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Dr Hsu Phern ChongNIHR Clinical Lecturer in Obstetrics & Gynaecology
Division of Reproductive Health
Evidence based medicine & ethical dilemmas in reproductive medicine
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Outline
• Research & ethical considerations • Preterm labour• Evidence for and against current practice
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Classification of evidence levels
• Evidence levels I - IVI: > RCTII: > 1 well-designed controlled studyIII: > 1 well-designed quasi-experimentalIV: Expert opinions
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Basic science research in reproductive medicine
• Advantages– Understanding of
pathophysiology– Side effects
• Immediate• Lethal doses• Intergenerational effects
• Disadvantages– Same yet different– Confirmation required in
human models
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Maternal vs fetal rights
• Maternal health takes precedence
• Fetus no legal rights– < 24 weeks, termination of pregnancy legal in England, Scotland &
Wales– > 24 weeks, termination is by way of delivering the fetus
• Obstetric practice indirectly involves optimising the health of the fetus– Folic acid & spina bifida– Glycaemic control, congenital abnormalities and stillbirth– HIV & materno-fetal transmission
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Maternal vs fetal rights
• Maternal health takes precedence
• Fetus no legal rights– < 24 weeks, termination of pregnancy legal in England, Scotland &
Wales– > 24 weeks, termination is by way of delivering the fetus
• Obstetric practice indirectly involves optimising the health of the fetus– Folic acid & spina bifida– Glycaemic control, congenital abnormalities and stillbirth– HIV & materno-fetal transmission
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The disasters
Children of women exposed to Thalidomide in-utero in the 1960s
Vaginal cancer in daughters of women exposed to diethylstilboestrol (DES)
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Thalidomide
• Anti-convulsant in 1950s• Sedative effects, given to women in the 1st
trimester as a treatment for nausea• Animal testing– Did not evaluate the effects in pregnancy
• Used without appropriate phase I trials in humans
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Diethylstilboestrol
• Synthetic oestrogen• Used to prevent preterm labour, recurrent
miscarriage• Randomised controlled trial– No evidence of benefit– No short term harm
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Diethylstilboestrol
• Synthetic oestrogen• Used to prevent preterm labour, recurrent
miscarriage• Randomised controlled trial– No evidence of benefit– No short term harm
• Retrospective observational studies– Association between DES exposure and
• Clear cell vaginal carcinoma in daughters• Cryptocordism in sons
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Preterm labour
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Preterm labour
• In the UK– Threshold of viability 24 weeks (WHO- 28 weeks)– Under 37 completed weeks
• Iatrogenic preterm delivery– Delivery of the fetus to improve maternal health
• Spontaneous:– onset of contractions– rupture of membranes– antepartum haemorrhage
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Complex aetiology
Dewhurst’s Textbook of O&G (2007). 7th edition
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Complications of prematurity
• Incidence 8-10% • Leading cause of neonatal mortality– 1.1 million deaths worldwide
• Determinants of survival– Gestational age– Birth weight
Grace HayesGrace Research Fund
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The Epicure studies
• Large prospective observational study (12 mths)• All hospitals in the UK & Ireland (n=276)• Death and disability– 20 to 25 completed weeks gestation
• Follow up study in 2006
Costeloe et al. Paediatrics (2000)Moore et al. BMJ (2012) www.epicure.ac.uk
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The Epicure studies
Moore et al. BMJ 2012http://www.bmj.com/content/345/bmj.e7961
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The Epicure studies
Moore et al. BMJ 2012http://www.bmj.com/content/345/bmj.e7961
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RCOG guidelines on Preterm Labour
• Primary prevention• Secondary prevention• Tertiary prevention
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Primary prevention
• Asymptomatic bacteriuria– 2-10% of all pregnancies– Increases risk of pyelonephritis 19% in untreated– Screening in the first trimester– Treatment reduces preterm birth by 40%
• Smoking– Affects 10-18% of PTB
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Secondary prevention
• Screening at risk populations– History of preterm birth– Markers of preterm labour• Fetal fibronectin• Phosphorylated Insulin Like Growth Factor Binding
Protein-1 (trade name Actim Partus)
– Transvaginal US (TV US)
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Biomarkers for preterm labour
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Cervical length on TV US
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Secondary prevention
• Screening at risk populations• History of preterm birth• Transvaginal USS• Fetal fibronectin • Actim Partus
• Interventions • Cervical cerclage (40% reduction)• Erythromycin in women who have ruptured
membranes• Progesterone (to be discussed)
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Cervical cerclage
• Occlude cervix• High risk patients
• Risks– Maternal pyrexia– Trauma– Bleeding– Anaesthetic
• Treat 25 women, prevent 1 delivery <33 weeks
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Preterm prelabour rupture of membranes
• Spontaneous loss of amniotic fluid• Incidence of preterm labour 50%• The Oracle trial– Randomised 4826 women to 4 different antibiotic
treatments• Erythromycin
– Increased interval between event to delivery• Co-amoxiclav
– Increased risk of necrotising enterocolitis in the newborn
Kenyon S et al. Acta Paediatr Suppl. (2002)
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What if?
