Professor Andrew Shennan

Womens Health Academic Centre

Kings College London,

St Thomas’ Campus

BMUS

2018

Cervical scanning in the management of preterm birth risk

Conflicts of interest

1 million preterm babies die each year

WHO 2009

Uterine Overdistension

Stress

Cervical Weakness

Infection / Inflammatory

response

Unknown

Vascular Disorders

Decline in Progesterone Action

What can we do for those at risk?

Prophylactic Reactive

Preterm labour Lifestyle Tocolysis

Cerclage Antibiotics (PROM)

Arabin Pessary

Progesterone

Improve outcomes Steroids Steroids

Mg SulphateIn utero transfers

We cant always prevent preterm birth, but we can improve outcomes

Composite outcome of mortality or severe neonatal morbidity

With Antenatal Steroids

Norberg H, Kowalski J, Marsal K, Norman M. Timing of antenatal corticosteroid administration and survival in extremely preterm infants: a national population-based cohort study. BJOG 2017

Steroid timing is crucial

Past Obstetric History as a predictor

McManemy J, Cooke E, Amon E, Leet T. Recurrence risk for preterm delivery.

Am Jog 2007;196:576-576.

LLETZ and preterm risk

Kyrgiou M et al Lancet 367:489-98 (2006)

PTB risk with FDCS

For each 1cm increase in dilation at time of cesarean, there was a 50% increase in the risk of sPTB

(OR 1.50 [1.07–2.10], p=0.02)

Watson HA, Carter J, David AL, Seed PT, Shennan AH.Full dilation cesarean section: a risk factor for recurrent second-trimester loss and preterm birth

Acta Obstet Gynecol Scand. 2017 Apr 27. doi: 10.1111/aogs.13160.

https://www.ncbi.nlm.nih.gov/pubmed/28449286

Bladder

Uterus

Anterior uterine defect

The problem with evaluating PTB tests:

Women with threatened preterm labour rarely deliver in the next week!

711

170

100

200

300

400

500

600

700

800

900

TPTL Delivery

Peaceman 1997

Wing 2017

A useless test will have a 97% NPV!

Matsuura et al. fFN identified as a glycoprotein found in the amniotic basement membrane. J Biol Chem

Lockwood et al. fFN sensitive and specific (81.7% and 82.5%) for predicting PTB

Cost depends on skill and availability of test

The UK market: preterm prediction tests

202 units use tests to triage ptb

Currently hospitals (60,000 tests)Fetal fibronectin: 136 (67%)

Actim Partus 47 (23%)

Partosure 19 (10%)

Prediction: Cervical ultrasound

Internal osExternal os

Post

Vaginal

Wall

Cervical ScreeningMeasurement Image Criteria

• Transvaginal Image

• Cervix occupies 75% of the image

• Anterior Width = Posterior Width

• Maternal Bladder Empty

• Internal Os Seen

• External Os Seen

• Cervical Canal Visible throughout

• Caliper Placement Correct

• Cervix Mobility Considered The clear Program www.perinatalquality.org

fFN in Symptomatic Patients: High Negative Predictive Value, Helpful Positive Predictive Value*

Benefits of a Negative Test

• Less intervention

• Avoid hospitalizations

• Physician and patient reassurance

NPV for delivery within:

• 7 days = 99.5%

• 14 days = 99.2%

*Peaceman AM et al. Am J Obstet Gynecol. 1997;177:13-18.

10 centers across the US, Patients included = 763

Sensitivity = 86. 2%

Specificity = 82.3%

Benefits of a Positive Test

• Identify group that can be targeted for

intervention

• Opportunity for antenatal steroids

• Preparation for optimal neonatal care

PPV for delivery within:

• 7 days = 12.7%

• 14 days = 16.7%

• < 37 weeks = 44.7%

Ffn @ 24 weeks in asymptomatic high risk women women

pro

port

ion u

ndeliv

ere

d

time to delivery (weeks)

24 28 32 36 40

0.00

0.25

0.50

0.75

1.00negative

positive

Figure 1a

Shennan et al 2005 BJOG 112; 293-8

High-risk Pregnancies

Kurtzman, Chiandiramani, Shennan et al, Am J Ob Gyn 200:263.e1-e6; 2009.

Rapid 10Q system

Single vs continuous variable 100% sensitivity/NPV

100% specificity/PPV

fFN 10ng/mL

fFN 50ng/mL

fFN 200ng/mL

0%

0%

SNOUTRule Out

SPINRule In

qfFN

(ng/mL)

n (%) < 30 weeks n (%)

Stratification according to CL measurement

Cervix ≥25 mm n

Diagnostic Test Partosure

N=710

Qual fFN (> 50 ng/mL)

N=710

Sensitivity 23.5(6.8 to 49.9)

52.9(27.8 to 77.0)

Specificity 98.1(96.8 to 99.0)

85.4(82.6 to 88.0)

PPV 23.5(10.1 to 45.9)

8.2(5.2 to 12.6)

NPV 98.1(97.6 to 98.6)

98.7(97.8 to 99.2)

TP 4 9

FN 13 8

FP 13 13

TN 680 592

Large US multicentre trial comparing PAMG and fFN(Unpublished USA).

