Predição e prevenção de prematuridade Ben Willem Mol Adelaide, Australia
Disclosures My institute has been paid for talks and advice (Schering-Plough, MSD, Ferring, ObsEva) I have been an invited speaker at commercially sponsored conferences I am neither a politician nor a diplomat
Clinical spectrum • Prevention • Prediction • Treatment
Data in 2003 that progesterone prophylaxis is effective at reducing preterm delivery in high risk singleton pregnancy
Pessary • 1959 first introduction pessary to prevent PTBcervix • Designed to move the weight of the pregnancy to anterior and the cervix to posterior
• Encompasses the cervix as a cerclage • Different types (e.g. Smith, Hodge, Risser): Arabin pessary most popular
Stars event, Perth, September 24 2014 (5) Vitsky M. Am J Obstet Gynecol 1961
PESSARIES IN MULTIPLE PREGNANCY TO PREVENT PRETERM BIRTH Sophie Liem, Ewoud Schuit, Joke Bais, Karin de Boer, Kitty Bloemenkamp, Jozien Brons, Hans Duvekot, Bas Nij Bijvank, Maureen Franssen, Ingrid Gaugler, Jan Molkenboer, Martijn Oudijk, Dimitri Papatsonis, Paula Pernet, Martina Porath, Liesbeth Scheepers, Marko Sikkema, Jan Sporken, Harry Visser, Wim van Wijngaarden, Mallory Woiski, Marielle van Pampus, Ben Willem Mol, Dick Bekedam
Baseline characteristics Pessary (N=403)
No Pessary (N=410)
23.7 (21.5-26.3)
22.9 (21.0-25.8)
222 (55%)
225 (55%)
Previous preterm delivery
29 (7%)
26 (6%)
Smoking during pregnancy
16 (4%)
25 (6%)
Higher-order multiple
9 (2%)
9 (2%)
Monochorionic
87 (22%)
100 (25%)
GA at CL measurement
18.8 (1.1)
18.7 (1.1)
CL measurement 16-22 wks
328 (81%)
293 (71%)
Cervical length overall (SD)
43.6 (8.1)
44.2 (8.5)
BMI (IQR) Nulliparous
Primary outcome Pessary (N=410)
No pessary (N=407)
Relative Risk (95% CI)
53 (13%)
55 (14%)
0.98 (0.69-1.4)
Periventricular leukomalacia
0 (0%)
5 (1%)
NA
Respiratory distress syndrome
27 (7%)
18 (4%)
1.5 (0.82-2.7)
Broncho pulmonal dysplasia
2 (0%)
6 (1%)
0.34 (0.07-1.7)
Intraventricular hemorrhage
6 (1%)
5 (1%)
1.2 (0.37-4.0)
Necrotizing enterocolitis
8 (2%)
6 (1%)
1.4 (0.47-3.9)
Sepsis
16 (4%)
18 (4%)
0.89 (0.45-1.8)
Stillbirth
10 (2%)
10 (2%)
1.0 (0.41-2.6)
Death before discharge
16 (4%)
18 (4%)
0.90 (0.46-1.8)
Neonatal outcome Composite poor perinatal outcome
Proportion of women pregnant (%)
Time to delivery
Gestational age in weeks
Subgroup analysis • 25th percentile at 38 mm • P value for interaction 0.01
Subgroup <25th percentile (38 mm) Pessary (N=78)
No pessary (N=55)
Relative Risk (95% CI)
9 (12%)
16 (29%)
0.40 (0.19-0.83)
Stillbirth
3 (4%)
2 (4%)
1.1 (0.18-6.2)
Periventricular leukomalacia
0 (0%)
1 (2%)
NA
Respiratory distress syndrome
7 (9%)
2 (4%)
2.5 (0.53-11.5)
Broncho pulmonal dysplasia
0 (0%)
2 (4%)
NA
Intraventricular hemorrhage
0 (0%)
3 (5%)
NA
Necrotizing enterocolitis
0 (0%)
1 (2%)
NA
Sepsis
2 (3%)
4 (7%)
0.38 (0.05-3.1)
Death before discharge
2 (3%)
10 (18%)
0.14 (0.03-0.65)
Neonatal outcome
Composite poor perinatal outcome
Time to delivery Proportion of women pregnant (%)
<25th percentile
P=0.01
Gestational age in weeks
â&#x2030;Ľ25th percentile
Delivery <25th percentile (38 mm) Pessary (N=78)
No pessary (N=55)
Relative Risk (95% CI)
36+3 (35+0-37+2)
35+0 (30+5-36+5)
0.49 (0.41-0.77)
< 28 wk
