Transcript Kein Folientitel

Objectives
• State the different etiologies of second
trimester pregnancy loss
• State the definition of and the risk factors
for cervical incompetence
• Give the management options for short
cervix diagnosed in the 2nd trimester
• Explain the risk-benefits of cerclage
• State the indications for 17P
Second Trimester Preterm Birth: Etiology
Primarily unknown: > 50%
Uterine malformations
– Unicorniuate or bicornuate (↓ space for fetal growth)
– Myomas (submucosal, subplacental):
• Poor implantation, ↑ antepartum bleeding & preterm labor
Cervical Incompetence: 0.1-2.0%
– Prior 2nd trimester abortion
– Prior gynecological surgery (cervical dilatation or conization)
– Maternal exposure to DES
Vaginal Infectious: association but no proven etiology
•
Genital tract colonization & infection
– Poorly defined association between chorioamnionitis and PTL
– Sexually transmitted disease and PTL have common risk factors
– Increased preterm delivery with colonization of:
Group B streptococcus
C. trachomatis
Ureaplasma urealyticum
N. gonorrhoeae
G. vaginalis
T. pallidum
T. vaginalis
Historical Features of Cervical Insufficiency
Hx of >2 second-trimester pregnancy losses
(excluding preterm labor or abruption)
– Hx of losing each pregnancy at an earlier gestational
age
– Hx of painless cervical dilation up to 4-6 cm
– Absence of clinical findings consistent with placental
abruption
– Hx of cervical trauma caused by:
• Cone biopsy
• Intrapartum cervical lacerations
• Excessive, forced cervical dilation during pregnancy
termination
Harger JH. Obstet Gynecol 2002, 100:1313
Cervical Insufficiency (Incompetence)
Definition and Diagnosis is changing
“Inability of uterine cervix to retain a pregnancy in the absence
of contractions or labor”
“Painless cervical dilation”
• Changing concept w/ ultrasound: cervical function as a
continuous variable with range of degrees of competency
– Incompetence is the lowermost end of the continuum
• Lack of clear objective diagnosis
• Incidence??
Previously defined by # of cerclages placed per live birth
– Denmark 1:217, US 1:1842, Israel 1:54
• Success of cerclage compared to past loss (own control)
Prevention of PTB
using TVU CL
• Asymptomatic
– Cerclage
– Indomethacin
– Antibiotics
– Progesterone
Role of Transvaginal Ultrasound
Cervical Length in Cervical
Insufficiency
TVU of cervix - validity
0
10
20
30
40
50
60
70
80
CL and GA
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
Gestational Age (week)
Berghella, Roman, et al, OG 2007
Normal vs abnormal
Cervical length (CL)
•
•
Normal
– 25-50mm at 14-30 wks
Not helpful to measure before 14 weeks
•
•
•
•
Difficult to distinguish upper/ lower cervix
Not helpful in women with 2st trimester loss
Abnormal
– CL <25mm between 14-24wk
The shorter CL, the highest risk for PTB
Studies with Preterm Birth prediction
using TVU CL
• Different from the question of Cervical
Insufficiency
• Show correlation between short cervix
and preterm birth
• Longer cervix reliably excludes PTB
within 2 weeks associated with PTL
Relative Risk of Preterm Delivery according to
percentiles of transvaginal cervical length at 24 weeks
30
Relative Risk of at or below percentile compared to >75th Percentile
25
20
15
10
5
0
Percentile 1st
Cervical length 1.3
5th
10th
2.2
25th
2.6
50th
3.0
75th
3.5
>75th
4.0 (mm)
Iams JD, NICHD, N Engl J Med 334:567-72, 1996
Ultrasound and Digital Exam at 24 weeks to
predict spontaneous preterm birth <35 weeks in
low risk population
Sensitivity
PPV
Cervical Length
< 20 mm
< 30 mm
23%
54%
26%
9%
Funneling
25%
17%
Bishop Score >4
27%
12%
Cervical Score <1.5
13%
21%
Iams JD, N Engl J Med 334:567, 1996 and
Newman RB, J Soc Gynecol Invest 4:152A, 1997
N=2916
Prediction of PTB
TVU CL <25mm, Screening GA 16-24 wks
Risk of PTB < 35 wks
Population
PTB%
% CL
<25mm
Low-risk
4
10
37
92
18
97
High-risk
26
25
69
80
55
88
Twins
32
15
30
92
60
80
Sens Spec PPV
NPV
Iams et al, NEJM 1996
Owen et al, JAMA 2001
Goldenberg et al, AJOG 1996
TVU CL Screening may be useful in women
with Hx of 2nd & 3rd trimester PTB
ACOG Practice Bulletin 2003
TVU of cervix - validity
Effect of GA when CL detected
Incidence of Preterm Birth <35w (%)
80
Week 16
Week 20
Week 24
60
Week 28
40
20
0
0
10
20
30
40
50
Cervical Length (mm)
Berghella, Roman, et al, OG 2007
60
Is there a role for routine TVU CL
screening?
