1. Predicting and Preventing Preterm Birth Steven R. Allen, MD Scott & White Hosp & Clinic Temple, TX

2. Educational Objectives • Identify remediable risk factors for PTB • Address potential “predictors” of PTB • cervical ultrasonographic screening • fibronectin • Discuss possible role for progesterone (Rx) in pregnancy maintenance • Review the potential utility of tocolysis

3. Significance of Preterm Birth (PTB) • 12.1% of US births - rising • One sixth of PTD’s occur at 24-31 weeks, with highest rate of complications * • Leading cause of neonatal mortality (75%), morbidity, and health care expenditures (57% of nursery costs; 10% of all healthcare costs for children) % PTB * * US Nat’t Vital Stats Reports 2000 & 2003

4. Mortality & morbidity related to PTB (S&W 1998-2001) % Survival % IVH Grade 3-4

5. Components of PTL pathophysiology • Prostaglandins • Inflammatory response • Adrenergic response: stimulates contractions • Ischemia: free radicals promote PGs • Decidual hemorrhage

6. Group survey question • Who is most likely to have a PTB? A) 34 yo P1203 (last preg preterm) B) 34 yo P1103 C) 34 yo P3003 D) 34 yo P1203 (last preg term)

7. Historical risk factors for PTL/PTB • Prior PTB (spontaneous PTL) • Low socioeconomic status • Teen • Age >34 • Prepregnancy weight < 100-110 lb. • Uterine or cervical abnormality • Maternal smoking

8. Multiple gestation Polyhydramnios Antepartum bleeding PROM Chorioamnionitis Pyelonephritis Untreated asymptomatic bacteriuria Some specific fetal anomalies Pregnancy complications predisposing to PTL/PTB

9. Rationale for new PTLscreening tools • <50% with PTL perceive typical symptoms • 10-20% of uncomplicated patients have similar symptoms • PTL is diagnosed only after gross structural change of the cervix • Majority of women with PTD have no currently identifiable risk factor

10. Summary of PTL Risk Scoring Indices 26 - 64 % 13 - 35 4 - 30 2 - 16 PTD Sensitivity Pos Screen PPV

11. Risk of subsequent PTB % Bakketeig, 1981

12. Group survey question • Who is most likely to have a PTB? A) 34 yo P1203 (last preg preterm) B) 34 yo P1103 C) 34 yo P3003 D) 34 yo P1203 (last preg term)

13. Group survey question • What “lab test” is most helpful in selecting mgmt plan for 33 yo P0010 @ 28 wks with q 4 min ctx and cx 1/2/-3 (digital exam)? A) cervical length (transabdominal scan) B) wet mount (r/o bacterial vaginosis) C) fFN D) cervical length (transvaginal scan)

14. Bacterial vaginosis (BV) • Anaerobic bacteria predominate vaginal flora • Incidence: 12-40% of pregnant women • Risk factors (all non-remediable) • black race • younger age • unmarried • multiparous • low socioeconomic status

15. Bacterial vaginosis: diagnosis • Relatively alkaline pH (>4.5) • Vaginal epithelial “clue cells” • Release of amine odor with alkalinization of vaginal fluid (“whiff test”) • Thin vaginal secretion of uniform consistency • Gram stain: Nugent criteria

16. BV: indirect screening (Pap smear) % Green. AJOG 2000;182:1048-9

17. Bacterial vaginosis as a risk factor for PTB – meta analysis OR * * * * NS: 95%CI < 1 Leitich. AJOG 2003;189:139-47

18. Effect of BV treatmentRR of PTD 300 mg bid AJOG 1995;173:157 250 mg tid + 333 mg tid NEJM 1995;333:1732 AJOG 1995;173:1527 Meta-analysis confirms reduction in PTB only in pts with prior PTB

19. Bacterial vaginosis: summary • BV increases risk of PTD • Screen high risk patients • Systemic treatment for BV • metronidazole 250 mg po tid x 7 d or • clindamycin 300 mg po bid x 7 d • Screening for risks of PTL by means other than • historic risk factors is not beneficial in the general • obstetric population ACOG Practice Bulletin # 31, 10/01

