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 PTBcervical ultrasonographic screening fibronectin

Discuss possible role for progesterone (Rx) in pregnancy maintenance

Review the potential utility of tocolysis

Significance of Preterm Birth (PTB)

0

2

4

6

8

10

12

14

1982 1987 1992 1997 2002

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)

% PTB *

* US Nat’t Vital Stats Reports 2000 & 2003

Mortality & morbidity related to PTB (S&W 1998-2001)

0

20

40

60

80

100

<24 24 25 26 27

0

20

40

60

80

100

% Survival

% IVH Grade 3-4

Components of PTL pathophysiology

Prostaglandins

Inflammatory responseAdrenergic response: stimulates contractionsIschemia: free radicals promote PGsDecidual 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 statusTeenAge >34Prepregnancy weight < 100-110 lb.Uterine or cervical abnormalityMaternal smoking

Pregnancy complications predisposing to PTL/PTB

Multiple gestation

Polyhydramnios

Antepartum bleeding

PROM

Chorioamnionitis

Pyelonephritis

Untreated asymptomatic bacteriuria

Some specific fetal anomalies

Rationale for new PTLscreening 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

%

Sensitivity PPVPTD Pos Screen

13 - 35

2 - 16

4 - 30

26 - 64

Risk of subsequent PTB

0

5

10

15

20

25

30

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 raceyounger ageunmarriedmultiparous 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)

010

20304050

607080

90100

Sens Spec PPV NPV

%

Green. AJOG 2000;182:1048-9

Bacterial vaginosis as a risk factor for PTB – meta analysis

0

12

3

45

6

78

Del <37

Del <37

twins

Scrn<16

Scrn<20

Scrn>=20

Del <34

Del <32

Leitich. AJOG 2003;189:139-47

OR

* * *

* NS: 95%CI < 1

Effect of BV treatmentRR of PTD

0

0.5

1

1.5

2

Clinda pv Clinda po Flagyl + Emycin po

Meta-analysis confirms reduction in PTB only in pts with prior PTB

300 mg bidAJOG 1995;173:157

250 mg tid + 333 mg tid NEJM 1995;333:1732

AJOG 1995;173:1527

Bacterial vaginosis: summary

BV increases risk of PTDScreen high risk patientsSystemic treatment for BVmetronidazole 250 mg po tid x 7 d orclindamycin 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)

0102030405060708090

100

fFN Cx 1-3 cm >8 ctx/h

Sens

PPV

NPV

AJOG 1995;173:141

Survival curve after fFN testing for threatened PTL

0

20

40

60

80

100

0 7 14 21 28 35 42 49

-fFN

+fFN

Peaceman. AJOG 1997;177:13-18Days after fFN test

%

fFN as a predictor of PTBMeta-analysis; 13 studies; n=22,390

0

2

4

6

8

10

12

Pos Neg Pos Neg

Asymptomatic;predicting PTB < 34 wks

Symptomatic; Predicting PTB < 11

dHonest. BMJ. 2002;325:1-10

OR

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

0

5

10

15

20

25

30

% a

dm

% d

el <

35 w

k

LOS, d

$1,0

00)

before fFN

after fFN

*

* *

* p<0.001AJOG 1999;180:581

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 termBishop score variesduration of normal labor varies

Prior PTL predicts subsequent PTL

Cervical length at 24 wks measured by TVUS

00

200200

400400

600600

800800

No

. of W

om

en

00 88 1616 2424 3232 4040 4848 5656 6464Length of Cervix (mm)

44 1212 2020 2828 3636 4444 5252 6060 6868

55 2525 757511 1010 5050Percentile

NEJM 1996;334:567

Cervical length correlates with PTB

00

22

44

66

88

1010

1212

1414

00

200200

400400

600600

800800

No

. of W

om

en

00 88 1616 2424 3232 4040 4848 5656 6464Length of Cervix (mm)

