1. PRETERM LABOR HOW CAN WE DO A BETTER JOB?

2. BACKGROUND Preterm defined as < 37 weeks Preterm defined as < 37 weeks PTD has continued to increase (until recently?) PTD has continued to increase (until recently?) 1/8 births are preterm 1/8 births are preterm Earlier delivery associated with increased risk of death and disability Earlier delivery associated with increased risk of death and disability Leading cause of neonatal deaths since 2001 Leading cause of neonatal deaths since 2001

4. Magnitude of the Problem Definition (< 37 weeks) Definition (< 37 weeks) 2004: more than 500,000 neonates were born preterm 2004: more than 500,000 neonates were born preterm Frequency: 12.5 % Frequency: 12.5 %

5. The Lancet Editorial 2006;368:339

6. Frequency of preterm birth by gestational age (1995-2000) < 28 weeks : 0.82 % < 28 weeks : 0.82 % < 32 weeks: 2.2 % < 32 weeks: 2.2 % 33-36 weeks: 8.9 % 33-36 weeks: 8.9 % < 37 weeks: 12.5% < 37 weeks: 12.5% IOM Report-July 2006- page 72/2006 Alexander GR et al 2006 (under review)

7. Survival by gestational age among live-born resuscitated infants Mercer BM Obstet Gynecol 2003;101:178 –93. Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee

8. Acute morbidity by gestational age among surviving infants Mercer BM Obstet Gynecol 2003;101:178 –93. Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee

9. BACKGROUND Preterm delivery accounts for Preterm delivery accounts for –1 in 5 cases of mental retardation –1 in 3 cases of visual impairment –1 in 2 cases of cerebral palsy Also increases risk for adult diseases Also increases risk for adult diseases –MI –Stroke –Hypertension –Diabetes –? cancer

10. Complications of “Late Preterm or Near Term Infants” Cold Stress Cold Stress Hypoglycemia Hypoglycemia RDS RDS Jaundice Jaundice Sepsis Sepsis IOM Report-July 2006- page 72/2006

11. Institute of Medicine of the National Academies, 2006 Richard E. Behrman, Adrienne Stith Butler, Editors Institute of Medicine Report Preterm Birth: Causes, Consequences, and Prevention

12. IOM Report – July 2006 “Babies born before 32 weeks have the greatest risk for death and poor health outcomes, however, infants born between 32 and 36 weeks, which make up the greatest number of preterm births, are still at higher risk for health and developmental problems compared to those infants born full term “Babies born before 32 weeks have the greatest risk for death and poor health outcomes, however, infants born between 32 and 36 weeks, which make up the greatest number of preterm births, are still at higher risk for health and developmental problems compared to those infants born full term IOM Report page 72

13. Magnitude of the Problem The infant mortality rate for very preterm infants (delivered < 32 weeks of gestation) was 186.4, nearly 75 times the rate for infants born at term (2.5) (37–41 weeks of gestation) The infant mortality rate for very preterm infants (delivered < 32 weeks of gestation) was 186.4, nearly 75 times the rate for infants born at term (2.5) (37–41 weeks of gestation) 20% all infants born <32 weeks do not survive the first year of life 20% all infants born <32 weeks do not survive the first year of life Mathews TJ. et al. National Vital Statistics Reports 2004;53:1-32

14. RISK FACTORS Multiple gestations Multiple gestations Prior PTB Prior PTB African American race African American race Smoking Smoking Substance abuse Substance abuse Poor oral hygiene Poor oral hygiene BMI < 20 BMI < 20 Short inter-pregnancy interval Short inter-pregnancy interval ? Stress (physical/emotional) ? Stress (physical/emotional)

15. RISK OF PRETERM BIRTH Term/term4% Term/term4% PTD/term 12% PTD/term 12% Term/PTD 23% Term/PTD 23% PTD/PTD 32% PTD/PTD 32% Carr-Hol RA BJOG 1985 50% of patients delivery within 1 week 50% of patients delivery within 1 week 75% of patients delivery within 2 weeks 75% of patients delivery within 2 weeks

16. Frequency of Preterm Birth by Ethnic Group Source: CDC 2004 Births: Preliminary Data for 2003 http://www.cdc.gov/nchs/data/nvsr/nvsr53/nvsr_09.pdf (accessed August 30, 2005) Non-Hispanic African-American17.8% American Indians/Native Alaskans13.5% Hispanics11.9% Whites11.5% Asian and Pacific Islanders10.5%

