Prevention of preterm birth in twin pregnancy NORSTAMP meeting October 2008 Prof Jane Norman University of Edinburgh Multiple births in Scotland 1855 - 2005 Perinatal outcomes in twin births Singleton Twin Triplet Perinatal mortality 5.4 14.8 51.8 Stillbirth rate 7.7 28.2 83.3 Infant mortality 4.5 21.6 61.8 Preterm birth and neonatal unit stay in multiples Singleton Twin Triplet Percentage of all babies 97.2 2. 7 0.1 Percentage of all preterm births 5.8 48.1 83.3 Percentage of neonatal cot stays 75 21.6 3.4 Preterm birth and neonatal unit stay in multiples Singleton Twin Triplet Percentage of all babies 97.2 2. 7 0.1 Percentage of neonatal cot stays 75 21.6 3.4 Percentage of all preterm births 5.8 48.1 83.3 Preterm birth and neonatal unit stay in multiples Singleton Twin Triplet Percentage of all babies 97.2 2. 7 0.1 Percentage of neonatal cot stays 75 21.6 3.4 Percentage of all preterm births 5.8 48.1 83.3 Singleton neonatal deaths by obstetric classification Scotland 2006 Figure 3a(2): Singleton Neonatal Deaths by Obstetric Classification: 2006 Unexplained <2500G (36%) Congenital anomaly (31%) Unexplained >2500G (15%) Antepartum haemorrhage (4%) Hypertension of pregnancy (1%) Postnatal cause only (4%) Maternal disorder (5%) Miscellaneous (1%) Trauma/mechanical (2%) Multiple neonatal deaths by obstetric classification (2006) Figure 3b(2): Multiple Neonatal Deaths by Obstetric Classification: 2006 Unexplained <2500G (74%) Congenital anomaly (12%) Miscellaneous (9%) Postnatal cause only (3%) Antepartum haemorrhage (3%) Spontaneous preterm birth is increasing Langhoff-Roos et al 2006 BMJ 332: 937 Prediction of preterm birth (before 32 weeks) in twin pregnancy fFN Both Sensitivity Cervical length (< 30mm) 75 % 43 % 83 % Specificity 85 % 94 % 81 % PPV 32 % 38 % 25 % NPV 97% 95 % 99 % McMahon et al 2002 Am J Obstet Gynecol 186: 1137 Prevention of preterm delivery • 1. Antibiotics • 2. Cervical cerclage • 3. Progesterone therapy Odds of preterm birth in after treatment with antibiotics (AB) OR 95% CI Any AB 1.03 0.86 – 1.24 Clindamycin 1.02 0.69 – 1.48 Metronidazole 1.06 0.81 – 1.39 AB in women with a history of PTB 0.99 0.72 – 1.37 AB in women with abnormal vaginal flora 0.97 0.78 – 1.21 Simcox et al 2007 Aust N Z J Obstet Gynecol 47: 368 What about women presenting in preterm labour with intact membranes? • Oracle II study showed no benefit in preventing preterm labour • Giving antibiotics to women with intact menbranes in preterm labour not generally recommended in the UK • Until recently no good evidence that this strategy was harmful Evidence of harm in children aged 7 after antibiotics in women with PTL and intact membranes OR 95 % CI Any functional impairment Erythromycin 1.18 1.02 - 1.37* Co-amoxiclav 1.03 0.89 - 1.19 Erythromycin 1.93 1.21 - 3.09* Co-amoxiclav 1.69 1.07 - 2.67* Cerebral palsy Kenyon et al 2008 Lancet What about women with pPROM? Antibiotics improve outcome in women with PPROM • In women with preterm ruptured membranes, antibiotics reduce risk of birth within 48 hrs (RR 0.71, 95% CI 0.58 – 0.87) and of birth within seven days (RR 0.80, 95% CI 0.71- 0.90) • Neonatal morbidity, neonatal infection, use of surfactant, oxygen therapy and incidence of abnormal cerebral ultrasound scan also reduced • Suggested regimen: erythromycin 250mg IV 6hrly for 48 hrs followed by 330mg 8hrly orally thereafter for 5 days Kenyon et al 2003 Cochrane Database Syst Rev CD001058 Antibiotics for pPROM in twin pregnancy • 453 (out of 4826) women in ORACLE 1 had a multiple pregnancy • No significant differences in outcome between the antibiotic and placebo groups • Uncertainty therefore about whether singelton pPROM advice (to give antibiotics) is relevant for multiples