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Objectives

Objectives. State the different etiologies of second trimester pregnancy loss State the definition of and the risk factors for cervical incompetence Give the management options for short cervix diagnosed in the 2 nd trimester Explain the risk-benefits of cerclage

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Objectives

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  1. Objectives • State the different etiologies of second trimester pregnancy loss • State the definition of and the risk factors for cervical incompetence • Give the management options for short cervix diagnosed in the 2nd trimester • Explain the risk-benefits of cerclage • State the indications for 17P

  2. Second Trimester Preterm Birth: Etiology Primarily unknown: > 50% Uterine malformations • Unicorniuate or bicornuate (↓ space for fetal growth) • Myomas (submucosal, subplacental): • Poor implantation, ↑ antepartum bleeding & preterm labor Cervical Incompetence: 0.1-2.0% • Prior 2nd trimester abortion • Prior gynecological surgery (cervical dilatation or conization) • Maternal exposure to DES Vaginal Infectious: association but no proven etiology • Genital tract colonization & infection • Poorly defined association between chorioamnionitis and PTL • Sexually transmitted disease and PTL have common risk factors • Increased preterm delivery with colonization of: Group B streptococcus N. gonorrhoeae T. pallidum C. trachomatis G. vaginalis T. vaginalis Ureaplasma urealyticum

  3. Historical Features of Cervical Insufficiency Hx of >2 second-trimester pregnancy losses (excluding preterm labor or abruption) • Hx of losing each pregnancy at an earlier gestational age • Hx of painless cervical dilation up to 4-6 cm • Absence of clinical findings consistent with placental abruption • Hx of cervical trauma caused by: • Cone biopsy • Intrapartum cervical lacerations • Excessive, forced cervical dilation during pregnancy termination Harger JH. Obstet Gynecol 2002, 100:1313

  4. Cervical Insufficiency (Incompetence) Definition and Diagnosis is changing “Inability of uterine cervix to retain a pregnancy in the absence of contractions or labor” “Painless cervical dilation” • Changing concept w/ ultrasound: cervical function as a continuous variable with range of degrees of competency • Incompetence is the lowermost end of the continuum • Lack of clear objective diagnosis • Incidence?? Previously defined by # of cerclages placed per live birth • Denmark 1:217, US 1:1842, Israel 1:54 • Success of cerclage compared to past loss (own control)

  5. Prevention of PTBusing TVU CL • Asymptomatic • Cerclage • Indomethacin • Antibiotics • Progesterone

  6. Role of Transvaginal Ultrasound Cervical Length in Cervical Insufficiency

  7. TVU of cervix - validity CL and GA Berghella, Roman, et al, OG 2007

  8. Normal vs abnormal Cervical length (CL) • Normal • 25-50mm at 14-30 wks • Not helpful to measure before 14 weeks • Difficult to distinguish upper/ lower cervix • Not helpful in women with 2st trimester loss • Abnormal • CL <25mm between 14-24wk • The shorter CL, the highest risk for PTB

  9. Studies with Preterm Birth prediction using TVU CL • Different from the question of Cervical Insufficiency • Show correlation between short cervix and preterm birth • Longer cervix reliably excludes PTB within 2 weeks associated with PTL

  10. Relative Risk of Preterm Delivery according to percentiles of transvaginal cervical length at 24 weeks Relative Risk of at or below percentile compared to >75th Percentile Percentile Cervical length 1.3 2.2 2.6 3.0 3.5 4.0 (mm) Iams JD, NICHD, N Engl J Med 334:567-72, 1996

  11. Ultrasound and Digital Exam at 24 weeks to predict spontaneous preterm birth <35 weeks in low risk population N=2916 Iams JD, N Engl J Med 334:567, 1996 and Newman RB, J Soc Gynecol Invest 4:152A, 1997

  12. Prediction of PTB TVU CL <25mm, Screening GA 16-24 wksRisk of PTB < 35 wks Iams et al, NEJM 1996 Owen et al, JAMA 2001 Goldenberg et al, AJOG 1996 TVU CL Screening may be useful in women with Hx of 2nd & 3rd trimester PTB ACOG Practice Bulletin 2003