17. SERIOUSLY, WHY CAN’T WE FIGURE THIS OUT??? Many different causes Patient demographics are different Socioeconomic factors Concerns regarding safety of medications Inability to do quality studies

19. The Preterm Parturition Syndrome UterineOverdistension Vascular Infection Cervical Disease Hormonal Immunological © VR RR MM Unknown

20. MAKING THE DIAGNOSIS OF PRETERM LABOR CAN WE DO A BETTER JOB?

21. PREDICTORS OF PRETERM DELIVERY Very poor Very poor Often based on prior OB history Often based on prior OB history –50% of patients are nulliparous Sensitivity and specificity are low Sensitivity and specificity are low Difficult to find interventions that decrease preterm delivery Difficult to find interventions that decrease preterm delivery

22. PRETERM LABOR MANAGEMENT GOALS Identify those at highest risk Identify those at highest risk Eliminate those at a lower risk Eliminate those at a lower risk Maximize condition of the fetus at birth Maximize condition of the fetus at birth –short term tocolysis (neuroprotection?) –antenatal corticosteroids –antibiotics to prevent early infection –prevent birth trauma / asphyxia

23. PRETERM LABOR DIAGNOSIS Gestational age 20 - 37 weeks with regular uterine contractions and and Ruptured membranes or intact membranes - cervical change - cervical change - > 80% effaced - > 80% effaced - > 2 cm. dilated - > 2 cm. dilated

24. DIAGNOSIS May be difficult May be difficult Placebo/false labor 50+% of patients Placebo/false labor 50+% of patients Try to make diagnosis early Try to make diagnosis early –more successful tocolysis –allow transfer to regional center –maximize condition of fetus at birth

25. PRETERM PREDICTORS OVERVIEW None have stood the test of time None have stood the test of time 2 proven options 2 proven options –ultrasound cervical length –fetal fibronectin (fFN) Good at ruling out PTL (useful NPV) Good at ruling out PTL (useful NPV) PPV less useful PPV less useful

26. Source: Iams JD et al. N Engl J Med. 1996;334:567-572. Preterm Delivery <35 Weeks Risk of PTD by Cervical Length Probability of Preterm Delivery 0.5 0.4 0.3 0.2 0.1 0.0 020406080 Cervical Length (mm)

27. Cervix NORMAL CERVIX Fetal Head

32. CERVICAL LENGTH Most of the data for cervical length is in asymptomatic patients Not as much experience using in triaging of patients Limited accessibility, especially after hours Significant cost/charges Delay in obtaining results

33. CERVICAL LENGTH Charges are variable between institutions. Costs, now that’s a whole nother matter At our 2 offices, charges are - $259.00 - $380.00

35. Amnion Chorion Fetal Fibronectin Decidua Fetal Fibronectin

36. FETAL FIBRONECTIN DOING THE TEST User friendly, all inclusive kits User friendly, all inclusive kits Normal speculum examination Normal speculum examination Dacron swab in posterior fornix 10 sec. Dacron swab in posterior fornix 10 sec. Place in buffered solution Place in buffered solution Send to lab Send to lab

37. Specimen Collection for fFN Testing n Lightly rotate swab across either the posterior fornix of the vagina or the ectocervical region of the external cerical os for 10 seconds.

38. Specimen Collection for fFN Testing n Remove swab and immerse Dacron ® tip in buffer n Break the shaft even with the top of the tube (at the score)

39. Specimen Collection for fFN Testing n Align the shaft with the hole inside the tube cap and push down tightly over the shaft to seal the tube

40. Test Results n Rapid fFN for the TLi™ System l Analyzer produces results in 20 to 30 minutes l Around-the-clock availability l Moderately complex—requires CLIA approved laboratory n fFN Enzyme Immunoassay l 24-hour turnaround through central laboratory

41. FETAL FIBRONECTIN HOW GOOD IS IT? Multicenter trial Multicenter trial 763 symptomatic patients 763 symptomatic patients Investigators blinded to results Investigators blinded to results Treatment as deemed clinically indicated Treatment as deemed clinically indicated fFN gathered prior to examination fFN gathered prior to examination Peaceman et al, AJOG 1997;177:13-18

42. FETAL FIBRONECTIN HOW GOOD IS IT? Peaceman et al, AJOG 1997;177:13-18

44. Sum of the cost of steroids, tocolytics and hospitalization and the machine To treat 91 patients without testing is approximately $106,000.00 To test and treat selectively is approximately $39,500.00 Estimation of Cost Effectiveness.

