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PRETERM LABOR
HOW CAN WE DO A BETTER
JOB?
BACKGROUND
• Preterm defined as < 37 weeks
• PTD has continued to increase (until
recently?)
• 1/8 births are preterm
• Earlier delivery associated with
increased risk of death and disability
• Leading cause of neonatal deaths
since 2001
Magnitude of the Problem
• Definition (< 37 weeks)
• 2004: more than 500,000 neonates
were born preterm
• Frequency: 12.5 %
The Lancet Editorial 2006;368:339
Frequency of preterm birth by
gestational age (1995-2000)
• < 28 weeks : 0.82 %
• < 32 weeks: 2.2 %
• 33-36 weeks: 8.9 %
• < 37 weeks: 12.5%
IOM Report-July 2006- page 72/2006
Alexander GR et al 2006 (under review)
Survival by gestational age among
live-born resuscitated infants
Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee
Mercer BM Obstet Gynecol 2003;101:178 –93.
Acute morbidity by gestational age among
surviving infants
Results of a community-based evaluation of 8523 deliveries, 1997–1998, Shelby County, Tennessee
Mercer BM Obstet Gynecol 2003;101:178 –93.
BACKGROUND
• Preterm delivery accounts for
– 1 in 5 cases of mental retardation
– 1 in 3 cases of visual impairment
– 1 in 2 cases of cerebral palsy
• Also increases risk for adult diseases
–
–
–
–
–
MI
Stroke
Hypertension
Diabetes
? cancer
Complications of “Late Preterm
or Near Term Infants”
• Cold Stress
• Hypoglycemia
• RDS
• Jaundice
• Sepsis
IOM Report-July 2006- page 72/2006
Institute of Medicine Report
Preterm Birth: Causes, Consequences, and
Prevention
Richard E. Behrman, Adrienne Stith Butler, Editors
Institute of Medicine of the National Academies, 2006
IOM Report – July 2006
• “Babies born before 32 weeks have the greatest
risk for death and poor health outcomes, however,
infants born between 32 and 36 weeks, which make
up the greatest number of preterm births, are still
at higher risk for health and developmental
problems compared to those infants born full term
IOM Report page 72
Magnitude of the Problem
• The infant mortality rate for very preterm infants
(delivered < 32 weeks of gestation) was 186.4,
nearly 75 times the rate for infants born at term
(2.5) (37–41 weeks of gestation)
• 20% all infants born <32 weeks do not survive the
first year of life
Mathews TJ. et al. National Vital Statistics Reports 2004;53:1-32
RISK FACTORS
•
•
•
•
•
•
•
•
•
Multiple gestations
Prior PTB
African American race
Smoking
Substance abuse
Poor oral hygiene
BMI < 20
Short inter-pregnancy interval
? Stress (physical/emotional)
RISK OF PRETERM BIRTH
•
•
•
•
Term/term
PTD/term
Term/PTD
PTD/PTD
4%
12%
23%
32%
Carr-Hol RA BJOG 1985
• 50% of patients delivery within 1 week
• 75% of patients delivery within 2 weeks
Frequency of Preterm Birth
by Ethnic Group
Non-Hispanic African-American
17.8%
American Indians/Native Alaskans
13.5%
Hispanics
11.9%
Whites
11.5%
Asian and Pacific Islanders
10.5%
Source: CDC 2004 Births: Preliminary Data for 2003
http://www.cdc.gov/nchs/data/nvsr/nvsr53/nvsr_09.pdf (accessed August 30, 2005)
SERIOUSLY, WHY CAN’T WE
FIGURE THIS OUT???
• Many different causes
• Patient demographics are different
• Socioeconomic factors
• Concerns regarding safety of
medications
• Inability to do quality studies
The Preterm Parturition Syndrome
Uterine
Overdistension
Vascular
Cervical
Disease
Hormonal
Immunological
Infection
© VR RR MM
Unknown
MAKING THE DIAGNOSIS
OF PRETERM LABOR
CAN WE DO A BETTER JOB?
PREDICTORS OF
PRETERM DELIVERY
• Very poor
• Often based on prior OB history
– 50% of patients are nulliparous
• Sensitivity and specificity are low
• Difficult to find interventions that
decrease preterm delivery
PRETERM LABOR
MANAGEMENT GOALS
• Identify those at highest risk
• Eliminate those at a lower risk
• Maximize condition of the fetus at
birth
– short term tocolysis (neuroprotection?)
