Dr Hsu Phern ChongNIHR Clinical Lecturer in Obstetrics & Gynaecology

Division of Reproductive Health

Evidence based medicine & ethical dilemmas in reproductive medicine

Outline

• Research & ethical considerations • Preterm labour• Evidence for and against current practice

Classification of evidence levels

• Evidence levels I - IVI: > RCTII: > 1 well-designed controlled studyIII: > 1 well-designed quasi-experimentalIV: Expert opinions

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

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

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

The disasters

Children of women exposed to Thalidomide in-utero in the 1960s

Vaginal cancer in daughters of women exposed to diethylstilboestrol (DES)

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

Diethylstilboestrol

• Synthetic oestrogen• Used to prevent preterm labour, recurrent

miscarriage• Randomised controlled trial– No evidence of benefit– No short term harm

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

Preterm labour

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

Complex aetiology

Dewhurst’s Textbook of O&G (2007). 7th edition

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

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

The Epicure studies

Moore et al. BMJ 2012http://www.bmj.com/content/345/bmj.e7961

The Epicure studies

Moore et al. BMJ 2012http://www.bmj.com/content/345/bmj.e7961

RCOG guidelines on Preterm Labour

• Primary prevention• Secondary prevention• Tertiary prevention

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

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)

Biomarkers for preterm labour

Cervical length on TV US

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)

Cervical cerclage

• Occlude cervix• High risk patients

• Risks– Maternal pyrexia– Trauma– Bleeding– Anaesthetic

• Treat 25 women, prevent 1 delivery <33 weeks

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)

What if?

Patient has an infection sensitive only to Co-amoxiclav?

Tertiary prevention

• Administer corticosteroids for lung maturity– Betamethasone OR dexamethasone

intramuscularly• Reduces complications of prematurity

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

Corticosteroids in preterm labour

• Evidence level: I– Singleton pregnancies– Multiple pregnancies• Non-significant trend towards benefit• Optimum dose unknown

What if?

Patient with a twin pregnancy is in labour?

Patient has a systemic infection

Tocolysis

• Stop uterine contractions• Pathways influencing myometrial contractility– Beta-agonists (ritodrine, terbutaline)– COX inhibitors (indomethacin)– Calcium channel blockers (nifedipine)– Oxytocin receptor antagonists

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

Evidence for benefit?

• Delays labour by 48 hours- 7 days• No difference in– Delivery <34 weeks– Delivery <37 (except for indomethacin, COX Inhb)

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

Risk/benefit analysis

Patient has who is 26 weeks pregnant and is in preterm labour

? Administer indomethacin

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

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

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

Results

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

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!

Summary

• Evidence synthesis– Animal models, in vitro experiments– RCTs, Observational studies and systematic

reviews in preterm labour• Overview of conflicts in preterm labour

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