Preventing Preterm Births:
Do Any Screening Tests Help?
Joseph R. Biggio, M.D.
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
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
• PTB 34-36 wk
12.8 %
3.7 %
9.2 %
Hamilton et al, NVSR, NCHS 2014
Scope of the problem: Preterm Birth
Hamilton et al, NVSR 63(2), 2014
Scope of the problem: Preterm Birth
• 2013
11.38%
• PTB < 34 wk
• PTB 34-36 wk
3.4 %
7.99%
• Most significant declines in late
preterm birth
Hamilton et al, NVSR, NCHS 2014
March of Dimes 2014 Premature Birth Report Card
To view or download your state’s report card, click your state on the map.
Vermont 8.1%
Mississippi 16.6%
Scope of the Problem: Preterm Birth
Indicated 25%
PROM 35%
PTL 40%
Scope of the Problem: Preterm Birth
• Major cause of perinatal morbidity
and mortality
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Cerebral Palsy
Developmental Disability
Neurologic impairment
Chronic lung disease
• Minor Morbidities
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%
What Screening Tests Have Been Suggested?
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History
Serial digital examination
Fetal fibronectin
Salivary estriol
Cervical length screening
BV screening
Home uterine activity monitoring
Periodontal disease screening
What Screening Tests Do NOT Work?
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Serial digital examination
Salivary estriol
BV treatment
Periodontal disease treatment
Home uterine activity monitoring
• +/- fFN in asymptomatic women
What Interventions Do NOT Work?
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Bedrest
Pelvic rest
Fish oil supplements
Enhanced prenatal care
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
So what does work to assess
risk for subsequent PTB?
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
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
History of Prior Preterm Birth
• Correlates with timing of cervical shortening
Wing et al.
Page 7
NIH-PA Author Manuscript
NIH-PA Author Manus
1.
Wing et al, Am JFigure
Obstet
Gynecol 2010
Relationship of earliest gestational age at previous spontaneous preterm birth (wk) and shortest
cervical length at randomization (cm)
Prior history of SPTB: Prevention of recurrence
• 17-hydroxy progesterone caproate
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Prior singleton PTB 20 -36 6/7 wk
Treatment started 16 -21 6/7 wk
310 progesterone; 150 placebo
PTB < 37 wk
• 36% vs 55%
RR 0.66 (0.54 – 0.81)
Meis et al, NEJM, 2003
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
Utilizing the test to prevent PTB: History
• Vaginal progesterone
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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
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
Probability of Preterm Delivery
Cervical Length
Vol. 334 No. 9
LENGTH OF TH E CERVI X AND RI
0.5
0.4
0.3
0.2
0.1
0.0
0
20
40
60
80
Cervical Length (mm)
Figure 3. Estimated Probability of Spontaneous Preterm Delivery before 35 Weeks of Gestation from the Logistic-Regression
Analysis (Dashed Line) and Observed Frequency of Spontaneous Preterm Delivery (Solid Line) According to Cervical Length
Measured by Transvaginal Ultrasonography at 24 Weeks.
ed from the analysis because the length of gestation
was greater than the specified limit for the first visit. Of
the 3000 subjects examined at the 24-week visit, 71
were lost to follow-up and 14 did not undergo cervical
sonography. There remained 2915 subjects (72 actually
seen at 22 weeks of gestation, 1523 at 23 weeks, and
1320 at 24 weeks) whose cervixes were measured ultrasonographically at the 24-week visit. Of these women,
384 were not examined again at 28 weeks: 35 of them
gave birth before the 28-week visit, 168 withdrew from
the study, and 171 did not come to the clinic for the 28week visit during the specified period (26 to 29 weeks).
Another 10 declined to undergo cer vical sonography.