  13. TVU of cervix - validity Effect of GA when CL detected Berghella, Roman, et al, OG 2007

  14. Is there a role for routine TVU CL screening? • Low sensitivity (~35%) and low positive predictive value (~18%) • Most women with short cervix by TVU do not deliver preterm • Result in unnecessary intervention • Not useful to routine screening

  15. Cerclage“Nomenclature” • History-indicated • Prophylactic, elective • Ultrasound-indicated • Physical exam-indicated • avoid terms such as salvage, urgent, emergent, rescue, etc Berghella et al Cont Ob Gyn 2005

  16. What does the evidence show? Cerclage vs. Expectant management for History indicated cerclage placement? • 3 RCTs* show no significant improvement in outcomes • MRC/RCOG (n=1292) largest trial • Benefit only in women with >3 prior 2nd trimester losses or PTB: • PTB <33wk: Cerclage (15%) vs Expectant (32%) • No benefit 5 other subgroups (1 PTB + Cone Bx; 2 PTB/no Cone; Hx of Cone Bx; 1st trim AB or uterine anomaly, twin gestation) • Perform cerclage at 13-16 weeks There is insufficient Level 1 evidence that: Cerclage is beneficial to women with history of painless cervical dilation leading to PTB. Only women with Hx of >3 PTB or STL may benefit from prophylactic cerclage. Lazar P. Br J Obset Gynaecol 1984 Rush RW. Br J Obset Gynaecol 1984 MRC/RCOG. Br J Obset Gynaecol 1993

  17. Cerclage vs. Expectant management for Urgent indicated cerclage placement? “There is insufficient Level 1 evidence. The group of patients who benefit from urgent cerclage has yet to be defined. Urgent cerclage should be considered a procedure under benefit.” Rust OA, Obtet Gynecol Clin N Am 2005 • 4 RCTs* examine Urgent cerclage (McDonald) • Entry: risk of PTB plus either • CL<25mm/funneling or prolapse/membrane to internal os • Mean ga @ entry 19.3 – 23.5 wk • 3 of 4 trials used antibiotic prophylaxis • (metronidazole+amoxicillin; clindamycin, erthryomycin) • 2 of 4 used indomethacin • Only 1 RCT1 showed benefit (n =35) • ↑GA del (33 v. 38 wk),↓PNM (0 v 19) • Other 3 RCT (n=554) showed no benefit 1. Rust OA, (Leigh Valley) Am J Obstet Gynecol 2001,2004 2. Althuisis SM, CIPRACT, Am J Obstet Gynecol 2001 3. Bergella V, Am J Obstet Gynecol 2004 4. To MS (Multinational) Lancet 2004

  18. Another analysis: same studiesShort cervical length on ultrasound Intervention: Ultrasound-IndicatedCerclage • Patient-level Meta-analysis of the 4 RCTs published • Althuisius et al AJOG 2001;185:1106-12 • Rust et al AJOG 2001;185:1098-105 • Berghella et al AJOG 2004;191;1311-7 • To et al Lancet 2004;363:1849-53

  19. Meta-analysis of Urgent Cerclage Berghella et al, Obstet Gynecol 2005 “Cerclage does not prevent PTB in all women with short cervix. Cerclage may reduce PTB in singleton gestations with short CL, especially in those with prior PTB. A well powered trial is indicated. Cerclage in twins is associated with significantly higher incidence of PTB.” Berghella et al, Obstet Gynecol 2005 Cerclage & risk of Preterm birth <35 wk • Include multiples: 0.84 (95%CI 0.67,1.06) • Cerclage - 29.2% (89/305) • Control - 34.8% (105/302) • Singleton: 0.61 (95%CI 0.40, 0.92) • Cerclage - 23.4% (25/107) • Control - 38.6% (39/101) • Singleton w/ prior STL: 0.57 (95%CI 0.33,0.99) • Twins: 2.15 (95%CI 1.15, 4.01) • Cerclage - 75% (18/24) • Control - 36% (9/25) 1. Rust OA, (Leigh Valley) AJOG 2001 2. Althuisis SM, CIPRACT, AJOG 2001 3. Bergella V, AJOG 2004 4. To MS (Multinational) Lancet 2004