45. CONCLUSIONS Fetal Fibronectin testing is reliable and can be used effectively as an aid for the diagnosis of preterm labor Fetal Fibronectin testing is reliable and can be used effectively as an aid for the diagnosis of preterm labor The cost of avoidable admissions and treatment for those testing negative outweighs the cost of the test. The cost of avoidable admissions and treatment for those testing negative outweighs the cost of the test.

46. FETAL FIBRONECTIN EFFECT ON TRANSPORTS 18 month prospective study 18 month prospective study 9 referring hospitals, 1 university center 9 referring hospitals, 1 university center 151 patients with presumptive PTL 151 patients with presumptive PTL 45 patients (30%) had (+) fFN 45 patients (30%) had (+) fFN 25% delivered within 7 days 25% delivered within 7 days 2% of (-) fFN’s delivered within 7 days 2% of (-) fFN’s delivered within 7 days

47. FETAL FIBRONECTIN EFFECT ON TRANSPORTS 90% of patients with a (-) fFN were not transported 90% of patients with a (-) fFN were not transported Cost savings: over $30,000 for transports alone Cost savings: over $30,000 for transports alone Mean length of stay for antepartum: 7 days Mean length of stay for antepartum: 7 days –Average hospital savings: > $150,000 Cost of fFN tests: $5,000 Cost of fFN tests: $5,000

48. FETAL FIBRONECTIN POSITIVE TESTS?? Unclear what is the best strategy Unclear what is the best strategy Many unproven options Many unproven options –bedrest –prophylactic tocolytics –screen and treat for lower genital infections –antenatal corticosteroids –close follow up and ongoing dialogue

49. COMBINATION APPROACH (Goldenberg RL, Iams JD, AJOG 2000;182:636-43) Serial fFN and cervical length in 2929 patients Serial fFN and cervical length in 2929 patients Observational study Observational study Multiple exams and combination of results Multiple exams and combination of results Summary Summary –Isolated short cervix or (+) fFN increased risk of PTB above baseline by factor of approximately 4 –Both being abnormal increased risk by about 25

50. COMPARISON OF TESTS (Goldenberg RL, Iams JD, AJOG 2000;182:636-43) ModalityRR (+) fFN and short cervix25 (+) fFN alone4.0 (+) short cervix alone4.0 * Of patients with a (+) fFN and short cervix at 24-26 weeks, over 60% delivered prior to 35 weeks

51. AHRQ EVIDENCE REPORT December 2002 Two biologic markers (fFN &EVUSD) are useful in identifying women in PTL who are at a low risk of experiencing a PTB Two biologic markers (fFN &EVUSD) are useful in identifying women in PTL who are at a low risk of experiencing a PTB Certain tocolytics (beta-mimetics, magnesium, calcium channel blockers, NSAID’s) appear effective in prolonging pregnancy Certain tocolytics (beta-mimetics, magnesium, calcium channel blockers, NSAID’s) appear effective in prolonging pregnancy Beta-mimetics have a higher risk of maternal harm Beta-mimetics have a higher risk of maternal harm

53. PROTOCOL (Mine anyway) Cervical length in high risk patients prior to 24 weeks Fetal fibronectin 24-34 weeks who are symptomatic for preterm labor Cervical length if fetal fibronectin (+) and no significant dilatation If short cervix is incidental finding, fetal fibronectin

54. PROTOCOL (Mine anyway) Steroids for maturity if fFN positive and cervix is short Observation if only one is abnormal Magnesium for tocolysis if necessary Repeat steroids if > 14 days from initial course and < 33 weeks Magnesium for neuroprotection until 32 weeks

