1. Preventing Preterm Births: Do Any Screening Tests Help?
Joseph R. Biggio, M.D.

2. Learning Objectives
To understand the availability and performance of screening tests for the prediction of subsequent preterm birth
To understand how to utilize screening tests to identify women most likely to benefit from interventions to reduce PTB
To understand the limitations and challenges of using screening tests for preterm birth in different patient populations

3. Scope of the problem: Preterm Birth
30% Increase from 1980’s – 2006
~450,000 – 500,000 infants/yr
Peaked in 2006
PTB < 37 wk %
PTB < 34 wk 3.7 %
PTB wk 9.2 %
Hamilton et al, NVSR, NCHS 2014

4. Scope of the problem: Preterm Birth
Hamilton et al, NVSR 63(2), 2014

5. Scope of the problem: Preterm Birth%
PTB < 34 wk 3.4 %
PTB wk 7.99%
Most significant declines in late preterm birth
Hamilton et al, NVSR, NCHS 2014

6. March of Dimes 2014 Premature Birth Report Card
Vermont 8.1% Mississippi 16.6%

7. Scope of the Problem: Preterm Birth
Indicated 25%
PTL 40%
PROM 35%

8. Scope of the Problem: Preterm Birth
Major cause of perinatal morbidity and mortality
Cerebral Palsy
Developmental Disability
Neurologic impairment
Chronic lung disease
Minor Morbidities

9. Scope of the Problem: Preterm Birth
Risks related to GA at birth
Mortality
24 wk 50%
28 wk 10%
Special education needs
32-36 wk 25%
28-31 wk 45%

10. What Screening Tests Have Been Suggested?
History
Serial digital examination
Fetal fibronectin
Salivary estriol
Cervical length screening
BV screening
Home uterine activity monitoring
Periodontal disease screening

11. What Screening Tests Do NOT Work?
Serial digital examination
Salivary estriol
BV treatment
Periodontal disease treatment
Home uterine activity monitoring
+/- fFN in asymptomatic women

12. What Interventions Do NOT Work?
Bedrest
Pelvic rest
Fish oil supplements
Enhanced prenatal care

13. What Screening Tests Have Been Suggested?
Many other different biomarkers and measurements examined
Many have reasonable + Likelihood ratios
Positive predictive value or specificity too poor for clinical practice

14. So what does work to assess risk for subsequent PTB?

15. History of Prior Preterm Birth
Major risk factor for subsequent preterm birth
1.5-2-fold risk
Number of prior PTB
GA at prior delivery
Sequence of deliveries
McManemy et al, AJOG, 2007; Lemos et al, AJOG 2013

16. History of Prior Preterm Birth
Timing of prior PTB contributes to risk
Earlier PTB  higher recurrence risk
Spong et al, Am J Obstet Gynecol, 2005

17. History of Prior Preterm Birth
Correlates with timing of cervical shortening
Wing et al, Am J Obstet Gynecol 2010

18. Prior history of SPTB: Prevention of recurrence
17-hydroxy progesterone caproate
Prior singleton PTB /7 wk
Treatment started /7 wk
310 progesterone; 150 placebo
PTB < 37 wk
36% vs 55% RR 0.66 (0.54 – 0.81)
Meis et al, NEJM, 2003

19. Prior history of SPTB: Prevention of recurrence
PTB <32 wk
11% vs 20% RR 0.58 (0.37 – 0.91)
Significant reduction in
Necrotizing enterocolitis
Intraventricular hemorrhage
Meis et al, NEJM, 2003

20. Utilizing the test to prevent PTB: History
Vaginal progesterone
High-risk for PTB
100 mg vaginal progesterone daily
Reduction in uterine contractions
45-50% reduction in PTB <34 wk
da Fonseca et al, AJOG, 2003

21. Cervical Length

22. Cervical Length Asymptomatic 24 wk Mean 34-36 mm CL <26 mm
PTB <37 wk
RR 6.2 (3.8 – 10)
≥25 mm
NPV >95% for PTB <32 wk
<25 mm
PPV 10% for PTB < 32 wk
Iams et al, 1996

23. Cervical Length
Iams et al, 1996

24. Transvaginal assessment
Cervical Length
Transvaginal assessment
Reproducible
Not affected by obesity, position, fetal presentation like transabdominal
Better able to assess for funneling and debris
ACOG PB 130, 2012; Owen and Iams, Semin Perinatol 2003; Berghella et al Obstet Gynecol 2007

25. Utilizing the test to prevent PTB: Short Cervix
Cervical length 15 mm or less
Screened at wk
Vaginal Progesterone 200 mg nightly
PTB < 34 wk RR 0.56 (0.36 – 0.86)
~15% with prior PTB
Non-significant reduction in adverse neonatal outcome RR 0.59 ( )
Fonseca et al, NEJM, 2007

