progesteronbehandling som prematurprofylax - sfog · can we prevent preterm delivery in women...

Progesteronbehandling

som prematurprofylax

Lil Valentin

Skånes Universitetssjukhus Malmö

Progesteronbehandling kan minska

risken för prematurbörd i vissa grupper

av gravida…….

Vilka gravida nytta av progesteron

som prematurprofylax?

• Screena en hel population

– behandla högriskgruppen?

• De som fött prematurt tidigare?

• Flerbörd?

• ”Prematura värkar”?

JA, vi kan förhindra prematur förlossning

hos kvinnor med simplex graviditet

genom att mäta längden på deras cervix

med vaginalt ultraljud vid 20 veckor

och behandla dem med progesteron

som har en cervix som är 10-20 mm lång

Hassan et al UOG 2011; 38: 18

RCT, asymptomatisk simplexgraviditet

2.3%

19-23 weeks

Gel varje dag

från 20 veckor

till 36+6 veckor

Hassan et al

UOG 2011; 38: 18

Certifierad

undersökare


Frekvensen prematur förlossning och neonatal

morbititet/mortalitet var lägre i progesterongruppen

Prematuritet Prog. Placebo

< 28 veckor 5% 10%

< 33 veckor 9% 16%

< 35 veckor 14.5% 23%

Neonatal morbiditet/

mortalitet 8% 14%

RDS 3% 8%



“Number needed to treat (NNT)”

med progesteron gel för att förhindra

En prematur förlossning <33 veckor: 14

Ett fall av RDS: 22


Är screening kostnadseffektiv?

JA, mycket kostnadseffektiv

För 100 000 screenade gravida

• 12 miljoner US dollar sparas

• 424 “quality-adjusted life-years” sparas

Cahill et al Am J Obstet Gynecol 2010;202:548.e1-8

Werner et al Ultrasound Obstet Gynecol 2011; 38: 32

Vem har nytta av progesteron


• Screena en hel population av simplex

– JA, behandla om cervix 10-20 mm vid 20

veckor


Progesteron behandling av simplex

med tidigare prematurbörd

Studie Beh. Beh. tid Preterm <32-34 v

Prog Plac

1 17OH-Prog 20-36 v. 11% 20%

i.m.1g/vecka

2 Prog 100mg 24-34 v. 3% 19%

vaginalt 1g/dag

3 Prog 90mg 20-37 v. 10% 11%

vaginalt 1g/dag

1) Meiz 2003 NEJM; 2) da Fonseca 2003 AJOG; 3) O´Brien 2007 UOG

4) deFranco 2007

Subanalys: Progesteron

effekt om cervix < 28 mm

Progesteronbehandling av kvinnor med kort

cervix (<25mm) som tidigare fött <37 veckor

Ingen specifikt designad RCT

IPD meta-analys (n=169)

Relativ Risk

Prematur < 33 weeks 0.54 (0.30 - 0.92)

Neonatal mortalitet/

morbiditet 0.41 (0.17 - 0.98)

Romero et al. Am JOG 2012; 206:124




– JA, behandla om cervix 10-20 mm vid 20 veckor


– JA, de som har cervix < 25mm vid 20 veckor

• Flerbörd?

Progesteron behandling

i tvillinggraviditet

INGEN effekt

• Prematurbörd

• Neonatal morbiditet/mortalitet

Combs et al 2011, Norman et al 2009, Rode et al 2011,

Rouse et al 2007, Lim et al 2011, Briery 2009, Hartikkainen 1980

Progesteronprofylax

för tvillinggravida med cervix < 25 mm


IPD meta-analys (n =52)

Relativ risk

Preterm < v33 0.70 (0.34 -1.44)

Neonatal morbiditet/ 0.52 (0.29 – 0.93)

mortalitet





– JA, behandla om cervix 10-20 mm vid 20 veckor

• Alla som fött prematurt tidigare?


• Flerbörd?



Progesteron efter tokolys vid

idiopatiska prematura värkar

3 RCT

• Förlängd tid till förlossning* † ‡

• Lägre frekvens

– RDS†

– låg födelsevikt †

– preterm < 37 veckor‡

*Seyede Hajar Sharami et al 2010: † Borna and Sahabi 2008;

Fachinetti 2007‡



• Screena en hel population av simplex – JA, behandla om cervix 10-20 mm vid 20 veckor

• De som fött prematurt tidigare? – JA, de som har cervix < 25mm vid 20 veckor

• Flerbörd? – JA, de som har cervix < 25mm vid 20 veckor

• ”Prematura värkar”? – ????????