There were therefore 2531 subjects examined at the 28-
Cervical Length
Iams et al, 1996
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
Utilizing the test to prevent PTB: Short Cervix
• Cervical length 15 mm or less
• Screened at 20-25 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 (0.26-1.25)
Fonseca et al, NEJM, 2007
Utilizing the test to prevent PTB: Short Cervix
• Cervical length 10-20 mm
• Screened at 19-23 6/7 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
Utilizing the test to prevent PTB: Short Cervix
• 17-OHP NOT effective in preventing
PTB
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MFMU SCAN Trial
Nulliparous
CL ≤30 mm
17-OHP 250mg weekly
No reduction in SPTB
Grobman et al,
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 (0.08-0.66)
16 – 24 mm
OR 0.84 (0.49-1.4)
• Perinatal death and pre-viable PTB
significantly reduced
Owen et al, AJOG, 2009
Short Cervix and Cerclage: Meta-analysis
• Individual patient data
• Singletons, Prior PTB, CL <25 mm
• PTB <35 wk RR 0.7 (0.55-0.89)
• Neonatal mortality and morbidity
RR 0.64 (0.45-0.91)
• PTB <37, 32, 28, and 24 all reduced
Berghella et al, Obstet Gynecol, 2011
Short Cervix, Cerclage & Progesterone
• No additional benefit with 17-OHP &
cerclage
• Value of vaginal progesterone and
cerclage unknown
Berghella et al, XXXXXXXXX
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
PECEP Trial
• 16,000 low-risk singletons
• CL surveillance
• ≤ 25mm randomized (n=385)
• Arabin pessary
• Expectant management
Goya et al, Lancet 2012
Pessary and Short Cervix: PECEP
• PTB < 34 wk
6% vs 27%
OR 0.18 (0.08-0.37)
• Composite neonatal outcome
3 % vs 16 %
OR 0.14 (0.04-0.39)
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
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
Why hesitation on universal cervical length screening?
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NNS and NNT is high
Quality assurance issues
Skill set availability
Potential for overtreatment or
overscreening
• How often and how many screens
needed?
What to do with a short cervix?
• Prior PTB
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“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?
What to do with a short cervix?
ACOG PB 130
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
Fetal Fibronectin
Fetal Fibronectin (fFN)
• Decidual-Chorionic interface glue
• Any disruption results in release
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Inflammation
Hemorrhage
Overdistension
HPA axis activation
Lockwood CJ et al. N Engl J Med. 1991;325:669-674.
Fetal Fibronectin detection
Fetal Fibronectin (ng/mL)
• Normal pregnancy not detectable
after 18 wk
4500
4000
3500
3000
2500
2000
1500
1000
500
0
0
5
10
15
20
25
30
Gestational Age (Weeks)
Adapted from Garite TJ et al. Contemp Obstet Gynecol. 1996;41:77-93.
35
40
50 ng/mL
Cutoff Level
Fetal Fibronectin (fFN)
• 725 singletons at 24 – 34 6/7
• Sx of PTL; <3 cm dilated
• In 20% positive—Delivery in
• 7d
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
• 7d
99.7 %
• 14 d
99.5 %
• <37 wk 86.6 %
Peaceman et al. Am J Obstet Gynecol. 1997
Utility of fFN in PTL triage
• Negative
• Less intervention and hospitalization
• Reassurance
• Positive
• Transfer to appropriate facility
• Corticosteroids, magnesium sulfate
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
Fetal Fibronectin (fFN)
• Asymptomatic Women 22-30 wk
• 3-4% positive
• PTB <28 wk:
• Sensitivity
63%
• Specificity 96%
• RR 59
• PPV 13% ; 36% < 37 wk
Goldenberg et al, Obstet Gynecol, 1996
Screening with fFN in asymptomatic
women
• No interventional studies improve
perinatal outcomes
• Screening therefore not
recommended
ACOG PB 130, 2012
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
Prematurity and Multiples
Preterm Birth
• Mean GA at delivery
• Twins
35 weeks
• Triplets 32 weeks
• Quads 29 weeks
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
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
Screening Tests Utility: Twins vs Singletons
• No significant difference in performance
• Delivery in
• 7d
RR 27.1
• 14 d
RR 20.4
• <37 wk
RR 2.9
• Negative predictive value for delivery
• 7d
99.5 %
• 14 d
99.2 %
• <37 wk
84.5 %
Peaceman et al. Am J Obstet Gynecol. 1997
Cerclage
• Twins
• 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
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 (1.2-4.0)
PNM
11/48 (23%) 3/50 (6%)
2.7 (0.8-8.5)
Berghella et al, Obstet Gynecol 106, 2005
17-OHPC—Twins with short cervix
• 2° analysis MFMU
• 221 of 661 had CL measured at 16-20 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
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
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
Pessary and Multiples
• ProTWIN Subgroup Analysis
• 25th percentile 38 mm utilized
• Poor perinatal outcome
RR 0.4 (0.19 – 0.83)
• GA at delivery
36.4 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
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 16-24 weeks
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