disclosures sonographic cervical length for the prediction...

1

Sonographic Cervical Length for

the Prediction of Preterm Birth:

Standardization of the Technique

and Pitfalls

Sonia S. Hassan, M.D.

Edgar Hernandez Andrade, M.D.

Roberto Romero, M.D., D.Med.Sci. Wayne State University

Perinatology Research Branch, NICHD/NIH/DHHS

Disclosures

Presenter Name: Sonia S. Hassan, M.D.

Relevant Financial Relationships: None

Hassan, Hernandez, Romero

Learning Objectives

After completing the presentation, learners will be able to discuss:

1. The definition of a sonographic short cervix

2. The gestational age at which a cervix should be examined

3. Additional ultrasound parameters to assess preterm birth risk

4. The correct technique for the measurement of cervical length

in pregnancy

5. Amniotic Fluid sludge

6. Treatments for a sonographic short cervix

7. Future methods to assess the cervix in pregnancy


Lecture Outline• The definition of a sonographic short cervix

• Gestational age at which a cervix should be examined

• Additional ultrasound parameters to assess the risk of

preterm birth

– Cervical Funnel

– Dynamic Change

– Amniotic Fluid Sludge

• The correct technique and pitfalls for the measurement of

cervical length in pregnancy

• Interventions to prevent preterm birth in women with a

sonographic short cervix

• Future methods to assess the cervix in pregnancy Hassan, Hernandez, Romero

Detroit Medical Center/Photo taken at Hutzel Women’s Hospital, copyright cannot be transferred

Preterm Birth is the Leading

Cause of Infant Mortality


Preterm Birth Results in…

• Respiratory distress syndrome

• Chronic lung disease

• Bowel injury/inflammation

• Long-term mental disabilities

• Cerebral palsy

Bull World Health Organ 2010;88:31-38Hassan, Hernandez, Romero

2

Yoon B.H. and Romero R; Seoul National University


Magnitude of the Problem

• ~ 13 million preterm births

worldwide

• 500,000 in the United States

• Highest rates: Africa and North

America

Bull World Health Organ 2010;88:31-38Hassan, Hernandez, Romero

Preterm Birth Rate in the US

1990-2008

CDC/NCHS, National Vital Statistics, NCHS Data Brief Number 39, May 2010

10

2

0

12

14

8

4

6

1990 1998 2000 2002 2004 2006 2008199619941992

Preterm (<37 weeks)

Late preterm (34-36 weeks)

Early preterm (<34 weeks)

Year

Perc

en

t


The Annual Societal Economic

Burden Associated with

Preterm Birth in the United

States

In excess of $26.2 billion in 2005

Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring

Healthy Outcomes; Behrman RE, Butler AS, editors. Preterm Birth: Causes,

Consequences, and Prevention. Washington (DC): National Academies Press (US); 2007


Epithelium

OsE

Stroma

Cervix

Extra cellularmatrix

E

M

Extra cellularmatrix

Labor

Common Pathway of Parturition

Myometriuma

Low connectivity

Connexin 43

SmoothMuscle cell

High connectivity

miR-200

Connexin 43

Labor

P4

Contraction–associated Proteins

Decidua

Labor

Adapted from Romero R, Dey SK, Fisher SJ, Science 2014; 345:760Hassan, Hernandez, Romero

Stages of Cervical Function During

Pregnancy and the Puerperium

Weeks gestation

0 8 16 24 32 40

10

8

6

4

2

0

Word RA. Semin Reprod Med 2007-25-69

SofteningRipening

Dilation

Repair

Ultrasound

assessment


3

Cervical glands

Perinatology Research Branch, NICHD/NIH, Wayne State University

Sonographic Cervical Length


Risk for Spontaneous Delivery at <32 Weeks According to

Cervical Length at 23 Weeks of Gestation

Heath VCF et al. Ultrasound Obstet Gynecol 1998;12:301-3.

0 10 20 30 40 50 60 70

Cervical length (mm)

0

20

40

60

80

100

Ris

k (

%)

Spontaneous Preterm Delivery Before 35 Weeks Based on

Cervical Length at 24 Weeks Measured by Ultrasound

!0 1220 40 60 80

0

0.1

0.2

0.3

0.4

0.5

Pro

bab

ilit

yo

fp

rete

rmd

elivery

Estimated probability of spontaneous

delivery before 35 weeks

Observed frequency of spontaneous

preterm delivery according to cervical

length

Iams J et al. NEJM 1996;334:567-72.


