Evidence based medicine & ethical dilemmas in reproductive medicine Dr Hsu Phern Chong NIHR Clinical Lecturer in Obstetrics & Gynaecology Division of Reproductive Health

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

Classification of evidence levels Evidence levels I - IV I: > RCT II: > 1 well-designed controlled study III: > 1 well-designed quasi-experimental IV: Expert opinions Essentially, not all research is good research, and studies can be grouped into hierarchies. At the top of the ladder is RCTs. RCTs are deemed good quality evidence because of smaller effect of bias. At the bottom of the chain are case reports because these are hugely biased and obviously underpowered

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 Research involving pregnant women, particularly those involving administration of medicines, will have an effect of the fetus.

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 Research involving pregnant women, particularly those involving administration of medicines, will have an effect of the fetus.

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 Iatrogenic preterm delivery Spontaneous: 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 Hayes Grace 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 2012 http://www.bmj.com/content/345/bmj.e7961 Contrary to what is often publicised in the media, babies born at very early gestations have a much higher chance of death or disability than a life without disability. These two barcharts compare the proportion of death or disability over a 10 year interval. The increase in

The Epicure studies Moore et al. BMJ 2012 http://www.bmj.com/content/345/bmj.e7961 Whilst the fetus does not have any legal rights, it is obvious that we care about minimising morbidity to the newborn

RCOG guidelines on Preterm Labour Primary prevention Secondary prevention Tertiary prevention

Primary prevention Asymptomatic bacteriuria Smoking 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 Interventions 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)

Patient has an infection sensitive only to Co-amoxiclav? 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 Corticosteroids blunt the immune response. A robust host immune response is required to fight infection

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

Tocolytic agents Tocolytic Side effects Delivery under 48 hours Delivery under 7 days Beta agonists Hyperglycaemia, tachycardia, Fetal SE as above Yes COX Inhibitors No side effects if used for 48 hrs. Reversible closure of the ductus arteriosus Preterm labour on stopping treatment DA closure Calcium channel blockers Hypotension, flushing, headache No fetal SE Oxytocin Receptor Antagonists Minimal to none * 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) Multifactorial aetiology

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 “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 11- 29th of October GLT2

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 Local progesterone catabolism?

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 Overview of conflicts in preterm labour Animal models, in vitro experiments RCTs, Observational studies and systematic reviews in preterm labour Overview of conflicts in preterm labour

Suggested reading Textbooks Guidelines Papers 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