Progesteronbehandling som prematurprofylax. Lil Valentin Skånes Universitetssjukhus Malmö

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1 Progesteronbehandling som prematurprofylax Lil Valentin Skånes Universitetssjukhus Malmö

2 Progesteronbehandling kan minska risken för prematurbörd i vissa grupper av gravida.

3 Vilka gravida nytta av progesteron som prematurprofylax? Screena en hel population behandla högriskgruppen? De som fött prematurt tidigare? Flerbörd? Prematura värkar?

4 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 mm lång Hassan et al UOG 2011; 38: 18

5 RCT, asymptomatisk simplexgraviditet weeks Certifierad undersökare 2.3% Gel varje dag från 20 veckor till 36+6 veckor Hassan et al UOG 2011; 38: 18

6 RCT, asymptomatisk simplexgraviditet 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% Hassan et al UOG 2011; 38: 18

7 RCT, asymptomatisk simplexgraviditet Number needed to treat (NNT) med progesteron gel för att förhindra En prematur förlossning <33 veckor: 14 Ett fall av RDS: 22 Hassan et al UOG 2011; 38: 18

8 Är screening kostnadseffektiv? JA, mycket kostnadseffektiv För 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

9 Vem har nytta av progesteron som prematurprofylax? Screena en hel population av simplex JA, behandla om cervix mm vid 20 veckor De som fött prematurt tidigare?

10 Progesteron behandling av simplex med tidigare prematurbörd Studie Beh. Beh. tid Preterm <32-34 v Prog Plac 1 17OH-Prog v. 11% 20% i.m.1g/vecka 2 Prog 100mg v. 3% 19% vaginalt 1g/dag Subanalys: Progesteron effekt om cervix < 28 mm 3 Prog 90mg v. 10% 11% vaginalt 1g/dag 1) Meiz 2003 NEJM; 2) da Fonseca 2003 AJOG; 3) O Brien 2007 UOG 4) defranco 2007

11 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 ( ) Neonatal mortalitet/ morbiditet 0.41 ( ) Romero et al. Am JOG 2012; 206:124

12 Vem har nytta av progesteron som prematurprofylax? Screena en hel population av simplex JA, behandla om cervix mm vid 20 veckor De som fött prematurt tidigare? JA, de som har cervix < 25mm vid 20 veckor Flerbörd?

13 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

14 Progesteronprofylax för tvillinggravida med cervix < 25 mm Ingen specifikt designad RCT IPD meta-analys (n =52) Relativ risk Preterm < v ( ) Neonatal morbiditet/ 0.52 ( ) mortalitet Romero et al. Am JOG 2012; 206:124

15 Vem har nytta av progesteron som prematurprofylax? Screena en hel population av simplex JA, behandla om cervix mm vid 20 veckor Alla 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?

16 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

17 Vem har nytta av progesteron som prematurprofylax? Screena en hel population av simplex JA, behandla om cervix 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?????????

18 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:??????

19 Om cervix längdsmätning skall vara utvalskriterium måste man kunna mäta cervix korrekt Man skall vara certifierad: FMF kurs, Praktisk handledd träning, praktisk examination

20 Frågor Administrationssätt för progesteron? Dos av progesteron? Biverkningar av progestronbehandling? Vilken behandling om cervix <5 mm? 6-10 mm? 10-20mm? mm? Hur länge behandla? 34 weeks? 35 Weeks? 36 weeks? Progesteron plus cerclage? Progesteron plus antibiotika?

21

22 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

23 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 mm lång Hassan et al UOG 2011; 38: 18

24 RCT in asymptomatic singeltons weeks Certified examiner 2.3% Gel every day from 20 weeks to 36+6 weeks Hassan et al UOG 2011; 38: 18

25 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% Hassan et al UOG 2011; 38: 18

26 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 Hassan et al UOG 2011; 38: 18

27 Is screening cost-effective? YES, highly cost-effective For 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

28 Vem har nytta av progesteron som prematurprofylax? Screena en hel population av simplex behandla högriskgruppen? JA Alla som fött prematurt tidigare? Flerbörd? Prematura värkar?

29 Progesteron behandling vid tidigare prematurbörd (simplex) Studie Beh. Beh. tid Preterm <32-34 v Prog Plac 1 17OH-Prog i.m v. 11% 20% 1g/vecka 2 Prog 100mg kapsel v. 3% 19% vag 1g/dag Subanalys: Progesteron effekt om cervix < 28 mm 3 P 90mg gel v. 10% 11% vag 1g/dag 1) Meiz 2003 NEJM; 2) da Fonseca 2003 AJOG; 3) O Brien 2007 UOG

30 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

31 Progesterone treatment of women with short cervix (<25mm) who have delivered < 37 weeks before Relative Risk Preterm < 33 weeks 0.54 ( ) Neonatal mortality/ morbidity 0.41 ( ) Romero et al. Am JOG 2012; 206:124

32 NNT?

33 Vem har nytta av progesteron som prematurprofylax? Screena en hel population av simplex behandla högriskgruppen? JA Alla som fött prematurt tidigare? JA, de som har cervix < 25mm vid 20 veckor Flerbörd? Prematura värkar?

