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I nduction of L abour versus Ex pectant management in women with P reterm P relabour R upture of M embranes between

I nduction of L abour versus Ex pectant management in women with P reterm P relabour R upture of M embranes between 34 and 37 weeks. David van der Ham Christine Willekes Ben Willem Mol. About PPROMEXIL …. PICO Background Study design Progression Systematic review Amendment

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I nduction of L abour versus Ex pectant management in women with P reterm P relabour R upture of M embranes between

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  1. Induction of Labourversus Expectant management in women withPreterm PrelabourRupture of Membranes between 34 and 37 weeks David van der Ham Christine Willekes Ben Willem Mol

  2. About PPROMEXIL … • PICO • Background • Study design • Progression • Systematic review • Amendment • Questions Presentation PPROMEXIL Consortium meeting 20 June 2007

  3. PICO • PPPROM 34-37 weeks GA • I termination of pregnancy after 24 hours • Cexpected management until 37 weeks GA • Oneonatal sepsis Presentation PPROMEXIL Consortium meeting 20 June 2007

  4. Background • Premature rupture of fetal membranes is a clinical problem • Incidence: 3% before 37 weeks GA • 0.5% before 26 weeks GA • 1.0% between 26 and 34 weeks • 1.5% between 34 and 37 weeks Presentation PPROMEXIL Consortium meeting 20 June 2007

  5. Background • Premature delivery is a clinical problem • Incidence: 8.8% (LVR 1999) • 2.1% before 32 weeks GA • 6.7% between 32 and 37 weeks • PPROM: 20-55% • In NL: 3.000 patients annually • 25% gives birth within 24 hours • 75% gives birth beyond 24 hours after rupture of fetal membranes Presentation PPROMEXIL Consortium meeting 20 June 2007

  6. Background • Major risks with PPROM? • Neonatal sepsis • Risk of neonatal sepsis in active management is estimated for 2.5% • Risk of neonatal sepsis in expected management is estimated for 7.5% • Respiratory distress syndrome: • 15% at 34 weeks GA • < 1% at 37 weeks GA Presentation PPROMEXIL Consortium meeting 20 June 2007

  7. Background • NVOG guideline 47 – Rupture of fetal membranes before onset of labour. • Conclusions • Expected management until 35+0 weeks, unless fetal or maternal contraindications exists. • Beyond 35+0 weeks GA management whether or not to terminate pregnancy will be discussed with the patient. Presentation PPROMEXIL Consortium meeting 20 June 2007

  8. Briefly • The PPROMEXIL trial strives to answer the clinical question: • Whether termination of pregnancy after PPROM will reduce the risk of neonatal sepsis without (unacceptable) increase of complications due to prematurity. Presentation PPROMEXIL Consortium meeting 20 June 2007

  9. Study design • Multicentre randomized controlled trial • Termination of pregnancy vs. expectant management • Primary outcome: • Neonatal sepsis • Secondary outcome: • Neonatal mortality en morbidity (e.g. RDS) • Maternal morbidity en mortality • Quality of Life • Preference • Cost effectiveness Presentation PPROMEXIL Consortium meeting 20 June 2007

  10. Statistical analysis • Power analysis: • Risk reduction of neonatal sepsis with 66% (from 7.5% at expectant management to 2.5% at active management) • Total group: 520 • 260 Active management • 260 Expected management Presentation PPROMEXIL Consortium meeting 20 June 2007

  11. In- and exclusion criteria • Inclusion: • PPROM > 24h • AD 34 - 37 weeks GA • Exclusion: • Non reassuring fetal status • Severe congenital malformations • Sign of infection (mother or fetus) • Meconium stained amniotic fluid • Labor • PPROM < 26 weeks GA • MCDA or MCMA twin pregnancy • HELLP syndrome / severe preeclampsia Presentation PPROMEXIL Consortium meeting 20 June 2007

  12. Management • Confirmation of ruptured membranes • Vaginal culture • Ultrasound (biometry) • Laboratory (Hemoglobin, Hematocrit, Leukocytes, Leukocyte differentiation, C-reactive protein, trombocytes) • CTG • Signed informed consent Presentation PPROMEXIL Consortium meeting 20 June 2007