– antenatal corticosteroids
– antibiotics to prevent early infection
– prevent birth trauma / asphyxia
PRETERM LABOR
DIAGNOSIS
Gestational age 20 - 37 weeks
with regular uterine contractions
and
Ruptured membranes or intact membranes
- cervical change
- > 80% effaced
- > 2 cm. dilated
DIAGNOSIS
• May be difficult
• Placebo/false labor 50+% of
patients
• Try to make diagnosis early
– more successful tocolysis
– allow transfer to regional center
– maximize condition of fetus at birth
PRETERM PREDICTORS
OVERVIEW
• None have stood the test of time
• 2 proven options
– ultrasound cervical length
– fetal fibronectin (fFN)
• Good at ruling out PTL (useful NPV)
• PPV less useful
Risk of PTD by Cervical Length
Probability of Preterm Delivery
Preterm Delivery <35 Weeks
0.5
0.4
0.3
0.2
0.1
0.0
0
20
40
Cervical Length (mm)
Source: Iams JD et al. N Engl J Med. 1996;334:567-572.
60
80
Fetal Head
Cervix
NORMAL CERVIX
CERVICAL LENGTH
• Most of the data for cervical length is
in asymptomatic patients
• Not as much experience using in
triaging of patients
• Limited accessibility, especially after
hours
• Significant cost/charges
• Delay in obtaining results
CERVICAL LENGTH
• Charges are variable between
institutions.
• Costs, now that’s a whole nother
matter
• At our 2 offices, charges are
- $259.00
- $380.00
Fetal Fibronectin
Amnion
Chorion
Fetal
Fibronectin
Decidua
FETAL FIBRONECTIN
DOING THE TEST
• User friendly, all inclusive kits
• Normal speculum examination
• Dacron swab in posterior fornix 10
sec.
• Place in buffered solution
• Send to lab
Specimen Collection for fFN Testing

Lightly rotate swab across either the posterior fornix
of the vagina or the ectocervical region of the external
cerical os for 10 seconds.
Specimen Collection for fFN Testing

Remove swab and immerse Dacron® tip in buffer

Break the shaft even with the top of the tube (at the score)
Specimen Collection for fFN Testing

Align the shaft with the hole inside the tube cap and
push down tightly over the shaft to seal the tube
Test Results

Rapid fFN for the TLi™ System




Analyzer produces results in
20 to 30 minutes
Around-the-clock availability
Moderately complex—requires CLIA
approved laboratory
fFN Enzyme Immunoassay

24-hour turnaround through central laboratory
FETAL FIBRONECTIN
HOW GOOD IS IT?
• Multicenter trial
• 763 symptomatic patients
• Investigators blinded to results
• Treatment as deemed clinically
indicated
• fFN gathered prior to examination
Peaceman et al, AJOG 1997;177:13-18
FETAL FIBRONECTIN
HOW GOOD IS IT?
Outcome
(+) fFN
(n = 150)
%
13.3
(-) fFN
(n = 613)
%
0.5
Relative risk
Del < 14 d.
16.7
0.8
20.4
BWT < 2500
38.0
11.2
3.4
NICU admit
29.3
11.1
2.6
Del < 7 d.
27.1
Peaceman et al, AJOG 1997;177:13-18
Estimation of Cost
Effectiveness
.
Sum of the cost of steroids, tocolytics and
hospitalization and the machine
To treat 91 patients without testing is
approximately $106,000.00
To test and treat selectively is approximately
$39,500.00
CONCLUSIONS
• Fetal Fibronectin testing is reliable
and can be used effectively as an
aid for the diagnosis of preterm
labor
• The cost of avoidable admissions
and treatment for those testing
negative outweighs the cost of the
test.
