective Caesarean Section
2005
BMJ
Multicentre, RCT, placebo controlled
Incidence of RDS is much higher in CS vs NVB (3.6% vs 0.5%)
Steroids vs no steroids pre term ELCS
Primary outcome: SCBU admission for respiratory support . RR 0.46
Secondary outcome: level of respiratory disease
- Incidence at all of RDS 0.21 RR
- TTN o.54 RR
Doyle et al. Cochrane. MgSO4
2009
cochrane review
Involved 5 RCTs that looked at MgSO4 vs placebo for neuroprotection or tocolysis or PET
- Included MagPIE study
- Included Crowther et al NZ study
Proven to decrease CP rates
- RR 0.68
No change in any other neonatal morbidity or mortality
NNT = 63
Limitations: large variety within the studies
Benefits: large number
WOMAN trial
Lancet 2017
Designed after CRASH2 trial - proved death from bleeding was decreased by 1/3, with TXA in trauma
20,000 women
International, double blinded, multicentre, RCT
TXA vs placebo
Further dose given after 30 minutes if still bleeding
Inclusion: PPH after vaginal birth or CS
Primary outcome: all cause mortality, hysterectomy
Secondary outcome: death from bleeding, laparotomy, other complciations such as organ failure, thromboembolic events
Results
- No difference primary outcome
- Decreased death from bleeding (1.9% to 1.5%)
- Reduction in laparotomy
Limitations
- Didn’t specify which level of care is available at the hospitals (a lot of hystrectomies)
Strengths
- RCT, double blinded
Term Breech trial
Lancet 2000
Hannah et al
Multicentre, international, RCT
CS vs planned vaginal breech
Inclusion: singleton, breech, >37/40
Exclusion: footling breech, EFW >4000g, palpated LGA, hyperextended head, other reason for CS, fetal anomaly not compatible with NVB, lethal fetal anomaly
Primary outcome: perinatal mortality or serious neonatal morbidity
Secondary outcome: serious maternal morbidity or maternal mortality
Results
2000 women, 121 centres
ITT
Primary outcome RR 0.33 - significant. 5% NVB vs 1.6% CS
Perinatal mortality: 0.3% CS, 1.3% NVB RR 0.23
Serious perinatal morbidity 1.4% CS, 3.6% NVB RR 0.36
No difference in secondary outcomes
14 extra CS to avoid one primary outcome
Limitations:
Didn’t adhere to inclusion / exclusion criteria very well. Lots of deaths included were not because of a vaginal breech birth, included twins, LGA over-represented in vaginal birth group.
Included inductions and augmentations
Senior obstetricians weren’t present at 31% of births
CTG wasn’t used for all births, prolonged second stage was allowed
Differences in low perinatal mortality countries much much higher than in developing countries.
Most recruited in labour. Is this ethical
By eliminating the last 1-3 weeks of pregnancy perinatal death of 1/1000 would be prevented
ASTECS
BMJ
2005
Stutchfield et al
Aim: do steroids reduce respiratory distress in babies born y ELCS at term?
