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

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

3. 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

4. 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

5. 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.

6. 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.

7. The disasters
Children of women exposed to Thalidomide in-utero in the 1960s
Vaginal cancer in daughters of women exposed to diethylstilboestrol (DES)

8. 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

9. Diethylstilboestrol Synthetic oestrogen
Used to prevent preterm labour, recurrent miscarriage
Randomised controlled trial
No evidence of benefit
No short term harm

10. 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

11. Preterm labour

12. 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

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

14. 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

15. 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)

16. The Epicure studies Moore et al. BMJ 2012
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

17. The Epicure studies Moore et al. BMJ 2012
Whilst the fetus does not have any legal rights, it is obvious that we care about minimising morbidity to the newborn

18. RCOG guidelines on Preterm Labour
Primary prevention
Secondary prevention
Tertiary prevention

19. 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

20. 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)

21. Biomarkers for preterm labour

22. Cervical length on TV US

23. 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)

24. Cervical cerclage Occlude cervix High risk patients Risks
Maternal pyrexia
Trauma
Bleeding
Anaesthetic
Treat 25 women, prevent 1 delivery <33 weeks

25. 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)

26. Patient has an infection sensitive only to Co-amoxiclav?
What if?
Patient has an infection sensitive only to Co-amoxiclav?

27. Tertiary prevention Administer corticosteroids for lung maturity
Betamethasone OR dexamethasone intramuscularly
Reduces complications of prematurity

28. 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

29. Corticosteroids in preterm labour
Evidence level: I
Singleton pregnancies
Multiple pregnancies
Non-significant trend towards benefit
Optimum dose unknown

30. 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

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

32. 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

33. 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

34. 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

35. Risk/benefit analysis
Patient has who is 26 weeks pregnant and is in preterm labour ? Administer indomethacin

36. Progesterone to prevent preterm labour
Csapo “Progesterone block”
Progesterone withdrawal resulted in initiation of labour
In rodents- fall in serum progesterone
In humans- no fall in serum progesterone
?? Mechanism

37. 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

38. Meis PJ et al. NEJM (2003) Double blind randomised controlled trial
Enrolment: weeks
Weekly im 250mg 17 hydroxyprogesterone vs castor oil (placebo) until 36 weeks
Outcomes
Preterm delivery before 37 weeks
Local progesterone catabolism?

40. Results

41. 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

42. 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!

43. 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

44. 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