FETAL FIBRONECTIN
EFFECT ON TRANSPORTS
• 18 month prospective study
• 9 referring hospitals, 1 university
center
• 151 patients with presumptive PTL
• 45 patients (30%) had (+) fFN
• 25% delivered within 7 days
• 2% of (-) fFN’s delivered within 7
days
FETAL FIBRONECTIN
EFFECT ON TRANSPORTS
• 90% of patients with a (-) fFN were
not transported
• Cost savings: over $30,000 for
transports alone
• Mean length of stay for antepartum:
7 days
– Average hospital savings: > $150,000
• Cost of fFN tests: $5,000
FETAL FIBRONECTIN
POSITIVE TESTS??
• Unclear what is the best strategy
• Many unproven options
– bedrest
– prophylactic tocolytics
– screen and treat for lower genital
infections
– antenatal corticosteroids
– close follow up and ongoing dialogue
COMBINATION APPROACH
(Goldenberg RL, Iams JD, AJOG
2000;182:636-43)
• Serial fFN and cervical length in 2929
•
•
•
patients
Observational study
Multiple exams and combination of results
Summary
– Isolated short cervix or (+) fFN increased risk
of PTB above baseline by factor of
approximately 4
– Both being abnormal increased risk by about
25
COMPARISON OF TESTS
(Goldenberg RL, Iams JD, AJOG
2000;182:636-43)
Modality
RR
(+) fFN and short cervix
25
(+) fFN alone
4.0
(+) short cervix alone
4.0
* Of patients with a (+) fFN and short cervix
at 24-26 weeks, over 60% delivered prior
to 35 weeks
AHRQ EVIDENCE REPORT
December 2002
• Two biologic markers (fFN &EVUSD)
are useful in identifying women in
PTL who are at a low risk of
experiencing a PTB
• Certain tocolytics (beta-mimetics,
magnesium, calcium channel
blockers, NSAID’s) appear effective
in prolonging pregnancy
• Beta-mimetics have a higher risk of
maternal harm
PROTOCOL
(Mine anyway)
• Cervical length in high risk patients prior
•
•
•
to 24 weeks
Fetal fibronectin 24-34 weeks who are
symptomatic for preterm labor
Cervical length if fetal fibronectin (+) and
no significant dilatation
If short cervix is incidental finding, fetal
fibronectin
PROTOCOL
(Mine anyway)
• Steroids for maturity if fFN positive and
•
•
•
•
cervix is short
Observation if only one is abnormal
Magnesium for tocolysis if necessary
Repeat steroids if > 14 days from initial
course and < 33 weeks
Magnesium for neuroprotection until 32
weeks
INTRAPARTUM
STUFF
• Tocolytics
• Magnesium for
neuroprotection
• Repeat steroids
LET’S TALK
TOCOLYTICS!
MAGNESIUM VS.
NIFEDIPINE
• 192 patients randomized to magnesium
•
•
•
•
vs. nifedipine
24 to 33 weeks
Magnesium: 4 gm bolus then 2 gm/hr
Nifedipine: 10 mg every 20 minutes x 3
then 20 mg every 4-6 hours
Maintenance tocolysis at attending
discretion
Lyell DJ Obstet Gynecol 2007;110:61-7
MAGNESIUM VS.
NIFEDIPINE
Lyell DJ Obstet Gynecol 2007;110:61-7
MAGNESIUM VS
NIFEDIPINE
• No difference
–
–
–
–
–
Delivery at < 48 hours
Delivery at < 32 weeks, 37 weeks
EGA at delivery
Birth weight
Recurrent preterm labor
• Shorter time to uterine quiescence with nifedipine
• Slightly longer length of stay for infants in
•
magnesium group
More maternal side effects in magnesium group
but none life threatening
Lyell DJ Obstet Gynecol 2007;110:61-7
REVIEW OF STUDIES
SUGGESTING
MAGNESIUM IS
NEUROPROTECTIVE
REVIEW OF MAG AND
CP STUDIES
FAVORING REDUCTION
Schendel
Grether
Boyle
Matsuda
Murata
JAMA 1996
J Pediatr 1996
Am J Epidemiol 2000
Euro J OB, GYN, Reprod 2000
Brain & Develop 2005
AGAINST REDUCTION
Paneth
Canterino
Grether
Pediatrics 1997
OB/GYN 1999
AJOG 2000
PROSPECTIVE STUDIES
SUPPORTING MAGNESIUM
FOR
NEUROPROTECTION
ACTOMgSO4
–1062 patients
PreMag
–573 patients
Beam Trial
–>2200 patients
SUMMARY
• Fairly clear that magnesium is
•
•
•
neuroprotective
Beneficial until 28-32 weeks
Optimal dosing is still unclear
Recommend
– 4 gram bolus
– Followed by 2 gram/hour infusion
• Try to wait 2 hours, if possible
• Continue until delivery
STEROIDS
BACKGROUND
• As early as the 1960’s, it was known that
•
steroids decrease RDS in animals
1972 landmark study by Liggins/Howie
– 2 doses of betamethasone
– Reduced RDS from 15+% to 10%
– Reduced mortality from 11+% to 6%
• Most of benefit in those 28-34 weeks
• How long do they last?