Prevention of preterm delivery • 1. Antibiotics • 2. Cervical cerclage • 3. Progesterone therapy Cerclage for short cervix on ultrasound – individual patient meta-analysis Outcome of PTB < Cerclage Control 35 weeks for subgroup: All pregnancies 29.2% 38.4% RR (95%CI) 0.84 (0.67 – 1.06) Singletons 24.8 % 33.9% 0.74 (0.57 – 0.96) Singletons with previous PTB 38.3% 60.4% 0.63 (0.48 – 0.85) Berghella et al 2005 Obstet Gynecol 106: 181 Cerclage for short cervix on ultrasound – individual patient meta-analysis Singleton gestations in women with a prior preterm birth at 16 –36 weeks Berghella et al 2005 Obstet Gynecol 106: 181 Cerclage for short cervix on ultrasound – individual patient meta-analysis Outcome of PTB < Cerclage Control 35 weeks for subgroup: All pregnancies 29.2% 38.4% RR (95%CI) 0.84 (0.67 – 1.06) Singletons 24.8 % 33.9% 0.74 (0.57 – 0.96) Singletons with previous PTB 38.3% 60.4% 0.63 (0.48 – 0.85) Twin pregnancy 75 % 36 % 2.15 (1.15 – 4.01) Berghella et al 2005 Obstet Gynecol 106: 181 Prevention of preterm delivery • 1. Antibiotics • 2. Cervical cerclage • 3. Progesterone therapy Use of progesterone in clinical practice • Meta-analysis of progesterone suggests reduction in incidence of preterm birth – OR 0.5 (95% CI 0.3 – 0.85) Keirse 1990 • Progesterone not mentioned in chapter on treatment / prevention preterm birth in “High Risk Pregnancy” James/Steer/Weiner/Gonik 2nd edn 1999 Is the use of progesterone to prevent preterm delivery biologically plausible? • increasing evidence that labour associated with functional progesterone withdrawal • antiprogestogens used to stimulate abortion and labour induction • progesterone inhibits prostaglandin production and has other anti-inflammatory properties (eg upregulates IL-10) • progesterone inhibits the stimulatory effect of estrogen on gap junction formation • some evidence that progesterone may sensitise the uterus to the action of exogenous tocolytics Acute effect of progesterone on myometrial contractions in vitro Anderson et al, unpublished data Acute tocolytic effect seen for progesterone but not 17 OHP Anderson et al, unpublished data Meta-analysis of progestational agents to prevent PTB (singletons with previous PTB) - Primary outcomes Outcome Odds ratio 95% CI Perinatal death 0.65 0.38–1.11 PTB < 34 weeks 0.15 0.04–0.64** Developmental delay 0.97 0.55–1.73 Dodd et al 2008 Obstet Gynecol 112: 127 Meta-analysis of progestational agents to prevent PTB (Singletons with previous preterm birth) Selected secondary outcomes Outcome Odds ratio 95% CI IVH 0.54 0.12–2.47 RDS 0.79 0.57–1.10 Fetal death 1.13 0.35–3.59 Dodd et al 2008 Obstet Gynecol 112: 127 Meta-analysis of progestational agents to prevent PTB Short cervix Outcome Odds ratio 95% CI Perinatal death 0.38 0.10–1.40 PTB < 34 weeks 0.58** 0.38–0.87 IVH 0.51 0.05–5.53 Dodd et al 2008 Obstet Gynecol 112: 127 Meta-analysis of progestational agents to prevent PTB Multiple pregnancy Outcome Odds ratio 95% CI Perinatal death 1.95 0.37–10.33 PTB < 37 weeks 1.01 0.92–1.12 Dodd et al 2008 Obstet Gynecol 112: 127 Double blind RCT of 17 OHP for prevention of preterm birth in twins 661 women with twin pregnancy – – – – – – Mean age 30 yrs 66% Caucasian 45% nulliparous 65% spontaneous conception 8 % previous preterm delivery 82 % dichorionic Rouse DJ et al NEJM 2007 357: 454 Double blind RCT of 17 OHP for prevention of preterm birth in twins • Women randomised to weekly 17 OHP 250mg IM or placebo starting at 16 -20 weeks gestation and continuing till 34 weeks gestation • Primary outcome: delivery before 35 weeks gestation (80% power to detect a 33% reduction on baseline rate of 35%) Rouse DJ et al NEJM 2007 357: 454 Proportion of women remaining pregnant with two live