Gynaecology Flashcards
ALIFE
Aspirin plus heparin or aspirin alone in women with recurrent miscarriage
NEJM, 2010
Kaandorp et al
Aim - assess whether aspirin + LMWH vs aspirin alone improves live birth rate in women with RPLs.
RCT
364 women Unexplained RPL (>/=2), trying to conceive or <6weeks
Aspirin 80mg + SC nadroparin vs aspirin 80mg vs placebo
Primary outcome - Live birth rate
Secondary outcome - miscarriage, IUFD, obstetric complication - HELLP, PET, SGA, abruption, PTB), maternal plts, bleeding, skin reaction
Results - Lives births 54%, 50%, 57% - no significant difference
Combined group delivered 1 week earlier than placebo. Bruising higher for combined group. No other significant difference in secondary outcomes
Conclusion - Neither therapies (alone or in conjunction) improve live birth rate in women with RPLs
Strengths - RCT, ITT,
Limitations - included 2prev as RPLs, small number, included some up to 6weeks pregnancy, included those with thrombophilias, 40% had prev live birth, did not get data for 22 pregnancies as data collection stopped early (thought futile), adherence 85%,
SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage
Blood, 2010
Clark et al
Aim - to assess whether enoxaparin + aspirin and intensive pregnancy surveillance reduces rate of pregnancy loss compared to intensive pregnancy surveillance alone
Multi centre RCT
294 women
<7weeks, 2+ consecutive pregnancy losses <24weeks (no evidence of cause)
Enoxaparin SC + aspirin 75mg + intensive surveillance
Intensive surveillance alone - USS Q2weeks until 12weeks, then Q4weeks until 28weeks
Thrombophilia screen done
Primary outcome - pregnancy loss rate
Secondary - treatment complications
Results - 20% vs 22% loss - no difference. No safety issues with clexane
Conclusion - no reduction in pregnancy loss with additional antithrombotic agents in those with RPLs
Strengths - multi-centre RCT, pragmatic, well-matched controls,
Limitations - included 2+ RPLs (may benefit 3+ losses), impracticalities of intensive surveillance in real life, small sample size (subanalysis not powered), doesn’t test implantation therapy of benefit as started up to 7weeks, don’t evaluate aspirin and heparin separately
CHOICE
Provision of no-cost, long acting contraception and teenage pregnancy
Secura et al
NEJM 2014
Aim - Reduce unintended teenage pregnancies through provision and education about LARC. Assessed pregnancy, birth, abortion rates among high-risk sexually active teens when barriers (information about LARC, access, cost) removed.
Prospective cohort study
1404 teenaged girls and women 14-19years
Provided contraception options at no cost, LARC benefits given
Primary outcome - rates of pregnancy, livebirth, induced abortion
Compared against national rates and sexually experiences teen rates
2-3year follow-up, questionnaires 3m, 6m, then every 6m. $10 per questionnaire.
Results - 72% chose a LARC, 9% DMPA, remainder other
Pregnancy 34/1000 cf 158/1000 sexually active teens
Birth 19.4/1000 cf 94/1000 sexually active teens
Abortion 9.7/1000 cf 41.5/1000 sexually active teens
Conclusions - access to and use of contraception when barriers are removed and LARC promoted reduces teen pregnancy, birth and abortion.
Strengths - large sample, results are of public health importance,
Limitations - cohort study, non-randomised, no null hypothesis (pre-established goal to reduce rates by), pregnancy self-reported - likely underestimated, likely higher adherence due to nature of being surveyed, financial incentive to complete questionnaire, counselling approach most to least effective may alter choice of contraceptive, most required parental consent to be enrolled, high risk population (may not be generalisable), results compared mean annual rate 2008-2013 with 2010 (during which time there was a 15% reduction), 50% had a previous unintended pregnancy, provided on day information given (not time to take home and discuss, think about it), high proportion of black race and socioeconomic deprivation, 75% follow up by 3years.
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WHI - principal
WHI: Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal results from the Women’s Health Initiative RCT
JAMA, 2002
RCT, multicentre
Aim - To assess whether estrogen and progesterone use in postmenopausal women has a favourable or unfavourable effect on CHD and overall risks and benefits in predominantly healthy women (intact uterus)
50-79yo postmenopausal
16,608 women
Conjugated equine oestrogen + medroxyprogesterone vs placebo
Primary outcome: coronary heart disease (nonfatal MI and CHD death)
Primary adverse outcome: invasive breast cancer
Other outcomes: global index score, hip fracture, other cardiovascular disease, stroke, PE, endometrial cancer, colorectal cancer, death due to other causes
Results - stopped 5.2 years as invasive breast cancer above safety limit and global score risks»_space; benefits.