SLUTSATS

• Urvalskriteriet för progestronbehandling = mätning av cervix längd med ultraljud

• Det lönar sig att screena simplexgravida – Behandla om cervix är 10-20mm

– Behandla om cervix är <25 mm om de tidigare prematuritet

• Det lönar sig möjligen att screena tvillinggravida – Behandla om cervix är < 25 mm

• Progesteron som underhållsbehandling efter en episod med prematura värkar: ??????

Om cervix längdsmätning skall

vara utvalskriterium måste man

kunna mäta cervix korrekt

Man skall vara certifierad: FMF kurs,

Praktisk handledd träning, praktisk examination

Frågor

• Administrationssätt för progesteron?

• Dos av progesteron?

• Biverkningar av progestronbehandling?

• Vilken behandling om cervix – <5 mm?

– 6-10 mm?

– 10-20mm?

– 21-25 mm?

• Hur länge behandla? – 34 weeks? 35 Weeks? 36 weeks?

• Progesteron plus cerclage?

• Progesteron plus antibiotika?

Progesteronbehandling vid

prematura värkar

• Longer latency to delivery but no effect

on preterm delivery rate*

• Longer latency to delivery**

• Lower rate of RDS**

• Lower rate of low birth weight**

*Seyede Hajar Sharami et al 2010: **Borna and Sahabi 2008

JA, vi kan förhindra prematur förlossning

hos kvinnor med simplex graviditet

genom att mäta längden på deras cervix

med vaginalt ultraljud vid 20 veckor

och behandla dem med progesteron

som har en cervix som är 10-20 mm lång


RCT in asymptomatic singeltons

2.3%

19-23 weeks

Gel every day

from 20 weeks

to 36+6 weeks

Hassan et al

UOG 2011; 38: 18

Certified

examiner

RCT in asymptomatic singeltons

The rate of preterm delivery and neonatal

morbitiy/ mortality was lower in the

progesterone group

Preterm delivery Prog. Placebo

< 28 weeks 5% 10%

< 33 weeks 9% 16%

< 35 weeks 14.5% 23%

Neonatal morbidity/

mortality 8% 14%


RCT in asymtpomatic singeltons

(unselected)

Number needed to treat (NNT)

with progesterone gel to prevent

one preterm delivery <33 weeks: 14

one case of RDS: 22


Is screening cost-effective?

YES, highly cost-effective

For 100 000 women screened • 12 million US Dollars saved

• 424 quality-adjusted life-years gained

Cahill et al Am J Obstet Gynecol 2010;202:548.e1-8

Werner et al Ultrasound Obstet Gynecol 2011; 38: 32




– behandla högriskgruppen? JA


• Flerbörd?


Progesteron behandling vid tidigare

prematurbörd (simplex)

Studie Beh. Beh. tid Preterm <32-34 v

Prog Plac

1 17OH-Prog i.m. 20-36 v. 11% 20%

1g/vecka

2 Prog 100mg kapsel 24-34 v. 3% 19%

vag 1g/dag

3 P 90mg gel 20-37 v. 10% 11%

vag 1g/dag

1) Meiz 2003 NEJM; 2) da Fonseca 2003 AJOG; 3) O´Brien 2007 UOG

Subanalys: Progesteron

effekt om cervix < 28 mm

Can we prevent preterm delivery in

women (singleton) who have delivered

preterm before by treatment with

progesterone if the cervix is short?

• NO RCT testing progesterone if short

cervix in women with previous preterm

• Progesterone had NO statistically significant effect in the RCT of Hassan et al

Progesterone treatment of women

with short cervix (<25mm) who have

delivered < 37 weeks before

Relative Risk

Preterm < 33 weeks 0.54 (0.30 - 0.92)

Neonatal mortality/

morbidity 0.41 (0.17 - 0.98)


• NNT?







• Flerbörd?


Progesteronprofylax

för tvillinggravida

RCT

• Tre stora: beh. med 17-OH-Prog i.m.

• Två stora: beh. vaginalt Progesteron

från 20-24 till 34-36 veckor

INGEN EFFEKT på

Prematuritetsfrekvens (< 28,32,34,35 veckor)

Neonatalt utfall

Lim 2011; Comb 2011; Rouse 2007; Norman 2009; Rode 2011

Progesteronprofylax

för tvillinggravida med cervix < 25 mm


IPD meta-analys

Relative risk Preterm < v33 0.70 (0.34 -1.44)

Neonatal morbiditet/ 0.52 (0.29 – 0.93)

mortalitet








• Flerbörd?



Progesteronbehandling vid

prematura värkar

Can we prevent preterm delivery in

women (singleton) who have delivered

preterm before by treating them with

cerclage if the cervix is short?

Meta-analysis • 5 RCTs, 504 patients with previous preterm

• Cervix <25 mm at midgestation

• randomized cerclage – no cerclage

• Cerclage at (22) - 24 (27) weeks

• Fundal pressure, shortest measurement (80%)

Berghella et al Obstet Gynecol 2011;117:663

Did cerclage prevent preterm delivery

Did it improve perinatal outcome?