Risk of Spontaneous Preterm Delivery at 32 Weeks Among

Women with Measured Cervical Length Between 14-24 Weeks

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80

Cervical length

Perc

en

t ri

sk

Hassan SS et al. AJOG 2000;182:1458



Anderson F et al. AJOG;1990:163-859

Logistic Regression Analysis of Risk of Preterm Delivery by

Cervical Length Measured by Endovaginal Ultrasonography

20 30 40 50 60 70

Vaginal Ultrasound Cervical length (mm)

0

20

30

40

50

60

Ris

k o

f P

rete

rm D

eli

ve

ry (%

)

Risk =1/(1+e (-3.31-0.13xVAGCX))

Actual PTD

Predicted Risk

A Short Cervix is the Most Powerful Predictor of

Spontaneous Preterm Birth

11mm

Perinatology Research Branch, NICHD/NIH, Wayne State UniversityHassan, Hernandez, Romero

What is a Short

Cervix?


Low risk

Prior preterm birth

Twins

Triplets

15 mm

25 mm

25 mm

25 mm

Definition of a Short Cervix

50% Risk for Spontaneous Preterm Delivery

< 32 - 33 weeks


Cervical Length

Cervical Length 11 mm


4

Low risk

Prior preterm birth

Twins

Triplets

15 mm

25 mm

25 mm

25 mm

Definition of Short Cervix


< 32 - 33 weeks


Cervical Length 22 mm


Low risk

Prior preterm birth

Twins

Triplets

15 mm

25 mm

25 mm

25 mm

Definition of Short Cervix


< 32 - 33 weeks


Short Cervix

Congenital

(DES exposure)

Surgical

(conization)

Infection

Acute Cervical

insufficiency’

Romero R, Espinoza J, Erez O, Hassan S, Am J Obstet Gynecol. 2006 Jan; 194(1):1-9

Extracellular

matrix changesProgesterone

deficiency


Intra-amniotic

infection

9%

Intra-amniotic

inflammation

22%

Hassan S, Romero R, Hendler I et al. J Perinat Med 2006;34(1):13-9

Vaisbuch E, Romero R, Erez O, et al. Ultrasound Obstet Gynecol. 2010 Oct;36(4):471-81

Frequency of Intra-amniotic Inflammation and Intra-

amniotic Infection in Patients with a Short Cervix


What Gestational Age

Should the Cervix be

Examined?


5

Isthmus

Cervix

First Trimester Assessment of the

Uterine Cervix


Isthmus

Cervix



Uterine Cervix


Isthmus

Cervix


Uterine Cervix


0 10 20 30 40 50 60 70 80


0

0.05

0.1

0.15

0.2

0.25P

rob

ab

ilit

y

> 19-24 weeks

14-19 weeks

Hassan S, Romero R, Berry S,et al. AJOG 2000;182:1458

Probability of Preterm Delivery <32 Weeks According

to the GA at which the US was Preformed

Hassan S, Romero R, Berry S, Dang K, Blackwell SC, Treadwell MC, Wolfe HM. AJOG 2000;182:1458


Additional Parameters Used

to Assess the Risk of

Preterm Birth During

Transvaginal Sonography


• Cervical funnel

• Dynamic change

• Amniotic fluid sludge

Are There Additional Parameters to Assess

the Risk of Preterm Birth During

Transvaginal Sonography?


6

Funnel

Shoulder of funnel

Shoulder of funnel

Perinatology Research Branch, NICHD/NIH

Wayne State University


Shoulder of funnel

Funnel length

Cervix

Funnel


Dynamic Change


Funneling and Dynamic Change Have

no Independent Predictive Value for

Preterm Delivery After Cervical Length

is Considered

To MS et al, Ultrasound Obstet Gynecol. 2001 Sep;18(3):200-3

Owen J et al, JAMA. 2001 Sep; 286(11):1340-8


How Should the Cervix be

Examined?

Techniques and Pitfalls


Normal Cervical Anatomy


7

Internal

Cx Os

External

Cx Os

Canal Length

Funnel

Width

Funnel

Length

Canal

Length

Gomez R, Galasso M, Romero R, et al. Am J Obstet Gynecol 1994;171(4):956-64


Shoulder of funnel Funnel length

Cervix

Cervical Length is the Most Important Measurement


• Transabdominal

• Transperineal

• Transvaginal

Methods of Sonographic

Examination of the Uterine Cervix

in Pregnancy


• Transabdominal examination requires a

full bladder

• Transabdominal cervical length is longer

than transvaginal cervical length in the

same patient

• Mean difference 5.2 mm (+/-14.3, p<0.001)

Transabdominal versus

Transvaginal Sonographic

Evaluation of the Cervix

Andersen HF, J Clin Ultrasound. 1992 Feb; 19(2):77-83Hassan, Hernandez, Romero

Transabdominal Cervical Length


Transabdominal Cervical Length


8

• Developed before transvaginal transducers

were available

• Should avoid pelvic examination before the

scan

• Allows visualization of the cervix, but it is more

difficult to interpret

Transperineal versus Transvaginal

Sonographic Evaluation of the Cervix

Hassan, Hernandez, Romero Meijer-Hoogeveen M et al. Ultrasound Obstet Gynecol 2008;32:657-62Hassan, Hernandez, Romero