  13. Active management • Termination of pregnancy or induction of labor within 12 hours after randomization • Prostaglandin may be used according to local protocol • Breech presentation or twin pregnancy if necessary elective caesarean section • In patients with previous caesarean section induction of labor according to local protocol. Presentation PPROMEXIL Consortium meeting 20 June 2007

  14. Expectant management until 37 weeks GA • Daily CTG and temperature • Laboratory: CRP, leucocytes according to local protocol (but at least twice weekly) • Preferably no antibiotics • Home-care is allowed • If still pregnant after 37+0 weeks of GA, induction of labor according to local protocol. Presentation PPROMEXIL Consortium meeting 20 June 2007

  15. Management post partum • Neonatal weight and length • Histological examination of the placenta • Neonatal surface cultures Presentation PPROMEXIL Consortium meeting 20 June 2007

  16. Outcome • Neonatal sepsis • RDS • Mortality • Chorioamnionitis • Costs • Quality of life Presentation PPROMEXIL Consortium meeting 20 June 2007

  17. Participating hospitals • Academic Medical Centre, Amsterdam • Albert Schweizer Hospital, Dordrecht / Sliedrecht / Zwijndrecht • Atrium Medical Centre, Heerlen • Amphia Hospital, Breda - Oosterhout • Bronovo Hospital, The Hague • Catharina Hospital, Eindhoven • Deventer Hospital, Deventer • Diakonesse Hospital, Utrecht • Elkerliek clinics, Helmond • Erasmus Universitair Medical Centre, Rotterdam • Flevo Hospital, Almere • GelderseVallei, Ede • Gelre Hospital, Apeldoorn • Groene Hart Hospital, Gouda • Haga /Leyenburg Hospital, The Hague • Ikazia Hospital, Rotterdam • IsalaClincics, Zwolle • Kennemer Gasthuis, Haarlem • Leids University Medical Centre, Leiden • Lucas Andreas Hospital, Amsterdam • Maasland Hospital, Sittard • Martini Hospital, Groningen • Maxima Medical Centre, Veldhoven • Spaarne Hospital, Hoofddorp • Sint Anna Hospital, Geldrop • Sint Antoniusgasthuis, Nieuwegein • Sint Elisabethgasthuis, Tilburg • Sint Jansgasthuis, Weert • St Radboud MC, Nijmegen • Tergooi Hospital, Blaricum • TweeSteden Hospital, Tilburg • University Hospital Maastricht, Maastricht • University Medisal Centre Groningen, Groningen • University Medical Centre Utrecht, Utrecht • VieCuri Medical Centre, Venlo • VU University Hospital, Amsterdam Presentation PPROMEXIL Consortium meeting 20 June 2007

  18. Inclusions Presentation PPROMEXIL Consortium meeting 20 June 2007

  19. diagnosis of (P)PROM

  20. Systematic review • Diagnosis of rupture of fetal membranes is sometimes difficult. • In dubious (P)PROM it is more relevant to make the right diagnosis. • Plurious tests are used in common practice. • The sensitivity and specificity of these tests vary widely. Presentation PPROMEXIL Consortium meeting 20 June 2007

  21. Systematic review • Aim: • To perform a meta-analysis on (all available) diagnostic tests to detect rupture of fetal membranes. • To determine sensitivity and specificity of those tests.

  22. Systematic review • Problem: • No gold standard available • Alternative: Bayesian estimation of disease preference and the parameters of diagnostic tests in the absence of a gold standard

  23. Search strategy • Database: Medline, EMBASE, DARE, Chocrane, SUMSEARCH • Diagnostic test for rupture of membranes. • Description of sensitivity and specificity or the capacity to subtract data for a 2x2 table Presentation PPROMEXIL Consortium meeting 20 June 2007

  24. Results (PubMed) • Broad search: 2027 articles • First selection on title • Broad searching strategy • 220 possible interesting articles Presentation PPROMEXIL Consortium meeting 20 June 2007

  25. Next steps … • All selected articles will be screened on abstract for suitability. • After second screening full texts will be collected for evaluation of manuscripts. Presentation PPROMEXIL Consortium meeting 20 June 2007

  26. Amendment • Amendment for PPROMEXIL is accepted by the medical ethical committee of the University Hospital Maastricht • The amendment is a supplement on the original protocol • No action needs to be taken • All local ethical committees will be informed on the amendment.