YES

Delivery Cerclage Ctrl

< 28 weeks 13% 20%

< 32 weeks 19% 30%

< 35 weeks 28% 42%

Perinatal mortality/

morbidity 16% 25%


RCTs in asymtpomatic singeltons with

previous preterm delivery and short cervix

Number needed to treat with cerclage

(NNT)

20 women to prevent one perinatal death


Is treatment of high risk women

cost-effective?

No cost-effectiveness studies

Summary

• Cervical length is used clinically

• Different measurement methods

• Use the method recommended for a

specific purpose

• Pitfalls-difficulties

• Identification of internal os

• Pressure on the anterior lip

• Appropriately trained staff

Summary

• Short cervix (<15 mm) at midgestation

increases risk of preterm delivery in

asymptomatic women (singleton)

• In asymptomatic women (singleton) with

cervix 10-20 mm at midgestation vaginal

progesterone decreases

– Preterm delivery rate (relative risk ~ 50%)

– Neonatal mortality/morbidity (relative risk ~60%)

– Cost-effective

Summary

• In asymptomatic women (singleton), previous

preterm and cervix <25 mm before midgestation

cerclage decreases

– Preterm delivery rate (relative risk ~ 70%)

– Perinatal mortality/morbidity (relative risk ~ 70%)

– Cost-effective?

progesterone decreases

– Preterm delivery < 33 weeks (relative risk ~ 50%)

– Neonatal mortality/morbidity (relative risk ~ 40%)

– Cost-effective?

THANK YOU!

Can cervical length measurents with

ultrasound identify women with TWINS

at high risk of preterm delivery?

Short cervix at midgestation in asymptomatic

women with TWINS = increased risk of preterm

delivery

Risk of spontaneous delivery

< 32 weeks in TWINS according to

cervical length at around 23 weeks

Skentou et al UOG 2001; 17: 7–10 Cervix length at 23 weeks, mm

Ris

k d

eliv

ery

<3

2 w

ee

ks

<25mm

• Can we prevent preterm delivery in

asymptomatic women expecting

TWINS with a short cervix at

midgestation?

• Can we thereby improve neonatal

outcome?

Cerclage in TWINs – short cervix

(sub-analysis of meta-analysis)

Increases

• Preterm delivery < 35 weeks

Berghella et al OG 2005; 106:181-9

Progesterone treatment in TWINs

NO effect

• Preterm delivery

• Neonatal morbidity/mortality

Combs et al 2011, Norman et al 2009, Rode et al 2011,

Rouse et al 2007, Lim et al 2011

Progesterone treatment in TWINs

with short cervix (<25mm) (subanalysis of meta-analysis, n=52)

Relative risk

Preterm < 33 weeks 0.70 (0.34 -1.44)

Neonatal morbidity

/mortality 0.52 (0.29 -0.93)


Questions

• Dose of progesterone

• What treatment for cervix

– <5 mm?

– 6-10 mm?

– 10-20mm?

– 21-25 mm?

• How long to treat for?

• 34 weeks? 35 Weeks? 36 weeks?

• Progesterone plus cerclage?

• Progesterone plus antibiotics?

Maintenance therapy by vaginal

progesterone after

threatened idiopathic preterm labor

• Longer latency to delivery but no effect

on preterm delivery rate*

• Longer latency to delivery**

• Lower rate of RDS**

• Lower rate of low birth weight**

*Seyede Hajar Sharami et al 2010: **Borna and Sahabi 2008

How can we discriminate between

true and false preterm labor?

Lil Valentin

Kvinnokliniken

Universitetssjukhuset MAS, Malmö

Women in preterm labor

deliver • < 7 days 10%

• < 34 weeks 10 – 15 %

• < 37 weeks 20 – 25%

Tests to discriminate between

true and false preterm labor • fetal fibronectin in cervix or vagina

• ultrasound examination of the cervix

– cervical length

– funnelling

The performance of diagnostic tests

• Positive likelihood ratio, LR+

• Negative likelihood ratio, LR-

LR+ = sensitivity/1 minus specificity

LR- = 1 minus sensitivity/specificity


• Pretest odds x LR+ = odds after a

positive test result

• Pretest odds x LR- = odds after a

negative test result


LR+ > 10, LR- < 0.1 Conclusive diagnosis

LR+ 5 – 10, LR- 0.1 – 0.2 Moderately good test

LR+ 2 – 5, LR- 0.2 – 0.5 Poor test

LR+ 1 – 2, LR- 0.5 – 1 Useless test

Do we want a test that can

• EXCLUDE preterm delivery?

• PREDICT preterm delivery?

