Transcript PRETERM LABOR PREDICTION AND PREVENTION

Predicting and Preventing
Preterm Birth
Steven R. Allen, MD
Scott & White Hosp & Clinic
Temple, TX
Educational Objectives
Identify remediable risk factors for PTB
Address potential “predictors” of PTB
cervical ultrasonographic screening
 fibronectin

Discuss possible role for progesterone (Rx)
in pregnancy maintenance
Review the potential utility of tocolysis
Significance of Preterm Birth
(PTB)
% PTB *
14
12
10
8
6
4
2
0
1982 1987
1992 1997 2002
* US Nat’t Vital Stats Reports 2000 & 2003
12.1% of US births - rising
One sixth of PTD’s occur at
24-31 weeks, with highest
rate of complications *
Leading cause of neonatal
mortality (75%), morbidity,
and health care
expenditures (57% of
nursery costs; 10% of all
healthcare costs for
children)
Mortality & morbidity related to
PTB (S&W 1998-2001)
100
100
% Survival
80
80
60
60
40
40
% IVH Grade 3-4
20
0
20
0
<24
24
25
26
27
Components of PTL
pathophysiology
Prostaglandins
Inflammatory response
Adrenergic response: stimulates
contractions
Ischemia: free radicals promote PGs
Decidual hemorrhage
Group survey question
Who is most likely to have a PTB?
A) 34 yo P1203 (last preg preterm)
B) 34 yo P1103
C) 34 yo P3003
D) 34 yo P1203 (last preg term)
Historical risk factors for PTL/PTB
Prior PTB (spontaneous PTL)
Low socioeconomic status
Teen
Age >34
Prepregnancy weight < 100-110 lb.
Uterine or cervical abnormality
Maternal smoking
Pregnancy complications
predisposing to PTL/PTB
Multiple gestation
Pyelonephritis
Polyhydramnios
Untreated
asymptomatic
bacteriuria
Antepartum bleeding
PROM
Chorioamnionitis
Some specific fetal
anomalies
Rationale for new PTL
screening tools
<50% with PTL perceive typical symptoms
10-20% of uncomplicated patients have
similar symptoms
PTL is diagnosed only after gross structural
change of the cervix
Majority of women with PTD have no
currently identifiable risk factor
Summary of PTL Risk Scoring Indices
26 - 64
%
13 - 35
4 - 30
2 - 16
PTD
Sensitivity
Pos
Screen
PPV
Risk of subsequent PTB
30
25
20
%
15
10
5
0
T/-
PT/-
T/T
PT/T
T/PT
PT/PT
Bakketeig, 1981
Group survey question
Who is most likely to have a PTB?
A) 34 yo P1203 (last preg preterm)
B) 34 yo P1103
C) 34 yo P3003
D) 34 yo P1203 (last preg term)
Group survey question
What “lab test” is most helpful in selecting
mgmt plan for 33 yo P0010 @ 28 wks with
q 4 min ctx and cx 1/2/-3 (digital exam)?
A) cervical length (transabdominal scan)
B) wet mount (r/o bacterial vaginosis)
C) fFN
D) cervical length (transvaginal scan)
Bacterial vaginosis (BV)
Anaerobic bacteria predominate vaginal flora
Incidence: 12-40% of pregnant women
Risk factors (all non-remediable)
black race
 younger age
 unmarried
 multiparous
 low socioeconomic status