  27. Amendment • As described in the amendment: • Breech presentation can be included • Twin pregnancies can be included • Caesarean section is no exclusion

  28. Tanks foryourattention • http://www.studies-obsgyn.nl/ppromexil/ Presentation PPROMEXIL Consortium meeting 20 June 2007

  29. References • Mercer BM, Goldberg RL, Meis PJ, Moawad AH, Shellhaas C, Das A, Meard MK, Caritis SN, Thyrnau GR, Dombrowski MP, et al. The Preterm Prediction Study: Prediction of preterm premature rupture of membrane through clinical findings and ancillary testing. Am J Obstet Gynecol. 2000;183:738-745. • Lee T. Silver H. Etiology and epidemiology of preterm premature rupture of membranes. Clin Perinatol. 2001;28:721-734 • Mercer BM. Preterm premature rupture of the membranes. Obstet Gynecol 2003;101:178-193. • Lewis DF, Futayyeh S, Towers CV, Asrat T, Edwards MS, Brooks GG. Preterm delivery from 34 to 37 weeks of gestation: Is respiratory distress syndrome a problem? Am J Obstet Gynecol 1996;174:525-528. • Neerhof MG, Cravello C, Haney EI, Siver RK. Timing of labour induction after premature rupture of membranes between 32 and 36 weeks gestation. Am J Obstet Gynecol 1999;180:349-352. • Lieman JM Brumfield CG, Carlo W. Preterm premature rupture of membranes: Is there an optimal gestational age for delivery? Obstet Gynecol 2005;105:12-17. • NVOG richtlijn no. 47; Het breken van de vliezen voor het begin van de baring; juni 2002. • American College of Obstetricians and Gynecologists. Premature rupture of membranes. ACOG Practice Bullitin 1. Washington DC: ACOG; 1998. • Garite TJ. Management of premature rupture of membranes. Clin Perinatol 2001;28:837-844. • NVOG – Richtlijn 12: Preventie van perinatale groep-B-streptokokkenziekte • Naef RW, Albert A, Ross EL, Weber M, Martin RW, Morrison. Premature rupture of membranes at 34 to 37 weeks gestation: Aggressive versus conservative management. Am J Obstet Gynecol 1998;178:126-130. Presentation PPROMEXIL Consortium meeting 20 June 2007

  30. References • Cox SM, Leveno KJ. Intentional delivery versus expectant management with preterm premature ruptured membranes at 30 – 34 weeks gestation. Obstet Gynecol 1995;86:875-879. • Mercer BM, Crocker LG, Boe NM, Sibai MB. Induction versus expectant management in premature rupture of the membranes with mature amniotic fluid at 32 to 36 weeks: a randomized trial. Am J Obstet Gynecol 1993;169:775-782. • Spinnato JA, Shaver DC, Bray EM, Lipshitz J. Preterm premature rupture of the membranes with fetal pulmonary maturity present: a prospective study. Obstet Gynecol1987:69:96-201. • Hartling L, Chari R, Friesen C, Vandermeer B, Lacaze-Masmonteil T. A systematic review of intentional delivery in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med 2006;19:177-87. • Goldstein B; Giroir B; Randolph A et al. International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005;6:2-8. • Sarnat HB, Sarnat HS. Neonatal encephalopathy following fetal distress: A clinical and EEG study. Arch Neurol 1976;33:696-705. • Neu J. Necrotizing enterocolitis: the search for a unifying pathogenic theory leading to prevention. Pediatr Clin North Am 1996;43:409-432. • Lieman JM, Brumfield CG, Carlo W, Ramsey PS. Preterm premature rupture of membranes: Is there an optimal gestational age for delivery? Obstet Gynecol; 2005;105:12-17. • Hays WL. Statistics 4th ed. New York: Holt, Rinehart and Winston, 1998. • Morris JM, Roberts CL, Crowther CA, Buchanan SL, Henderson-Smart DJ, Salkeld G. Protocol for the immediate delivery versus expectant care of women with preterm prelabour rupture of the membranes close to term (PPROMT) Trial [ISRCTN44485060]. BMC Pregnancy Childbirth 2006;6:9. Presentation PPROMEXIL Consortium meeting 20 June 2007

