35/39 Trial Launch Meeting Royal College of Obstetricians and Gynaecologist, Sussex Place Friday 11...

35/39 Trial Launch Meeting

Royal College of Obstetricians and Gynaecologist,

Sussex Place

Friday 11th May, 2012

Programme1000-1015 hours Welcome and introduction

Professor Jim Thornton (JGT), Chief Investigator1015-1045 hours Background – literature/protocol

Dr Kate Walker (KW), Trial Manager1045-1115 hours Coffee 1115 -1230 hours Participant pathway – recruitment/randomisation/

data collection/CEQ - KW1230- 1330 hours Lunch1330-1345 hours How to get CLRN support - JGT1345-1400 hours Approaching the trial from a CLRN midwife’s perspective

Nicky Grace, CLRN Research Midwife1400-1500 hours Problems / Discussion – we will present examples of

frequently encountered problems and propose solutions but will also invite the audience to ask their own

questions and discuss solutions KW/NG – chaired by JGT

1500 hours Closing Remarks – JGTIdeas for other trials

PICO

Population Nulliparous women with a singleton live fetus who will be over 35 years of age at their expected date of delivery

Intervention Induction of labour between 390/7 and 396/7 weeks gestation

Comparison Women will be assigned to expectant management

Outcome Primary end point: Caesarean delivery

Secondary end points:

o Operative vaginal delivery

o Perinatal mortality

o Serious neonatal morbidity

o Maternal satisfaction

Relevant literature

Background

• 1996: 12% of live births were to women over 35 years

• 2006: 20%.

• 2006: 5.6% of live births were to nulliparous women over the age of 35 years.

Maternal effects

Gestational diabetes OR 3.8 (Favilli et al)

OR 3.4 (Jacobbson et al)

Pregnancy induced hypertension

OR 3.29 (Jacobbson et al)

Severe pre-eclampsia AOR 1.4 (Jacobbson et al)

Placenta praevia AOR 4.1 (Jacobbson et al)

Placental abruption AOR 1.8 (Joseph et al)

Fetal effects

Preterm birth <32 weeks

ARR 2.4

Preterm birth < 37 weeks

ARR 1.8

SGA < 3rd centile ARR 2.1

SGA < 10th centile ARR 1.6

Perinatal death

ALL PERINATAL DEATHS

• 0.6% women aged 30-34 yrs (LOWEST RISK GROUP)

• 0.8% women 35-40 years

• 1% women over 40 years

Perinatal death at term

• Main increase in risk of stillbirth for women over 35 years is 39 to 41 weeks.

• Women over 40 years old have a similar stillbirth risk at 39 weeks as women who are between 25 and 29 years old at 41 weeks

• Once they pass 40 weeks gestation their risk of stillbirth exceeds that of all women < 40 years old at term1.

1. Reddy et al, AJOG, 2006

Risk of antepartum stillbirth by maternal age


Quantifying the risk in women of AMA

• Risk of stillbirth at 37-41 weeks for women 35-39 1 in 382 ongoing pregnancies (RR 1.32)

• Risk of stillbirth at 37-41 for women 40 years or older 1 in 267 ongoing pregnancies (RR 1.88)


Obstetric intervention

1. GCS Smith et al, PLOS, 2008

Obstetric intervention

Nulliparous women • > 35 years = 38% • > 40 years = 50%

(Joseph et al, 2005)

Nulliparous women in labour at term (excl. breech) • 35-39 years = 23%• > 40 years = 27%

(GCS Smith, unpublished data, maternities 2004-2008)

Correct denominator

• Need to consider the cumulative risk of stillbirth at any gestational age.

