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PPROM : Diagnosis and Management

PPROM : Diagnosis and Management. Scott A Sullivan MD MSCR Associate Professor - Dept Ob/Gyn Medical University of South Carolina. Disclosure. I have no financial stake in any products being discussed today I will not talk about non-FDA approved products. Educational Goals.

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PPROM : Diagnosis and Management

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  1. PPROM : Diagnosis and Management Scott A Sullivan MD MSCR Associate Professor - Dept Ob/Gyn Medical University of South Carolina

  2. Disclosure • I have no financial stake in any products being discussed today • I will not talk about non-FDA approved products

  3. Educational Goals • Epidemiology / Mechanism of PPROM • Diagnosis of PPROM • Management of PPROM

  4. Preterm Labor and Delivery • Preterm Delivery (<37 weeks) • >540,000 (12.3%) live births annually in US • Single largest cause of perinatal mortality and morbidity • ~ $36 billion annual acute care costs

  5. Preterm Birth – US (1996-2008)

  6. Preterm Birth - US

  7. South Carolina, 2007 Average Preterm is less than 37 completed weeks gestation. Source: National Center for Health Statistics, final natality data. Retrieved November 22, 2010, from www.marchofdimes.com/peristats.

  8. Pathways to Preterm Birth Spontaneous Preterm Labor 40% Premature Rupture of the Membranes 35% Preterm Birth Medical Intervention 25% While this suggests distinct pathways, many of the risk factors for all 3 are similar Goldenberg, RL. The Management of Preterm Labor. Obstet Gynecol 100 (5):1020-36, Nov 2002)

  9. Functions of Membranes and Amniotic Fluid PPROM Rotschild A, et al Neonatal outcome after prolonged preterm rupture of the membranes Am J Obstet Gynecol 162:46-52, 1990 Membranes • Barrier to infection • Maintenance of amniotic fluid • Storage site for phosphoglycerolipids Amniotic Fluid • Allows pulmonary development • Provides for full fetal movement and growth • Protects fetus & cord from compression and trauma

  10. Aquaporins Growth factors Oxidation? Paracrine functions? Membrane Functions Zhu, X, et al The expression of aquaporin 8 and aquaporin 9 in fetal membranes and placenta in term pregnancies complicated by idiopathic polyhydramnios. Early Hum Dev 2010 Oct;86(10):657-63.

  11. Membrane Structure Chorion (200 µm) cytotrophoblasts basement membrane Amnion (50 µm) five layers spongy layer (sliding) compact layer (2nd -4th) macrophages mesenchymal cells

  12. Membrane Strength Chua W Do we know the strength of the chorioamnion?: A critical review and analysis Eur J Ob Gyn Reprod Bio May 2009, Pages S128-S133

  13. Mechanics of PretermPROM El Khwad M, et al Term human fetal membranes have a weak zone over-lying the lower uterine pole and cervix before the onset of labor Biol Reprod 72:720-726, 2005 Bacterial production of proteases Host response to blood or bacteria (MMP 1,2,9) or (TIMP1,3) Pre-existing weakness Strain from preterm uterine activity Direct membrane trauma (cerclage or amnio) Developmental “weak spot”

  14. Mechanism • Ascending infection • Stretch • Necrosis • Decidual adherence Goldenberg, R et al Epidemiology and causes of Preterm Birth Lancet 2008; 371 75-84

  15. Risk Factors for PPROM Mercer, BM et al The preterm prediction study; prediction of PPROM through clinical findings and ancillary testing AJOG 2000 183;738-45

  16. Risk Factors for PPROM • History of PPROM/PTD • Other risk factors: • low pre-pregnant weight • obesity • infections • bleeding • anemia • major stress • lack of social supports • tobacco use • illicit drug use • alcohol abuse • conization • multifetal pregnancy • maternal age (<17 and >35yrs) • African-American • low SES • unmarried • previous fetal or neonatal death • 3+ spontaneous terminations • uterine abnormalities • shortened cervix (< 2.5 cm) • genetic predisposition

  17. Risks of PPROM • Preterm delivery • Chorioamnionitis (13-60%) • Non-reassuring fetal status (8 %) • Prolapsed cord • Abruptio placenta (4%) • Pulmonary hypoplasia • Cesarean section • IUFD (1%)

  18. Neonatal Sepsis - PPROM 40% PROM 20% Intact 0% <20 28-30 31-33 34-36 >36 Mercer B Preterm premature rupture of the membranes Obstet Gynecol 101:178-193, 2003

  19. Natural History of PPROM • Latency increases with early EGA, AFI • ~30-50 % deliver in 48 hours • ~90-93 % deliver in 1 week • 10 % may deliver > 4 weeks out • Reseal? 3-10 %