55. INTRAPARTUM STUFF Tocolytics Magnesium for neuroprotection Repeat steroids

56. LET’S TALK TOCOLYTICS!

57. MAGNESIUM VS. NIFEDIPINE 192 patients randomized to magnesium vs. nifedipine 192 patients randomized to magnesium vs. nifedipine 24 to 33 weeks 24 to 33 weeks Magnesium: 4 gm bolus then 2 gm/hr Magnesium: 4 gm bolus then 2 gm/hr Nifedipine: 10 mg every 20 minutes x 3 then 20 mg every 4-6 hours Nifedipine: 10 mg every 20 minutes x 3 then 20 mg every 4-6 hours Maintenance tocolysis at attending discretion Maintenance tocolysis at attending discretion Lyell DJ Obstet Gynecol 2007;110:61-7

58. MAGNESIUM VS. NIFEDIPINE Lyell DJ Obstet Gynecol 2007;110:61-7

59. MAGNESIUM VS NIFEDIPINE No difference No difference –Delivery at < 48 hours –Delivery at < 32 weeks, 37 weeks –EGA at delivery –Birth weight –Recurrent preterm labor Shorter time to uterine quiescence with nifedipine Shorter time to uterine quiescence with nifedipine Slightly longer length of stay for infants in magnesium group Slightly longer length of stay for infants in magnesium group More maternal side effects in magnesium group but none life threatening More maternal side effects in magnesium group but none life threatening Lyell DJ Obstet Gynecol 2007;110:61-7

60. REVIEW OF STUDIES SUGGESTING MAGNESIUM IS NEUROPROTECTIVE

61. REVIEW OF MAG AND CP STUDIES FAVORING REDUCTION SchendelJAMA 1996 Grether J Pediatr 1996 BoyleAm J Epidemiol 2000 MatsudaEuro J OB, GYN, Reprod 2000 MurataBrain & Develop 2005 AGAINST REDUCTION PanethPediatrics 1997 CanterinoOB/GYN 1999 GretherAJOG 2000

62. PROSPECTIVE STUDIES SUPPORTING MAGNESIUM FOR NEUROPROTECTION

63. ACTOMgSO4 –1062 patients PreMag –573 patients Beam Trial –>2200 patients

64. SUMMARY Fairly clear that magnesium is neuroprotective Fairly clear that magnesium is neuroprotective Beneficial until 28-32 weeks Beneficial until 28-32 weeks Optimal dosing is still unclear Optimal dosing is still unclear Recommend Recommend –4 gram bolus –Followed by 2 gram/hour infusion Try to wait 2 hours, if possible Try to wait 2 hours, if possible Continue until delivery Continue until delivery

65. STEROIDS BACKGROUND As early as the 1960’s, it was known that steroids decrease RDS in animals As early as the 1960’s, it was known that steroids decrease RDS in animals 1972 landmark study by Liggins/Howie 1972 landmark study by Liggins/Howie –2 doses of betamethasone –Reduced RDS from 15+% to 10% –Reduced mortality from 11+% to 6% Most of benefit in those 28-34 weeks Most of benefit in those 28-34 weeks How long do they last? How long do they last? Why no benefit after 34 weeks? Why no benefit after 34 weeks?

66. STEROIDS BACKGROUND Other studies confirmed findings Other studies confirmed findings Steroids slow to be implemented Steroids slow to be implemented Study in 1992 showed less than 50% of preterm infants received steroids Study in 1992 showed less than 50% of preterm infants received steroids In 1994, NIH released first consensus statement on steroids In 1994, NIH released first consensus statement on steroids Area of further research Area of further research –Repeat steroids –How long do they last

67. STEROIDS BACKGROUND In 2000, NIH released their 2 nd (and last) consensus statement In 2000, NIH released their 2 nd (and last) consensus statement Repeat steroids should only be given to patient’s enrolled in a randomized controlled trial with informed consent and in a dose so as to minimize exposure of both the mother and fetus Repeat steroids should only be given to patient’s enrolled in a randomized controlled trial with informed consent and in a dose so as to minimize exposure of both the mother and fetus

68. HOW LONG IS THE BENEFIT? Retrospective chart review Retrospective chart review 197 infants received steroids 197 infants received steroids –98 delivered within 7 days –99 delivered after 7 days Matched for everything Matched for everything –RacePayer mix –GenderRoute of delivery –EGA at deliveryBirth weight Peaceman et al AJOG 2005;193:1165-9

69. HOW LONG IS THE BENEFIT? Delivery < 7 days Delivery > 7 days P Ventilation or CPAP > 24 hours 63%81% < 0.01 Surfactant use 39%47%.28 O2 at 28 days 23%22%.92 NEC, IVH, or sepsis 31%28%.56 Length of stay 34 days 38 days.80 Peaceman et al AJOG 2005;193:1165-9