  31. Data analysis • Intention to treat • RR en 95%CI will be calculated for all relevant outcome • T-test for continues data • χ2-test for categorical data • No interim analysis Presentation PPROMEXIL Consortium meeting 20 June 2007

  32. Hartling L, Chari R, Friesen C, Vandermeer B, Lacaze-Masmonteil T. A systematic review of intentional delivery in women with preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med 2006;19:177-87.

  33. Metaanalysis • Systematic review of all available literature between 1950 and November 2005 • Only RCTs were included • Evaluation of expected management vs. active management in PPROM (30-36 weeks GA) • At least results of the following described: • Length of stay • perinatal mortality • neonatal mortality • fetal distress • RDS • confirmed or suspected early-onset neonatal sepsis • GA • clinical chorio amnionitis • Caesarean Section • maternal length of stay Presentation PPROMEXIL Consortium meeting 20 June 2007

  34. Literature • 2.042 potential studies • 18 studies suitable for reading manuscript. • 14 excluded • 4 Non-randomized controlled trial • 2 No expectant management • 3 compared 2 types of induction • 2 No active management • 1 Study about use of antibiotics in PPROM • 1 compared early vs. late induction • 1 expected management vs. steroids and active management. • 4 included • Cox (1995); Mercer (1993); Naef (1998); Spinnato (1987) Presentation PPROMEXIL Consortium meeting 20 June 2007

  35. Neonatalsepsis Presentation PPROMEXIL Consortium meeting 20 June 2007

  36. Neonatal mortality Presentation PPROMEXIL Consortium meeting 20 June 2007

  37. Respiratorydistresssyndrom Presentation PPROMEXIL Consortium meeting 20 June 2007

  38. Results • No difference in proven neonatal sepsis • Less suspect neonatal sepsis in active management (-0,31 CI -0,50, -0,12) • No difference in neonatal mortality • No difference in RDS • No difference in length of stay Presentation PPROMEXIL Consortium meeting 20 June 2007

  39. Results • Maternal length of stay was shorter with active management (-1,39 dag (CI -2,03, -0,75) • Clinical confirm chorio-amnionitis was seen more often in expected management. (0,16 CI 0,23; 0,10) • No differences in maternal outcome • No differences in number of caesarean sections Presentation PPROMEXIL Consortium meeting 20 June 2007

  40. International trials • 2 current internation trials • Safety and Efficacy Study of Intentional Delivery in Women With Preterm and Prelabour Rupture of the Membranes (Canada) • PPROMT – Preterm Prelabour Rupture Of the Membranes close to Term (Australia) Presentation PPROMEXIL Consortium meeting 20 June 2007

  41. Comparison with PPROMEXIL Presentation PPROMEXIL Consortium meeting 20 June 2007

  42. Power analysis PPROMT • Proven or probable neonatal sepsis in expectant management is 5% • Active management will reduce this with 50% to 2,5% • Sample size with 80% power of 1812 Presentation PPROMEXIL Consortium meeting 20 June 2007

  43. Questions / Hypothesis • Will termination of pregnancy in patients with PPROM between 34 and 37 weeks AD … • reduce neonatal sepsis? (66% reduction) • adversely effect other neonatal morbidity? (e.g. RDS) • reduce maternal infections? • increase the number of instrumental deliveries? Presentation PPROMEXIL Consortium meeting 20 June 2007

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