  20. SingletonPrior PTB and CL <25mm (n=208) PTB<35wk (%) PTB<32wk (%) RR 0.61, 95%CI 0.40-0.92 RR 0.58, 95%CI 0.34-0.98 42% decrease in PTB<32wk 39% decrease in PTB<35wk 23% 39% 16% 28% Berghella et al, Obstet Gynecol 2005

  21. Awaiting NIH Trial • Prior SPTB 16-34w • CL < 25mm • 16-23 weeks • Recruitment completed Nov. 2007 • >1,000 screened • 300 randomized Owen J, et al, UAB

  22. Awaiting Second Cerclage RCTwww.controlled-trials.com • The CIRCLE trial • UK • Singleton with prior PTB<34w • U/S indicated cerclage if CL<20mm at 16-24w • History-indicated cerclage if history suggestive of cervical insufficiency • Target: 1890 pts

  23. Benefits of Ultrasound-screening of CL • Identify high-risk patients who benefit from NO intervention • Avoid routine history-indicated cerclage • Avoid any intervention if cervix stays closed and long • >60% of high-risk women (women with prior PTB)

  24. Other therapies for short CL(without cerclage) • Indomethacin • Antibiotics • Progesterone • Pessaries

  25. Infection: Chicken vs egg? Long cervix Short cervix

  26. Short cervix associated with infection • Higher Amniotic Fluid Intraleuking-6 • + Amnio./Chorioamnionitis • Acute inflammatory lesions of the placenta • Short cervix more predictive of early PTB (<28 w): • most associated (80%) with infection

  27. Other aspects related to cerclage • Amniocentesis pre-cerclage • Technique • Type • McDonald • Shirodkar • transabdominal • Suture material • Placement • Tocolytics • Antibiotics

  28. Short CL on TVU • <25mm • 14-24weeks • >80% of women are having asymptomaticcontractions Lewis, Pelham, Done, Sawney, Talucci, Berghella J Mat Fetal Neo Med 2005

  29. Indomethacin(secondary meta-analysis using no cerclage group) 139 women with CL <25mm 99 indomethacin 40 NO indomethacin 29 (29.3%) PTB <35w 17 (42.5%) PTB <35w RR 0.69, 95% CI 0.44-1.13 Berghella, Rust, Althuisius AJOG 2006

  30. Indomethacin (n=139)CL < 25 mm(secondary meta-analysis using no cerclage group) %PTB<35wk %PTB<24wk RR 0.69, 95% CI 0.44-1.13 RR 0.14, 95% CI 0.02-0.92 42.5% 29.3% 1.0% 7.5% Berghella, Rust, Althuisius AJOG 2006

  31. Antibiotic therapy(secondary meta-analysis using no cerclage group) 276 women with CL <25mm 123 antibiotics 153 NO antibiotics 36 (29%) PTB <35w 51 (33%) PTB <35w Adjusted RR 0.80, 95% CI 0.40-1.59 No apparent role for antibiotics

  32. Use of Progesterone to Reduce Preterm BirthNo. 419 • October 2008 • Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and a prior spontaneous preterm birth due to spontaneous preterm labor or premature rupture of membranes. • Current evidence does not support the routine use of progesterone in women with multiple gestations. • Progesterone supplementation for asymptomatic women with an incidentally identified very short cervical length (less than 15 mm) may be considered; however, routine cervical length screening is not recommended. • The American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice and the Society for Maternal Fetal Medicine believe that further studies are needed to determine if there are other indications for progesterone therapy for the prevention of preterm delivery.

