Preterm Birth

Medical Paper
Presentation
Associate Professor,
Maternal Fetal Medicine

Preterm birth rates in the United States

< 37 weeks
12.9%

Preterm birth in the US

One preterm birth every minute!

To put it in perspective..
One preterm birth each minute
60 preterm births by the time this talk
is over
Healthy people 2010 objective is to
reduce rate to 7.6%

Preterm birth
75-80% of all perinatal mortality
50% of all long term
neurodevelopmental morbidity
Tremendous financial, emotional
burden on society

Newborn morbidity
Infants born preterm are at increased risk of:
Respiratory Distress syndrome
Chronic lung disease
Intraventricular hemorrhage
Necrotizing enterocolitis
Retinopathy of prematurity
Severe brain injury

Long term consequences

50% of long term major morbidity among nonanomalous fetuses:

Cerebral palsy
Mental retardation
Blindness
Deafness
Sensory deficits
Developmental delay

Etiologies

Stress

Infection

Bleeding

Uterine
overdistension

Preterm birth is a syndrome

Inflammation/Infection (~40%)
Maternal/fetal stress (~25%)
Uteroplacental ischemia (~25%)
Thrombophilia, decidual hemorrhage,
abruption
Abnormal uterine distension (~10%)

Some pathways through which preterm birth

may occur

Some pathways through which preterm birth may occur

Risk factors
Prior preterm birth
Poor socioeconomic status
Black race
Low education
Smoking
Bleeding
Assisted
reproduction
Multiple gestation

Genital tract
infections
Periodontal
disease
Cervical surgery
Pregnancy
termination
Uterine anomalies

Preterm babies are more likely to have preterm births

as adults

1405 preterm
mothers
2781 term mothers

Porter et al. Obstet Gynecol 1997;90:63-67

Maternal and Paternal

Influences
77,452 boys and girls in Norway who
later became parents
Gestational age of the child at birth
increased
- 0.58 days for each additional week
in the fathers GA
- 1.22 days for each additional week
in the mothers GA
Lie et al. Obstet Gynecol 2006

Over 80% of patients who present with

regular painful contractions go on to
deliver at term
Most interventions do not prevent
preterm birth and are potentially
harmful
How then do we determine who will
actually deliver preterm (isnt THAT the
question?)

More than 1/2 of patients who deliver

preterm have no risk factors
More than 2/3 of patients with
traditional risk factors do not deliver
preterm
Most important traditional risk factor is
preterm delivery in a prior pregnancy

Fetal fibronectin

Fetal Fibronectin:
Key Biochemical Marker for Risk Assessment
Adhesive glycoprotein
glueat the maternalfetal interface
Presence in
cervicovaginal
secretions highly
associated with risk of
preterm delivery

Goldenberg RL, et al. Obstet Gynecol. 1996;87:643-648.

Peaceman AM, et al. Am J Obstet Gynecol. 1997;177:13-18.

Fetal fibronectin

Fetal Fibronectin (ng/mL)

Cervicovaginal Presence of Fetal Fibronectin

from 22 to 35 Weeks Is Abnormal
4500
4000

Clinically Relevant Time Frame

(22 to 35 weeks)

3500
3000
2500
2000
1500
1000
500
0
0

10

15

20

25

30

Gestational Age (Weeks)

Adapted from Garite TJ et al. Contemp Obstet Gynecol. 1996;41:77-93.

35

40

50 ng/mL
Cutoff Level

Comparison of Risk Factors

16

Spontaneous Preterm Birth < 32 Weeks

14.1

Relative Risk

14
12
10
8

7.1

7.7

6
4
2

2.6

2.7

BMI <19.8

(+) BV

1.5

0
African
American

Previous
SPTB

CL 25 mm

(+) fFN

Cervical length measurement and fFN testing were performed at 22 to 24 weeks

Goldenberg RL et al. Am J Public Health. 1998;88:233-238.

fFN in Symptomatic Patients:

High NPV
QuickTime and a
decompressor
are needed to see this picture.

NPV for delivery within:

7 days = 99.5%
14 days = 99.2%
<37 weeks = 84.5%
N = 763
Mean gestational age at fFN testing= 30.33.0 weeks
Mean gestational age at delivery=38.42.6 weeks

Peaceman AM et al. Am J Obstet Gynecol. 1997;177:13-18.

Benefits of a
Negative Test
Less intervention
Avoid hospitalizations
Physician and patient
reassurance

fFN in Symptomatic Patients:

Helpful PPV
QuickTime and a
de co mpre ss or
are needed to s ee this picture.

PPV for delivery within:

7 days = 12.7%
14 days = 16.7%
<37 weeks = 44.7%
N = 763
Mean gestational age at fFN testing = 30.33.0 weeks
Mean gestational age at delivery = 38.42.6 weeks

Benefits of a
Positive Test
Identify group that can be
targeted for intervention
Opportunity for antenatal
steroids
Preparation for optimal
neonatal care

Peaceman AM et al. Am J Obstet Gynecol. 1997;177:13-18.

