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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. Background. Premature rupture of fetal membranes is a clinical problem

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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. 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 Consortium for Obstetric Studies November 15th 2007

  3. 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 Consortium for Obstetric Studies November 15th 2007

  4. Background • Major risks with PPROM? • Neonatale 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 syndrom: • 15% at 34 weeks GA • < 1% at 37 weeks GA Consortium for Obstetric Studies November 15th 2007

  5. Study Design

  6. Study Design • Multicentre randomized controlled trial • Termination of pregnancy vs. expectant management • Outcome: • Neonatal sepsis (primary); Neonatal mortality en morbidity (e.g. RDS); Maternal morbidity en mortality; Quality of Life; Preference; Cost effectiveness • Power analysis: • Estimated reduction of neonatal sepsis with 66% • Total group 520 patients Consortium for Obstetric Studies November 15th 2007

  7. Study Design In- and exclusion Management Overall management Confirmation PPROM Lab; cultures; US Post partum: neonatal cultures; histological examination of the placenta Active management Termination of pregnancy If necessary elective caesarian section Expectant management Daily CTG and temperature Lab Preferably no antibiotics Induction after 37 weeks GA • 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 Consortium for Obstetric Studies November 15th 2007

  8. Inclusions Consortium for Obstetric Studies November 15th 2007

  9. Inclusions Consortium for Obstetric Studies November 15th 2007

  10. International Trials

  11. International Trials • 2 current international 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) Consortium for Obstetric Studies November 15th 2007

  12. Comparison with PPROMEXIL Consortium for Obstetric Studies November 15th 2007

  13. Current dilemmas

  14. Diagnosis of PPROM • The diagnosis PPROM is based on a range of different diagnostic tests. • There is no gold standard available. • The accuracy of confirming the diagnosis may vary between the participating hospitals. Consortium for Obstetric Studies November 15th 2007

  15. Diagnosis of PPROM • How do we need to deal with a different accuracy in the diagnosis of PPROM? • If the actual incidence of neonatal sepsis or the decrease in neonatal sepsis is less than estimated how do we deal with this? Consortium for Obstetric Studies November 15th 2007

  16. Patient selection • A multi-centre trial will enhance the representativity of general population. • If e.g. 50% refuse to participate in a trial, will this influence the representativity? • If so, how do we have to manage this? Consortium for Obstetric Studies November 15th 2007

  17. International trials • Do we have to combine our results with the international trials? • If so; the PPROMT study is most suitable • Is it useful to try to set up an international trial together with the PPROMT study? • What is the best way to get in contact with the rearchers? Consortium for Obstetric Studies November 15th 2007

  18. 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. ClinPerinatol. 2001;28:721-734 • Mercer BM. Preterm premature rupture of the membranes. ObstetGynecol 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 ObstetGynecol 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 ObstetGynecol 1999;180:349-352. • Lieman JM Brumfield CG, Carlo W. Preterm premature rupture of membranes: Is there an optimal gestational age for delivery? ObstetGynecol 2005;105:12-17. • NVOG richtlijn no. 47; Het breken van de vliezenvoor 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. ClinPerinatol 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 ObstetGynecol 1998;178:126-130. Consortium for Obstetric Studies November 15th 2007

  19. 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. Consortium for Obstetric Studies November 15th 2007

  20. Back-upextra slides

  21. PICO

  22. PICO • PPPROM 34-37 weeks GA • I termination of pregnancy after 24 hours • Cexpected management untill 37 weeks GA • Oneonatal sepsis Consortium for Obstetric Studies November 15th 2007

  23. Background • NVOG richtlijn 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. Consortium for Obstetric Studies November 15th 2007

  24. Briefly • The PPROMEXIL trial strive 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. Consortium for Obstetric Studies November 15th 2007

  25. Participating Hospitals • Number of participating hospitals: 45 • Ongoing procedures: • Target: At least 70% of all hospitals in the Netherlands (70) Consortium for Obstetric Studies November 15th 2007

  26. Systematic Review diagnosis of (P)PROM D.P. van der Ham M. van Melick B.W. Mol L. Smits C. Willekes

  27. 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. Consortium for Obstetric Studies November 15th 2007

  28. 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. Consortium for Obstetric Studies November 15th 2007

  29. 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 Consortium for Obstetric Studies November 15th 2007

  30. Search Stategy • 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 Consortium for Obstetric Studies November 15th 2007

  31. Results (PubMed, EMBASE) • Broad search: 2886 articles • First selection on title • Broad searching strategy • 230 possible interesting articles Consortium for Obstetric Studies November 15th 2007

  32. Current dilemmas • How do we need to deal with the absence of a gold standard? Consortium for Obstetric Studies November 15th 2007

  33. Meta-analysis 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.

  34. Meta-analysis • 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 Consortium for Obstetric Studies November 15th 2007

  35. 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) Consortium for Obstetric Studies November 15th 2007

  36. Neonatal Sepsis Consortium for Obstetric Studies November 15th 2007

  37. Neonatalmortality Consortium for Obstetric Studies November 15th 2007

  38. Respiratory Distress Syndrom Consortium for Obstetric Studies Wednesday November 15th 2007

  39. 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 Consortium for Obstetric Studies November 15th 2007

  40. 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 Consortium for Obstetric Studies November 15th 2007

  41. Hypothesis

  42. 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? Consortium for Obstetric Studies November 15th 2007

  43. Questions / Hypothesis • Which management prefers the patient? • Differs QoL between the different managements • Which management is most cost effective? Consortium for Obstetric Studies November 15th 2007

  44. Definitions

  45. Definitions endpoints • Neonatale sepsis: A positive blood culture, biochemical infection parameters (CRP above 20 mg/l) or clinical signs of infection (apnoe, fever, intolerance for feeding, respiratory distress and/or hemodynamic instability) with positive surface cultures. • Respiratory distress: (Organ dysfunction criteria (Respiratory)PaO2/FIO2 < 300 in absence of cyanotic heart disease of pre-existing lung disease ORPaCO2 > 65 torr or 20mmHg over baseline PaCO2 ORProven need or > 50% FIO2 to maintain saturation ? 92%)Grunting, tachypnea, retractions, nose flaring, need of > 21 % oxygen to maintain sat > 86%. • Chorio-amnionitis: Fever before or during labour as a temperature greater than 37,5 0C on two occasion more than one hour apart or a temperature > 38,0 0C with either uterine tenderness (or contractions), leucocytosis, maternal or fetal tachycardia, or a foul-smelling vaginal discharge in absence of any other cause of hyperpyrexia. • Hystological chorio-amnionitis: The presence of neutrophil infiltrate in extraplacental membranes. Consortium for Obstetric Studies November 15th 2007

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