• Strong correlation with transvaginal

measurements

• Failure to obtain a clear image

– 30% of mid-trimester pregnancies

– 19% of third-trimester cases

• Landmarks can be obscured by bowel gas

Transperineal Sonographic


Meijer-Hoogeveen M et al. Ultrasound Obstet Gynecol 2008;32:657-62Hassan, Hernandez, Romero

• Objective

• Reproducible

• Reliable

• Minimal discomfort

Transvaginal Sonographic


Andersen et al 1990, Am J Obstet Gynecol. 1990;163:859-67

Gomez R et al, Am J Obstet Gynecol. 1994 Oct; 171(4):956-64 Hassan, Hernandez, Romero

• Transvaginal ultrasound

• Empty bladder

• Sagittal view identified

Measurement of Sonographic

Cervical Length


Endocervical Canal

External

Os

External

Os

Internal

Os

External

Os

Internal

Os

Endocervical Canal

Measurement of Sonographic Cervical

Length

Gomez R, Galasso M, Romero R, et al. Am J Obstet Gynecol 1994;171(4):956-64Hassan, Hernandez, Romero

9

1) Flat internal os or isosceles triangle

2) Observe entire length of canal

3) Symmetric image of external os

4) Equal size and density of the

anterior and posterior lips of the

cervix

Recommendations for Standardization of

Cervical Examination with Ultrasound

Burger M et al, Ultrasound Obstet Gynecol. 1997 Mar; 9(3):188-93

12

3

4

42


• Three measurements – shortest length

recorded

• Examine for three minutes at minimum

• Recognition of sludge

Measurement of Sonographic

Cervical Length


Full bladder

Cervical length 35 mm

Empty bladder

Cervical length 17 mm

Bladder

Avoid the Presence of a Full Bladder

B

B = bladder F = fetal head

F

F


Avoid Excess Probe Pressure


Avoid Unequal Distance and Density

of Anterior and Posterior Cervical Lips

Unequal

Distance

Unequal

Density


Avoid Poor Visualization of the

Endocervical Canal


10

Measure the Portion of the

Endocervical Canal that is Closed


Measure the Portion of the Endocervical

Canal that is Closed


Cervical canal


Cervical canal







Cervical canal


Non-Measurable Cervix/Dilated Canal

Vaisbuch E, Romero R, Mazaki-Tovi S, Erez O, Kusanovic JP, Mittal P, Gotsch F, Ward C, Romero V, Chaiworapongsa T,

Pacora P, Yeo L, Hassan SS. Am J Obstet Gynecol. 2010;203:446.e1-9.


Bulging amniotic sac

Bulging Amniotic Sac


11

© Pat Schoff Perinatology Research Branch, NICHD/NIH, Wayne State UniversityHassan, Hernandez, Romero

Cervical canalSludge


• Presence of dense aggregates of particulate

matter in close proximity to the internal

cervical os

Espinoza J. et al Ultrasound Obstet Gynecol 2005;25:346-52

Kusanovic JP. et al Ultrasound Obstet Gynecol 2007;30:706-714

Amniotic Fluid “Sludge”


Sludge in Asymptomatic Patients at Risk

(Previous History)

• 17 % positive AF cultures vs. 0% (no sludge)

• 63% Histological chorioamnionitis

• 15% Clinical chorioamnionitis vs. 5%

• 60% spontaneous PTB (<32 wks) vs. 15%

• 37% neonates admitted to NICU vs. 16%

Kusanovic JP et al. Ultrasound Obstet Gynecol 2007;30:706-14Hassan, Hernandez, Romero

40

30

20

10

0

Frequency

<15 mm

71

Cervical length

Presence

Absence

60

50

29

50

12

15-25 mm

70

80

Frequency of Spontaneous Preterm Delivery at

<32 Weeks of Gestation According to Cervical Length

and Presence or Absence of Amniotic Fluid "Sludge”

14-24 weeks

Kusanovic JP et al. Ultrasound Obstet Gynecol 2007;30:706-14Hassan, Hernandez, Romero


Increases the predictive

value for preterm delivery


12

Sludge

Perinatology Research Branch, NICHD/NIH, Wayne State UniversityHassan, Hernandez, Romero Perinatology Research Branch, NICHD/NIH, Wayne State University

Sludge


Sludge


Sludge



What is Sludge?