• Why no benefit after 34 weeks?
STEROIDS
BACKGROUND
• Other studies confirmed findings
• Steroids slow to be implemented
• Study in 1992 showed less than 50% of
•
•
preterm infants received steroids
In 1994, NIH released first consensus
statement on steroids
Area of further research
– Repeat steroids
– How long do they last
STEROIDS
BACKGROUND
• In 2000, NIH released their 2nd (and
last) consensus statement
• Repeat steroids should only be given
to patient’s enrolled in a randomized
controlled trial with informed
consent and in a dose so as to
minimize exposure of both the
mother and fetus
HOW LONG IS THE
BENEFIT?
• Retrospective chart review
• 197 infants received steroids
– 98 delivered within 7 days
– 99 delivered after 7 days
• Matched for everything
– Race
– Gender
– EGA at delivery
Payer mix
Route of delivery
Birth weight
Peaceman et al AJOG 2005;193:1165-9
HOW LONG IS THE
BENEFIT?
Delivery
< 7 days
Delivery
> 7 days
P
Ventilation or CPAP
> 24 hours
63%
81%
< 0.01
Surfactant use
39%
47%
.28
O2 at 28 days
23%
22%
.92
NEC, IVH, or sepsis
31%
28%
.56
34 days
38 days
.80
Length of stay
Peaceman et al AJOG 2005;193:1165-9
FINALLY, THE MEAT:
WHAT ABOUT A REPEAT DOSE?
• Now, 4 randomized controlled trials in the
literature looking at this
–
–
–
–
Guinn 2001 (N = 502)
Wapner 2006 (N= 556)***
Crowther 2006 (N= 1047)
Garite 2009 (N= 437)
• All suggest a modest reduction in RDS
• No improvement in other morbidities or in
mortality
– *** non-significant increase in CP at age 2
IMPACT OF A ‘RESCUE COURSE’
OF STEROIDS
• Multi-center randomized placebo trial
• 437 patients
– 223 in repeat group
– 214 in single course
• Included multiple gestations (N = 141)
• 25 to 33 weeks
• Randomized if
– Received 1st course > 14 days earlier
– High likelihood of delivering in next 7 days
Garite et al AJOG 2009;200:248.e1-248.e9
IMPACT OF A ‘RESCUE COURSE’
OF STEROIDS
• No difference in demographics
• Significant reduction in
– Composite morbidity (44% vs 66%)
– RDS (41% vs 61%)
– Surfactant use (38% vs 55%)
– Ventilation (38% vs 53%)
• No difference in mortality or other
significant morbidities
Garite et al AJOG 2009;200:248.e1-248.e9
WHAT IS THE RISK OF SEVERE
RDS IN LEGACY NICU?
• Let’s look at 30-32 weeks
• Northwest Newborn uses a lot of
“gentler ventilation” i.e. nasal CPAP
• From 30-32 weeks
– About 1/3 do not require respiratory
support
– Failed CPAP is about 15%
WHAT IS THE RISK OF SEVERE
RDS IN OUR NICU?
• So for counseling
– 30% require no respiratory support
– 55-60% require nasal CPAP (duration usually
2-6 days)
– About 15% require surfactant along with short
term mechanical ventilation
• In the VON, the rate is about 35%
• Thus, the reason for limiting repeat
steroids to those < 30 weeks
SUMMARY
• Steroid benefit probably does have
limited time of efficacy
• Most studies consistently show this
to be about 7-14 days
• Main benefit is in reduction of short
term respiratory complications
• No reduction in death or serious
morbidities (severe IVH, NEC…)
SUMMARY
• Risk of severe RDS, chronic lung
disease is low after 30 weeks
• Still some lingering concern
about long term problems with
repeat doses
• Consider giving repeat course up
to 32-33 weeks
CAN WE PREVENT
PRETERM BIRTH?