• Although the PMR is lowest at 41 weeks, the gestational age associated with the lowest cumulative risk of perinatal death is 38 weeks1

number of all perinatal deaths in a given week

number of all births in a given weekPMR =

1. GCS Smith, 2001

Rescue the ground floor

Average cost of a Level 3

NICU admission = £17,861

Cost of IOL = £289

Neonatal cost of IOL at 39/40

Lowest cumulative risk of stillbirth 38/401

Largest increase in SB risk starts at 39/402

The risk of developing neonatal respiratory symptoms for babies

born by vaginal delivery falls from a probability of 0.07 at 37 weeks to 0.04

at 39 weeks and thereafter plateaus3

1. Smith GC 2001

2. Reddy et al, 2006

3. Heinzmann et al, 2009

Maternal cost of IOL

• Longer• More painful – Italian

cohort study – greater epidural analgesic dose required1, greater epidural usage (23% induced labour, spontaneous delivery, 11% spontaneous labour and delivery2)

• Complications• ??? LSCS

1. Capogna et al, 2001

2. NHS Maternity Statistics 2005-06

http://www.google.co.uk/imgres?q=image+woman+in+labour&hl=en&rls=com.microsoft:en-gb:IE-SearchBox&rlz=1I7MEDB_en&biw=1366&bih=545&tbm=isch&tbnid=ZNJqBwS7mAGTbM:&imgrefurl=http://www.sciencemediacentre.co.nz/2012/03/16/pain-relief-in-labour-what-works/woman-in-labor/&docid=FyVT2fbDGdCq7M&imgurl=http://www.sciencemediacentre.co.nz/wp-content/upload/2012/03/Woman-in-Labor.jpg&w=270&h=270&ei=sBasT5vOK6jC0QXMnsU1&zoom=1&iact=hc&vpx=649&vpy=211&dur=1034&hovh=216&hovw=216&tx=154&ty=193&sig=108138558170241537140&page=2&tbnh=159&tbnw=159&start=10&ndsp=19&ved=1t:429,r:10,s:10,i:115

Existing evidence for IOL at term

• Growing body of evidence that induction of labour at term does not increase emergency caesarean section rates and does not increase intrapartum deaths.

Existing evidence for IOL at termTrial / Meta-analysis Author +

journalCaesarean section rates or relative risk

Term PROM: IOL vs. expectant management for term prelabour rupture of membranes

Hannah et al, NEJM, 1996

IOL with oxytocin 10.1%

Expectant Mx then oxytocin 9.7%

IOL with PG 9.6%

Expectant Mx with PG 10.9%

Post dates: Cochrane Review of 18 trials comparing IOL with expectant Mx

Gülmezoglu et al, Cochrane Review 2006

IOL 37-40 completed weeks RR 0.58

IOL at 41completed weeks RR 0.92

IOL at 42 completed weeks RR 0.97

HYPITAT: IOL vs. expectant Mx for PIH and mild PET after 36/40

Koopmans et al, Lancet, 2009

IOL 14%

Expectant 19%

DIGITAT: IOL versus expectant monitoring for IUGR at term

Boers et al, 2010

IOL 14%

Expectant 13.7%

Existing evidence for IOL at term

• A recent trial of IOL at term for women identified as high risk for emergency CS (higher the risk score, earlier the induction), found in the treatment group a similar CS rate, a higher vaginal birth rate and a reduced NICU admission and adverse outcome rate1.

1. Nicholson et al, 2008

Current practice

• 3% offer IOL at term to women aged 35-39 yrs• 37% - women aged 40 – 44 yrs• 55% - women aged 45 yrs +

Acceptability to women

• Surveyed 663 women – either pregnant or delivered in the last 5 years

• 43% women would consider IOL for maternal age alone

• 29% would consider participating in an RCT in a future pregnancy

• [If] there is no risk to the baby I would welcome helping in a study […] to potentially reduce stillbirths

• I'm a great believer in taking the expert's advice […]. I would trust the doctors if they recommended induction

• Going late is horrendous for most pregnant women. • I understand the importance of such studies and although I haven't experienced

stillbirth I would do anything to avoid it. I have been induced in 3/4 of my pregnancies and there were no complications and had normal deliveries.

• Unfortunately, I have direct experience of stillbirth when I was aged 33. I subsequently had another baby aged 35 [and] was induced at 40wks+3days, having been very closely monitored throughout the pregnancy

• Because at 39 weeks I felt ready to have my baby and consider 37 to 42 weeks to be full term. I would also not like to be overdue again, particularly if I was over 35 and there were increased risks.

• Am aware that older mothers have more problems. Long time waiting for this pregnancy. Would hate anything to go wrong.

• I was induced at 40+11 at age 40 and feel very angry that they left the induction so late […]

Views for

• I'd want to help, but would be slightly worried that by NOT having the earlier induction I would be putting my baby at risk.