Studies on diagnostic performance differ

with regard to outcome variable

< 37 weeks

< 35 weeks

< 34 weeks

< 32 weeks

< 28 days

< 21 days

< 14 days

< 7 days

< 2 days

Delivery

Study

Cut-off

cervix length

LR+

LR-

Risk

if +

test

Risk

if - test

Test

negative

Rizzo -96

20 mm

3.2

0.41

44%

10%

63%

Rozenberg -97 26 mm

2.4

0.31

37%

6%

39%

Önderoglu -97 28 mm

4.5

0.26

53%

5%

52%

Honest -03, meta-

analysis

30 mm

(3 studies)

2.2

0.32

35%

6%

69%,

54%, ?%

Murakawa -93

30 mm

3.4

0.13

46%

3%

53%

Ability of cervical length to predict delivery < 37 weeks in

women with preterm labor; singletons;

pre-test risk is assumed to be 20%

50% har cervix > 30 mm

5% föder < 37 veckor

Fibronectin to predict preterm delivery

in women with preterm labor

LR+

LR-

Post test

risk if

test +

Post-test

risk if

test-

Del. < 37 v

3.3

0.5

45%

11%

Del. < 34 v

3.6

0.3

29%

3%

Meta-analysis (17 studies) ; Honest et al 2002

Pretest risk of delivery < 37 weeks is assumed to be 20%

Pretest risk of delivery < 34 weeks is assumed to be 10%

Hur många har negativt

fibronektintest?

11% föder < 37 veckor

Cervical length to predict delivery < 7 days in women

with preterm labor; singletons; assumed pre-test risk 10%

Study

Cut-off LR+

LR-

Risk if

test+

test -

Test +

Gomez 05 15 mm

7.4

0.5

45%

5%

15%

Gomez 05

15 mm

8.7

0.4

49%

4%

4%

Fuchs 04

15 mm

10

0.21

50%

2%

14%

Tsoi 03

15 mm

6.7

0.07

43%

0.8%

16%

Tsoi 04

15 mm

4.3

<0.1

33%

1%

48%

15% har cervix < 15mm

50% föder < 7 dagar

Fibronektin to predict delivery < 7 days in women

with preterm labor;

Pretest risk is assumed to be 10%

The diagnostic performance of fibronectin is assumed

to be the same in singleton and multiple pregnancies

LR+

LR-

Risk if

positive

test

Risk if

negative

test

5.42

0.25

37%

3%

Honest; meta-analysis of 17 studies

Hur många har positiv fibronektin test?

40% föder < 7 dagar

How can we best predict preterm delivery

in women with preterm labor?

• Ultrasound examination of cervix?

• Fibronectin test?

• A combination of both?

Combining fibronectin and cervix length = improvement

Pre-test risk of delivery < 37 weeks is assumed to be 20%

Pre-test risk of delivery < 35 weeks is assumed to be 15%

Study

Outcome

Test

LR+

LR-

% -

test

Rozenberg

< 37 w

Cx > 26 mm

AND ffn -

2.3

0.16

47%

Gomez

< 35 w

Cx > 30 mm

AND ffn -

2.0

0.06

43%

Risk

if -

test

1%

4%



Study

Outcome

Test

LR+

LR-

Risk

if

test+

%

+test

Gomez

< 7 d

Cx < 15mm AND

ffn +

17.6

0.66

7%

88%



Study

Outcome

Test

LR+

LR-

% -

test

Rist

at

test-

3% Hinz

< 28 d

cx <20mm

cx 20 - 31 mm

AND ffn+,

cx 21 - 31 mm

AND ffn-

cx >31mm

8.6

0.16

77%

High risk

Low risk

Does the use of ultrasound examination of the cervix

or fibronectin affect pregnancy outcome or the use of

resources ? Giles et al (2000)

• Fibronectin results in a 50% reduction in referrals to centers with neonatal intensive care (historical controls)

Sanin-Blair et al (2004)

• Ultrasound examination of the cervix results in shorter antenatal hospital stay

Summary

• Sonographic cervical length and cervico-vaginal fibronectin cannot distinctly discriminate between preterm and term delivery

• We must choose if we want our test to identify women at low OR high risk

• Clinically most useful: to identify the low risk

• Fibronectin and sonographic cervical length have similar diagnostic performance

• A combination of the two seems to be the best

Summary

• Cervix >3 cm AND negative fibronectin decreases the odds of preterm birth 10 times;

40 - 50% belong to this low risk group

• Cervix <15 mm AND positive fibronectin increases the odds of delivery < 7 days 17.5 times; 7% belong to this high risk group

• 40 - 50% belong to an ”intermediate risk group”

• potential = use of less resources without a negative effect on pregnancy outcome (insufficient scientific evidence)

THANK YOU!

progesteronbehandling som prematurprofylax - sfog · can we prevent preterm delivery in women...

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