• Low sensitivity (~35%) and low positive
predictive value (~18%)
– Most women with short cervix by TVU do
not deliver preterm
– Result in unnecessary intervention
• Not useful to routine screening
Cerclage
“Nomenclature”
• History-indicated
– Prophylactic, elective
• Ultrasound-indicated
• Physical exam-indicated
• avoid terms such as salvage, urgent,
emergent, rescue, etc
Berghella et al Cont Ob Gyn 2005
What does the evidence show?
Cerclage vs. Expectant management for
History indicated cerclage placement?
• 3 There
RCTs*isshow
no significant
insufficient
Level 1improvement
evidence that:in
outcomes
Cerclage is beneficial to women with
• MRC/RCOG
(n=1292)
largest
trial leading
history of painless
cervical
dilation
nd trimester
– Benefit only in women
with
>3
prior
2
to PTB.
losses or PTB:
Only
with(15%)
Hx of
>3 PTB(32%)
or STL
• PTB women
<33wk: Cerclage
vs Expectant
may
benefit
from
prophylactic
– No
benefit
5 other
subgroups
(1 PTBcerclage.
+ Cone Bx; 2
PTB/no Cone; Hx of Cone Bx; 1st trim AB or uterine
anomaly, twin gestation)
• Perform cerclage at 13-16 weeks
Lazar P. Br J Obset Gynaecol 1984
Rush RW. Br J Obset Gynaecol 1984
MRC/RCOG. Br J Obset Gynaecol 1993
Cerclage vs. Expectant management for
Urgent indicated cerclage placement?
• 4 RCTs* examine Urgent cerclage (McDonald)
– “There
Entry: risk
of PTB plus either
is insufficient
Level 1 evidence.
• CL<25mm/funneling or prolapse/membrane to internal os
The
group of patients who benefit from
– Mean
gacerclage
@ entry 19.3
23.5towk
urgent
has–yet
be defined.
–Urgent
3 of 4 trials
used antibiotic
prophylaxis
cerclage
should be
considered a
• (metronidazole+amoxicillin; clindamycin, erthryomycin)
procedure under benefit.”
– 2 of 4 used indomethacin
1 showed benefit (n =35)
• Only
1
RCT
Rust OA, Obtet Gynecol Clin N Am 2005
– ↑GA del (33 v. 38 wk),↓PNM (0 v 19)
• Other 3 RCT (n=554) showed no benefit
1. Rust OA, (Leigh Valley) Am J Obstet Gynecol 2001,2004
2. Althuisis SM, CIPRACT, Am J Obstet Gynecol 2001
3. Bergella V, Am J Obstet Gynecol 2004
4. To MS (Multinational) Lancet 2004
Another analysis: same studies
Short cervical length on ultrasound
Intervention:
Ultrasound-Indicated
Cerclage
• Patient-level Meta-analysis of the 4 RCTs published
–
–
–
–
Althuisius et al
Rust et al
Berghella et al
To et al
AJOG 2001;185:1106-12
AJOG 2001;185:1098-105
AJOG 2004;191;1311-7
Lancet 2004;363:1849-53
Meta-analysis of Urgent Cerclage
Berghella et al, Obstet Gynecol 2005
Cerclage & risk of Preterm birth <35 wk
“Cerclage
does not0.84
prevent
PTB
in all women
– Include multiples:
(95%CI
0.67,1.06)
with
short -cervix.