Fetal Fibronectin Enzyme Immunoassay and Rapid fFN for the TLiIQ System. Information for Health Care Providers. Cytyc ,
Marlborough, MA.

NICHD Preterm Prediction Study:

Asymptomatic Patients
If fFN positive at 22 to 24 weeks:
Delivery

Sensitivity

Relative Risk

<28 weeks

63

59.2

<30 weeks

54

39.9

<32 weeks

38

21.2

34 weeks

21

8.9

N=2929. Single testing at 22 to 24 weeks.

NICHD=National Institute of Child Health and Human Development.

Goldenberg RL et al. Obstet Gynecol. 1996;87:643-648.

Cervical Length as Predictor of

SPB
The risk of SPB is increased in women with short
cervix. Abnormal cervical length <25 mm (10%ile)

(Iams JD &
Conspiracy?
NICHD MFMU Network, 1996)

The shorter the cervix, the higher is the risk for SPB

Cervical Length: Ultrasound Marker for

Risk Assessment
Probability of Preterm Delivery (%)

Preterm Delivery <35 Weeks

50
40
30
20
10
0
0

20

40

60

Cervical Length (mm)

Cervical length was measured at 24 weeks.
Iams JD et al. N Engl J Med. 1996;334:567-572.

80

Cervical Length as a Marker for Risk

Assessment in Asymptomatic Women
What is "short"?
In the medical literature, defined as 1.5 to 3.0 cm 1
2.5 cm seems to have the best predictive accuracy

For SPTB before 35 weeks, cervical length

of less than 2.5 cm from 16 to 24 weeks:2
Sensitivity 69%
Specificity 80%
PPV 55%
NPV 88%
1. Hibbard JU et al. J Perinatol. 2000;20:161-165.
2. Owen et al. JAMA. 2001;286:1340-1348.

Predictive Value of Cervical Length:

Symptomatic Patients
In women with contractions:
Cervical length of less than 1.5 cm was associated with
a 37%-47% chance of delivering within 7 days 1,2
With a cervical length of greater than 3 cm, preterm
birth is highly unlikely 3

1. Tsoi E et al. Ultrasound Obstet Gynecol. 2003:21(6):552-555.

2. Fuchs I et al. Ultrasound Obstet Gynecol. 2004:24(5):554-557.
3. Schmitz T et al. Am J Obstet Gynecol. 2006;194:138-143.

Transvaginal sonographic cervical assessment

Changes in Cervical Morphology

Normal Cervix

Short and Funneled Cervix

Reprinted with permission from Berghella V. Contemporary Ob/Gyn. 2004;49:26-34.

Interventions that have been

used
Bed rest
Intravenous hydration

Are there any therapeutic interventions

to prevent SPTB?

Types of Cervical
Cerclage
History-indicated
Physical exam-indicated
Ultrasound-indicated

The Use of Cervical Cerclage for a Short

Cervix (Ultrasound-Indicated Cerclage)
4 RCTs
AUTHOR-YEAR

POPULATION

Unselected
High-risk
Unselected
Unselected

Rust-2000
Althuisius-2001
To-2004
Berghella-2004

OUTCOME

No benefit
Benefit*
No benefit
No benefit

*REDUCTION OF PREMATURITY, MORTALITY & MORBIDITY

Multicenter RCT on the Use of Cervical

Cerclage in High Risk Pregnancies
(Report of the MRC/RCOB, Br J Obstet Gynaecol 1993; 100:516)

Benefit observed in 1:25 cases

Cerclage is beneficial only in women with a
history of >3 second trimester
losses/preterm births

History-Indicated Cerclage

Cerclage for dilated cervix with membranes

at or beyond the external os
Cerclage &
Indomethacin
(n=13)

Bedrest alone (n=10)

Prolongation (weeks)

7.7

3.0

Neonatal survival

56%

28%

Preterm birth <34

weeks

54%

100%

Composite neonatal
morbidity

62%

100%

Althusius et al, Am J Obstet Gynecol 2003

Management of Cervical Insufficiency

and Bulging Fetal Membranes (at 18-26
weeks)
(Daskalakis et al Obstet Gynecol 2006;107:219)
Cerclage
No Cerclage
(n=29)
(n=17)

Prolongation (wks)
Mean BW (g)
Live birth
Neon survival
PTB <32 wks
NICU admission

8.8
2,101
86%
96%
31%
28%

3.1
739
41%
57%
94%
86%

Physical Exam-Indicated Cerclage

Use of Cerclage for Prevention of SPB in Women

With Prior SPB.
A Meta-analysis of 4 RCTs
(Berghella V, Odibo A, To M, Rust O and Althiusius S)
Obstet Gynecol 2005;106:181

