Jack Ludmir, MD

Senior Vice President

Associate Provost

Professor Obstetrics & Gynecology

Jefferson Health

Thomas Jefferson University

Sanford Cole Lectures

Baptist Health South Florida, 2018

Pessary for PrematurityPrevention in Singleton and Multiple Gestation

Disclosure

• No commercial conflict to declare

Objectives:

• Understand the role of cervical pessary in

prematurity prevention in singleton gestation

• Discuss the different modalities to prevent

prematurity in multiple gestation

• Understand if cervical pessary plays a role in

prematurity prevention in multiple gestation

SMFM ACOG 2012

Preterm Birth by Maternal Age: USA. NCHS, 2017

Simple Treatment of the Incompetent Os

Vitsky. Amer J Obstet Gynec 81, 1961

Oster S, Javert CT. Obstet Gynec 28, 1966

“the pessary may someday find wider acceptance in the

treatment of the incompetent cervix. Unfortunately, there are no true controls, but neither are they existent for those who perform cerclage. The efficacy of the pessary is obscured by its simplicity. The rewards of its use are found only in patients’ happiness and

physicians’sense of accomplishment.”

Vitsky, Obstet Gynec , 1968

EXCLUSION CRITERIA

-Fetal abnormalities

-Contractions

-Bleeding

-Placenta previa

-PROM

-Cerclage in situ

726 WITH CERVIX ≤ 25 MM

18.235

ASKED

ASKED INFORMED CONSENT

190 Pessary 190 No treatment

PECEP TRIAL“Pesario Cervical para Evitar Prematuridad”

11.875

AGREED SCAN

6360 DECLINED

385 RANDOMISED

341 DECLINED

5 LOST

TO FOLLOW-UP

Goya et al. Lancet 2012

PECEP TRIAL: Cervical Pessary to Prevent Prematurity

PECEP: Results

ObstetricOutcomes

Pessaryn=190

No Treatment

n=190

P valor Odds Ratio

PTD < 28wks 4 (2.1%) 16 (8.4%) 0.0058 0.23(.06-.74)

PTD < 34wks 12 (6.3%) 51 (26.8%) 0.0001 0.18(.08-.37)

Gest AgeDelivery

37.7 (27.4-42)

34.9 (24.1-41)

0.0001

Adverse neonatal outcome

5 (3%) 30 (16%) 0.0001 0.14(.04-.39)

Goya et al. Lancet, 2012

NEJM 2016

• 3 RCTs, n = 1,420• Goya 2012 (n=380); Hui 2013 (n=108); Nicolaides 2016 (n=932)

• CL ≤25mm; GA 22w

• Similar SPTB <37w, <34w, <32w, <28w

• Similar GA delivery, Interval, BW, LBW, NEC,

RDS, IVH, NICU, perinatal death

• At least 7 more RCTs ongoing….

Pessary - Singletons

Saccone et al, JUM 2017

N=17,388Screened with TVU CL at 180 – 236 weeks

N=394 (2.3 %)

TVU CL ≤25mm

N=122

Randomized

N=61

Pessary

N=61

No pessary

N=28:

Declined

N=6: Not

offered

N=5: Not

eligible- Bulging membranes- Selective IUGR

- Monoamniotic- 16 years old

N=60

Pessary

N=58

No pessary

N=1 withdrawnN=3

Lost to follow-up

Dugoff et al. Ultrasound

Obstet Gynecol 2017

Dimensions

Bioteque (#3) Arabin

Outer diameter (mm) 65 65

Inner diameter (mm) 33 32

Height (mm) 17 25

Pessary Placement

• Pessaries inserted by MFM staff

• Centrally trained in proper placement

• Pessary insertion training:

• Didactic session

• Hands-on session

• All staff required to demonstrate competence in pessary

placement on a live model

• Model actually could tell us

• if it was placed properly!

Obstetric Outcomes

PessaryN = 60

No PessaryN = 58

RR (95% CI) P-value

PTB < 37 weeks 26 (43) 23 (40) 1.09 (0.71, 1.68)

0.71

PTB < 34 weeks 20 (33) 17 (29) 1.14 (0.67, 1.94) 0.69

PTB < 28 weeks 12 (20) 14 (24) 0.83 (0.42, 1.64) 0.66

PTB < 24 weeks 2 (3) 5 (9) 0.39 (0.08, 1.91) 0.27

PPROM <34 weeks 18 (30) 10 (18) 1.71 (0.86, 3.38) 0.13

PPROM < 37 weeks 19 (32) 15 (26) 1.20 (0.68, 2.13) 0.55

Vaginal discharge 44 (90) 28 (61) 1.48 (1.15, 1.89) 0.002

Any GU infection 15 (25) 14 (23) 1.09 (0.58, 2.06) 0.83

Chorioamnionitis 7 (12) 4 (4) 1.63 (0.50, 5.28) 0.53

Gestational age at

delivery

37.2 (30.0,

39.1)

38.1 (27.8, 39.4) 0.99

Cesarean delivery 10 (17) 10 (17) 0.97 (0.43, 2.15) 1

N (%) of Median (IQR, interquartile range).