13

Amniotic Fluid “sludge” Sample

Romero R, Schaudinn C, Kusanovic JP, Gorur A, Gotsch F, Webster P, Nhan-Chang CL, Erez O, Kim CJ, Espinoza J,

Gonçalves LF, Vaisbuch E, Mazaki-Tovi S, Hassan SS, Costerton JW Am J Obstet Gynecol 2008;198:135.e1-5

Mycoplasma hominis,

Streptococcus mutans,

Aspergillus flavus


Amniotic Fluid “sludge” Sample

Romero R, Schaudinn C, Kusanovic JP, Gorur A, Gotsch F, Webster P, Nhan-Chang CL, Erez O, Kim CJ, Espinoza J,

Gonçalves LF, Vaisbuch E, Mazaki-Tovi S, Hassan SS, Costerton JW Am J Obstet Gynecol 2008;198:135.e1-5

Mycoplasma hominis,

Streptococcus mutans,

Aspergillus flavus


Romero R et al. Cover AJOG January 2008

Scanning Electron Microscopy

Biofilm:

Bacterial Cells and Exopolymeric Matrix Material


Prediction

Prevention

?


Treatments for a

Sonographic Short

Cervix


Interventions to Prevent Preterm Birth

in Women with a short cervix

O

C

CH3

O

ProgesteroneCerclage

www.dr-arabin.de

Pessary


14

Fonseca EB et al. NEJM 2007;357:462-9

Hassan SS, et al. Ultrasound Obstet Gynecol. 2011 Jul;38(1):18-31Hassan, Hernandez, Romero

Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O'Brien JM, Cetingoz E, Da Fonseca E, Creasy GW, Klein

K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan SS; Am J Obstet Gynecol. Feb 2012


Effect of Vaginal Progesterone on the Rate

of Preterm Birth

34

28

24

20

16

12

8

4

0

<32 <33<30<28 <34

5%

11%

13%

7%

18%

10%

22%

12%

27%

16%

Weeks gestation

Perc

en

tag

e o

f p

rete

rm b

irth

Progesterone

Placebo

Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O’Brien J, Cetingoz E, DA Fonseca E,

Creasy G, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan S. Am J Obstet Gynecol 2011;12:003

50%

39%

42%

42%

42%

<35

30%

20%

31%ALL STATISTICALLY SIGNIFICANT


Effect of Vaginal Progesterone on Neonatal

Outcomes

28

24

20

16

12

8

4

0

29%

21%

13%

6%

12%

9%

17%

10%

16%

9%

Perc

en

tag

e o

f n

eo

nata

l m

orb

idit

y

Progesterone

Placebo

RDSNICU

admission

Composite

neonatalmorbidity/mortality

Mechanical

ventilation

Birth weight

<1500g

Romero R, Nicolaides K, Conde-Agudelo A, Tabor A, O’Brien J, Cetingoz E, DA Fonseca E,

Creasy G, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, Hassan S. Am J Obstet Gynecol 2011;12:003

25%

52%

34%

43% 45%

32ALL STATISTICALLY SIGNIFICANT


Ultrasound Obstet Gynecol. 2016; 48(3) :308-17.

Fonseca 2007

O’Brien 2007

Hassan 2011

Cetingoz 2011

OPPTIMUM 2016

Combined

24/14 39/112 29.5 0.60 (0.39-0.94)

4/12 6/19 3.5 1.06 (0.37-2.98)

28/235 46/223 35.3 0.58 (0.37-0.89)

1/4 2/4 1.5 0.5 (0.07-3.55)

33/133 38/118 30.2 0.77 (0.52-1.14)

90/498 131/476 100 0.66 (0.52-0.83)

Relative risk (fixed)

(95% CI)

Vaginal

Progesterone

(n/N)

Placebo

(n/N) Weight

(%)

Relative risk

(95% CI)

Favors placebo Favors vaginal progesterone

Study

0.05 0.1 0.2 0.3 0.5 1 2 3 5Test for heterogeneity I2 =0%

Test for overall effect Z= 3.48, P=0.0005


The Next Step:

A Meta-analysis of Individual Patient Data

Romero R, Conde-Agudelo A, Da Fonseca E, O’Brien J, Cetingoz E, Creasy G, Hassan Sonia, Nicolaides KH et al. Am J Obstet Gynecol.