70. FINALLY, THE MEAT: WHAT ABOUT A REPEAT DOSE? Now, 4 randomized controlled trials in the literature looking at this Now, 4 randomized controlled trials in the literature looking at this –Guinn 2001 (N = 502) –Wapner 2006 (N= 556)*** –Crowther 2006 (N= 1047) –Garite 2009 (N= 437) All suggest a modest reduction in RDS All suggest a modest reduction in RDS No improvement in other morbidities or in mortality No improvement in other morbidities or in mortality –*** non-significant increase in CP at age 2

71. IMPACT OF A ‘RESCUE COURSE’ OF STEROIDS Multi-center randomized placebo trial Multi-center randomized placebo trial 437 patients 437 patients –223 in repeat group –214 in single course Included multiple gestations (N = 141) Included multiple gestations (N = 141) 25 to 33 weeks 25 to 33 weeks Randomized if Randomized if –Received 1 st course > 14 days earlier –High likelihood of delivering in next 7 days Garite et al AJOG 2009;200:248.e1-248.e9

72. IMPACT OF A ‘RESCUE COURSE’ OF STEROIDS No difference in demographics No difference in demographics Significant reduction in Significant reduction in –Composite morbidity (44% vs 66%) –RDS (41% vs 61%) –Surfactant use (38% vs 55%) –Ventilation (38% vs 53%) No difference in mortality or other significant morbidities No difference in mortality or other significant morbidities Garite et al AJOG 2009;200:248.e1-248.e9

73. WHAT IS THE RISK OF SEVERE RDS IN LEGACY NICU? Let’s look at 30-32 weeks Let’s look at 30-32 weeks Northwest Newborn uses a lot of “gentler ventilation” i.e. nasal CPAP Northwest Newborn uses a lot of “gentler ventilation” i.e. nasal CPAP From 30-32 weeks From 30-32 weeks –About 1/3 do not require respiratory support –Failed CPAP is about 15%

74. WHAT IS THE RISK OF SEVERE RDS IN OUR NICU? So for counseling So for counseling –30% require no respiratory support –55-60% require nasal CPAP (duration usually 2-6 days) –About 15% require surfactant along with short term mechanical ventilation In the VON, the rate is about 35% In the VON, the rate is about 35% Thus, the reason for limiting repeat steroids to those < 30 weeks Thus, the reason for limiting repeat steroids to those < 30 weeks

75. SUMMARY Steroid benefit probably does have limited time of efficacy Steroid benefit probably does have limited time of efficacy Most studies consistently show this to be about 7-14 days Most studies consistently show this to be about 7-14 days Main benefit is in reduction of short term respiratory complications Main benefit is in reduction of short term respiratory complications No reduction in death or serious morbidities (severe IVH, NEC…) No reduction in death or serious morbidities (severe IVH, NEC…)

76. SUMMARY Risk of severe RDS, chronic lung disease is low after 30 weeks Risk of severe RDS, chronic lung disease is low after 30 weeks Still some lingering concern about long term problems with repeat doses Still some lingering concern about long term problems with repeat doses Consider giving repeat course up to 32-33 weeks Consider giving repeat course up to 32-33 weeks

78. CAN WE PREVENT PRETERM BIRTH?

80. WHAT HAS BEEN TRIED? Bedrest Bedrest Prophylactic tocolytics Prophylactic tocolytics Prophylactic cerclage Prophylactic cerclage HUAM HUAM PROGESTERONE!! PROGESTERONE!!

81. THE BANDWAGON NEVER BE THE 1 ST ONE ON THE BANDWAGON NOR THE LAST ONE OFF IT!!

82. PROGESTERONE STUDIES Early studies with mixed results Early studies with mixed results Lumped SAB, PTL…. together Lumped SAB, PTL…. together Various progestational agents Various progestational agents High risk vs. low risk High risk vs. low risk Timing of initiation of therapy Timing of initiation of therapy Risk of anomalies Risk of anomalies –Prior scares DES DES Repeat steroids Repeat steroids Thalidomide Thalidomide SSRI’s SSRI’s TRH TRH Continuous fetal monitoring Continuous fetal monitoring Magnesium Magnesium IV alcohol IV alcohol