• Don't want someone else making choice for me• Age alone is not reason enough to prompt medical intervention. • Completely irrational to base a major cascade of intervention purely on one

relatively minor factor. [..] participating in such a study could be terrifying for a mother assigned to the non-intervention group.

• So many inductions end in Caesarean, so I'd be reluctant to have one. • I would rather be scanned every day and be induced at term if necessary if the

risks of still birth were great enough• Pregnancy lasts between 38 and 42 weeks, I don't understand this medical

obsession with giving birth at exactly 40 weeks. • Statistics are useful for doctors looking at big patterns but are not useful for me

personally • I do not agree with the ethics of the study. I do not believe that any woman

should be induced unless there is a specific medical risk for that woman. I do not agree with induction at 39 weeks or 42 weeks just because "there's a risk of stillbirth after that point".

• I do believe that induction can cause health problem for the mother and problems with breastfeeding.

Views against

PICO

Population Nulliparous women with a singleton live fetus who will be over 35 years of age at their expected date of delivery

Intervention Induction of labour between 390/7 and 396/7 weeks gestation

Comparison Women will be assigned to expectant management

Outcome Primary end point: Caesarean delivery

Secondary end points:

o Operative vaginal delivery

o Perinatal mortality

o Serious neonatal morbidity

o Maternal satisfaction

Overview

AIMS

Primary: to establish what affect a policy of induction of labour at 39 weeks for nulliparous women of advanced maternal age has on the rate of Caesarean section deliveries.

Secondary: to act as a pilot study for a trial to answer the question, does induction of labour in this group of women improve perinatal outcomes?

DURATION

24 months – from June 11th 2012

PARTICIPATING CENTRES

14 currently

CENTRE PRINCIPAL INVESTIGATOR

LEAD CLRN MIDWIFE/NURSE

Bradford Royal Infirmary Professor Derek Tuffnell Tracey Germaine

Derriford Hospital, Plymouth Dr Ross Welch TBC

Sunderland Royal Hospital Mr Kim Hinshaw Eileen Walton, Gill Campbell, Karen Armstrong

Derby Royal Hospital Mr Daniel Hay Jill Smith

RUH, Bath Mr David Walker Sara Burnard

Frimley Park Hospitals NHS Foundation Trust

Alison Kirkpatrick TBC

York Teaching Hospitals Mr James Dwyer Louise O'Higgins and Sara Collier-Hield

Princess Anne Hospital, Southampton Mr Matthew Coleman Jane Forbes

Shrewsbury and Telford Hospitals NHS Trust

Dr Sheena Hodgett Karen Henderson

Newcastle Upon Tyne Hospitals NHS Foundation Trust

Dr Suzie Jackson Claire Leader

Leighton Hospital, Crewe Dr Karen McIntyre Janet Brown and Caroline Dixon

Addenbrookes Hospital Mr Christoph Lees TBC

Leicester Royal Infirmary Dr Marwan Habiba TBC

Nottingham University Hospitals NHS Trust

a) Queen's Medical Centre Campus Mr George Bugg Yvette Gunn

b) Nottingham City Hospital Campus Professor Jim Thornton Nicky Grace

Intervention and ComparisonTREATMENT GROUP

Induction of labour between 390/7 and 396/7 weeks gestation

CONTROL GROUP

Expectant management i.e. awaiting spontaneous onset of labour unless a situation develops necessitating either induction of labour or Caesarean Section.

• Offer induction of labour anywhere between T+7 and T+14, the exact time to be determined by consultant’s usual practice.

• No additional monitoring in the expectant management group prior to T+14 will be offered.

• If the patient declines induction of labour at T+14 the patient will be offered a scan for growth and liquor volume and offered alternate day or daily CTG monitoring depending on the consultants usual practice.

Outcomes

Maternal• Mode of delivery • Onset of labour• Indication for induction of

labour• Method of induction of labour • Indication for Caesarean

section• Intrapartum complications • Postpartum morbidity

Neonatal• Live birth or stillbirth• Birth weight • Sex• Death before discharge from

hospital• Apgar scores• Cord blood artery pH and BD • Cord blood vein pH and BD • NICU admission • Birth trauma

Outcomes

Outcomes for pilot study

• The recruitment rate per hospital.