CHD hazard ratio 1.29 (nonfatal). Breast ca 1.26 but crossing null interval.
Colorectal 73% reduction. All cause mortality not affected.
Over 1 year, 10 000 women taking E+P compared with placebo might experience:
+7 CHD events
+8 strokes
+18 VTEs
+8 invasive breast cancers
-6 colorectal cancers
-5 hip fractures
Conclusion - risks exceed benefits with combined MHT with average 5.2years. Should not be used as a primary prevention against CHD.
Later analysis - less CHD if MHT <10years of menopause.
Strengths - high adherence, large trial, multi centre
Limitations - mean age of starting was 63 (much older than now recommended). High proportion became unblinded for various reasons e.g. PV bleeding. Breast ca outcomes not statistically significant. groups commenced MHT thorough their own GP. Only tested one regimen (conjugated equiine oestrogen +nmedroxyprogesterone), no assessment of transdermal oestrogen. 42% discontinuation on treatment arm. Not screen so included women with significant RFs (HTN, smoking, high BMI). Early trial cessation limits power. Some were already using MHT at commencement.
WHI: hysterectomy
Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The WHI randomised controlled trial.
JAMA, 2004
The Women’s Health Initiative
Multicentre RCT, double-blind
Aim - to investigate the effects of conjugated equine oestrogen on major disease events in mostly healthy post menopausal women
10,739 women 50-79yo
Previous hysterectomy
Conjugated equine oestrogen vs placebo
Primary outcome - CHD
Results - stopped after 7 years as stroke risk similar to combined group. Concerns about lack of benefit. No significant effect on CHD. Stroke increased by 39%. Excess stroke 12 per 10,000 women years. Increased VTE. Reduced fracture. Non significant reduction in breast cancer. Global index balanced.
Conclusion - MHT with oestrogen only increases risk of stroke, reduces hip and other fractures. No significant impact on CHD or mortality. Overall risks and benefits of oestrogen only therapy are balanced.
Strengths - large RCT, double-blinded, placebo, low rate of unblinding
Limitations - only one oestrogen regime tested, high rates of discontinuation, lower than anticipated rates of some events so limits power, trial stopped early.
MILLION WOMEN
Breast cancer and HRT in the Million Women Study
The Lancet, 2003
Prospective cohort
Aim - to investigate the relation between various patterns of HRT use and breast cancer incidence and mortality
1,084,100 women in the UK age 50-64
Sent invitations for breast screening + questioannaires
Ever used (current, prev) vs never used, menopausal status
9364 invasive breast cancers, 637 deaths.
Higher in ever vs never. Greater if combined. Rate in current users higher with duration. Prev users no increased risk. Rates higher in tibolone too.
For 5 years of use <65y:
6/1000 extra cases with E+P
1.5/1000 extra cases with E
Conclusion - current MHT use is associated with breast cancer and fatal breast cancer. Effect is higher for combined.
Strengths - very large cohort, prospective collection, participants had mammogram very soon after (reporting bias is removed). Main analysis limited to postmenopausal women to limit confounding. Use of cancer registry to limit recall bias,
Limitations - small number and limited follow up for mortality, observational study, information and detection bias (women more likely to participate if on MHT), majority white ethnicity, less likely to come from deprived area. Use of MHT reduces sensitivity of mammography so likely increased diagnosis on interval scans opposed to screening
MISCARRIAGE
A Comparison of Medical Management with Misoprostol and Surgical Management for Early Pregnancy Failure
Zhang et al
NEJM, 2005
Multicentre RCT - noninferiority trial
Aim - Establish efficacy, safety and acceptability of misoprostol compared to vacuum aspiration for treatment of early pregnancy failure
652 women seeking care for miscarriage (including incomplete and inevitable)
Assigned 3:1 ratio medical:surgical
Primary outcome - Success of treatment (empty cavity without need for surgery within 30days)
Results - Success 84% miso vs 97% surgery. High acceptability. Equal rates of haemorrhage and endometritis. Lower success if anembryonic pregnancy.
Conclusion - misoprostol is an effective, safe and acceptable alternative to surgical treatment for a miscarriage.