83. PROGESTERONE STUDIES Studies currently using Studies currently using –17 hydroxyprogesterone caproate –Vaginal progesterone 100 mg per day –Vaginal progesterone 200 mg per day –Vaginal progesterone 90 mg/day Limited randomized placebo controlled trials (4 published) Limited randomized placebo controlled trials (4 published)

84. Prevention of recurrent PTL by 17 alpha-hydroxyprogesterone caproate NEJM June 2003 pp2379-2385 Randomized prospective placebo controlled trial Randomized prospective placebo controlled trial Over 450 patients with 2:1 ratio of progesterone to placebo Over 450 patients with 2:1 ratio of progesterone to placebo All had prior preterm birth All had prior preterm birth Singleton fetus Singleton fetus No significant medical problems No significant medical problems

85. Prevention of recurrent PTL by 17 alpha-hydroxyprogesterone caproate NEJM June 2003 pp2379-2385 Initial part of study involving 150 patients terminated due to violation of manufacturing process Initial part of study involving 150 patients terminated due to violation of manufacturing process 86 completed treatment 86 completed treatment –57 (61%) with 17-P –29 (39%) with placebo Delivery at < 37 weeks Delivery at < 37 weeks –17-P43% –Placebo38%

86. Prevention of recurrent PTL by 17 alpha-hydroxyprogesterone caproate NEJM June 2003 pp2379-2385 CharacteristicProgesteronePlaceboRR # of PTD 1.41.6NS Del. < 37 wks (%)36.354.90.66 Del. < 35 wks (%)20.630.70.67 Del. < 32 wks (%)11.419.60.58 IVH (%) 1.35.40.25 NEC (%) 0.02.6NS

88. FDA ADVISORY PANEL COMMENTS Pregnancy outcome 17-P N, (%) Placebo Nominal P value SAB < 20 wks 5 (1.6) 00.17 Stillbirth 6 (2.0) 2 (1.3) 0.72 Antepartum Antepartum 5 (1.6) 1 (0.6) ---- Intrapartum Intrapartum 1 (0.3) 1 (0.6) ---- Neonatal deaths 8 (2.6) 9 (5.9) 0.12 Total deaths 19 (6.2) 11 (7.2) 0.69

89. FDA ADVISORY PANEL COMMENTS No difference in Apgar scores, congenital malformations, median days in NICU (9.1 vs 14.1), mean days in hospital (9.1 vs 14.1), and mean birthweight, and birthweight < 1500 gms (8.6% vs 13.9%) No difference in Apgar scores, congenital malformations, median days in NICU (9.1 vs 14.1), mean days in hospital (9.1 vs 14.1), and mean birthweight, and birthweight < 1500 gms (8.6% vs 13.9%) Percentage of babies < 2500 gms was less in the 17-P group (27.2% vs 41.1%) Percentage of babies < 2500 gms was less in the 17-P group (27.2% vs 41.1%)

90. FDA ADVISORY PANEL COMMENTS If adjusted for multiple comparisons, it is unlikely that any of the listed morbidities would have been statistically lower in the 17-P group If adjusted for multiple comparisons, it is unlikely that any of the listed morbidities would have been statistically lower in the 17-P group The composite neonatal morbidity score, though numerically lower in the 17-P group, it did not reach statistical significance The composite neonatal morbidity score, though numerically lower in the 17-P group, it did not reach statistical significance

91. Prophylactic administration of progesterone by vaginal suppositories AJOG 2003;188:419-424 142 high risk patients (mostly a prior preterm birth) 142 high risk patients (mostly a prior preterm birth) Randomized to daily suppository of 100 mg progesterone vs. placebo Randomized to daily suppository of 100 mg progesterone vs. placebo Delivery: Progesterone Placebo Delivery: Progesterone Placebo < 37 wks 13.8% 28.5% < 37 wks 13.8% 28.5% < 34 wks 2.8% 18.6% < 34 wks 2.8% 18.6%

92. PROGESTERONE GEL FOR RECURRENT PRETERM BIRTH Randomized placebo controlled trial of 659 patients Randomized placebo controlled trial of 659 patients –328 placebo –331 Prochieve (8% progesterone) 60% in each group had prior delivery at < 32 weeks 60% in each group had prior delivery at < 32 weeks No demographic differences No demographic differences O’Brien JM Ultra OB/GYN, 2007;30(5):687