• The age distribution of participating women.

• Compliance with the treatment arms of the trial.

• The overall gestational age distribution of the two groups.

• Completeness of outcome data

Maternal satisfaction• Childbirth Experience

Questionnaire1

• 22 questions• Approx 5-10 minutes

1. Dencker et al, BMC Pregnancy and Childbirth 2010

INCLUSION CRITERIA

1. Nulliparous

2. Maternal age over 35 years old at the EDD

3. Singleton, live fetus

4. Cephalic presentation

5. Gestational age between 360/7 and 390/7

6. No medical contra-indication to induction of labour

7. No medical contra-indication to pregnancy being allowed to proceed to term plus 10 days

8. Willingness to participate in the trial

9. Written informed consent

EXCLUSION CRITERIA

1. Fetus with a known lethal congenital abnormality

2. Women with a contraindication to labour or vaginal delivery

3. Women with a contraindication to expectant management

4. Women with a previous myomectomy

5. Women who book late for antenatal care and have no dating scan performed before 22 weeks

6. Women who have undergone IVF using donor eggs in the current pregnancy

Any questions

Coffee until 11.15



Sussex Place


Participant PathwayProvide PIS at booking to

women aged ≥35 years

At booking appt – identify eligible patient

Consent and randomise patient

at 360/7 – 396/7

IOL between 390/7 and 396/7

Expectant management

Outcome data and CEQOutcome data and CEQ

Trial Website www.35-39.org

http://www.nottingham.ac.uk/mczseafood/35-39/index.html.

http://www.35-39.org/

http://www.nottingham.ac.uk/mczseafood/35-39/index.html

Trial database

Participant Consent Form

1. I confirm that I have read and understand the information sheet dated ____________ (version _______ ) for the above study and have had the opportunity to ask questions.

2. I understand that my participation is voluntary and that I am free to withdraw at any time without my medical care or legal rights being affected.

3. I understand that my medical records and my baby’s medical records may be looked at by authorised individuals from the Sponsor for the study, or the Independent Ethics Committee in order to check that the study is being carried out correctly.

4. I understand that even if I withdraw from the above study, the data collected from me will be used in analysing the results of the trial, unless I specifically withdraw consent for this.

5. I consent to the storage including electronic, of personal information for the purposes of this study. I understand that any information that could identify me will be kept strictly confidential and that no personal information will be included in the study report or other publication.

6. I agree that my GP, or any other doctor treating me, will be notified of my participation in this study.

7. I understand that I may be contacted in the future if further research projects arising from this one are conducted. (OPTIONAL)

8. I agree to take part in the study.

Childbirth Experience Questionnaire (CEQ)

Validated in 920 nulliparous women

22 questions

Format – four point response choices or visual analogue scale

Childbirth Experience Questionnaire (CEQ)



Sussex Place


Problems• Approval / regulatory problems• GCP training. How to get it.• Patients who insist on IOL outside trial• Patients who change their mind after randomisation• Patients who insist on IOL at T + 1-10• Can patients be recruited to more than one trial?• How should the induction group be induced?• What if she draws IOL and the cervix is like a carrot even after 24

hours of Propess?• Can people be induced with Foley catheter?• How should the control group be monitored?• What if a control develops pre-eclampsia, term PROM, turns

breech, or other problem after randomisation?• Women’s who’s IOL is delayed due to a busy LS

Problems• Approval / regulatory problems• GCP training. How to get it.• Patients who insist on IOL outside trial• Patients who change their mind after randomisation• Patients who insist on IOL at T + 1-10• Can patients be recruited to more than one trial?• How should the induction group be induced?• What if she draws IOL and the cervix is like a carrot even after 24

hours Propess?• Can people be induced with Foley catheter?• How should the control group be monitored?• What if a control develops pre-eclampsia, term PROM, turns

breech, or other problem after randomisation?• Women’s who’s IOL is delayed due to a busy LS

Delegate’s questions

Thank you for listening and safe

journey home

35/39 Trial Launch Meeting Royal College of Obstetricians and Gynaecologist, Sussex Place Friday 11...

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