Cerclage may reduce PTB
• Cerclage
29.2% (89/305)
• in
Control
- 34.8% gestations
(105/302)
singleton
with short CL,
– Singleton:
0.61 (95%CI
0.92)
especially
in those0.40,
with
prior PTB.
• Cerclage - 23.4% (25/107)
A well powered trial is indicated.
• Control - 38.6% (39/101)
• Singleton w/ prior STL: 0.57 (95%CI 0.33,0.99)
Cerclage
in twins
is 4.01)
associated with
– Twins:
2.15 (95%CI
1.15,
• significantly
Cerclage - 75% (18/24)
higher
• Control - 36% (9/25)
incidence of PTB.”
Berghella et al, Obstet
1. Rust OA, (Leigh Valley) AJOG 2001
2. Althuisis SM,
CIPRACT, AJOG 2001
Gynecol
2005
3. Bergella V, AJOG 2004
4. To MS (Multinational) Lancet 2004
Singleton
Prior PTB and CL <25mm
(n=208)
70
PTB<35wk (%)
60
RR 0.61, 95%CI 0.40-0.92
RR 0.58, 95%CI 0.34-0.98
50
39% decrease in PTB<35wk
42% decrease in PTB<32wk
PTB<32wk (%)
40
30
20
10
23%
39%
16% 28%
0
Cerclage
No Cerclage
Cerclage
No Cerclage
Berghella et al, Obstet Gynecol 2005
Awaiting NIH Trial
•
•
•
•
Prior SPTB 16-34w
Owen J, et al, UAB
CL < 25mm
16-23 weeks
Recruitment completed Nov. 2007
– >1,000 screened
– 300 randomized
Awaiting Second Cerclage RCT
www.controlled-trials.com
• The CIRCLE trial
• UK
• Singleton with prior PTB<34w
– U/S indicated cerclage if CL<20mm at 1624w
– History-indicated cerclage if history
suggestive of cervical insufficiency
• Target: 1890 pts
Benefits of
Ultrasound-screening of CL
• Identify high-risk
patients who benefit
from NO intervention
• Avoid routine historyindicated cerclage
• Avoid any intervention if
cervix stays closed and
long
– >60% of high-risk women
(women with prior PTB)
Other therapies for short CL
(without cerclage)
•
•
•
•
Indomethacin
Antibiotics
Progesterone
Pessaries
Infection: Chicken vs egg?