93. PROGESTERONE GEL FOR RECURRENT PRETERM BIRTH No difference between groups in: –Mean gestational age at delivery –Deliveries < 37 weeks –Deliveries < 32 weeks –Mean birthweight –Neonatal morbidity –Neonatal mortality O’Brien JM Ultra OB/GYN, 2007;30(5):687

94. META-ANALYSIS Mackenzie R. AJOG, 2006:194;1234 Progestational agents initiated in the 2 nd trimester reduce the risk of delivery at < 37 weeks but no effects of perinatal outcomes Progestational agents initiated in the 2 nd trimester reduce the risk of delivery at < 37 weeks but no effects of perinatal outcomes Treatment with progestational agents should continue to be limited to women enrolled in well-designed randomized controlled trials Treatment with progestational agents should continue to be limited to women enrolled in well-designed randomized controlled trials

95. TWINS AND 17-P Rouse D, NEJM 2007;357:454 655 sets of twins 655 sets of twins –325 17-P –330 placebo Enrolled between 16.0 and 20.3 weeks Enrolled between 16.0 and 20.3 weeks No other complications No other complications Nearly 50% nulliparous Nearly 50% nulliparous < 10% had prior PTB < 10% had prior PTB 2/3’s spontaneous 2/3’s spontaneous 80% di-di placentation 80% di-di placentation

96. TWINS AND 17-P Rouse D, NEJM 2007;357:454 Delivery at < 35 weeks Delivery at < 35 weeks –41% in 17-P –37% in placebo Composite neonatal morbidity Composite neonatal morbidity –20.2% in 17-P –18.0% in placebo No improvement in outcomes when using 17-P in twins No improvement in outcomes when using 17-P in twins

97. SHORT CERVIX AND VAGINAL PROGESTERONE Fonseca, NEJM. 2007;357:462 413 patients with TVUSCL < 15 mm 413 patients with TVUSCL < 15 mm –250 vaginal PG @ 200 mg nightly –163 placebo Mean EGA = 22 weeks Mean EGA = 22 weeks Randomized between 20 -25 weeks Randomized between 20 -25 weeks Delivery at < 34 weeks Delivery at < 34 weeks –Progesterone19.2% –Placebo34.4%

98. SHORT CERVIX AND VAGINAL PROGESTERONE Hassan et al. US OB/GYN 2011 458 patients randomized –235 vaginal progesterone –223 to placebo Progesterone: 90 mg at night TVUSCL: 1.0 to 2.0 cm EGA: 19.0 to 24 weeks Continued until 36 weeks

99. SHORT CERVIX AND VAGINAL PROGESTERONE Hassan et al. US OB/GYN 2011 Vaginal progesterone had less –< 35 weeks (14.5% vs 23.3%) –< 33 weeks (8.9% vs. 16.1%) –< 28 weeks (5.1% vs 10.3%) –RDS (3.0% vs. 7.6%) –BWT < 1500 gms (6.4% vs. 13.6%) –Any morbidity (7.7% vs. 13.6%)

100. Obstet Gynecol 2003;102:1115-6

103. SUMMARY Progesterone is safe It is probably effective is properly selected patients May not have a significant impact on the preterm delivery rate Legally, I think it needs to be offered to patients due to ACOG’s statement

104. SUMMARY OF THE SUMMARIES Preterm births are still a huge problem in the U.S. No clear, definitive way to decrease the overall rate due to the complexity of the problem Progesterone probably works to decrease the recurrence rate Vaginal progesterone may decrease the rate with a short cervix

105. SUMMARY OF THE SUMMARIES It is really, really, really important to make (or rule out) the diagnosis Liberal use of fetal fibronectin and cervical lengths to identify those at the highest risk so as to target therapy Magnesium is the tocolytic of choice for those under 28 weeks and probably 32 weeks due to its neuroprotection effects Steroids are a good thing!!!!

106. SUMMARY OF THE SUMMARIES Effects of steroids fade after 14 days Strongly consider a repeat course (2 doses) if still at risk for preterm delivery, EGA < 33 weeks, and greater than 14 days from initial course Using fFN and cervical length to focus therapy can reduce the number of patients who needlessly get medications that they don’t really need

107. THANK YOU!!

108. QUESTIONS?