44 1212 2020 2828 3636 4444 5252 6060 6868

55 2525 757511 1010 5050Percentile

RelativeRisk of

PTB

NEJM 1996;334:567

Predictive value of cervical length with threatened PTD

0

20

40

60

80

100

20 mm 25 mm 30 mm 35 mm

PPV

NPV

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 cervixMeta-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

0

0.2

0.4

0.6

0.8

1

1.2RR (all NS)

Belej-Rak. AJOG 2003;189:1679-87

Preterm Prediction StudyNICHD; MFM Units Network

0102030405060708090

100

BS >= 4 Cx Length fFN fFN +CL BS + CL

Sens

PPV

NPV

Low risk pts; n=2197 Iams. AJOG 2001;184:652-5

“No screening test (except history)recommended for low-risk patient”

%

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 caproateMulticenter; 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

0

10

20

30

40

50

60

Del <37

Del <35

Del <32

17-OH-P

Placebo

Meis. NEJM 2003;348:2379-2385

%

Prevention of PTB by vaginal administration of progesterone

RCT; n=142Inclusion: singleton + prior PTB, cerclage, or uterine anomalyNightly vag suppository @ 24-34 wks: prog100 mg or placeboWkly ctx monitoring: lower for prog group (p0.01)PTB < 34 wks lower for prog (2.7 vs 18.5%; p<0.05)

0

20

40

60

80

100

24 26 28 30 32 34 36 38

Prog

Placebo

da Fonseca. AJOG 2003;188:419-24

% undelivered

P=0.03

Wks EGA

Can Progesterone prevent PTB?Prior PTB (spontaneous

PTL)Low SESTeenAge >34Prepregnancy weight <

100-110 lb.Uterine or cervical

abnormalityMaternal 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) Preeclampsia

B) Abruption

C) Gastroschisis

D) Chorioamnionitis

Contraindications to tocolysisAbsolute

Severe preeclampsia

Severe abruption

Severe bleeding

Chorioamnionitis

Fetal death

Fetal anomaly incompatible with life

Severe fetal growth restriction

RelativeMild CHTNMild abruptionStable placenta previaMaternal disease – cardiac, hyperthyroid, uncontolled DMFetal distressMild fetal growth restrictionCx > 5 cmFetal anomaly

Creasy & Resnick, Mat-Fetal Med

Group survey question

Which of the following is not a contraindication to tocolysis:

A) Preeclampsia

B) Abruption

C) Gastroschisis

D) Chorioamnionitis

Group survey question

What is best 1st line tocolytic agent?A) MgSO4

B) nifedipine

C) ritodrine

D) indomethacin

Mechanisms of tocolytic agents

TocolysisRationale

PROPHYLACTIC Prevent PTL/PTB

Women at risk

THERAPEUTIC Prevent PTB

Acute PTL Prolong 48 h for steroids

Improve neonatal outcome

MAINTENANCE

After acute treatment Prevent recurrent PTL

Improve neonatal outcome

? ?

Effect of tocolytics to prevent PTBMeta-analysis1966-1999

1

10

100

Beta-mim Ca CB MgSO4 NSAID

Berkman. AJOG 2003;188:1648-59

Many of these studies were performed before widespread corticosteroid use – perhaps contributing to lack of proven improved neonatal outcomes

OR for delivery at term

Tocolysis

Limited benefits – have a plan

Don’t forget fetal risks (?benefits)

Upcoming considerationsAtosibanSelective COX-2 inhibition

MgSO4 for neuroprotection

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)

0

0.2

0.4

0.6

0.8

1

1.2

NeoDeath

CP Grossmotordysfxn

Deathor GMD

RR * p<0.05

* *

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 etiologyIdentification 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 patientsSystemic treatment for BV ’s risk for PTD if hi riskFor patients at high risk for PTD, measurement of cervical length and fFN may be useful because of their high NPVConsider progesterone supplementation for women at high risk for PTBUse tocolytics within bounds of reasonable goals