Bacterial vaginosis: diagnosis
Relatively alkaline pH (>4.5)
Vaginal epithelial “clue cells”
Release of amine odor with alkalinization
of vaginal fluid (“whiff test”)
Thin vaginal secretion of uniform
consistency
Gram stain: Nugent criteria
BV: indirect screening (Pap smear)
%
100
90
80
70
60
50
40
30
20
10
0
Sens
Spec
PPV
NPV
Green. AJOG 2000;182:1048-9
Bacterial vaginosis as a risk factor
for PTB – meta analysis
OR
8
7
6
5
4
3
2
1
0
*
*
Del <
37
* NS: 95%CI < 1
Del <
37
twins
Scrn
<16
Scrn
<20
Scrn
>=20
Del <
34
*
Del <
32
Leitich. AJOG 2003;189:139-47
Effect of BV treatment
RR of PTD
2
1.5
1
0.5
0
Clinda pv
AJOG 1995;173:1527
Clinda po
Flagyl + Emycin po
300 mg bid
250 mg tid + 333 mg tid
AJOG 1995;173:157 NEJM 1995;333:1732
Meta-analysis confirms reduction in PTB only in pts with prior PTB
Bacterial vaginosis: summary
BV increases risk of PTD
Screen high risk patients
Systemic treatment for BV
metronidazole 250 mg po tid x 7 d or
 clindamycin 300 mg po bid x 7 d

Screening for risks of PTL by means other than
historic risk factors is not beneficial in the general
obstetric population
ACOG Practice Bulletin # 31, 10/01
Fibronectins
Ubiquitous glycoproteins, present in plasma
and ECM
Adhesion molecules
Fetal fibronectin (fFN) contains uniquely
glycosylated epitope (“oncofetal domain”)
fFN located in ECM of decidua basalis and
cytotrophoblasts
Fetal fibronectin
fFN rarely present (3-4%) in cervical/ vaginal
secretions of women without PTL/PROM
fFN common in cervical/vaginal secretions
of women with PTL (50%) or PROM (94%)
HYPOTHESIS: mechanical or inflammatory
damage to placenta or membranes releases
fFN into cervical/vaginal secretions
fFN as a predictor of PTD among women with
PTL (n=192)
100
90
80
70
60
50
40
30
20
10
0
Sens
PPV
NPV
fFN
Cx 1-3 cm
>8 ctx/h
AJOG 1995;173:141
Survival curve after fFN testing for
threatened PTL
100
80
%
60
-fFN
+fFN
40
20
0
0
7
14
21
Days after fFN test
28
35
42
49
Peaceman. AJOG 1997;177:13-18
fFN as a predictor of PTB
Meta-analysis; 13 studies; n=22,390
12
10
8
OR
6
4
2
0
Pos
Neg
Asymptomatic;
predicting PTB < 34 wks
Pos
Neg
Symptomatic;
Predicting PTB < 11 d
Honest. BMJ. 2002;325:1-10
Impact of fFN assay on
admissions for PTL
Cohort study with a
historical control cohort
24-34.9 wks with signs
or symptoms of PTL
fFN results in 24-48 hr
No difference in
neonatal outcome
AJOG 1999;180:581
30
*
before fFN
25
after fFN
20
15
10
5
*
*
0
)
k
d
m
0
,
w
0
S
ad
0
5
,
%
<3
LO
$1
l
de
%
* p<0.001
fFN NOT strictly related to
infection/inflammation
Many studies evaluating risk included women
with multiple gestation or uterine anomalies
(without obvious risk of infection)
fFN present in cervical/vaginal secretions at
term
Fibronectin: summary
fFN is fairly sensitive marker for PTD in
high risk patients (55-97%)
High short term NPV (71-100%) may
identify women not needing tocolysis
Screening not recommended
Group survey question
What “lab test” is most helpful in selecting
mgmt plan for 33 yo P0010 @ 28 wks with
q 4 min ctx and cx 1/2/-3 (digital exam)?
A) cervical length (transabdominal scan)
B) wet mount (r/o bacterial vaginosis)
C) fFN
D) cervical length (transvaginal scan)
Group survey question
Which patient is most likely to threaten PTB?
A) 28 yo P0 @ 17 wks with cx 1dil/2.5 long on US
B) 28 yo P0111 @ 17 wks with cx 1 dil/2.5 long
C) 28 yo P2002 @ 29 wks with cx 1 dil/2.5 long
D) 28 yo P2002 @ 29 wks with cx cl/4 long
Hypothesis: cervical competence is a
continuous variable
Most human features are continuous, not
categorical
Cervical resistance to delivery varies at term
Bishop score varies
 duration of normal labor varies