  20. Diagnosis • Patient history • Diagnostic tests • US • Don’t forget FLM!

  21. Nitrazine (pH) Friedman, ML Diagnosis of ruptured membranes AJOG 1969 104;544-550 Technique: Amniotic fluid is alkaline and, as such, turns Nitrazine pH indicator blue Performance Metrics: • False positive results are up to 17.4% • False negative results are 12.9% • Sensitivity 90.7% • Specificity 77.2% Drawbacks: Speculum exam. False-positive results with other fluids, infections

  22. Ferning Reece EA, Amniotic fluid arborization Obstet Gynecol 64:248-250, 1984 Technique: Arborization pattern (crystallization) of dry amniotic fluid as seen through a microscope Performance Metrics: • False positive results are 5-30% • False negative results are 12.9% • Sensitivity 51.4% (no labor) • Specificity 70.8% (no labor) Drawbacks: Speculum exam, microscope. Contamination.

  23. Pooling Technique: Visualization of an amniotic pool in the posterior fornix of the vagina Accuracy: Subjective Drawbacks: Speculum exam. Subjective. Other fluids.

  24. Ultrasound Technique: Ultrasound can detect oligohydramnios, suggesting loss of amniotic fluid due to membrane rupture Accuracy: Not a reliable screening test if used alone. Used only to help confirm diagnosis Drawbacks: Time-consuming. Cost. Etiology?

  25. Amnio-dye Infusion Technique: Instillation of dilute indigo carmine into the amniotic cavity and confirmation of rupture of membranes by documenting leakage of dye into the vagina (staining of tampon) Accuracy: “Gold Standard” for diagnosis of rupture of membranes Drawbacks: Accurate, but highly invasive (requires amniocentesis). Expensive.

  26. Problems with Traditional Practices NACB. Laboratory Medicine Practice Guidelines 2007. p 142-143. “…fern test is neither sensitive nor specific enough for diagnostic determination of premature rupture of membranes. We recommend against routinely providing fern testing alone for the detection of ruptured membranes.” “…pH/nitrazine test is sensitive only when used in women for whom membrane status is known. …the test does not appear to be sufficiently sensitive or specific enough for diagnostic determination of premature rupture of membranes.”

  27. Search for New Protein Markers of ROM • Since 1970s, multiple proteins of amniotic fluid were discovered • Placental Alpha Microglobulin-1 PAMG-1 • Placental Alpha Microglobulin-2 PAMG-2 • Alpha Feta Protein (AFP) • Prolactin (PL) • Placental Protein 12 (PP12, later called IGFBP-1) • Fetal Fibronectin (fFn)

  28. Objectives of Search Search for Protein Markers of ROM • GOAL 1: to find amniotic fluid antigen with the following criteria: • Very high concentration in amniotic fluid • Very low concentration in the background level of cervico-vaginal secretions (i.e. when fetal membranes are intact) • GOAL 2: To develop antigen-specific monoclonal antibodies (MABs) unaffected by contaminants • GOAL 3: Develop immunoassay that will utilize MAB-antigen specific reaction to accurately and rapidly diagnose ROM

  29. fFN is found to be associated with dislocation of amniotic sac relative to cervix and is used today for detecting premature labor. Lockwood et al., 1994 fFN is high in maternal blood and seminal fluid. Chorionic release of fFN can be mistaken for PPROM even though the membranes are intact Erdemoglu et al 2004 The sensitivity and specificity of fFn for the detection of PROM are 90.5% and 61.0% respectively (PPV of 54.3% and NPV of 92.6%) Omu et al., 1997 Fetal Fibronectin (fFN)

  30. PAMG-1 • Placental Alpha Microglobulin-1 (PAMG-1) is a protein expressed by the cells of the decidual part of placenta • Extremely low background levelmeasured in cervico-vaginal secretions when the fetal membranes are intact • During pregnancy, PAMG-1 is secreted into the amniotic fluid in great quantities Source: D. Petrunin, Akush Ginekol (Mosk) 1977 Jan(1):64-5

  31. PAMG-1 Immunoassay PAMG-1 Test Characteristics Immunochromatographic assay Monoclonal antibodies used to detect PAMG-1 protein Works within a wide range of PAMG-1 concentrations in vaginal secretion (from 5 ng/ml to 100 mcg/ml)

  32. PAMG-1 Immunoassay Administering the PAMG-1 Test • Procedure • Step One: Vaginal swab (2-3 inches deep). • Step Two: Swab is dipped into the vial of solvent for one minute. • Step Three: Test strip is placed in the vial containing the specimen extracted from the swab by the solvent. • Step Four: Remove the strip after 5-10 minutes and read the results. Reading the Results 1 line in the test region meansNo Rupture 2 lines in the test region meansThere is a Rupture!

