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 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)
* 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 < lb.
Uterine or cervical abnormality
Maternal smoking

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

9. Rationale for new PTL screening 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 %
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 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*
* *
* NS: 95%CI < 1
Leitich. AJOG 2003;189:139-47

18. Effect of BV treatment RR of PTD
300 mg bid
AJOG 1995;173:157
250 mg tid 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 PTB Meta-analysis; 13 studies; n=22,390
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
wks with signs or symptoms of PTL
fFN results in 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 term NPV (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 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 17 wks with cx 1dil/2.5 long on US
B) 28 yo 17 wks with cx 1 dil/2.5 long
C) 28 yo 29 wks with cx 1 dil/2.5 long
D) 28 yo 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. Cervical length at 24 wks measured by TVUS
800
600
No. of Women
400
200 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68
Length of Cervix (mm) 5 25 75 1 10 50
Percentile
NEJM 1996;334:567

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

37. Preterm Prediction Study NICHD; 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 17 wks with cx 1dil/2.5 long on US
B) 28 yo 17 wks with cx 1 dil/2.5 long
C) 28 yo 29 wks with cx 1 dil/2.5 long
D) 28 yo 29 wks with cx cl/4 long

39. Group survey question
What is best prophylaxis for P0202 (prior PTB x 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, 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:

43. Prevention of PTB by vaginal administration of progesterone
% undelivered
RCT; n=142
Inclusion: singleton + prior PTB, cerclage, or uterine anomaly
Nightly vag 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 < lb.
Uterine or cervical abnormality
Maternal smoking

45. Group survey question
What is best prophylaxis for P0202 (prior PTB x 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. Contraindications to tocolysis
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
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

51. ? ? Tocolysis Rationale PROPHYLACTIC Prevent PTL/PTB Women at risk
THERAPEUTIC
Prevent PTB
Acute PTL
Prolong 48 h for steroids
Improve neonatal outcome
MAINTENANCE
After acute treatment
Prevent recurrent PTL
? ?

52. Effect of tocolytics to prevent PTB Meta-analysis1966-1999
OR for delivery at term
Many of these studies were performed before widespread corticosteroid use – perhaps contributing to lack of proven improved neonatal outcomes
Berkman. AJOG 2003;188:

53. Tocolysis Limited benefits – have a plan
Don’t forget fetal risks (?benefits)
Upcoming considerations
Atosiban
Selective COX-2 inhibition

54. MgSO4 for neuroprotection
RR * p<0.05
RCT; n=1047
Inclusion: EGA < 30 wks; PTB anticipated in < 24h
Mg 4g bolus + 1 g/h (not managed for tocolysis; median administration duration 3+ hrs)
* *
Crowther. JAMA 2003;290:

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

56. PTB prediction and prevention: Conclusions
PTD has multifactorial etiology
Identification of patients at risk does not:
determine etiology
direct therapy*
necessarily result in improved outcome*
* Possible exceptions:
17OHP for treatment
BV as contributing risk factor

57. PTB prediction and prevention: Conclusions
Routine screening (BV, US, fFN) not indicated for low risk patients
Systemic treatment for BV ’s risk for PTD if hi risk
For patients at high risk for PTD, measurement of cervical length and fFN may be useful because of their high NPV
Consider progesterone supplementation for women at high risk for PTB
Use tocolytics within bounds of reasonable goals