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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 12.8 %• PTB < 34 wk 3.7 %• PTB 34-36 wk 9.2 %
Hamilton et al, NVSR, NCHS 2014
Scope of the problem: Preterm Birth
• 2013 11.38%• PTB < 34 wk 3.4 %• PTB 34-36 wk 7.99%
• Most significant declines in late preterm birth
Hamilton et al, NVSR, NCHS 2014
• Major cause of perinatal morbidity and mortality• 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%
Scope of the Problem: Preterm Birth
• History• Serial digital examination• Fetal fibronectin• Salivary estriol• Cervical length screening• BV screening• Home uterine activity monitoring• Periodontal disease screening
What Screening Tests Have Been Suggested?
• Serial digital examination• Salivary estriol• BV treatment• Periodontal disease treatment• Home uterine activity monitoring
• +/- fFN in asymptomatic women
What Screening Tests Do NOT Work?
• Bedrest• Pelvic rest• Fish oil supplements• Enhanced prenatal care
What Interventions Do NOT Work?
• Many other different biomarkers and measurements examined• Many have reasonable + Likelihood
ratios• Positive predictive value or specificity
too poor for clinical practice
What Screening Tests Have Been Suggested?
• 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, Am J Obstet Gynecol 2010
History of Prior Preterm Birth
Prior history of SPTB: Prevention of recurrence
• 17-hydroxy progesterone caproate• 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• 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 wkRR 6.2
(3.8 – 10) • ≥25 mm
• NPV >95% for PTB <32 wk• <25 mm
• PPV 10% for PTB < 32 wkIams 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• 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 reducedBerghella 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 outcome3 % 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?
• 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• “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?
• 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 (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;325:669-674.
Fetal Fibronectin detectionFe
tal F
ibro
necti
n (n
g/m
L)
0 5 10 15 20 25 30 35 40
Gestational Age (Weeks)
0
500
1000
1500
2000
2500
3000
3500
4000
4500
50 ng/mLCutoff Level
Adapted from Garite TJ et al. Contemp Obstet Gynecol. 1996;41:77-93.
• Normal pregnancy not detectable after 18 wk
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 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
Cervical Shortening in Twins
• MFMU Preterm Prediction24 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
• 7 d RR 27.1• 14 d RR 20.4• <37 wk RR 2.9
• Negative predictive value for delivery• 7 d 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 mortalityRR
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