34 Progesteronprofylax för tvillinggravida RCT Tre stora: beh. med 17-OH-Prog i.m. Två stora: beh. vaginalt Progesteron från till veckor INGEN EFFEKT på Prematuritetsfrekvens (< 28,32,34,35 veckor) Neonatalt utfall Lim 2011; Comb 2011; Rouse 2007; Norman 2009; Rode 2011

35 Progesteronprofylax för tvillinggravida med cervix < 25 mm Ingen specifikt designad RCT IPD meta-analys Relative risk Preterm < v ( ) Neonatal morbiditet/ 0.52 ( ) mortalitet Romero et al. Am JOG 2012; 206:124

36 Vem har nytta av progesteron som prematurprofylax? Screena en hel population av simplex behandla högriskgruppen? JA Alla 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?

37 Progesteronbehandling vid prematura värkar

38 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

39 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% Berghella et al Obstet Gynecol 2011;117:663

40 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 Berghella et al Obstet Gynecol 2011;117:663

41 Is treatment of high risk women cost-effective? No cost-effectiveness studies

42 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

43 Summary Short cervix (<15 mm) at midgestation increases risk of preterm delivery in asymptomatic women (singleton) In asymptomatic women (singleton) with cervix mm at midgestation vaginal progesterone decreases Preterm delivery rate (relative risk ~ 50%) Neonatal mortality/morbidity (relative risk ~60%) Cost-effective

44 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?

45 THANK YOU!

46 Risk delivery <32 weeks 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 <25mm Cervix length at 23 weeks, mm Skentou et al UOG 2001; 17: 7 10

47 Can we prevent preterm delivery in asymptomatic women expecting TWINS with a short cervix at midgestation? Can we thereby improve neonatal outcome?

48 Cerclage in TWINs short cervix (sub-analysis of meta-analysis) Increases Preterm delivery < 35 weeks Berghella et al OG 2005; 106:181-9

49 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

50 Progesterone treatment in TWINs with short cervix (<25mm) (subanalysis of meta-analysis, n=52) Relative risk Preterm < 33 weeks 0.70 ( ) Neonatal morbidity /mortality 0.52 ( ) Romero et al. Am JOG 2012; 206:124

51 Questions Dose of progesterone What treatment for cervix <5 mm? 6-10 mm? 10-20mm? mm? How long to treat for? 34 weeks? 35 Weeks? 36 weeks? Progesterone plus cerclage? Progesterone plus antibiotics?

52 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

53 How can we discriminate between true and false preterm labor? Lil Valentin Kvinnokliniken Universitetssjukhuset MAS, Malmö

54 Women in preterm labor deliver < 7 days 10% < 34 weeks % < 37 weeks 20 25%

55 Tests to discriminate between true and false preterm labor fetal fibronectin in cervix or vagina ultrasound examination of the cervix cervical length funnelling

56 The performance of diagnostic tests Positive likelihood ratio, LR+ Negative likelihood ratio, LR- LR+ = sensitivity/1 minus specificity LR- = 1 minus sensitivity/specificity

57 The performance of diagnostic tests Pretest odds x LR+ = odds after a positive test result Pretest odds x LR- = odds after a negative test result

58 The performance of diagnostic tests LR+ > 10, LR- < 0.1 LR+ 5 10, LR LR+ 2 5, LR LR+ 1 2, LR Conclusive diagnosis Moderately good test Poor test Useless test

59 Do we want a test that can EXCLUDE preterm delivery? PREDICT preterm delivery?

60 Studies on diagnostic performance differ with regard to outcome variable Delivery < 37 weeks < 35 weeks < 34 weeks < 32 weeks < 28 days < 21 days < 14 days < 7 days < 2 days

61 Ability of cervical length to predict delivery < 37 weeks in women with preterm labor; singletons; pre-test risk is assumed to be 20% Study Cut-off cervix length LR+ LR- Risk if + test Risk if - test Rizzo mm % 10% 63% Rozenberg mm % 6% 39% Test negative 50% har cervix > 30 mm 5% föder < 37 veckor Önderoglu mm % 5% 52% Honest -03, metaanalysis 30 mm (3 studies) % 6% 69%, 54%,?% Murakawa mm % 3% 53%

62 Fibronectin to predict preterm delivery in women with preterm labor Pretest risk of delivery < 37 weeks is assumed to be 20% Pretest risk of delivery < 34 weeks is assumed to be 10% Meta-analysis (17 studies) ; Honest et al 2002 Hur många har negativt LR+ LR- Post test risk if test + fibronektintest? 11% föder < 37 veckor Del. < 37 v % 11% Post-test risk if test- Del. < 34 v % 3%

63 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 mm % 5% 15% Gomez mm % 4% 4% 15% har cervix < 15mm 50% föder < 7 dagar Fuchs mm % 2% 14% Tsoi mm % 0.8% 16% Tsoi mm 4.3 <0.1 33% 1% 48%

64 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 Hur många har positiv fibronektin test? LR+ LR- Risk if positive test % 3% Risk if negative test 40% föder < 7 dagar Honest; meta-analysis of 17 studies

65 How can we best predict preterm delivery in women with preterm labor? Ultrasound examination of cervix? Fibronectin test? A combination of both?

66 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 Risk if - test Rozenberg < 37 w Cx > 26 mm AND ffn % 4% Gomez < 35 w Cx > 30 mm AND ffn % 1%

67 Combining fibronectin and cervix length = improvement Pretest risk is assumed to be 10% Study Outcome Test LR+ LR- Risk if test+ Gomez < 7 d Cx < 15mm AND ffn + % +test % 7%

68 Combining fibronectin and cervix length = improvement Pretest risk is assumed to be 17% Study Outcome Test LR+ LR- % - test Rist at test- Hinz < 28 d cx <20mm % 3% High risk Low risk cx mm AND ffn+, cx mm AND ffn- cx >31mm

69 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

70 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

71 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)

72 THANK YOU!