26. Utilizing the test to prevent PTB: Short Cervix
Cervical length mm
Screened at /7 wk
16% with prior PTB
90 mg progesterone gel daily
45 % reduction in PTB < 33 wk and neonatal morbidity and mortality
Hassan et al, US OG, 2011

27. Utilizing the test to prevent PTB: Short Cervix
17-OHP NOT effective in preventing PTB
MFMU SCAN Trial
Nulliparous
CL ≤30 mm
17-OHP 250mg weekly
No reduction in SPTB
Grobman et al,

28. Utilizing the test to prevent PTB: Short Cervix
Cerclage Trial
Prior SPTB 17 – 33 6/7 wk
CL 16 – 22 6/7 wk; <25 mm
PTB < 35 wk OR 0.67 (0.42 – 1.07)
< 15 mm OR 0.23 ( )
16 – 24 mm OR 0.84 ( )
Perinatal death and pre-viable PTB significantly reduced
Owen et al, AJOG, 2009

29. Short Cervix and Cerclage: Meta-analysis
Individual patient data
Singletons, Prior PTB, CL <25 mm
PTB <35 wk RR 0.7 ( )
Neonatal mortality and morbidity
RR 0.64 ( )
PTB <37, 32, 28, and 24 all reduced
Berghella et al, Obstet Gynecol, 2011

30. Short Cervix, Cerclage & Progesterone
No additional benefit with 17-OHP & cerclage
Value of vaginal progesterone and cerclage unknown
Berghella et al, XXXXXXXXX

31. Utilizing the test to prevent PTB: Short Cervix
Pessary
Mechanism of effect
Change in angle of uterus-cervix junction
Shift of weight to LUS
Prevention of exposure of membranes

32. 16,000 low-risk singletons CL surveillance ≤ 25mm randomized (n=385)
PECEP Trial
16,000 low-risk singletons
CL surveillance
≤ 25mm randomized (n=385)
Arabin pessary
Expectant management
Goya et al, Lancet 2012

33. Pessary and Short Cervix: PECEP
PTB < 34 wk 6% vs 27%
OR 0.18 ( )
Composite neonatal outcome
3 % vs 16 %
OR 0.14 ( )

34. What to do with a short cervix?
No Prior PTB
No role for cerclage unless acute cervical insufficiency
Vaginal progesterone 200 mg capsule or 90 mg gel daily
? Role of pessary

35. Incidence of CL ≤ 20 mm ~2% Cost-effectiveness models suggest utility
Should we be doing universal cervical length screening in women without a history of prior PTB?
Incidence of CL ≤ 20 mm ~2%
Cost-effectiveness models suggest utility
Assumptions on costs and behavior vary
ACOG “consider” screening
If detected treat with progesterone
Can be incidental finding
ACOG PB 130; Cahill et al, AJOG 2010; Werner et al, Obstet Gynecol 2011

36. Why hesitation on universal cervical length screening?
NNS and NNT is high
Quality assurance issues
Skill set availability
Potential for overtreatment or overscreening
How often and how many screens needed?

37. What to do with a short cervix?
Prior PTB
“What is short?”
Consider cerclage, especially if <15 mm
Should already be on 17-OHP
? Role of vaginal progesterone
CL <25 but >15 mm?
Switch forms?

38. What to do with a short cervix?
ACOG PB 130

39. What to do with a short cervix?
Meta-analysis of data from 3 cohorts with prior PTB, short cervix
Comparison of Rx
No difference
<37 wk
<34 wk
Perinatal death
Alfirevic et al, US OG, 2013

40. Fetal Fibronectin

41. Fetal Fibronectin (fFN)
Decidual-Chorionic interface glue
Any disruption results in release
Inflammation
Hemorrhage
Overdistension
HPA axis activation
Lockwood CJ et al. N Engl J Med. 1991;325:

42. Fetal Fibronectin detection
Normal pregnancy not detectable after 18 wk
Fetal Fibronectin (ng/mL) 5 10 15 20 25 30 35 40
Gestational Age (Weeks)
500
1000
1500
2000
2500
3000
3500
4000
4500
50 ng/mL
Cutoff Level
Adapted from Garite TJ et al. Contemp Obstet Gynecol. 1996;41:77-93.

