Transcript Singleton pregnancies

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
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 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
The Epicure studies
Moore et al. BMJ 2012
http://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 Coamoxiclav?
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 agents
Tocolytic
Side effects
Delivery under 48
hours
Delivery 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 arteriosus
Preterm labour on
stopping treatment
DA closure
Yes
Yes
Calcium channel
blockers
Hypotension, flushing,
headache
No 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