Prior PTL predicts subsequent PTL
800
600
400
200
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68
0
Length of Cervix (mm)
1
5 10 25
50
75
Percentile
NEJM 1996;334:567
No. of Women
Cervical length at 24 wks
measured by TVUS
Cervical length correlates with PTB
Relative
Risk of
PTB
12
600
10
8
400
6
4
No. of Women
800
14
200
2
0
0
4
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68
0
Length of Cervix (mm)
1
5 10 25 50
Percentile
75
NEJM 1996;334:567
Predictive value of cervical length
with threatened PTD
100
NPV
80
PPV
60
%
40
20
0
20 mm
25 mm
30 mm
35 mm
Obstet Gynecol 1993;82:829
Predictive value of cervical
“funneling” with threatened PTD
‘Funneling” present in half of women studied
with preterm contractions
Funneling correlates with cervical length, but
is not as good a predictor of PTD
Funneling may vary over time, and thus be
less reproducible than cervical length
US cervical canal measurement:
summary
Cervical length correlates inversely with
PTD risk
Identification of abnormal cervix does
not determine etiology or direct
treatment
Routine screening not recommended
Effectiveness of cerclage for
sonographically shortened cervix
Meta-analysis
6 studies (2 RCT)
n=357; mostly hi risk
for PTB (3 studies,
n=212)
Inclusion: cx < 2.5 cm
long, dil < 2 cm, or
funneling
Belej-Rak. AJOG 2003;189:1679-87
RR (all NS)
1.2
1
0.8
0.6
0.4
0.2
0
7
4
8
rt
rb
3
3
2
o
o
<
<
<
l
m
l
l
m
de
o
de
de Neo
Ne
Preterm Prediction Study
NICHD; MFM Units Network
%
100
90
80
70
60
50
40
30
20
10
0
“No screening test (except history)
recommended for low-risk patient”
Sens
PPV
NPV
BS >= 4
Low risk pts; n=2197
Cx Length
fFN
fFN +CL
BS + CL
Iams. AJOG 2001;184:652-5
Group survey question
Which patient is most likely to threaten PTB?
A) 28 yo P0 @ 17 wks with cx 1dil/2.5 long on US
B) 28 yo P0111 @ 17 wks with cx 1 dil/2.5 long
C) 28 yo P2002 @ 29 wks with cx 1 dil/2.5 long
D) 28 yo P2002 @ 29 wks with cx cl/4 long
Group survey question
What is best prophylaxis for P0202 (prior PTB
x 2 @ 28-29 wks after spontaneous PTL)?
A) Bedrest
B) Terbutaline pump
C) 17-OH Progesterone 250 mg IM q wk
D) Progesterone suppository 100 mg pv qd
Progesterone
Steroid hormone – “for gestation”
Progesterone production rises from 2-3 mg/d at
ovulation to 30 mg/d 1 wk later
Progesterone production during pregnancy: 300 –
400 mg/d during 3rd TM (ovary  placenta)
Hydrophobic – diffuses thru plasma membrane, binds
to cytoplasmic receptor, then moves to nucleus to
function as a transcription factor
Progesterone:
relaxes myometrium
Inhibits gap junction formation
Decreases number of oxytocin
receptors
Immunusuppression
Prevention of recurrent PTB by
17-OH Progesterone caproate
Multicenter; n=463
RCT; dbl blind
Inclusion: singleton, prior
PTB
Wkly injection, 16-20 until
36 wks; 17-OH prog
caproate or placebo
17-OH-P assoc’d with
neonatal risk reduction:
NEC, IVH, & O2 need
60
17-OH-P
50
Placebo
40
%
30
20
10
0
Del < Del < Del <
37
35
32
Meis. NEJM 2003;348:2379-2385
Prevention of PTB by vaginal
administration of progesterone
RCT; n=142
Inclusion: singleton + prior
PTB, cerclage, or uterine
anomaly
Nightly vag suppository @
24-34 wks: prog100 mg or
placebo
Wkly ctx monitoring: lower
for prog group (p0.01)
PTB < 34 wks lower for prog