3 (4%)
9 (16%)
0.23 (0.06-0.87)
< 32 wk
11 (14%)
16 (29%)
0.49 (0.24-0.97)
< 37 wk
50 (64%)
43 (78%)
0.82 (0.54-1.2)
GA at delivery (median (IQR))
Perinatal outcome subgroup (CL <38mm) Pessary Number of children No pessary
Gestational age in weeks
Distribution of CL in Twins 30 mm
25 mm
Posthoc analysis Pro TWIN
Preterm birth: RCT of cervical pessary in twins
Elena Carreras Maria Goya Andrea Gascón Manel Mendoza Carlota Rodó
Hospital Universitari Vall d’Hebron. Barcelona, Catalonia, Spain
Arabin pessary in twins : PECEP-TWIN Trial Barcelona: Vall d’Hebron, Dexeus, St J. Reus Mallorca: Son Llàtzer Madrid: La Paz 2931 eligible women 644 declined to participate
2287 consented
Exclusion criteria: cervix > 25 mm fetal abnormalities contractions bleeding
154 cervix ≤ 25 mm 17 declined to participate
137 randomly assigned
68 assigned to Arabin pessary
3 lost follow up
66 assigned to expectant management
Primary endpoint: spontaneous premature delivery before 34 weeks
PECEP-TWIN Trial: baseline characteristics P value
Arabin Cervical Pessary group
Expectant Management group
(n=68)
(n=66)
Maternal age (years)
30 (24-40)
31 (19-43)
ns
Body mass index (kg/m2)
25 (21-28)
25 (22-30)
ns
Nulliparous
31 (46%)
29 (44%)
ns
Parous with no previous preterm birth
25 (37%)
26 (36%)
ns
Parous with â&#x2030;Ľ 1 preterm birth
12 (18%)
11 (17%)
ns
Cigarette smoking during pregnancy
10 (15%)
9 (14%)
ns
White
41 (63%)
38 (58%)
ns
Latin American
15 (22%)
16 (24%)
ns
other
12 (18%)
12 (18%)
ns
Monochorionic pregnancy
13 (19%)
12 (18%)
ns
Assisted Reproductive Techniques
21 (31%)
20 (30%)
ns
22.0 (21.1-23.6)
23.0 (21.2-23.4)
ns
15 (8-18)
19 (10-25)
ns
Ethnic origin (self reported)
Weeks at randomisation Cervical length at randomisation (mm)
PECEP-TWIN Trial: outcomes II
Arabin cervical pessary group (n=68)
Expectant management group (n=66)
P value
Spontaneous delivery before 28 weeks
4 (5.9%)
9 (13.6%)
0.02
Spontaneous delivery before 34 weeks
11 (16.2%)
17 (25.7%)
0.001
36.4 (26.4-38)
35.0 (22.6-38)
0.01
Pregnancy outcome
Gestational age at delivery (weeks)
PECEP-TWIN Trial: outcomes III
Arabin cervical pessary group (n=136)
Expectant management group (n=130)
P value
Fetal death
0
0
-
Neonatal death
0
-
-
Birthweight less than 1500 g
6 (4.4%)
8 (6.1%)
ns
Birthweight less than 2500 g
20 (14.7%)
24 (18.2%)
ns
Necrotising enterocolitis
0
2 (1.5%)
ns
Intraventricular haemorrhage
0
4 (3%)
ns
Respiratory distress syndrome
8 (5.8%)
8 (6.1%)
ns
0
0
-
4 (2.9%)
6 (7.5%)
ns
8 (5.9%)
12 (9.1%)
ns
Perinatal outcome
Adverse outcomes
Retinopathy Treatment for sepsis Composite adverse outcomes
Progesterone for prevention of pre-term birth in twins
Stars event, Perth, September 24 2014
Norman JE et al 2009, Lancet 373: 2034
Rouse DJ et al 2007 N Engl J Med 357:454
Combs A et al 2011, Am J Obstet Gynecol 204: 221 Rode L et al 2011, Ultras Obstet Gynecol 38: 272
What does all this tell us ? â&#x20AC;˘ How many trials do we need to tell us that progesterone does not prevent preterm birth in twin pregnancy? â&#x20AC;˘ Could we have got to a faster answer if we had joined forces at the beginning ? â&#x20AC;˘ Could we have got a more relevant answer if we had joined forces at the beginning ?