2017; pii: S0002-9378(17)32343-8

15

Studies included in the individual patient data meta-analysis

Study,

year

Trial enrollmentParticipants randomly assigned in

original trial

Participants

eligible for

IPDMATreatment groups Compliance

Fonseca,

2007

8 centres in the

UK, Chile,

Brazil, and

Greece

250 with a singleton or twin

gestation and a cervical length ≤15

mm

226 Vaginal progesterone 200

mg/day or placebo from 24-33

6/7 weeks of gestation

92% for the vaginal

progesterone

group and 94% for

the placebo group

O'Brien,

2007

53 centres in

US, South

Africa, India,

Czech Republic,

Chile, and El

Salvador

659 with a singleton gestation and a

history of spontaneous preterm

birth



to 37 0/7 weeks of gestation,

rupture of membranes or

preterm delivery, whichever

occurred first

100% for the

vaginal

progesterone

group and 95% for

the placebo group

Cetingoz,

2011

Single centre in

Turkey

160 with twin gestation, or

singleton gestation with previous

spontaneous preterm birth or

uterine malformation

8 Vaginal progesterone

suppository 100 mg/day or

placebo from 24-34 weeks of

gestation

100% for both

study groups

Hassan,

2011

44 centres in

US, Belarus,

Chile, Czech

Republic, India,

Israel, Italy,

Russia, South

Africa, and

Ukraine

465 with a singleton gestation and a

cervical length between 10-20 mm



6/7 to 36 6/7 weeks of

gestation, rupture of

membranes or preterm

delivery, whichever occurred

first

89% for the vaginal

progesterone

group and 93% for

the placebo group

Norman,

2016

66 centres in

the UK and

Sweden

1228 with a singleton gestation and

previous spontaneous preterm

birth, or cervical length ≤25 mm, or

a positive fetal fibronectin test

combined with other clinical risk

factors for preterm birth



to 34 weeks of gestation or

preterm delivery, whichever

occurred first

63% for the vaginal

progesterone

group and 69% for

the placebo group

Romero R, Conde-Agudelo A, Da Fonseca E, O’Brien J, Cetingoz E, Creasy G, Hassan Sonia, Nicolaides KH et al. Am J Obstet Gynecol. 2017; pii: S0002-9378(17)32343-8

Effect of vaginal progesterone on preterm birth

before 33 weeks’ gestation

Study Relative risk (fixed) 95% CI

Vaginal

progesterone

n/N

Placebo

n/N

Weight

%

Relative

risk

(95% CI)

Fonseca

200719/114 31/112 28.5

0.60

(0.36-1.00)

O’Brian

20071/12 4/19 2.8

0.40

(0.05-3.13)

Hassan

201121/235 26/223 33.6

0.55

(0.33-0.92)

Cetingoz

20110/4 1/4 1.4

0.33

(0.2-6.37)

Norman

201629/133 35/118 33.7

0.74

(0.48-1.12)

Combined 70/498 107/476 100.00.62

(0.47-0.81)

0.05 0.1 0.2 0.3 0.5 1 2 3 5

Favours vaginal progesterone Favours placebo


2017; pii: S0002-9378(17)32343-8

Outcome IPD Meta-analysis

OutcomeRR or mean

difference (95% CI)

Vaginal

Progesterone

Group

Placebo Groupp

value

NNT(95%CI

)

Pregnancy outcome

Delivery before 36

weeks0·80 (0·67 to 0·97) 28% 35% 0·02 14 (9-96)

Delivery before 34

weeks0·65 (0·51 to 0·83) 17% 26%

0·000

611 (8-22)

Delivery before 28

weeks0·67 (0·45 to 0·99) 8% 11% 0·04

27(16-

881)

Any maternal adverse

event 1·21 (0·87 to 1·69) 12% 11% 0·26 ··


2017; pii: S0002-9378(17)32343-8


OutcomeRR or mean

difference (95% CI)

Vaginal

Progesterone

Group

Placebo Groupp

value

NNT(95%CI

)

Pregnancy outcome

Delivery before 36

weeks0·80 (0·67 to 0·97) 28% 35% 0·02 14 (9-96)

Delivery before 34

weeks0·65 (0·51 to 0·83) 17% 26%

0·000

611 (8-22)

Delivery before 28

weeks0·67 (0·45 to 0·99) 8% 11% 0·04

27(16-

881)


event 1·21 (0·87 to 1·69) 12% 11% 0·26 ··

Perinatal outcome ? ? ? ?


2017; pii: S0002-9378(17)32343-8


OutcomeRR or mean

difference (95% CI)

Vaginal

Progesterone

Group

Placebo Groupp

value

NNT(95%CI

)

Pregnancy outcome

Delivery before 36

weeks0·80 (0·67 to 0·97) 28% 35% 0·02 14 (9-96)

Delivery before 34

weeks0·65 (0·51 to 0·83) 17% 26%

0·000

611 (8-22)

Delivery before 28

weeks0·67 (0·45 to 0·99) 8% 11% 0·04

27(16-

881)


event 1·21 (0·87 to 1·69) 12% 11% 0·26 ··

Perinatal outcome

Respiratory distress

syndrome0·47 (0·27 to 0·81) 5% 10% 0·007 18 (13-51)


2017; pii: S0002-9378(17)32343-8


OutcomeRR or mean

difference (95% CI)

Vaginal

Progesterone

Group

Placebo Groupp

value

NNT(95%CI

)

Pregnancy outcome

Delivery before 36

weeks0·80 (0·67 to 0·97) 28% 35% 0·02 14 (9-96)

Delivery before 34

weeks0·65 (0·51 to 0·83) 17% 26%

0·000

611 (8-22)

Delivery before 28

weeks0·67 (0·45 to 0·99) 8% 11% 0·04

27(16-

881)


event 1·21 (0·87 to 1·69) 12% 11% 0·26 ··

Perinatal outcome


syndrome0·47 (0·27 to 0·81) 5% 10% 0·007 18 (13-51)

