1. 35/39 Trial Launch Meeting Royal College of Obstetricians and Gynaecologist, Sussex Place Friday 11 th May, 2012

2. Programme 1000-1015 hoursWelcome and introduction Professor Jim Thornton (JGT), Chief Investigator 1015-1045 hoursBackground – literature/protocol Dr Kate Walker (KW), Trial Manager 1045-1115 hours Coffee 1115 -1230 hoursParticipant pathway – recruitment/randomisation/ data collection/CEQ - KW 1230- 1330 hoursLunch 1330-1345 hoursHow to get CLRN support - JGT 1345-1400 hoursApproaching the trial from a CLRN midwifes perspective Nicky Grace, CLRN Research Midwife 1400-1500 hoursProblems / 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 hoursClosing Remarks – JGT Ideas for other trials

3. 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 39 0/7 and 39 6/7 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

4. Relevant literature

5. 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.

6. Maternal effects Gestational diabetesOR 3.8 (Favilli et al) OR 3.4 (Jacobbson et al) Pregnancy induced hypertension OR 3.29 (Jacobbson et al) Severe pre-eclampsiaAOR 1.4 (Jacobbson et al) Placenta praeviaAOR 4.1 (Jacobbson et al) Placental abruptionAOR 1.8 (Joseph et al)

7. Fetal effects Preterm birth <32 weeks ARR 2.4 Preterm birth < 37 weeks ARR 1.8 SGA < 3 rd centileARR 2.1 SGA < 10 th centileARR 1.6

8. 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

11. 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 term 1. 1. Reddy et al, AJOG, 2006

12. Risk of antepartum stillbirth by maternal age 1. Reddy et al, AJOG, 2006

13. 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

14. Obstetric intervention 1. GCS Smith et al, PLOS, 2008

15. 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)

16. 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 weeks 1 number of all perinatal deaths in a given week number of all births in a given week PMR = 1. GCS Smith, 2001

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

18. Neonatal cost of IOL at 39/40 Lowest cumulative risk of stillbirth 38/40 1 Largest increase in SB risk starts at 39/40 2 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 plateaus 3 1.Smith GC 2001 2.Reddy et al, 2006 3.Heinzmann et al, 2009

19. Maternal cost of IOL Longer More painful – Italian cohort study – greater epidural analgesic dose required 1, greater epidural usage (23% induced labour, spontaneous delivery, 11% spontaneous labour and delivery 2 ) Complications ??? LSCS 1. Capogna et al, 2001 2. NHS Maternity Statistics 2005-06

20. 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.

21. Existing evidence for IOL at term Trial / Meta-analysisAuthor + journal Caesarean 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%

22. 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 rate 1. 1. Nicholson et al, 2008

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

24. 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

25. [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

26. 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

27. 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 39 0/7 and 39 6/7 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

28. 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 11 th 2012 PARTICIPATING CENTRES 14 currently

29. CENTREPRINCIPAL INVESTIGATOR LEAD CLRN MIDWIFE/NURSE Bradford Royal InfirmaryProfessor Derek TuffnellTracey Germaine Derriford Hospital, PlymouthDr Ross WelchTBC Sunderland Royal HospitalMr Kim HinshawEileen Walton, Gill Campbell, Karen Armstrong Derby Royal HospitalMr Daniel HayJill Smith RUH, BathMr David WalkerSara Burnard Frimley Park Hospitals NHS Foundation Trust Alison KirkpatrickTBC York Teaching HospitalsMr James DwyerLouise O'Higgins and Sara Collier-Hield Princess Anne Hospital, SouthamptonMr Matthew ColemanJane Forbes Shrewsbury and Telford Hospitals NHS Trust Dr Sheena HodgettKaren Henderson Newcastle Upon Tyne Hospitals NHS Foundation Trust Dr Suzie JacksonClaire Leader Leighton Hospital, CreweDr Karen McIntyreJanet Brown and Caroline Dixon Addenbrookes HospitalMr Christoph LeesTBC Leicester Royal InfirmaryDr Marwan HabibaTBC Nottingham University Hospitals NHS Trust a) Queen's Medical Centre CampusMr George BuggYvette Gunn b) Nottingham City Hospital CampusProfessor Jim ThorntonNicky Grace

30. Intervention and Comparison TREATMENT GROUP Induction of labour between 39 0/7 and 39 6/7 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 consultants 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.

31. 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

32. 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 Questionnaire 1 22 questions Approx 5-10 minutes 1. Dencker et al, BMC Pregnancy and Childbirth 2010

33. 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 36 0/7 and 39 0/7 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

34. Any questions Coffee until 11.15

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

36. Programme 1000-1015 hoursWelcome and introduction Professor Jim Thornton (JGT), Chief Investigator 1015-1045 hoursBackground – literature/protocol Dr Kate Walker (KW), Trial Manager 1045-1115 hours Coffee 1115 -1230 hoursParticipant pathway – recruitment/randomisation/ data collection/CEQ - KW 1230- 1330 hoursLunch 1330-1345 hoursHow to get CLRN support - JGT 1345-1400 hoursApproaching the trial from a CLRN midwifes perspective Nicky Grace, CLRN Research Midwife 1400-1500 hoursProblems / 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 hoursClosing Remarks – JGT Ideas for other trials

37. Participant Pathway Provide PIS at booking to women aged 35 years At booking appt – identify eligible patient Consent and randomise patient at 36 0/7 – 39 6/7 IOL between 39 0/7 and 39 6/7 Outcome data and CEQ Expectant management Outcome data and CEQ

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

39. Trial database

40. 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 babys 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.

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

42. Childbirth Experience Questionnaire (CEQ)

44. 35/39 Trial Launch Meeting Royal College of Obstetricians and Gynaecologist, Sussex Place Friday 11 th May, 2012

45. Programme 1000-1015 hoursWelcome and introduction Professor Jim Thornton (JGT), Chief Investigator 1015-1045 hoursBackground – literature/protocol Dr Kate Walker (KW), Trial Manager 1045-1115 hours Coffee 1115 -1230 hoursParticipant pathway – recruitment/randomisation/ data collection/CEQ - KW 1230- 1330 hoursLunch 1330-1345 hoursHow to get CLRN support - JGT 1345-1400 hoursApproaching the trial from a CLRN midwifes perspective Nicky Grace, CLRN Research Midwife 1400-1500 hoursProblems / 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 hoursClosing Remarks – JGT Ideas for other trials

46. 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? Womens whos IOL is delayed due to a busy LS

47. 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? Womens whos IOL is delayed due to a busy LS

48. 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? Womens whos IOL is delayed due to a busy LS

49. 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? Womens whos IOL is delayed due to a busy LS

50. 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? Womens whos IOL is delayed due to a busy LS

51. 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? Womens whos IOL is delayed due to a busy LS

52. 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? Womens whos IOL is delayed due to a busy LS

53. 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? Womens whos IOL is delayed due to a busy LS

54. 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? Womens whos IOL is delayed due to a busy LS

55. 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? Womens whos IOL is delayed due to a busy LS

56. 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? Womens whos IOL is delayed due to a busy LS

57. 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? Womens whos IOL is delayed due to a busy LS

58. Delegates questions

59. Thank you for listening and safe journey home