(Background: incidence of RDS is 3.6 vs 0.5% in CS vs vaginal)
Multicentre RCT, not blinded
Primary outcome: admission to SCBU with respiratory distress
Secondary: severity of RDS and level of care in response
1000 women
Results - Primary outcome: RR 0.46 - TTN RR 0.54 Incidence of RDS 0.21 NICU requirement 2 vs 14
- Strengths: o Randomised o Good effect sizes o Pragmatic – applicable to real life - Weaknesses: o Not blinded or placebo controlled
WHI E+P
JAMA 2002
Multicentre RCT, “double blinded”
ITT
16000 women
E+P (CEE and MPA) vs placebo
Primary outcome: coronary heart disease
Primary adverse outcome: breast cancer
Other outcomes presented as a global index score
- fractures, colorectal cancer, endometrial cancer, stroke, PE, DVT, death
Stopped just after 5 years because
- breast cancer rates exceeded safe threshold
- global index score indicated more risk than benefit
Results (hazard ratio) CHD: 1.29 Breast ca: 1.26 (CI crossed 1) CRC reduced 0.63 Endometrial cancer reduced 0.83 PE: 2 Hip # 0.66 No difference in all cause mortality
Criticisms
- Average age 63
- Majority >10y from menopause
- 1/3 hypertensive
- Some previous dx CHD already
- 50% smokers
- Good proportion obese
- 75% asymptomatic
- Lots of confounders
- Lots unblinded
- Some given information about risks of E+P so stopped
WHI E only
JAMA 2004 10,000 women E only vs placebo Inclusions: no uterus, 50-69yo Exclusions: any medical condition which predicted survival <3y, active breast or other cancers within last 10y
RCT, blinded, ITT, multicentre
Primary outcome: CHD - no change
- Stroke increased risk by 39%, not ss
VTE increased risk by 33% ss
Secondary outcomes
- Breast cancer, reduction but not ss
- Reduced hip and vertebral and all #
- No diff CRC or other cancers
Million women study
Cohort study
Lancet 2003
Million women - questionairre: mHT use, sociodemographic, timeline of menopause
Followed for 2 -4 yr
Results Overall increase in breast cancer incidence RR 1.66 (decreased to 1 after stopping MHT) Estrogen only: RR 1.3 E+P RR 2 Increased mortality from breast cancer
Risk of death from breast cancer RR 1.22, RR 1 for past users
For 5 years of use <65y:
6/1000 extra cases with E+P
1.5/1000 extra cases with E
Strengths:
Huge study
Cancer registry and prospective study so no recall bias
Limitations:
Million women study participants slightly more likely to use HRT than general population and come from less deprived areas (although this should not bias internal comparisons within the cohort)
Use of HRT reduces sensitivity of mammography, therefore increasing the probability that a breast cancer is diagnosed as an interval rather than at screening.
Twin birth study
NEJM 2013
Multicentre RCT
Not blinded
2800 women
Inclusion: DCDA or MCDA pregnancy. 32 - 38+6. 1500g - 4000g. leading twin cephalic. both alive
Exclusion: fatal anomaly, reduction >13/40, leading twin not cpehlaic, contraindication to labour, MCMA
Primary outcome: neonatal mortality or serious morbdiity
Secondary: 2y neurodevelopmental outcome or death
No ss differences
60% in vaginal group had VB
90% in CS group had CS
Limitations
Subgroup analyses not powered to detect difference in those outcomes
Only generalizable to centers where CS facilitated within 30mins AND experienced obstetrician can be present for vaginal delivery
Not stratified out by prev CS
Strengths Multi center RCT High numbers Good follow-up Included DCDA and MCDA Across gestations including spontaneous preterm birth
Ovarian conservation at time of hysterectomy for benign disease
2005
O&G Magazine
Parker
Observational study Aim: Does benefit outweigh risk for BSO at time of hysterectomy for benign disease Inclusion 40-80y 4 groups - Oophorectomy + E - Oophorectomy - E - Conservation + E - Conservation - E
Risks balanced at age 65
Overall results: increased mortality by age 80 secondary to CHD and hip #
Death 62% vs 54% with oophorectomy and no E replacement, compared to no oophorectomy and no E
BUYs et al
JAMA 2011
Does ovarian cancer population screening reduce mortality from ovarian cancer
Baseline and annual TVUSS for 3 years
Baseline and annual Ca125 for 5 years
Initially included bimanual but then stopped
Aged 55 to 74
Primary outcome: death from ovarian cancer
- No change
- No change in stage
- 5% FP rate which resulted in overtreatment
68,000 women included
Multicentre RCT
LARC
NEJM 2014
Background: teenage pregnancy rate is higher than other nationts. 3/10 teens will become pregnant before they reach the age of 20