Composite neonatal

morbidity/mortality†0·59 (0·38 to 0·91) 8% 14% 0·02 18 (12-81)


2017; pii: S0002-9378(17)32343-8

16


OutcomeRR or mean

difference (95% CI)

Vaginal

Progesterone

Group

Placebo Groupp

value

NNT(95%CI

)

Pregnancy outcome

Delivery before 36

weeks0·80 (0·67 to 0·97) 28% 35% 0·02 14 (9-96)

Delivery before 34

weeks0·65 (0·51 to 0·83) 17% 26%

0·000

611 (8-22)

Delivery before 28

weeks0·67 (0·45 to 0·99) 8% 11% 0·04

27(16-

881)


event 1·21 (0·87 to 1·69) 12% 11% 0·26 ··

Perinatal outcome


syndrome0·47 (0·27 to 0·81) 5% 10% 0·007 18 (13-51)

Composite neonatal

morbidity/mortality†0·59 (0·38 to 0·91) 8% 14% 0·02 18 (12-81)

Neonatal death 0·44 (0·18 to 1·07) 1% 3% 0·07 ··

†Occurrence of any of the following events: respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocoli tis, proven

neonatal sepsis, or neonatal death

Romero R, Conde-Agudelo A, Da Fonseca E, O’Brien J, Cetingoz E, Creasy G, Hassan Sonia, Nicolaides KH et al. Am J Obstet Gynecol. 2017; pii: S0002-9378(17)32343-8

What is the totality of the data?

Vaginal progesterone reduces the risk

of preterm birth and improves

perinatal outcome in women with a

short cervix

Vaginal progesterone is safe for use in

pregnancy


2017; pii: S0002-9378(17)32343-8

Prior Preterm Birth and a Short Cervix:

Cerclage or Vaginal Progesterone?

Hassan, Hernandez, RomeroConde-Agudelo A, Romero R, Nicolaides K, et al. Am J Obstet Gynecol 2013;208:42.e1-18.



in Women with a Short Cervix

O

C

CH3

O

Progesterone Cerclage

www.dr-arabin.de

Pessary


1) Vaginal progesterone:

• significant 53% reduction in the risk of preterm birth at <32

weeks

• 57% decrease in the risk of composite perinatal morbidity

and mortality

2) Cervical cerclage:

• significant 34% reduction in the risk of preterm birth at <32

weeks

• 36% decrease in the risk of composite perinatal morbidity

and mortality

3) Vaginal progesterone and cervical cerclage both effective

4) Surgery vs. medical

Prior preterm birth and a Short Cervix:

Cerclage or Vaginal Progesterone?

Conde-Agudelo A, Romero R, Nicolaides K, Chaiworapongsa T, O’Brien JM, Cetingoz E, Da Fonseca E, Creasy G, Soma-

Pilly P, Fusey S, Cam C, Hassan SS. Am J Obstet Gynecol. 2012 Nov 13. [Epub ahead of print].Hassan, Hernandez, Romero

17

1) Pre-cerclage 6 mm

2) Post-cerclage 14.1 mm

(1)

(2)

Cervical Length After Cerclage


1) Pre-cerclage 12.1 mm



(1)

(2)




1) Pre-cerclage 9.6 mm


(1)

(2)

Cervical length After Cerclage



in Women with a Short Cervix

O

C

CH3

O

Progesterone Cerclage

www.dr-arabin.de

Pessary

Evidence for the use of a

pessary to

reduce preterm birth

in women with a short

cervix is not conclusive


Twins


18

O

C

CH3

O

ProgesteroneSonographic Short

Cervix


13 mm

Hassan, Hernandez, RomeroR. Romero A. Conde-Agudelo W. El-refaie L. Rode M. L. Brizot E. Cetingoz V. Serra E. Da Fonseca M. S. Abdelhafez

A. Tabor A. Perales S. S. Hassan K. H. Nicolaides. Ultrasound Obstet Gynecol. In Press

Effect of Vaginal Progesterone on the Risk of

TWINS

0.05 0.1 0.2 0.3 0.5 1 2 3

9/15 4/6 8.8 0.90 (0.45-1.81)

3/5 1/1 3.5 0.78 (0.27-2.22)

50/159 62/144 100.0 0.69 (0.51-0.93)

5 Test for heterogeneity: I2 = 0%

Test for overall effect: Z = 2.44, P = 0.01

Study

Relative risk (fixed)

(95% CI)

Vaginal

progesterone

n/N

Placebo/no

treatment

n/NWeight

(%)

Relative risk

(95% CI)

