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)
14

% PTB *

12
10
8
6
4
2
0
1982 1987

1992 1997 2002

* US Natt Vital Stats Reports 2000 & 2003

12.1% of US births - rising

One sixth of PTDs 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

430

2 - 16

PTD

Sensitivity

Pos
Screen

PPV

Risk of subsequent PTB

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

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

* 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
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

Length of Cervix (mm)

5 10 25

50

Percentile

75

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
10

600

400

6
4

200

No. of Women

800

14

2
0

0
8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68

Length of Cervix (mm)

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

1.2
1
0.8
0.6
0.4
0.2
0

RR (all NS)

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 assocd with
neonatal risk reduction:
NEC, IVH, & O2 need

60
50

17-OH-P
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 (p0.01)
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

??

MAINTENANCE
After acute treatment

Prevent PTB
Prolong 48 h for steroids
Improve neonatal outcome
Prevent recurrent PTL
Improve neonatal outcome

Effect of tocolytics to prevent PTB

Meta-analysis1966-1999
OR for delivery at
100
term
Many of these studies were performed before
widespread corticosteroid use perhaps
contributing to lack of proven improved neonatal
outcomes
10

1
Beta-mim

Ca CB

MgSO4

NSAID

Berkman. AJOG 2003;188:1648-59

Tocolysis
Limited benefits have a plan
Dont 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