Strengths - multi centre RCT
Limitations - high LTFU in surgery group, resource intensive follow-up (USS day 3 if not passed POC), not many incomplete or inevitable miscarriages included (can’t really generalise to them), doesn’t address those presenting with heavy PV bleeding, no assessment of lowest effective dose or optimal route of misoprostol, doesn’t capture longer term complications (4 needed evac after 30days), underpowered to detect adverse outcomes particularly in surgical group
LACE
Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease Free Survival Among Women with Stage I Endometrial cancer: a Randomized Clinical Trial
JAMA, 2017
Janda et al
Multicenter, international RCT
Aim - assess whether TLH is equivalent to TAH in women with treatment-naïve stage I endometrial cancer
760 women
Stage 1 endometrioid endometrial cancer
TAH vs TLH
+ nodes unless not indicated or not safe (morbid obesity)
Primary outcome - disease free survival (assessed at 4.5years after surgery).
Secondary outcome - recurrence, overall survival
Results - Primary outcome 81.3 and 81.6% both groups - no difference. No difference in recurrence 7.9% vs 8.1% or overall survival. Similar intra-op adverse events. TLH less post op adverse events. TLH lower cost.
Conclusion - The use of TLH for stage I endometrioid endometrial cancer is appropriate. There is an equivalent disease-free survival at 4.5 years and no difference in overall survival.
Strengths - multi centre, RCT, ITT, all performed by GONC, appropriately powered.
Limitations - difference in who had a lymphadenectomy – will alter survival rates possibly because of differences in requirement for adjuvant treatment, not blinded. May not be generalisable to all surgeons (as these surgeons were screened to ensure competency and proficiency in methods)
OVARIAN CONSERVATION
Ovarian conservation at the time of hysterectomy for benign disease.
Obstetrics and Gynaecology, 2005
Parker et al
Retrospective cohort analysis
Aim - determine optimal age for oophorectomy in women with average risk for ovarian malignancy during hysterectomy for benign disease
Can’t see numbers anywhere?
Assessed hypothetical groups of women aged 40-80years under going hysterectomy for benign disease with an average risk of ovarian cancer.
Stratified women out into 4 groups
- Oophorectomy + oestrogen - Oophorectomy without oestrogen - Ovarian conservation + oestrogen - Ovarian conservation without oestrogen
Reviewed medical literature to ascertain their probability of certain events (ovarian cancer, stroke, CHD, hip fracture, breast cancer). Applied age-specific mortality rates to each condition.
They estimated the optimal strategy for maximal survival and did so within 5-year age groups - using Markov analytical model.
Primary outcome = probability of surviving until 80
Results - ovarian conservation, no oestrogen: Less CHD, hip fracture (outweighs mortality from ovarian ca) until >64y. Oophorectomy <55years 8.5% excess mortality.
Conclusion - Ovarian conservation until at least age 65 benefits long-term survival for women at average risk of ovarian cancer undergoing hysterectomy for benign disease. Earlier oophorectomy associated with increased mortality from CHD and hip fracture. There is no age at which oophorectomy causes a survival benefit because after 65 risks and benefits are approximated - mortality associated with ovarian cancer overshadows mortality from CHD, hip fracture.
Strengths - presumably large numbers of women. If oestrogen does not reduce CDH mortality then benefits of ovarian conservation should be higher. Unlikely to have a prospective study due to long latency between oophorectomy and potential disease.
Limitations - probability estimates are derived from case-controls (selection bias, reporting bias and chance), one study didn’t prove case selection of oestrogen, predominant white caucasian population - not generalisable. Does not take into account morbidity or QoL from a disease. Not known the duration or ages of oestrogen use. Due to amount of studies likely very heterogenous groups. No published data on coronary risks if oophorectomy occurs after menopause.
PLCO
Effect of screening on ovarian cancer mortality
JAMA, 2011
Buys et al
RCT
78216 women
55-74y
Annual screen: USS for 4years and CA-125 for 6years vs routine care
13year follow up
Primary outcome - mortality from ovarian cancer (including peritoneal and fallopian tube)
Secondary outcome - ovarian cancer incidence, complications assoc with screening
Results - no difference in mortality. 3823 false positives in intervention group - 1080 had surgery (15% of whom had major complications)
Conclusion - there is no role for screening for ovarian cancer in asymptomatic low risk women. There is no difference in incidence, lower disease stage or associated mortality. furthermore there are associated harms in relation to false positives.
Strengths - RCT, high adherence, large sample
Limitations - unable to blind, self administered questionnaires create bias, uncertain if CA-125 and TV-USS cut-offs were appropriate