WHAT HAS BEEN TRIED?
• Bedrest
• Prophylactic tocolytics
• Prophylactic cerclage
• HUAM
•PROGESTERONE!!
THE BANDWAGON
ST
1
NEVER BE THE
ONE
ON THE BANDWAGON
NOR
THE LAST ONE OFF IT!!
PROGESTERONE STUDIES
•
•
•
•
•
•
Early studies with mixed results
Lumped SAB, PTL…. together
Various progestational agents
High risk vs. low risk
Timing of initiation of therapy
Risk of anomalies
– Prior scares
•
•
•
•
•
•
•
•
DES
Repeat steroids
Thalidomide
SSRI’s
TRH
Continuous fetal monitoring
Magnesium
IV alcohol
PROGESTERONE STUDIES
• Studies currently using
– 17 hydroxyprogesterone caproate
– Vaginal progesterone 100 mg per day
– Vaginal progesterone 200 mg per day
– Vaginal progesterone 90 mg/day
• Limited randomized placebo
controlled trials (4 published)
Prevention of recurrent PTL by 17
alpha-hydroxyprogesterone caproate
NEJM June 2003 pp2379-2385
• Randomized prospective placebo
controlled trial
• Over 450 patients with 2:1 ratio of
progesterone to placebo
• All had prior preterm birth
• Singleton fetus
• No significant medical problems
Prevention of recurrent PTL by 17
alpha-hydroxyprogesterone caproate
NEJM June 2003 pp2379-2385
• Initial part of study involving 150 patients
•
terminated due to violation of
manufacturing process
86 completed treatment
– 57 (61%) with 17-P
– 29 (39%) with placebo
• Delivery at < 37 weeks
– 17-P
– Placebo
43%
38%
Prevention of recurrent PTL by 17
alpha-hydroxyprogesterone caproate
NEJM June 2003 pp2379-2385
Characteristic
Progesterone
Placebo
RR
# of PTD
1.4
1.6
NS
Del. < 37 wks
(%)
36.3
54.9
0.66
Del. < 35 wks
(%)
20.6
30.7
0.67
Del. < 32 wks
(%)
11.4
19.6
0.58
IVH (%)
1.3
5.4
0.25
NEC (%)
0.0
2.6
NS
FDA ADVISORY PANEL
COMMENTS
Pregnancy outcome
17-P
N, (%)
Placebo
N, (%)
Nominal
P value
SAB < 20 wks
5 (1.6)
0
0.17
Stillbirth
6 (2.0)
2 (1.3)
0.72
Antepartum
5 (1.6)
1 (0.6)
----
Intrapartum
1 (0.3)
1 (0.6)
----
Neonatal deaths
8 (2.6)
9 (5.9)
0.12
19 (6.2)
11 (7.2)
0.69
Total deaths
FDA ADVISORY PANEL
COMMENTS
• No difference in Apgar scores, congenital
malformations, median days in NICU (9.1
vs 14.1), mean days in hospital (9.1 vs
14.1), and mean birthweight, and
birthweight < 1500 gms (8.6% vs 13.9%)
• Percentage of babies < 2500 gms was less
in the 17-P group (27.2% vs 41.1%)
FDA ADVISORY PANEL
COMMENTS
• If adjusted for multiple comparisons, it is
unlikely that any of the listed morbidities
would have been statistically lower in the
17-P group
• The composite neonatal morbidity score,
though numerically lower in the 17-P
group, it did not reach statistical
significance
Prophylactic administration of progesterone
by vaginal suppositories
AJOG 2003;188:419-424
• 142 high risk patients (mostly a prior
preterm birth)
• Randomized to daily suppository of
100 mg progesterone vs. placebo
• Delivery: Progesterone Placebo
< 37 wks
13.8%
28.5%
< 34 wks
2.8%
18.6%
PROGESTERONE GEL FOR
RECURRENT PRETERM BIRTH
• Randomized placebo controlled trial
of 659 patients
– 328 placebo
– 331 Prochieve (8% progesterone)
• 60% in each group had prior delivery
at < 32 weeks
• No demographic differences
O’Brien JM Ultra OB/GYN, 2007;30(5):687
PROGESTERONE GEL FOR