Favors vaginal progesterone Favors placebo

Brizot 2015

Combined

1/5 1/2 2.2 0.04 (0.04-3.74) Cetingoz 2011

Serra 2013

3/7 5/14 5.2 1.20 (0.40-3.63)Rode 2007

3/11 7/13 9.9 0.51 (0.17-1.50Fonseca 2007

R. Romero A. Conde-Agudelo W. El-refaie L. Rode M. L. Brizot E. Cetingoz V. Serra E. Da Fonseca M. S. Abdelhafez

A. Tabor A. Perales S. S. Hassan K. H. Nicolaides. Ultrasound Obstet Gynecol. In Press

10

31/116 44/108 70.4 0.66 (0.45-0.96) El-refaie 2016

Effect of Vaginal Progesterone on the Risk of Adverse

Perinatal Outcomes

Events (n)/total n Pooled RR (95% CI)

Outcome TrialsVaginal

progesterone

Placebo/no

treatment

Assuming

independence

between twins

Adjustment for

non-independence

between twins

I2

(%)

NNT

(95% CI)

RDS 6 102/311 131/2800.67

(0.55-0.82

0.70

(0.56-0.89)0

6

(4-16)

Neonatal death 6 34/318 62/2880.50

(0.34-0.71)

0.53

(0.35-0.81)25

8

(5-19)

Perinatal death 6 43/318 72/2880.51

(0.36-0.70)

0.36

(0.39-0.84)24

7

(5-20)

Composite

neonatal

morbidity/mortality

5 23/84 28/700.57

(0.36-0.93)

0.61

(0.34-0.98)0

6

(3-109)

Birth weight <1500

grams6 48/315 73/280

0.52

(0.38-0.72)

0.53

(0.25-0.80)17

7

(5-17)

Mechanical

ventilation6 49/311 76/280

0.52

(0.37-0.71)

0.54

(0.36-0.810

7

(5-17)

R. Romero A. Conde-Agudelo W. El-refaie L. Rode M. L. Brizot E. Cetingoz V. Serra E. Da Fonseca M. S. Abdelhafez

A. Tabor A. Perales S. S. Hassan K. H. Nicolaides. Ultrasound Obstet Gynecol. 2017 Jan 9. [Epub ahead of print]

Should all Women be

Screened with Transvaginal

Ultrasound for Cervical

Length?


Practical Consideration


19

How Difficult and Time-Consuming is it

to Perform a Transvaginal Ultrasound?

Romero R, Hernandez-Andrade E, Hassan SS

Pain Score Indicated in the Third-trimester Group for the Different

Methods of Examining the Cervix:

Transvaginal Ultrasound, Transperineal Ultrasound, and Digital

Examination

Meijer-Hoogeveen M et al. Ultrasound Obstet Gynecol 2008;32:657-62

60

Score 5(Extremely

Painful)

0 10 20 30 40Percent 50

Score 4(Severely

Painful)

Score 3(Moderately

Painful)

Score 2(Mildly

Painful)

Score 1(Mildly

Painful)

Transvaginal ultrasound

Transperineal ultrasound Digital examination

Am J Obstet Gynecol 2012 Feb; 206(2):101-3Hassan, Hernandez, Romero

World Health Organization

Ten Principles for Good Screening Test

1. Condition = Important Health Problem

2. Available Treatment

3. Facilities Available for Diagnosis

4. Recognizable Latent Phase

5. Suitable Test or Examination

6. Test Acceptable to Population

7. Natural History of Disease Adequately Understood

8. Policy for Treatment

9. Cost of Case-Finding Economically Balanced with Care

10. Case-Finding Should be Continuing ProcessWilson JMG, Jungner G. World Health Organization 1968

Coombs, AC. Am J Obstet Gynecol 2012 Feb; 206(2):101-3


Comparison of Strategies used for

Screening in Medicine

Test Number needed to screen

Pap Smear for Cervical Cancer1 1140

Mammography more than 50 years1 543

Mammography between 40 and 49 years1 3125

Prostate-specific Antigen for Prostate Cancer2 1254

Ultrasound cervical length to prevent one case of PTB

< 33 weeks (<25 mm)3357

Ultrasound cervical length to prevent one case of

neonatal morbidity/mortality (<25 mm)3218

1. Gates TJ, et al. Am Fam Physician 2001;63:513-22

2. Loeb S, et al. J Clin Oncol 29:464-467

3. Romero R, Conde-Agudelo A, unpublished.Hassan, Hernandez, Romero

Future Sonographic Methods to

Evaluate the Uterine Cervix for

the Prediction of

Preterm Birth?