Patient has an infection sensitive only to Co-amoxiclav?
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Tertiary prevention
• Administer corticosteroids for lung maturity– Betamethasone OR dexamethasone
intramuscularly• Reduces complications of prematurity
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Corticosteroids in preterm labour
• Animal studies– Sheep– Betamethasone reduces• RDS by induction of surfactant production in Type II
pneumocytes• Periventricular leucomalacia
– Repeated courses• Brain atrophy
– Unknown if this equates to reduction in function
• Lower birthweight
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Corticosteroids in preterm labour
• Evidence level: I– Singleton pregnancies– Multiple pregnancies• Non-significant trend towards benefit• Optimum dose unknown
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What if?
Patient with a twin pregnancy is in labour?
Patient has a systemic infection
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Tocolysis
• Stop uterine contractions• Pathways influencing myometrial contractility– Beta-agonists (ritodrine, terbutaline)– COX inhibitors (indomethacin)– Calcium channel blockers (nifedipine)– Oxytocin receptor antagonists
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Tocolytic agentsTocolytic Side effects Delivery under 48
hoursDelivery under 7 days
Beta agonists Hyperglycaemia, tachycardia,Fetal SE as above
Yes Yes
COX Inhibitors No side effects if used for 48 hrs. Reversible closure of the ductus arteriosusPreterm labour on stopping treatmentDA closure
Yes Yes
Calcium channel blockers
Hypotension, flushing, headacheNo fetal SE
Yes Yes
Oxytocin Receptor Antagonists
Minimal to none Yes Yes
* Apart from calcium channel blockers, all other treatments compared with placebo
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Evidence for benefit?
• Delays labour by 48 hours- 7 days• No difference in– Delivery <34 weeks– Delivery <37 (except for indomethacin, COX Inhb)
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COX inhibitors
• Inhibit prostaglandin synthesis • Indomethacin infusion– Inhibits contractions– BUT• Premature closure of the ductus arteriosus in the fetus• PGE2 and prostacyclin expressed in the fetal ductus
arteriosus» pulmonary hypertension» reversible
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Risk/benefit analysis
Patient has who is 26 weeks pregnant and is in preterm labour
? Administer indomethacin
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Progesterone to prevent preterm labour
• Csapo 1956. “Progesterone block”• Progesterone withdrawal resulted in initiation
of labour– In rodents- fall in serum progesterone– In humans- no fall in serum progesterone
– ?? Mechanism
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Progesterone to prevent preterm labour
• Progesterone– “anti-inflammatory”– Smooth muscle relaxant• Changes at a gene level(genomic)• Changes that do not affect genes (non-genomic)
– Changes at a cervical level• Reduce cervical stromal degradation• Barrier to inflammation/infection
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Meis PJ et al. NEJM (2003)
• Double blind randomised controlled trial• Enrolment: 16-20 weeks• Weekly im 250mg 17 hydroxyprogesterone vs
castor oil (placebo) until 36 weeks• Outcomes– Preterm delivery before 37 weeks
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Results
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Current practice
• Not routinely used in the UK– Conflicting evidence– Cochrane systematic review (2014)
• No reduction in preterm birth in symptomatic or established pre-term labour– Could be due to comparisons between different types of
progesterone used» 17-a hydroxyprogesterone caproate (natural metabolite of
progesterone)• Intramuscular
» Natural progesterone• Vaginal, rectal or oral route
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Progesterone for preterm labour
• America and Australasia– Used in selected populations• Singleton pregnancies• Short cervix on transvaginal ultrasound
• Reduces the risk of preterm labour <32 weeks
Same evidence, different interpretation!
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Summary
• Evidence synthesis– Animal models, in vitro experiments– RCTs, Observational studies and systematic
reviews in preterm labour• Overview of conflicts in preterm labour
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Suggested reading• Textbooks
– Luesley (ed). Evidence Based Obstetrics & Gynaecology. 7th edition (2007). – Berghella V (ed). Obstetric Evidence Based Guidelines. (2007) (American)
• Guidelines– RCOG
• Antenatal corticosteroids• Preterm prelabour rupture of membranes
• Papers– Cochrane review
• Progesterone for preterm labour
– Epicure studies