Dugoff et al. Ultrasound

Obstet Gynecol 2017 Neonatal Outcomes

PessaryN = 60

No PessaryN = 58

RR (95%CI) P=value

Birth weight

(grams)

2788 (1285, 3188) 2843 (1035,3329) 0.58

Composite adverse

neonatal outcome

14 (25) 15 (29) 0.87 (0.46, 1.62) 0.67

Proven sepsis 7 (12) 6 (11) 1.08 (0.39, 3.03) 1

Intraventricular

hemorrhage

4 (7) 2 (4) 1.83 (0.35, 9.60) 0.68

Necrotizing

enterocolitis

2 (3) 1 (2) 1.83 (0.17, 19.6) 1

Retinopathy 2 (4) 4 (7) 0.47 (0.09, 2.48) 0.43

Bronchopulmonary

dysplasia

5 (8) 5 (10) 0.87 (0.27, 2.83) 1

Respiratory distress

syndrome

10 (17) 9 (17) 1.01 (0.45, 2.31) 1

Neonatal death 3 (5) 6 (10) 0.48 (0.13, 1.84) 0.31

Dugoff et al. Ultrasound

Obstet Gynecol 2017

Singleton Pessary Trials November 2017

Goya n=385

Huin=108

Nicolaidesn=932

PoPPSn=120

Mean CL (mm) 19.0 20.5 20.0 18.3

Mean GA 22.3 21.9 23.5 20.7

Primary outcome sPTB<34 PTB<34 sPTB<34 PTB<37

Pessary type Arabin Arabin Arabin Bioteque

Race 57% white

30% Latin

American

Chinese 65% white

27% black

4.5% Asian

60% black

28% white

SPTB<37 22% vs 59% NA NA 43% vs 40%

SPTB<34 6% vs 27% NA 12.0% vs 10.8% 33% vs 29%

SPTB<28 2% vs 8% NA NA 20% vs 24%

PTB<34 weeks 7% vs 28% 9.4% vs 5.5% 12.9% vs 11.3% 33% vs 29%

PTB<37 weeks NA 15.1% vs 18.2% NA 43% vs 40%

Saccone et al (IPP) JAMA Dec 2017

Saccone et al, JAMA Dec 2017

10: Pessary to prevent preterm birth after an episode of threatened preterm labor

(APOSTEL VI): a randomized controlled trial

Frederik J. Hermans, Ewoud Schuit, Hubertina Scheepers, Mallory Woiski, Marieke Sueters, Mireille Bekker, Maureen Franssen, Marjon

de Boer, Eva Pajkrt, Ben Willem Mol, Marjolein Kok

American Journal of Obstetrics & Gynecology

Volume 218, Issue 1, Pages S9-S10 (January 2018) DOI: 10.1016/j.ajog.2017.10.421

Copyright © 2017 Terms and Conditions

American Journal of Obstetrics & Gynecology 2018 218, S9-S10DOI: (10.1016/j.ajog.2017.10.421)

Copyright © 2017 Terms and Conditions

Pessary-PTB Research: World View

ClinicalTrials.gov- 2018

17 registered trials

PROMPT

Multiple Gestation

• 10% of preterm birth in the USA

• 23% of preterm births prior to 32 weeks gestation (NCHS 2012)

Strategies to reduce PTD in multiple gestation

• CL screening by TV

• Bedrest

• Progesterone: 17-P; vaginal progesterone

• Cerclage

• Pessary

CL screening in multiples

Conde-Agudelo, Am J Obstet Gynecol 2010

CL in twins, benefit?