RECURRENT PRETERM BIRTH
• No difference between groups in:
– Mean gestational age at delivery
– Deliveries < 37 weeks
– Deliveries < 32 weeks
– Mean birthweight
– Neonatal morbidity
– Neonatal mortality
O’Brien JM Ultra OB/GYN, 2007;30(5):687
META-ANALYSIS
Mackenzie R. AJOG, 2006:194;1234
• Progestational agents initiated in the
2nd trimester reduce the risk of
delivery at < 37 weeks but no effects
of perinatal outcomes
• Treatment with progestational
agents should continue to be limited
to women enrolled in well-designed
randomized controlled trials
TWINS AND 17-P
Rouse D, NEJM 2007;357:454
• 655 sets of twins
•
•
•
•
•
•
– 325 17-P
– 330 placebo
Enrolled between 16.0 and 20.3 weeks
No other complications
Nearly 50% nulliparous
< 10% had prior PTB
2/3’s spontaneous
80% di-di placentation
TWINS AND 17-P
Rouse D, NEJM 2007;357:454
• Delivery at < 35 weeks
– 41% in 17-P
– 37% in placebo
• Composite neonatal morbidity
– 20.2% in 17-P
– 18.0% in placebo
• No improvement in outcomes when
using 17-P in twins
SHORT CERVIX AND VAGINAL
PROGESTERONE
Fonseca, NEJM. 2007;357:462
• 413 patients with TVUSCL < 15 mm
– 250 vaginal PG @ 200 mg nightly
– 163 placebo
• Mean EGA = 22 weeks
• Randomized between 20 -25 weeks
• Delivery at < 34 weeks
– Progesterone
– Placebo
19.2%
34.4%
SHORT CERVIX AND VAGINAL
PROGESTERONE
Hassan et al. US OB/GYN 2011
• 458 patients randomized
– 235 vaginal progesterone
– 223 to placebo
•
•
•
•
Progesterone: 90 mg at night
TVUSCL: 1.0 to 2.0 cm
EGA: 19.0 to 24 weeks
Continued until 36 weeks
SHORT CERVIX AND VAGINAL
PROGESTERONE
Hassan et al. US OB/GYN 2011
• Vaginal progesterone had less
–
–
–
–
–
–
< 35 weeks (14.5% vs 23.3%)
< 33 weeks (8.9% vs. 16.1%)
< 28 weeks (5.1% vs 10.3%)
RDS (3.0% vs. 7.6%)
BWT < 1500 gms (6.4% vs. 13.6%)
Any morbidity (7.7% vs. 13.6%)
Obstet Gynecol 2003;102:1115-6
Obstet Gynecol 2003;102:1115-6
SUMMARY
• Progesterone is safe
• It is probably effective is properly
selected patients
• May not have a significant impact on
the preterm delivery rate
• Legally, I think it needs to be offered
to patients due to ACOG’s statement
SUMMARY OF THE
SUMMARIES
• Preterm births are still a huge problem in
•
•
•
the U.S.
No clear, definitive way to decrease the
overall rate due to the complexity of the
problem
Progesterone probably works to decrease
the recurrence rate
Vaginal progesterone may decrease the
rate with a short cervix
SUMMARY OF THE
SUMMARIES
• It is really, really, really important to make
•
•
•
(or rule out) the diagnosis
Liberal use of fetal fibronectin and cervical
lengths to identify those at the highest
risk so as to target therapy
Magnesium is the tocolytic of choice for
those under 28 weeks and probably 32
weeks due to its neuroprotection effects
Steroids are a good thing!!!!
SUMMARY OF THE
SUMMARIES
• Effects of steroids fade after 14 days
• Strongly consider a repeat course (2
•
doses) if still at risk for preterm delivery,
EGA < 33 weeks, and greater than 14 days
from initial course
Using fFN and cervical length to focus
therapy can reduce the number of patients
who needlessly get medications that they
don’t really need
THANK
YOU!!
QUESTIONS?