Do vitamins C and E prevent pre-eclampsia?
International information sharing and collaboration
PSANZ IMPACT 2014
GONet
Progestogens in twins • Published • Rouse et al • Fonseca et al • Norman et al • Briery et al • Cetingoz et al • Lim et al • Combs et al • Rode et al • Aboulghar et al • Wood et al • Serra et al • Senat et al • Ongoing • Nassar et al
NEJM 2007 NEJM 2007 Lancet 2009 South Med J 2009 Arch Gyn Obs 2010 Obstet Gynecol 2011 AJOG 2011 Ultrasound Obstet Gynecol 2011 Reprod Biomed Online 2012 J Perinat Med 2012 BJOG 2013
USA UK UK USA Turkey Netherlands USA Denmark/Austria Egypt Canada Spain
AJOG in press
France
NCT00141908
Libanon
Results: subgroups Subgroups: no effect of progestogen for (p-value interaction > 0.05) – Mono-/dichorionic twins – Prior spontaneous preterm birth <37 weeks
Short cervix ≤25 mm at randomisation (adverse perinatal outcome) Vag vs. control: 15/56 vs 22/60; RR 0.57; 95% CI 0.47–0.70; NNT 10
Cerclage, pessary or progesterone? (singletons high risk) Cerclage
Pessary
(Progesterone)
-
-
0.70
Secondary (short cervix)
0.80
0.70
0.70
Tertiary (emergency)
? ?
Primary (previous preterm)
no
Cerclage, pessary or progesterone? (twins) Pessary Cerclage
(Progesterone)
Primary
no
no
no
Secondary (short cervix)
no
0.50
0.50
Tertiary (emergency)
?
no
no
PROspective Meta-analysis for Pessary Trials
Singleton Trials (some include twins) USA, MFMU Mini-Monster
Matt Hoffman
USA
PoPPS
The Netherlands UK
Quadruple P Singleton RECAP
Lorraine Dugoff, Jack Ludmir Eva Pajkrt
Canada
P3S
Brazil
P5
USA
KUMC
Zarko Alfirevic Liz Asztalos, Jon Barrett Rodolfo Pacagnella Carl Weiner, Gene Lee
Twins Trials UK USA,MFMU France
STOPPIT-2 PROSPECT PESSARâ&#x20AC;&#x2122;-ONE
Jane Norman Joseph Biggio Christophe Vayssiere
USA Netherlands
PoPPT Quadruple P Twins
Lorraine Dugoff Eva Pajkrt
Elvira van Vliet L Askie, BW Mol, MA Oudijk
Spontaneous preterm birth • Vascular placental lesions • Failure of spiral artery remodeling • Abnormal plasma profile, comparable to women with pre-eclampsia
Backgroun
Study
Results
Conclusion
PARIS IPD
Antiplatelets in pregnancy in women at risk of PE • A lower risk of PE (RR 0.90), 95% CI 0.84-0.97) • A lower risk of birth <34 weeks (RR 0.90, 95%-CI 0.83-0.98)
Outcome measures • Spontaneous PTB 20 - 37 weeks • Spontaneous PTB 20 - 34 weeks • Spontaneous PTB 20 - 28 weeks • Subgroup analysis • Kaplan Meier Curve
Results aspirin for spontaneous preterm birth • Lower risk of SPTB < 37 weeks: RR 0.93, 95% CI 0.86-0.996 • Lower risk of SPTB <34 weeks: RR 0.86, 95% CI 0.76 – 0.99 • RR for SPTB <28 0.81 (95% CI 0.59-1.12)
Results aspirin for spontaneous preterm birth
A day without randomisation is a day without progress
Un dĂa sin asignaciĂłn es un dĂa sin avances
Twitter @bwmol ben.mol@adelaide.edu.au www.globalobstetricsnetwork.org/