20

Cervical Elastography and the

Prediction of Preterm Birth


Elastography

• Tissue displacement (strain) or velocity of

propagation of a mechanic stimulus within the

cervix as a ‘shear wave” can provide

information on the softness/stiffness of the

cervix

• Changes in “elasticity” are displayed in a color

elastogram

Ophir J, Cespedes I, PonnekantiH, Yazdi Y, Li X. Elastography: a quantitative method for imaging the elasticity of

biological tissues. Ultrason Imaging 1991; 13: 111–134.Hassan, Hernandez, Romero

Hernandez-Andrade E, Hassan SS, Ahn H, Korzeniewski SJ, Yeo L, Chaiworapongsa T, Romero R. Ultrasound

Obstet Gynecol 2013; 41: 152-161

Cervical Shear Wave Elastography


Sagittal view of the cervix showing in red slow shear wave velocity (soft tissue) and

in blue high shear wave velocity (stiff tissue)

Cervical Shear Wave Elastography

in the internal and in the external os

Hernandez-Andrade E, Hassan SS, Ahn H, Korzeniewski SJ, Yeo L, Chaiworapongsa T, Romero R.

Ultrasound Obstet Gynecol 2013; 41: 152-161

Soft areas are displayed in red/orange

Stiff areas are displayed in blue

Transverse view of the Internal os showing in

blue high shear wave velocity (stiff tissue)

Transverse view of the external os showing in

red slow shear wave velocity (soft tissue)


Color elastogram

ElastogramRegion of Interest

Averaged oscillatory displacement

Applied to the entire elastogram

Stiffness color bar

Strain or

percentage o deformation

Within the ROI

Cervical Strain Elastography in the

internal os


<12 12-<16 16-<20 20-<24 24-<28 28-<30 38-<36 >360.0

0.1

0.2

0.3

0.4

0.5

0.6

Gestational age (weeks)

Str

ain

(%

)

External cervical os

Complete cervix

Internal cervical os

In Normal Pregnancies the Internal Cervical os

Becomes Softer (Increased Strain) as Gestation

Progresses

Hernandez-Andrade E, Hassan SS, Ahn H, Korzeniewski SJ, Yeo L, Chaiworapongsa T, Romero R. Ultrasound

Obstet Gynecol 2013; 41: 152-161Hassan, Hernandez, Romero

21

Increased Prevalence of Preterm Delivery <37 weeks in

Women with Strain in the Internal os >50th Percentile for

Gestational Age at 17-24 Weeks

Hernandez E, Hassan S, Chaiworapongsa T, Romero R, J. Perinat. Med. 2014; 42(2): 159–169

0

2

4

6

8

10

12

14

1614.9%c

11.5%

3.0%

8.0%

Cervical strain

%

25th 50th 75th 100th

Pregnant women with low

strain values in the internal cervical os

have the lowest risk

of preterm delivery

Pregnant women with strain values >50th

percentile in the internal cervical os

have the highest risk of preterm delivery


• Sonographic cervical length is the most powerful predictor of

preterm birth

• The definition of a short cervix varies by obstetrical history

• In patients with a short cervix in the midtrimester:

• 22 have intra-amniotic inflammation and 9% have intra-amniotic infection

• The optimal time to examine the cervix is 19-24 weeks gestation

• Correct technique for cervical length examination is critical

• The cervix should be measured

• With an empty bladder by transvaginal ultrasound, in a sagittal view


Conclusions (I)

• Amniotic fluid sludge increases the predictive value for preterm

delivery

• In women with a sonographic short cervix:

• Vaginal progesterone decreases preterm birth and neonatal morbidity in women

with a short cervix (singletons and twins)

• Cerclage reduces preterm birth (prior history of preterm birth and a short cervix)

• Pessary has not been definitively proven to decrease preterm birth

• It is of benefit for pregnant women to undergo a sonographic

cervical length measurement in the midtrimester to assess her risk

for preterm birth


Conclusions (II) Key References

1. Burger M, Weber-Rössler T, Willmann M. Measurement of the pregnant cervix by transvaginal sonography:

an interobserver study and new standards to improve the inter-observer variability. Ultrasound Obstet

Gynecol. 1997 Mar;9(3):188-93.

2. Hassan SS, Romero R, Berry SM et al. Patients with an ultrasonographic cervical length < or = 15 mm have

nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol 200; 182:1458.

3. Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-

Pillay P, Sambarey P, Dayal A, Potapov V, O'Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H,

Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW;

PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographicshort cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol.

2011 Jul;38(1):18-31

4. Romero R, Conde-Agudelo A, El-Refaie W, Rode L, Brizot ML, Cetingoz E, Serra V, Da Fonseca E,

Abdelhafez MS, Tabor A, Perales A, Hassan SS, Nicolaides KH. Vaginal progesterone decreases preterm

birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated

meta-analysis of individual patient data. Ultrasound Obstet Gynecol. 2017 Mar;49(3):303-314

5. Romero R, Conde-Agudelo A, Da Fonseca E, O’Brien JM, Cetingoz E, Creasy GW, Hassan SS, Nicolaides

KH. Vaginal Progesterone for Preventing Preterm Birth and Adverse Perinatal Outcomes in Singleton

Gestations with a Short Cervix: A Meta-Analysis of Individual Patient Data. AJOG. 2017 Nov; pii: S0002-

9378(17)32343-8.


Thank You


disclosures sonographic cervical length for the prediction...

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