(2.7 vs 18.5%; p<0.05)
% undelivered
100
80
P=0.03
60
40
20
Prog
Placebo
0
24 26 28 30 32 34 36 38
Wks EGA
da Fonseca. AJOG 2003;188:419-24
Can Progesterone prevent PTB?
Prior PTB (spontaneous
PTL)
Low SES
Teen
Age >34
Prepregnancy weight <
100-110 lb.
Uterine or cervical
abnormality
Maternal smoking
Multiple gestation
Polyhydramnios
Antepartum bleeding
PROM
Chorioamnionitis
Pyelonephritis
Untreated ASB
Some fetal anomalies
Group survey question
What is best prophylaxis for P0202 (prior PTB
x 2 @ 28-29 wks after spontaneous PTL)?
A) Bedrest
B) Terbutaline pump
C) 17-OH Progesterone 250 mg IM q wk
D) Progesterone suppository 100 mg pv qd
Group survey question
Which of the following is not a
contraindication to tocolysis:
A)
B)
C)
D)
Preeclampsia
Abruption
Gastroschisis
Chorioamnionitis
Contraindications to tocolysis
Absolute
Severe preeclampsia
Severe abruption
Severe bleeding
Chorioamnionitis
Fetal death
Fetal anomaly incompatible
with life
Severe fetal growth
restriction
Relative
Mild CHTN
Mild abruption
Stable placenta previa
Maternal disease – cardiac,
hyperthyroid, uncontolled
DM
Fetal distress
Mild fetal growth restriction
Cx > 5 cm
Fetal anomaly
Creasy & Resnick, Mat-Fetal Med
Group survey question
Which of the following is not a
contraindication to tocolysis:
A)
B)
C)
D)
Preeclampsia
Abruption
Gastroschisis
Chorioamnionitis
Group survey question
What is best 1st line tocolytic agent?
A) MgSO4
B) nifedipine
C) ritodrine
D) indomethacin
Mechanisms of tocolytic agents
Tocolysis
PROPHYLACTIC
Women at risk
THERAPEUTIC
Acute PTL
Rationale
Prevent PTL/PTB
Prevent PTB
Prolong 48 h for steroids
Improve neonatal outcome
??
MAINTENANCE
After acute treatment
Prevent recurrent PTL
Improve neonatal outcome
Effect of tocolytics to prevent PTB
Meta-analysis1966-1999
OR for delivery at term
100
10
Many of these studies were performed before
widespread corticosteroid use – perhaps
contributing to lack of proven improved neonatal
outcomes
1
Beta-mim
Ca CB
MgSO4
NSAID
Berkman. AJOG 2003;188:1648-59
Tocolysis
Limited benefits – have a plan
Don’t forget fetal risks (?benefits)
Upcoming considerations
Atosiban
 Selective COX-2 inhibition

MgSO4 for neuroprotection
RR
RCT; n=1047
Inclusion: EGA < 30
wks; PTB anticipated
in < 24h
Mg 4g bolus + 1 g/h
(not managed for
tocolysis; median
administration
duration 3+ hrs)
* p<0.05
1.2
1
*
*
0.8
0.6
0.4
0.2
0
Neo
Death
CP
Gross Death
motor or GMD
dysfxn
Crowther. JAMA 2003;290:2669-76
Group survey question
What is best 1st line tocolytic agent?
A) MgSO4
B) nifedipine
C) ritodrine
D) indomethacin
PTB prediction and prevention:
Conclusions
PTD has multifactorial etiology
Identification of patients at risk does not:



determine etiology
direct therapy*
necessarily result in improved outcome*
* Possible exceptions:
• 17OHP for treatment
• BV as contributing risk factor
PTB prediction and prevention:
Conclusions
Routine screening (BV, US, fFN) not indicated for
low risk patients
Systemic treatment for BV ’s risk for PTD if hi risk
For patients at high risk for PTD, measurement of
cervical length and fFN may be useful because of
their high NPV
Consider progesterone supplementation for women
at high risk for PTB
Use tocolytics within bounds of reasonable goals