Long
cervix
Short
cervix
Short cervix associated with infection
• Higher Amniotic Fluid Intraleuking-6
• + Amnio./Chorioamnionitis
• Acute inflammatory lesions of the placenta
• Short cervix more predictive of early PTB
(<28 w):
– most associated (80%) with infection
Other aspects related to cerclage
• Amniocentesis precerclage
• Technique
– Type
• McDonald
• Shirodkar
• transabdominal
– Suture material
– Placement
• Tocolytics
• Antibiotics
Short CL on TVU
• <25mm
• 14-24weeks
• >80% of women are having
asymptomatic contractions
Lewis, Pelham, Done, Sawney, Talucci, Berghella
J Mat Fetal Neo Med 2005
Indomethacin
(secondary meta-analysis using no cerclage group)
139 women with CL <25mm
99 indomethacin
29 (29.3%) PTB <35w
40 NO indomethacin
17 (42.5%) PTB <35w
RR 0.69, 95% CI 0.44-1.13
Berghella, Rust, Althuisius AJOG 2006
Indomethacin
(n=139)
CL < 25 mm
(secondary meta-analysis using no cerclage group)
70
%PTB<35wk
60
RR 0.69, 95% CI 0.44-1.13
%PTB<24wk
RR 0.14, 95% CI 0.02-0.92
50
40
30
42.5%
20
29.3%
1.0%
10
7.5%
0
Indomethacin
No Indomethacin
Indomethacin
No Indomethacin
Berghella, Rust, Althuisius AJOG 2006
Antibiotic therapy
(secondary meta-analysis using no cerclage group)
276 women with CL <25mm
123 antibiotics
36 (29%) PTB <35w
153 NO antibiotics
51 (33%) PTB <35w
Adjusted RR 0.80, 95% CI 0.40-1.59
No apparent role for antibiotics
Use of Progesterone to Reduce
Preterm Birth No. 419 • October 2008
• Progesterone supplementation for the prevention of
recurrent preterm birth should be offered to women with
a singleton pregnancy and a prior spontaneous preterm birth
due to spontaneous preterm labor or premature rupture of membranes.
• Current evidence does not support the routine use of progesterone in
women with multiple gestations.
• Progesterone supplementation for asymptomatic women with an
incidentally identified very short cervical length (less than 15 mm) may
be considered; however, routine cervical length screening is not
recommended.
• The American College of Obstetricians and Gynecologists’ Committee
on Obstetric Practice and the Society for Maternal Fetal Medicine
believe that further studies are needed to determine if there are other
indications for progesterone therapy for the prevention of preterm
delivery.
NICHD MFM: Placebo-controlled RCT with 17P in highrisk pregnancies to prevent PTB
•
17a-hydroxy-progesterone caproate (“17P”)
– 459 Women with documented history of a previous spontaneous singleton
preterm birth < 37 wk GA
– Enrolled 16-20 wk, given 250 mg i.m. weekly
– ↓Preterm and early preterm birth, ↓ low birth-weight
– ↓ Infant complications (↓ IVH, ↓NEC, ↓NICU admit, ↓ oxygen Rx
– Four-year follow-up: no adverse health outcomes of surviving
children
Meiss PJ. N Eng J Med 2003, 348:2370
Summary of Progesterone
for Women with Prior SPTB
and current Singleton Gestation
• 17P efficacy:
– proven by 6 RCTs
– meta-analyses support
– recommended by ACOG
• Oct 2008 Practice Bulletin
• Vaginal Prog (dosing, preparation)
– One negative and one positive trial
SHORT CERVIX
Vaginal Progesterone Gel 90mg
• 172 women with cervical length 32 mm
• No significant difference between treatment groups
GA @
Delivery
(wk)
Progesterone
Placebo
≤37
44.6%
51.7%
.36
≤35
22.9%
30.3%
.30
≤32
7.2%
13.5%
.21
≤28
1.2%
6.7%
.12
Treatment
P
DeFranco AE, et al. Ultrasound Obstet Gynecol. 2007;30:697-705.
Vaginal Progesterone Gel:
Cervical Length <28 mm
Gestation Age at
Delivery
Cervical Length <28 mm
Placebo, n = 27
Progesterone, n = 19
DeFranco AE, et al. Ultrasound Obstet Gynecol. 2007;30:697-705.
Vaginal Progesterone Gel:
Infant Outcomes at <28 mm
Group
Fetal Outcomes
P
Progesterone
(n=19)
Placebo
(n=27)
Birth weight (g, mean [SD])
2726 (645)
2290 (937)
.1
Hospital days (n, mean [SD])
5.8 (9)
18.2 (25.5)
.055
3 (15.8%)
14 (51.9%)
.016
Days in NICU per admission (n,
mean [SD])
1.1 (2.7)
16.5 (24.9)
.013
Respiratory distress syndrome
(n)
1 (5.3%)
8 (29.6%)
.060
NICU admission (n)
NICU = neonatal intensive care unit.