20. Fibronectins • Ubiquitous glycoproteins, present in plasma and ECM • Adhesion molecules • Fetal fibronectin (fFN) contains uniquely glycosylated epitope (“oncofetal domain”) • fFN located in ECM of decidua basalis and cytotrophoblasts

21. Fetal fibronectin • fFN rarely present (3-4%) in cervical/ vaginal secretions of women without PTL/PROM • fFN common in cervical/vaginal secretions of women with PTL (50%) or PROM (94%) • HYPOTHESIS: mechanical or inflammatory damage to placenta or membranes releases fFN into cervical/vaginal secretions

22. fFN as a predictor of PTD among women with PTL (n=192) AJOG 1995;173:141

23. Survival curve after fFN testing for threatened PTL % Days after fFN test Peaceman. AJOG 1997;177:13-18

24. fFN as a predictor of PTBMeta-analysis; 13 studies; n=22,390 OR Asymptomatic; predicting PTB < 34 wks Symptomatic; Predicting PTB < 11 d Honest. BMJ. 2002;325:1-10

25. Impact of fFN assay on admissions for PTL * • Cohort study with a historical control cohort • 24-34.9 wks with signs or symptoms of PTL • fFN results in 24-48 hr • No difference in neonatal outcome * * AJOG 1999;180:581 * p<0.001

26. fFN NOT strictly related to infection/inflammation • Many studies evaluating risk included women with multiple gestation or uterine anomalies (without obvious risk of infection) • fFN present in cervical/vaginal secretions at term

27. Fibronectin: summary • fFN is fairly sensitive marker for PTD in high risk patients (55-97%) • High short termNPV (71-100%) may identify women not needing tocolysis • Screening not recommended

28. Group survey question • What “lab test” is most helpful in selecting mgmt plan for 33 yo P0010 @ 28 wks with q 4 min ctx and cx 1/2/-3 (digital exam)? A) cervical length (transabdominal scan) B) wet mount (r/o bacterial vaginosis) C) fFN D) cervical length (transvaginal scan)

29. Group survey question • Which patient is most likely to threaten PTB? A) 28 yo P0 @ 17 wks with cx 1dil/2.5 long on US B) 28 yo P0111 @ 17 wks with cx 1 dil/2.5 long C) 28 yo P2002 @ 29 wks with cx 1 dil/2.5 long D) 28 yo P2002 @ 29 wks with cx cl/4 long

30. Hypothesis: cervical competence is a continuous variable • Most human features are continuous, not categorical • Cervical resistance to delivery varies at term • Bishop score varies • duration of normal labor varies • Prior PTL predicts subsequent PTL

31. 1 5 10 25 50 75 Percentile Cervical length at 24 wks measured by TVUS 800 600 No. of Women 400 200 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 Length of Cervix (mm) NEJM 1996;334:567

32. 1 5 10 25 50 75 Percentile Cervical length correlates with PTB 800 14 RelativeRisk of PTB 12 600 10 8 No. of Women 400 6 4 200 2 0 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 Length of Cervix (mm) NEJM 1996;334:567

33. Predictive value of cervical length with threatened PTD NPV PPV % Obstet Gynecol 1993;82:829

34. Predictive value of cervical “funneling” with threatened PTD • ‘Funneling” present in half of women studied with preterm contractions • Funneling correlates with cervical length, but is not as good a predictor of PTD • Funneling may vary over time, and thus be less reproducible than cervical length

35. US cervical canal measurement: summary • Cervical length correlates inversely with PTD risk • Identification of abnormal cervix does not determine etiology or direct treatment • Routine screening not recommended

36. Effectiveness of cerclage for sonographically shortened cervix • Meta-analysis • 6 studies (2 RCT) • n=357; mostly hi risk for PTB (3 studies, n=212) • Inclusion: cx < 2.5 cm long, dil < 2 cm, or funneling RR (all NS) Belej-Rak. AJOG 2003;189:1679-87