fetuses Rouse DJ et al NEJM 2007 357: 454 The STOPPIT study • Investigators: Norman / Mackenzie/ Owen / Norrie/ Hanretty/ Danielian / Cooper/ Mires/ Mactier/ Sturgiss / Petrou • ISRCTN: 35782581 • Funding: Chief Scientist Office, Scottish Executive • Study sponsor: Greater Glasgow Health Board (NGUHD) and University of Glasgow • https://medserv.abdn.ac.uk/stoppit/index.php Study power – Rate of delivery in twins before 34 weeks is 20% – RR after Rx between 0.3 and 0.5 – Assume RR is 0.5, sample size of 500 has 85% power at 5% significance level to show reduction in rate of PTD from 20% to 10%. – Alternatively 98% power to show reduction from 20% to 7% (RR 0.3) – So sample size of 500 would be needed – (Altman’s nomogram / nQuery advisor / statistician) Subjects • Women with twin pregnancy from following hospitals recruited over 30 months – PRM, QMH, Forresterhill in Aberdeen, Ninewells Dundee, NRIE in Edinburgh, RVI in Newcastle – Aim for 500 women during this time – Number of twins per year in these hospitals is 498 – Need to recruit 45% • Some ineligible • Inward referrals from other hospitals could add a further 300 subjects over 30 months Treatment regimen • Vaginal progesterone gel, 90mg daily from 24 – 34 weeks gestation • Route of administration IM / vaginal • Dose • Source of drugs Use of placebo • Allows blinding • Reduces bias (subject / investigator / others managing patient) • Placebo has to appear similar Inclusion / exclusion • Inclusion – Twin pregnancy, – Gestation established by scan before 20 weeks – Known chorionicity • Exclusion – – – – – Significant structural / chromosomal fetal abn Contraindications to progesterone Planned cervical suture Planned elective delivery before 34 weeks gestation Intervention for twin to twin transfusion before 22 wks Recruitment / randomisation Formally recruit at 22 weeks Randomisation stratified by hospital and chorionicity Randomisation thro’ CHaRT in Aberdeen Study number allocated Pharmacy (WIG) to make up treatment packs Interventions • Vaginal progesterone 90mg daily from 24+0 weeks to 33+6 weeks inclusive Or • “Placebo” vaginal progesterone 90mg daily from 24+0 weeks to 33+6 weeks inclusive Outcomes • Primary – no of women in each group delivering before 34 weeks gestation • Secondary – Perinatal mortality and morbidity – Pregnancy duration in each group – Maternal complications inc LSCS rates, duration of labour, vaginal bleeding, PPROM – Neonatal complication rates – Maternal side effects – Acceptability of Rx and alternative – Costs Indications for stopping treatment • Planned elective preterm delivery • Fetal membrane rupture • Symptomatic placenta praevia • NB admission in PTL not indication for stopping in bu oy al sg ow R G la rg h N ew ca st le Q M H G la sg N ow in ew el ls D un de e A be rd ee N n ot tin Fo gh rt am h Pa /B rk ir m /C ov en tr y Ed 140 120 100 80 60 40 20 0 Midwife of the year! STOPPIT results • Final data collection nearing completion • Data lockdown and code breaking 1st Nov • Results late Nov 2008 Is there proof that anything works in twin pregnancy? Use of corticosteroids in twin pregnancy Outcome RR 95 % CI No of studies No of babies RDS 0.85 0.60 – 1.20 4 320 Cerebrovascular haemorrahge 0.39 0.07 – 2.06 1 127 Roberts D, Dalziel S (2006) Cochrane Database Syst Rev. CD004454 Conclusion • Twins are at increased risk of spontaneous preterm birth • Preterm birth is a major cause of perinatal morbidity and mortality in twins • Currently no effective therapies • STOPPIT soon to report • More research (RCT and epidemiology) needed • OPPTIMUM study in singletons (www.opptimum.org.uk) Acknowledgements • STOPPIT collaborators and study midwives • Chief Scientist Office, Scottish Executive