  33. PAMG-1 Immunoassay PAMG-1 Performance • FDA approved use of the test by nurses and midwives as well as physicians • Clinical multi-site prospective study conducted on patients 15-42 weeks of gestation • Cousins et al, Am J Perinat, 2005 Primary Study results: Sensitivity: 99% Specificity: 100% PPV: 100% NPV: 99%

  34. Diagnostic Performance Test Sensitivity Specificity PPV NPV Ferning/pooling151-98% 70-88% 84-93% 87-97% Nitrazine (pH)190-97% 16-70% 63-75% 80-93% Vaginal fFN2,1 91-98% 61-97% 54-93% 93-100% IGFBP-1174-97% 74-97% 73-92% 56-87% PAMG-1398-99% 88-100% 98-100% 91-99% 1Caughey, et al. 2008; 2Omu et al., 1997; 3Cousins et al., 2005

  35. PAMG-1 Immunoassay Avoidable Costs of ROM Diagnosis

  36. PAMG-1 Immunoassay Ideal Scenario for ROM Diagnosis • Divide patients into 2 categories: • Those who a grossly ruptured and have obvious ROM diagnosis. • Those whose suspected rupture is not of a gross nature, requiring confirmation • Diagnose second group of patients with one reliable method

  37. PPROM Management • Clinicians must weigh the risk of prolonging gestation against the risks of serious maternal-fetal complications while managing PROM. • Management of PROM can include: • Bed rest and pelvic rest * (hospital?) • Induction of labor – to reduce risk of infection • Tocolytics – prophylactic tocolysis after preterm PROM has been shown to prolong latency • Corticosteroids – to reduce respiratory distress syndrome • Antibiotics – to prolong pregnancy, reduce infection and morbidity

  38. PPROM Initial Management • Avoid cervical checks 2.1 +/- 4.0 days 11.3 +/- 13.4 days • Speculum exam – cultures, FLM • Ultrasound – position, placenta AFI < 5 critical [5 vs 14 days] Lewis DF, Effects of digital examination on latency period for PPROM Obstet Gynecol 1992;80 630-34

  39. PPROM Management • 34-36 weeks – Deliver Chorio – 2 % vs 16 % (p<.001) Higher pH – 7.35 vs 7.25 (p<.009) • < 30-31 weeks expectant management • < 23 weeks – Counseling Survival ~ 21 % Naef, 1991

  40. Amniocentesis? • Culture positive 25-40 % • Clinical chorio 8-9 % • Individualize Adapted from Romero, et al 1988

  41. Fetal Assessment • Safest interval is not known – daily? • BPP < 7 associated with neonatal sepsis and chorio • NST - conflicting data Vintzileos – 78 % Lewis – 39 % • NPV for IUFD is 2/1000

  42. Tocolytics • Limited Data Levy, Weiner – prolonged latency How – No difference in perinatal outcome • Steroids? • Risks? • CP reduction? (Neuroprotection) Combs CA AJOG 2004

  43. Antibiotics • NIH-MFM Trial • IV x 48 hours, po x 5 days • Ampicillin, Emycin • Increased latency, decreased sepsis composite morbidities 53% to 44%, P 0.04) • Duration? Other agents?

  44. Antibiotics Canavan, T Evidence based approach to PPROM OBG Survey 2004 59

  45. PPROM - Steroids • Meta-analysis indicates benefit < 32 weeks RDS (RR, .56; CI, 0.46–.7) IVH (RR, .47; CI, 0.31–.7) neonatal infection (RR, 1.05; CI, 0.66–1.68) • NIH Consensus 1994 • 32-34 weeks? Harding JE, AJOG 2001

  46. PPROM: When to deliver? • Mercer (1993) - RCT @ 32-36 wks (n=93) • Management: Expectant vs. active • Latency (hrs) 36 14* • Chorio (%) 28 11* • Suspect sepsis(%) 60 28* • Confirmed sepsis 4.3 6.8 • Antibx tx (%) 79 35* • Home w/mom(%) 4 30*

  47. PPROM: When to deliverIncidence of RDS • 28 weeks 65% • 30 wks 50% • 32 weeks 40% • 34 weeks 13%* • 35 weeks 7%* • 36 weeks <1%* * majority needed suppl O2, 1.3% ventilator

  48. PPROM: When to deliver? • Cochrane Review (n=690) @ 32-36 wks • Expectant vs. active management: • neonatal sepsis (RR 1.33, (CI) 0.72 to 2.47) • respiratory distress (RR 0.98, 95% CI 0.74 to 1.29) • perinatal mortality (RR 0.98, 95% CI 0.41 to 2.36) • “Insufficient data to make a recommendation. Studies are underpowered and flawed.”

  49. PPROM: When to deliver? • Leiman (2005) –retrospective (n=430): • Latency: 3.3 + 6.8 days overall • No improvement in either major or minor neonatal morbidity after 34 weeks • Both maternal and neonatal LOS longer after 34 weeks with expectant management

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