DeFranco AE, et al. Ultrasound Obstet Gynecol. 2007;30:697-705.
Progesterone for PTB prevention
Other indications by MFMs
40
35
30
25
20
2003
2005
15
10
5
0
No prior Dilated
PTB
Cevix
Short
CL
Multiple
PTL
2003 Survey: Ness, Baxter, Hyslop, Berghella. J Reprod Med 2006;51:411-5
2005 Survey: Ness, Dias, Damus, Burd, Berghella. Am J Obstet Gynecol 2006;195:1174-9
RCT vaginal progesterone for Women
with a Short Cervix
• 24,620 asymptomatic women screened
at 22 (20-25)w by TVU
• 250 (24 with twins) with CL ≤15 mm
• Randomized
– 200 mg vaginal progesterone or
placebo nightly 24 to 34w
• Primary outcome: spontaneous
PTB< 34 weeks
– Did not report neonatal outcome
Fonseca EB, et al. N Engl J Med. 2007;357:462-469.
Efficacy: Natural Progesterone—
Cervical Length ≤15 mm
Kaplan-Meier Plot of the Probability
of Continued Pregnancy without
Delivery among Patients Receiving
Vaginal Progesterone (200 mg) as
Compared with Placebo.
Progesterone reduces the risk of spontaneous
delivery before 34 weeks by 44.2%
• Hazard ratio for Progesterone:
0.57(95% CI, 0.35-0.92, P=.02
Cumulative Percentage of Continued Pregnancies
100
Progesterone
90
80
P=0.02
70
Placebo
60
0
0
160 170 180 190 200 210 220 230 240
Gestational Age (days)
Fonseca EB, et al. N Engl J Med. 2007;357:462-469.
Current/Planned RCTs
Where
Israel
Population
Prior PTB
Prog dose
90mg Vag
Oklahoma
Australia
Prior PTB
Prior PTB
17P
100mg Vag
UK Nicolaides
Netherlands
NICHD
Columbia Labs
Short CL 16-25mm
Short CL <25mm
Short CL <30mm
Short CL 10-20mm
200mg
200mg Vag
17P
90mg Vag
Paris
Short CL <27mm and either:
PTL/priorPTB/twins
17P
Yale/Matria
Switzerland
PTL
PTL
17P
200mg Vag
Malaysia
PTL
N
984
300
560
375
17P
256
www.controlledtrials.com
Current/Planned RCTs: Multiples
Where
Spain
Beirut
Calgary
Denmark
Glasgow, UK
Netherlands
Obstetrix
Population
Twins
Prog dose
200/400mg
Vag
Twins
17P
Twins
90mg Vag
Twins
200mg Vag
Twins
90mg Vag
Multiples
17P
Twins/Triplets 17P
N
290
100
750
500
700
321
www.controlledtrials.com
Conclusion
Focus on the diagnosis
• Diagnosis: Insufficient cervix (Hx PTB + short CL?)
– Cerclage
• Diagnosis: Inflammation
– Progesterone: recommended by ACOG
• Consistent evidence of 17Prog (weekly i.m. injections)
– Indomethacin?
• Diagnosis: Infection
– Antibiotic?
• Diagnosis: Endothelial / clotting disorder
– ?
Conclusion
• Use of TVU CL in high risk pregnancies to
assess for PTB risk
– Asymptomatic
• Singleton with prior PTB
– CL ≥ 25mm: Avoid intervention
– CL < 25mm: Consider Cerclage
» awaiting NIH RCT
• Singleton
– Progesterone recommended by ACOG
– Indomethacin? (with cerclage)
– other interventions? (bed rest, pessary, etc)
Our Patient: Prevention
• From history: prior PTB
• Obtain MFM consult
• 17 P 250 mg i.m. Weekly starting at 16 wk
• TVU CL at 16 week
– Consider cerclage if <25mm
• Treat any vaginal infections