35/39 Trial Launch Meeting

35/39 Trial Launch Meeting Royal College of Obstetricians and Gynaecologist, Sussex Place Friday 11th May, 2012

Programme 1000-1015hours Welcome and introduction Professor Jim Thornton (JGT), Chief Investigator 1015-1045hours Background – literature/protocol Dr Kate Walker (KW), Trial Manager 1045-1115 hours Coffee 1115 -1230 hours Participant pathway – recruitment/randomisation/ data collection/CEQ - KW 1230- 1330 hours Lunch 1330-1345 hours How to get CLRN support - JGT 1345-1400 hours Approaching the trial from a CLRN midwife’s perspective Nicky Grace, CLRN Research Midwife 1400-1500 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 1500hours Closing Remarks – JGT Ideas for other trials

PICO

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

Fetal effects

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 1. Reddy et al, AJOG, 2006

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) 1. Reddy et al, AJOG, 2006

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 40 years = 27% (GCS Smith, unpublished data, maternities 2004-2008)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 week PMR = 1. GCS Smith, 2001

Rescue the ground floor Average cost of a Level 3 NICU admission = £17,861 Cost of IOL = £289

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 Neonatal cost of IOL at 39/40 • Smith GC 2001 • Reddy et al, 2006 • 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

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 term

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

Views for • [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 against • 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.

PICO

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

Intervention and Comparison TREATMENT 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.

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 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

Any questions Coffee until 11.15

Participant Pathway

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

Trial database

Participant Consent Form

Childbirth Experience Questionnaire (CEQ) Validated in 920 nulliparous women 22 questions Format – four point response choices or visual analogue scale

Childbirth Experience Questionnaire (CEQ)

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

35/39 Trial Launch Meeting