37. Preterm Prediction StudyNICHD; MFM Units Network “No screening test (except history) recommended for low-risk patient” % Low risk pts; n=2197 Iams. AJOG 2001;184:652-5

38. Group survey question • Which patient is most likely to threaten PTB? A) 28 yo P0 @ 17 wks with cx 1dil/2.5 long on US B) 28 yo P0111 @ 17 wks with cx 1 dil/2.5 long C) 28 yo P2002 @ 29 wks with cx 1 dil/2.5 long D) 28 yo P2002 @ 29 wks with cx cl/4 long

39. Group survey question • What is best prophylaxis for P0202 (prior PTB x 2 @ 28-29 wks after spontaneous PTL)? A) Bedrest B) Terbutaline pump C) 17-OH Progesterone 250 mg IM q wk D) Progesterone suppository 100 mg pv qd

40. Progesterone • Steroid hormone – “for gestation” • Progesterone production rises from 2-3 mg/d at ovulation to 30 mg/d 1 wk later • Progesterone production during pregnancy: 300 – 400 mg/d during 3rd TM (ovary  placenta) • Hydrophobic – diffuses thru plasma membrane, binds to cytoplasmic receptor, then moves to nucleus to function as a transcription factor

41. Progesterone: relaxes myometrium • Inhibits gap junction formation • Decreases number of oxytocin receptors • Immunusuppression

42. Prevention of recurrent PTB by 17-OH Progesterone caproate • Multicenter; n=463 • RCT; dbl blind • Inclusion: singleton, prior PTB • Wkly injection, 16-20 until 36 wks; 17-OH prog caproate or placebo • 17-OH-P assoc’d with neonatal risk reduction: NEC, IVH, & O2 need % Meis. NEJM 2003;348:2379-2385

43. Prevention of PTB by vaginal administration of progesterone % undelivered • RCT; n=142 • Inclusion: singleton + prior PTB, cerclage, or uterine anomaly • Nightly vag suppository @ 24-34 wks: prog100 mg or placebo • Wkly ctx monitoring: lower for prog group (p0.01) • PTB < 34 wks lower for prog (2.7 vs 18.5%; p<0.05) P=0.03 Wks EGA da Fonseca. AJOG 2003;188:419-24

44. Can Progesterone prevent PTB? • Multiple gestation • Polyhydramnios • Antepartum bleeding • PROM • Chorioamnionitis • Pyelonephritis • Untreated ASB • Some fetal anomalies • Prior PTB (spontaneous PTL) • Low SES • Teen • Age >34 • Prepregnancy weight < 100-110 lb. • Uterine or cervical abnormality • Maternal smoking

45. Group survey question • What is best prophylaxis for P0202 (prior PTB x 2 @ 28-29 wks after spontaneous PTL)? A) Bedrest B) Terbutaline pump C) 17-OH Progesterone 250 mg IM q wk D) Progesterone suppository 100 mg pv qd

46. Group survey question • Which of the following is not a contraindication to tocolysis: A) Preeclampsia B) Abruption C) Gastroschisis D) Chorioamnionitis

47. Absolute Severe preeclampsia Severe abruption Severe bleeding Chorioamnionitis Fetal death Fetal anomaly incompatible with life Severe fetal growth restriction Relative Mild CHTN Mild abruption Stable placenta previa Maternal disease – cardiac, hyperthyroid, uncontolled DM Fetal distress Mild fetal growth restriction Cx > 5 cm Fetal anomaly Contraindications to tocolysis Creasy & Resnick, Mat-Fetal Med

48. Group survey question • Which of the following is not a contraindication to tocolysis: A) Preeclampsia B) Abruption C) Gastroschisis D) Chorioamnionitis

49. Group survey question • What is best 1st line tocolytic agent? A) MgSO4 B) nifedipine C) ritodrine D) indomethacin

50. Mechanisms of tocolytic agents