Design: CHOICE project - large prospective cohort study designed to promote the use of LARC methods in 15-19yo girls
Edcucation given and then their choice of LARC with no cost was placed same day
Followed for 2 -3 years
Study questionaires 3 and 6 months then 6 monthly
$10 each questionairre
Analyzed pregnancy, birth, induced abortion rates among girls in the group and compared to other teens of same age
1400 included in the study
Had to be sexually active or planning to be in next 6 months
Results: 72% chose a LARC 28% chose depo or pills or ring Pregnancy rates 34/1000 c.f 158/1000 Birth 19.4/1000 vs 94/1000 abortion 9.7/1000 vs 41.5 Singiifcantly decreased pregnancy, birth and abortion rates
ARRIVE
NEJM
2019
Multicentre randomised controlled unmasked trial
Conducted because unclear evidence of benefits for IOL between 39 and 41/40
<39/40 - worse perinatal outcomes
>41/40 increasing perinatal risk
Aim: does elective IOL at 39/40 result in a lower composite outcome of perinatal death or severe neonatal complications than expectant management among low risk nulliparous women
Included women 34 - 38+6
6000 women
Modified bishop score calculated and women assigned 1:1 to IOL at 39-39+4 or expectant management until 40+5, delivery no later than 42+2
Primary outcome: composite of perinatal death or severe neonatal complications including
- perinatal death
- resp support in 72h
- apgar <3 at 5 mins
- HIE
- Seizure
- Infection
- Mec aspiration
- Birth trauma
- ICH and subgaleal
- Hypotension
RR 0.8 for IOL group - NOT ss as CI crosses 1
Maternal outcomes:
- CS - RR 0.84 in IOL group ss
- Hypertensive disorders: RR 0.64 in IOL group ss
Conclusion: no ss difference in frequency of primary outcome
ss lower amount of CS and hypertensive disorders of pregnancy
NNT to avoid one CS = 28
Strengths: Large trial with ability to detect differences that previous trials have not. Various bishop scores. Varieties of IOL protocols making results generalisable
Limitations: blinding not feasible, not powered to detect infrequent outcomes, cost effectiveness not included
TERM PROM
NEJM 1996
Multicentre RCT
5000 women
Induction of labour compared with expectant management for prelabour ROM at term
Intervention arms
- Labour induced immediately - oxytocin
- Labour induced immediately - PG x 2, then oxytocin
- Expectant management for 4/7 - then oxytocin (IP or OP monitoring)
- Expectant management for 4/7, then PG gel
Outcomes
- Primary: definite or probable neonatal infection
Chorio 2 x less likely in IOL with oxy group and less likely in PG IOL group
- Secondary : CS - no difference
Also looked at other measures of maternal, fetal, neonatal health
IOL with oxy = shortest time to delivery
No difference in neonatal infection with IOL compared to expectant management
SPIN
Smith 2010 - Blood
Aspirin and Heparin for Recurrent Miscarriage
RCT
Inclusion: ≥2 pregnancy loss <24/40 and currently <7/40 in pregnancy
excluded endocrine, anatomical, chromosomal, immunological cause for recurrent miscarraige
Interventions
- Aspirin and LMWH 40mg daily + intensive surveillance
- Intensive surveillance
Outcome: pregnancy loss
294 women
No reduction in pregnancy loss with intervention
Kaandorp et al
Aspirin + heparin or aspirin alone in women with recurrent miscarriage
NEJM 2010
Background: 1% of women have ≥3 miscarriages, 5% have ≥2 miscarriages
50% no underlying cause found
RCT
Age 18-42, ≥2 miscarriages <20/40
Unexplained
Intervention: 80mg / day of aspirin from randomization until 36/40 and LMWH from 6 weeks until labour OR
Aspirin alone
OR
Placebo
Primary outcome: live births
Secondary: miscarraige, IUFD, PET / HELLP, SGA, abruption, PTB, thrombocytopenia
364
84% became pregnant
54% had live birth
No difference in any of the groups
combination therapy delivered on average one week prior to placebo
Zhang et al
A comparison of medical management with misoprostol and surgical management for early pregnancy failure
NEJM 2005
Zhang et al
625 women in frist trimester with missed or incomplete miscarraige
RCT
800mcg vaginal miso (+ second dose if incomplete and vacuum day 8) vs vacuum aspiration
3:1 ratio
Outcomes:
completion of miscarraige / treatment failure
SE
Results: success rate miso 85% SE toelrable 78% would use miso again maternal outcomes rare - similar between grouwp
Miso is a safe and acceptable method of miscarraige management
Strengths: RCT
Limitations: Not our critreeia for medical management miscarraige