Diagnostic Test Partosure

N=710

Qual fFN (> 50 ng/mL)

N=710

Sensitivity 23.5(6.8 to 49.9)

52.9(27.8 to 77.0)

Specificity 98.1(96.8 to 99.0)

85.4(82.6 to 88.0)

PPV 23.5(10.1 to 45.9)

8.2(5.2 to 12.6)

NPV 98.1(97.6 to 98.6)

98.7(97.8 to 99.2)

TP 4 9

FN 13 8

FP 13 13

TN 680 592

Latest data:Large US multicentre trial comparing PAMG and fFN(Unpublished USA).

False negative rates (Rule out)

All PTB < 7 daysfFN 8/17 (47%)Partosure 13/17 (76%)

sPTB

500

0

20

40

60

80

100

qfFN and CL to predict delivery in TPTL

qfFN and CL to predict delivery in TPTL

Ultrasound Obstet Gynecol 2015; 0: 000–000Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.14865

Development and validation of a predictive tool forspontaneous preterm birth incorporating cervical lengthand quantitative fetal fibronectin in asymptomatic high-riskwomenK. KUHRT• AQ1 , E. SMOUT, N. HEZELGRAVE, P. T. SEED, J. CARTER and A. H. SHENNANAQ2 Woman’s Health Academic Centre, Kings College London, London, UK •

App store QUiPP (Free)!

Ability of a preterm surveillance clinic to triage risk of preterm birth: a prospective cohort study

Outpatient Inpatient RR (95% CI) p value(n=1064) (n=66)

Mean gestation atdelivery (weeks)

38.42.5(24-42)

31.25.6 (23-41)

p

Ultrasound-indicated cerclage

4 RCT IPD n=607

Singletons

RR 0.57; 95% CI 0.33–0.99

Delivery

Cerclage: elective vs USS indicated

Multicentre RCT comparing abdominal with vaginal cerclage (The MAVRIC Trial)

KCL Division of Women’s Health

1Women's Health Academic Centre, King’s Health Partners, London.

Jenny Carter, Manju Chandiramani, Paul Seed, Andrew H Shennan,

& The MAVRIC Consortium

Primary outcome and powered endpointsP

20

22

24

26

28

30

32

34

36

38

40

Ce

rvic

al le

ngt

h (

mm

)

Gestation (wks)

Change in CL with Intervention

LVC

HVC

14- 18- 22-26wks >26wks

Error bars removed for clarity

91% of women who delivered preterm,

developed a CL

< 32 weeks Baby death

NNT Efficacy NNT Efficacy

TAC vs LVC 3.5 (2.1-10.3)

78% 4 (2.4-11.7)

90%

TAC vs HVC 3.2 (2-7.8)

79% 5.6(3.1-24.3)

87%

NNT and efficacy

Progesterone

Progesterone

Progesterone in the Short Cervix

Progesterone in the Short Cervix

Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised,double-blind trialJane Elizabeth Norman, Neil Marlow, Claudia-Martina Messow, Andrew Shennan, Phillip R Bennett, Steven Thornton, Stephen C Robson, Alex McConnachie, Stavros Petrou, Neil J Sebire, Tina Lavender, Sonia Whyte, John Norrie, for the OPPTIMUM study groupLancet Feb 2016 (n=1228)

InterpretationVaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age.

Placebo Progesterone p

Fetal death/ptb

RCT Cerclage vs Progesterone: outcome Limited relationship between cervico-vaginal fluid cytokine profiles and cervical shortening in women at high risk of spontaneous preterm birth.

Chandiramani M, Seed PT, Orsi NM, Ekbote UV, Bennett PR, Shennan AH, Tribe RM.PLoS One. 2012;7(12):e52412.

0%

50%

100%

Pro

port

ion o

f w

om

en d

eliv

ere

d

0 5 10 15

Gestation from intervention to delivery (weeks)

Cerclage

Progesterone

Progesterone:50% in 2 weeks Cerclage: 50% in 10 weeks

http://www.ncbi.nlm.nih.gov/pubmed/23300664

MRI: Arabin pessary

VitskyFirst theorised mechanism of action. Am J Obstet Gynae

1959

Pessary Timeline

RG CrossFirst used ring pessary to treat incompetent cervix. The Lancet

Von ForsterFirst quasi randomised RCT

comparing stutz pessary with cerclage. Zentralbl Gynakol

1959

1961

1986

GoyaThe PECEP RCT

The Lancet

2012

2013HuiAmer J Perinatol

Quaas 1990

N=107. 92% of women treated delivered >36/40

Arabin 2003

Singletons: GA 38 v 33+4/40 (p=0.02)

Twins: 35+6 v 33+2/40 (p=0.02).

Antczak-Judcka 2003

Cerclage v pessary

No difference in gestational age at delivery

Acharya 2006

Prospective cohort study, If CL

Author Country, Journal

N Inclusion criteria

Pregnancy outcome

Goya(PECEP)

2012

Spain

The Lancet

385 CL

Sample Size (n)

3328

8523

385

Cerclage Progesterone Pessary

Reassurance

Page 56

“After the devastation of my many pregnancies losses, I cannot begin to describe the relief I felt with this test. At last, I would become a mother.”

Impact: Commissioning Guidelines

Thanks!