Am J Obstet Gyneol 2016

Results: No difference using CL by TV

Bedrest multiple gestation: Cochrane Review 2013

No difference in perinatal mortality

STOPPIT: Lancet 2009

No difference

PREDICT : Prevention PTD in Twins with Progesterone

Rode et al Ultrasound Obstet Gynecol 2011

32#No difference

BJOG 2014Vaginal progesterone on PTB < 33 weeks in Twins

with TVCL ≤25mm

Romero, et al. Meta-analysis, UOG. 1/2017

RR 0.69 (0.51–0.93)

RR 0.83 (0.69-0.99)

RR 0.71 (0.56-0.91)

RR 0.51 (0.34-0.77)

RR: 0.47 (0.25-0.86)

Romero, et al. Meta-analysis, UOG. 1/2017

Vaginal progesterone on PTB < 33 weeks in Twins

with TVCL ≤25mm

• aOR 1.17, 95% CI 0.23-3.79

• <34 weeks of gestation

• Twins, TVU CL ≤25mm; n=140

• 57 had cerclage; 83 no cerclage

• Same PTB incidence

Latest largest retrospective study

Roman et al. AJOG 2015

Pessary: ProTWIN

38#

Lancet 2013

Pessaries: ProTWIN: No difference in gestational age

39#

Pessaries: ProTWIN: Benefit for patients with short cervix

40#

LC < 38 mm

Pessary in Twins: RCT

No difference

Am J Obstet Gynecol 2015 CRITERIOS DE EXCLUSIÓN-Anomalías fetales-Contracciones-Sangrado-Placenta previa-RPM-P-Cerclaje in situ

154 CON CERVIX ≤ 25 MM

2931 PACIENTESCI SOLICTADO

68 Pesario 66 No tratamiento

PECEP-TWINS TRIAL

Pesario Cervical para Evitar PrematuridadEN Gemelos

2287 ACEPTAN ECO TV

644 RECHAZAN

137 ALEATORIZADAS

17 RECHAZAN EC

3 PÉRDIDAS

PECEP-TWINS: RCT Goya et al: AJOG Jan 2016

TASA DE PP

PP espontáneo < 28w

PP espontáneo < 34w

EG al parto

Pesario (n=68)

4 (5.9%)

11 (16.2%)

36.4 (26.4-38)

No tratamiento (n=66)

9 (13.6%)

26 (39.4%)

35.0 (22.6-38)

P

0.02

0.001

0.01

RESULTADO PERINATAL

Parto inmaduro

Muerte neonatal

Peso al nacer < 2500 g

Peso al nacer < 1500 g

Resultados adversos

Enterocolitis necrotizante

Hemorragia intraventricular

Distress respiratorio

Retinopatía

Tratamiento para sepsis

Resultado adverso compuesto

Pesario (n=136)

0

0

20 (14.7%)

6 (4.4%)

0

0

8 (5.8%)

0

4 (2.9%)

8 (5.9%)

No tratamiento (n=130)

1

0

24 (18.2%)

8 (6.1%)

2 (1.5%)

4 (3.0%)

8 (6.1%)

0

6 (7.5%)

12 (9.1%)

P

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

PECEP-TWINS: RCT Demonstrates Benefit

• 3 RCTs, n = 481

• Liem 2013 (n=133); Nicolaides 2016 (n=214); Goya 2012 (n=134)

• CL ≤38mm, CL ≤25mm, CL ≤25mm; Gest age randomization 17w, 22w, 22w

• PTD <37w, <34w, <32w, <28w similar results

• Gest age delivery, LBW, perinatal morbidity and

mortality similar results

• Additional on-going RCTS

Multiple Gestation: Pessary

Meta-analysis

Saccone et al, JUM 2017

Obstetric results

Pessary (n=23) No pessary (n=23) RR (95% CI)

PTB<34w 9 (39%) 8 (35%) 1.13 (0.53, 2.40)

PTB<37w 19 (83%) 19 (83%) 1.00 (0.76, 1.30)

PTB<28w 4 (17%) 4 (17%) 1.00 (0.28, 3.52)

PTB<24w 2 (9%) 1 (4%) 2.00 (0.19, 20.6)

PPROM 4 (17%) 6 (26%) 0.67 (0.17, 2.38)

GA delivery (w) 35.9 (28.9, 36.9) 35.0 (33.0, 36.7) p = 0.83

Cesarean delivery 13 (56%) 16 (70%) 0.81 (0.52, 1.29)

Vaginal discharge 19 (90%) 10 (48%) 1.90 (1.15, 3.14)

Berghella, Dugoff, Ludmir. UOG 2017

Log-rank test: p=0.81

Berghella, Dugoff, Ludmir. UOG 2017

Neonatal OutcomesPessary (n=46)

No Pessary (n=46)

RR (95% CI)

Birth weight (grams) 2190 (1115, 2540) 2220 (1864, 2583) p = 0.68

Composite adverse outcome

21 (46%) 13 (28%) 1.62 (0.92, 2.82)

Proven sepsis 5 (11%) 2 (4%) 2.50 (0.51, 12.2)

IVH (grade 3 or 4) 2 (4%) 1 (2%) 2.00 (0.19, 21.3)