43. Fetal Fibronectin (fFN)
725 singletons at 24 – 34 6/7
Sx of PTL; <3 cm dilated
In 20% positive—Delivery in
7 d RR 38.8; sensitivity 90.5%; PPV 13.4%
14 d RR 31.3; sensitivity 88.5%; PPV 16.2%
<37 wk RR 2.9; sensitivity 43.9%; PPV 43%
Negative predictive value for delivery
7 d %
14 d %
<37 wk %
Peaceman et al. Am J Obstet Gynecol. 1997

44. Utility of fFN in PTL triage
Negative
Less intervention and hospitalization
Reassurance
Positive
Transfer to appropriate facility
Corticosteroids, magnesium sulfate

45. Adequacy of neonatal care
Preterm infants transferred to tertiary center rather than inborn
2X risk of death, Grade 3 or 4 IVH
5X risk of RDS
2-3X risk of nosocomial infection
Chien et al, Obstet Gynecol, 2001

46. Fetal Fibronectin (fFN)
Asymptomatic Women wk
3-4% positive
PTB <28 wk:
Sensitivity 63%
Specificity 96%
RR 59
PPV 13% ; 36% < 37 wk
Goldenberg et al, Obstet Gynecol, 1996

47. Screening with fFN in asymptomatic women
No interventional studies improve perinatal outcomes
Screening therefore not recommended
ACOG PB 130, 2012

48. Fetal Fibronectin (fFN) & CL in combination
Asymptomatic Women at 24 & 28 wk
Both negative—low risk of PTB
Either positive—intermediate risk
Both positive—highest level of risk
Goldenberg et al, Am J Obstet Gynecol, 2000

49. Prematurity and Multiples

50. Mean GA at delivery Twins 35 weeks Triplets 32 weeks Quads 29 weeks
Preterm Birth
Mean GA at delivery
Twins 35 weeks
Triplets 32 weeks
Quads 29 weeks

51. Cervical Shortening in Twins
MFMU Preterm Prediction
24 wk scan:
Singletons: 25 mm 10th percentile
Twins: 18% CL ≤25 mm
PTB <32 wk OR 7.7
PTB <35 wk OR 3.4
Iams et al, NEJM 1996; Goldenberg et al, AJOG 1996

52. Cervical Shortening in Twins
More common
Greater risk even with longer cervix
50% PTB <32 wk
Singleton ≤15 mm
Twins ≤25 mm
Hassan et al, 2000; Souka et al, 1999

53. Screening Tests Utility: Twins vs Singletons
No significant difference in performance
Delivery in
7 d RR 27.1
14 d RR 20.4
<37 wk RR 2.9
Negative predictive value for delivery
7 d %
14 d %
<37 wk %
Peaceman et al. Am J Obstet Gynecol. 1997

54. Twins Cerclage Elective placement
Limited prospective studies; several retrospective
No prolongation of pregnancy
Roman et al, Am J Perinatol 30, 2013;
Dor J et al, Gyn Obstet Invest 13, 1982;
Strauss A et al, Twin Res 5, 2002

55. Cerclage Indicated for CL <25mm
Meta-analysis
4 studies
49 twins
Cerclage
No Cerclage
RR (95% CI)
PTB <35 wk
18/24 (75%)
9/25 (36%)
2.2 ( )
PNM
11/48 (23%)
3/50 (6%)
2.7 ( )
Berghella et al, Obstet Gynecol 106, 2005

56. 17-OHPC—Twins with short cervix
2° analysis MFMU
221 of 661 had CL measured at wk
25th percentile 36mm
Increased risk of PTB—56 vs 37%
17OHPC did not reduce risk—64 vs 46%
Durnwald et al, J Mat Fetal Neonatal Med 23, 2010

57. Vaginal progesterone—Twins
Empiric use
3 randomized trials—16-24 wk
Approximately 1200 women
90 mg P4 gel or 200 mg P4 capsules
No significant difference in PTB, GA at delivery, neonatal outcomes
Rode L et al, USOG 38, 2011;
Norman JE et al, Lancet 373, 2009;
Wood S et al, J Perinat Med 40, 2012

58. Meta-analysis: Vaginal P, short cervix, twins
Individual patient data from 5 trials
PTB < 33wk
RR 0.7, CI 0.3 – 1.4
Neonatal morbidity and mortality
RR 0.52, CI 0.3 – 0.9
Romero R et al, AJOG 206, 2012

59. ProTWIN Subgroup Analysis Poor perinatal outcome RR 0.4 (0.19 – 0.83)
Pessary and Multiples
ProTWIN Subgroup Analysis
25th percentile 38 mm utilized
Poor perinatal outcome
RR 0.4 (0.19 – 0.83)
GA at delivery vs 35.0 wk
PTB <28 wk RR 0.23 (0.06 – 0.87)
PTB <32 wk RR 0.49 (0.24 – 0.97)
Liem S et al, Lancet 382, 2013

60. Summary
While a number of screening tests have been proposed, history and cervical length screening are the only methods that offer an intervention capable of reducing subsequent PTB
Women with a history of prior SPTB should be strongly encouraged to take 17-OHP and cervical length screening should be performed between weeks

61. Summary
Women with a history of prior SPTB in whom a short cervix is identified should be offered cerclage, especially for CL <15 mm, or at least vaginal progesterone
Women without a prior history of PTB should be offered vaginal progesterone for a short cervical length