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 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

Hamilton et al, NVSR 63(2), 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

March of Dimes 2014 Premature Birth Report Card

Vermont 8.1%Mississippi 16.6%

Scope of the Problem: Preterm Birth

PTL 40%

PROM 35%

Indicated 25%

• 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?

So what does work to assess risk for subsequent PTB?

• 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

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

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• 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?

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

• 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

Prematurity and Multiples

Preterm Birth

• Mean GA at delivery• Twins 35 weeks• Triplets 32 weeks• Quads 29 weeks

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

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