NEC 1 (2%) 0 -

Retinopathy 1 (2%) 0 -

BPD 4 (9%) 5 (11%) 0.80 (0.23,2.79)

RDS 11 (24%) 8 (17%) 1.38 (0.61, 3.10)

Death 4 (9%) 3 (7%) 1.33 (0.32, 5.63)

Berghella, Dugoff, Ludmir. UOG 2017

• aOR 1.17, 95% CI 0.23-3.79

• <34 weeks of gestation

• Twins, TVU CL ≤15mm; n=71

• PTB < 34w: RR 0.51 (4 week prolongation)

Latest largest retrospective study

Roman et al. AJOG 2015

• 3 RCTs, n = 481• Liem 2013 (n=133); Nicolaides 2016 (n=214); Goya 2012 (n=134)

• CL ≤38mm, CL ≤25mm, CL ≤25mm; GA 17w, 22w, 22w

• Similar SPTB <37w, <34w, <32w, <28w

• Similar GA delivery, LBW, VLBW, NEC, RDS,

perinatal death

• At least 5 more RCTs ongoing….

Pessary - Twins

Saccone et al, JUM 2017

Obstetric Outcomes

Pessary (n=23) No pessary (n=23) RR (95% CI)

PTB<34w 9 (39%) 8 (35%) 1.13 (0.53, 2.40)

PTB<37w 19 (83%) 19 (83%) 1.00 (0.76, 1.30)

PTB<28w 4 (17%) 4 (17%) 1.00 (0.28, 3.52)

PTB<24w 2 (9%) 1 (4%) 2.00 (0.19, 20.6)

PPROM 4 (17%) 6 (26%) 0.67 (0.17, 2.38)

GA delivery (w) 35.9 (28.9, 36.9) 35.0 (33.0, 36.7) p = 0.83

Cesarean delivery 13 (56%) 16 (70%) 0.81 (0.52, 1.29)

Vaginal discharge 19 (90%) 10 (48%) 1.90 (1.15, 3.14)

Berghella, Dugoff, Ludmir. UOG 2017

Log-rank test: p=0.81

Berghella, Dugoff, Ludmir. UOG 2017

Neonatal OutcomesPessary (n=46)

No Pessary (n=46)

RR (95% CI)

Birth weight (grams) 2190 (1115, 2540) 2220 (1864, 2583) p = 0.68

Composite adverse outcome

21 (46%) 13 (28%) 1.62 (0.92, 2.82)

Proven sepsis 5 (11%) 2 (4%) 2.50 (0.51, 12.2)

IVH (grade 3 or 4) 2 (4%) 1 (2%) 2.00 (0.19, 21.3)

NEC 1 (2%) 0 -

Retinopathy 1 (2%) 0 -

BPD 4 (9%) 5 (11%) 0.80 (0.23,2.79)

RDS 11 (24%) 8 (17%) 1.38 (0.61, 3.10)

Death 4 (9%) 3 (7%) 1.33 (0.32, 5.63)

Berghella, Dugoff, Ludmir. UOG 2017

LB03: Cervical pessary versus vaginal progesterone for the prevention of preterm birth

in women with a twin pregnancy and a cervix <38 mm: a randomized controlled trial

Vinh Q. Dang, Linh K. Nguyen, Yen TN He, Khang N. Vu, Minh TN. Phan, Toan D. Pham, Lan TN Vuong, Thanh Q. Le, Ben W. Mol

American Journal of Obstetrics & Gynecology

Volume 218, Issue 1, Pages S603-S604 (January 2018) DOI: 10.1016/j.ajog.2017.11.598

Copyright © 2017 Terms and Conditions

SMFM 2018

American Journal of Obstetrics & Gynecology 2018 218, S603-S604DOI: (10.1016/j.ajog.2017.11.598)

Copyright © 2017 Terms and Conditions

RCT Twins short cervix and cerclage

TVU CL 16-23 6/7 weeks

>30 mm

No therapy

≤25mm

Vaginal Progesterone

26-30mm

Second

TVU CL before

24 weeks

Second

TVU CL before

24 weeks

Cerclage No Cerclage

No therapy

Offer RCT

16-25mm≤15mmNO more

TVU CL

amanda.roman@jefferson.edu

vincenzo.berghella@jefferson.edu

Conclusions:

• The role of pessaries for prematurity prevention in

singletons remains controversial

• The role of pessaries for prematurity prevention in

twins remains controversial

• The best way to prevent prematurity in multiple

gestation remains elusive

• Awaiting for results of additional RCTs and meta-

analysis of individual data

Thank you

Jack.ludmir@jefferson.edu