  33. NICHD MFM: Placebo-controlled RCT with 17P in high-risk pregnancies to prevent PTB • 17a-hydroxy-progesterone caproate (“17P”) • 459 Women with documented history of a previous spontaneous singleton preterm birth < 37 wk GA • Enrolled 16-20 wk, given 250 mg i.m. weekly • ↓Preterm and early preterm birth, ↓ low birth-weight • ↓ Infant complications (↓ IVH, ↓NEC, ↓NICU admit, ↓ oxygen Rx • Four-year follow-up: no adverse health outcomes of surviving children Meiss PJ. N Eng J Med 2003, 348:2370

  34. Summary of Progesteronefor Women with Prior SPTBand current Singleton Gestation • 17P efficacy: • proven by 6 RCTs • meta-analyses support • recommended by ACOG • Oct 2008 Practice Bulletin • Vaginal Prog (dosing, preparation) • One negative and one positive trial

  35. SHORT CERVIXVaginal Progesterone Gel 90mg • 172 women with cervical length 32 mm • No significant difference between treatment groups DeFranco AE, et al. Ultrasound Obstet Gynecol. 2007;30:697-705.

  36. Vaginal Progesterone Gel: Cervical Length <28 mm Gestation Age at Delivery Cervical Length <28 mm Placebo, n = 27 Progesterone, n = 19 DeFranco AE, et al. Ultrasound Obstet Gynecol. 2007;30:697-705.

  37. Vaginal Progesterone Gel: Infant Outcomes at <28 mm NICU = neonatal intensive care unit. DeFranco AE, et al. Ultrasound Obstet Gynecol. 2007;30:697-705.

  38. Progesterone for PTB prevention Other indications by MFMs 2003 Survey: Ness, Baxter, Hyslop, Berghella. J Reprod Med 2006;51:411-5 2005 Survey: Ness, Dias, Damus, Burd, Berghella. Am J Obstet Gynecol 2006;195:1174-9

  39. RCT vaginal progesterone for Women with a Short Cervix • 24,620 asymptomatic women screened at 22 (20-25)w by TVU • 250 (24 with twins) with CL ≤15 mm • Randomized • 200 mg vaginal progesterone or placebo nightly 24 to 34w • Primary outcome: spontaneous PTB< 34 weeks • Did not report neonatal outcome Fonseca EB, et al. NEngl J Med. 2007;357:462-469.

  40. Efficacy: Natural Progesterone—Cervical Length ≤15 mm 100 90 80 70 60 Progesterone • Kaplan-Meier Plot of the Probability of Continued Pregnancy without Delivery among Patients Receiving Vaginal Progesterone (200 mg) as Compared with Placebo. • Progesterone reduces the risk of spontaneous delivery before 34 weeks by 44.2% • Hazard ratio for Progesterone: • 0.57(95% CI, 0.35-0.92, P=.02 Cumulative Percentage of Continued Pregnancies P=0.02 Placebo 0 160 170 180 190 200 210 220 230 240 0 Gestational Age (days) Fonseca EB, et al. NEngl J Med. 2007;357:462-469.

  41. Current/Planned RCTs www.controlledtrials.com

  42. Current/Planned RCTs: Multiples www.controlledtrials.com

  43. Conclusion Focus on the diagnosis • Diagnosis: Insufficient cervix (Hx PTB + short CL?) • Cerclage • Diagnosis: Inflammation • Progesterone: recommended by ACOG • Consistent evidence of 17Prog (weekly i.m. injections) • Indomethacin? • Diagnosis: Infection • Antibiotic? • Diagnosis: Endothelial / clotting disorder • ?

  44. Conclusion • Use of TVU CL in high risk pregnancies to assess for PTB risk • Asymptomatic • Singleton with prior PTB • CL ≥ 25mm: Avoid intervention • CL < 25mm: Consider Cerclage • awaiting NIH RCT • Singleton • Progesterone recommended by ACOG • Indomethacin? (with cerclage) • other interventions? (bed rest, pessary, etc)

  45. Our Patient: Prevention • From history: prior PTB • Obtain MFM consult • 17 P 250 mg i.m. Weekly starting at 16 wk • TVU CL at 16 week • Consider cerclage if <25mm • Treat any vaginal infections

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