4 RCTs (n=208 women with prior SPB)

No cerclage
Cerclage (for CL <25 mm)

SPB <35 weeks

39/101 (39%)
25/107 (22%)
RR=0.61 (95% CI=0.40, 0.92)

(Hx of prior 2nd trim loss)

RR=0.57 (95% CI=0.33, 0.99)

Multicenter Randomized Trial of Cerclage For Preterm Birth

Prevention In High-Risk Women With Shortened Mid-Trimester
Cervical Length
(Owen J, Abst #4, Am J Obstet Gynecol Suppl Dec 2008)
P=0.05

Reduction in PTB < 35 wks in

cerclage patients
OR (95%
CI)
If CL < 15 mm
0.66)
If CL 16-24 mm
1.40)

0.23 (0.08,
0.84 (0.49,

CONCLUSION:
Cerclage will mostly benefit
high-risk women with
mid-trimester CL < 15 mm
(77% reduction in PTB rate)

Tocolytics
-adrenergic agents
Magnesium sulfate
Prostaglandin synthetase inhibitors
Calcium channel blockers
Nitroglycerin
Oxytocin antagonists

Magnesium sulfate!

Good or evil?

Contraindications to Tocolysis
Conditions where delivery is indicated such as
Severe preeclampsia/hypertension
Fetal non-reassuring status
Maternal non-reassuring status
Significant hemorrhage
Maternal cardiac disease
Gestational age >36 weeks (? >34 weeks)
Infection/ chorioamnionitis
Fetal demise or lethal anomaly

Goals of tocolysis
To allow steroid administration
To allow transport or to facilitate delivery
under safer circumstances
To prolong gestation in very preterm
pregnancies

Calcium channel blockers

Inhibit calcium entry into cells
Nifedipine most commonly used
Rapidly absorbed after oral adminstration
Peak concentration in 15-90 minutes
Half life of 81 minutes
Duration of action of single dose 6 hours
Good contraction suppression and few side effects
12 reported trials show reduced deliveries within 7
days (RR 0.76; CI 0.60, 0.97)
Reduced deliveries before 34 weeks (RR 0.83, CI
0.69, 0.99)
Reduced fetal RDS, IVH, NEC, jaundice, when
compared with other tocolytics
Fewer women stop treatment due to side effects

Calcium channel blockers

Side effects:
Hypotension
Headaches
Dizziness
Nausea
No significant fetal effects
Administration
10 -20 mg every 4-6 hours

Cyclooxgenase inhibitors
Inhibit prostaglandin synthesis
Vary in activity/potency
Indomethacin most widely used
Powerful tocolytic
Crosses placenta
Associated with reduction in births before 37 weeks,
increased gestational age, birth weight
Maternal side effects:
GI disturbances
Bleeding
Thrombocytopenia
Asthma
Renal injury

Cyclooxgenase inhibitors
Fetal side effects:
Oligohydramnios
Premature closure of ductus arteriosus
These complications are rare
Generally not recommended beyond 37 weeks
NEC
Treatment protocol
50 mg loading
25-50 mg every 6 hours
Assess AFI, ductus if using for prolonged periods
Stop treatment if delivery is imminent

Steroids

Reduce risk of :
Respiratory distress syndrome
Intraventricular hemorrhage
Necrotizing enterocolitis

Progesterone

Progesterone for the reduction of risk of preterm birth

NICHD 17P Study: Rate of Recurrent

Preterm Birth Substantially Reduced

Preterm Birth (%)

80

34%

60

40

20

33%
42%

54.9

36.3
30.7
20.6

19.6
11.4
Placebo

17P

<32 Weeks

Placebo

17P

<35 Weeks

NICHD=National Institute of Child Health and Human Development

Meis PJ et al. N Engl J Med. 2003;348:2379-2385.

Placebo

17P

<37 Weeks

Reduction of SPTBs By Progesterone Administration

Among Asymptomatic High Risk Women

60% reduction for births < 37 weeks-daily 100mg

progesterone vaginal suppositories
(da Fonseca et al,
Am J Obstet Gynecol 2003;188:419)

34% reduction for births < 37 weeks-weekly IM

injections of 17-P
(Meis PJ & NICHD MFMU Network, N Engl J Med 2003;348:2379)

CL unknown (was not reported) in the above two studies

Prevention of Recurrent Preterm Delivery by

Progesterone Vaginal Gel-A R-DB-PC Trial
(OBrien et al Ultrasound Obstet Gynecol 2007;30:687
DeFranco et al Ultrasound Obstet Gynecol 2007;30:697)

Daily vag prog gel (90mg) starting at 18-23 weeks

N=659 women with Hx of SPTB
No reduction in PTB at <32 weeks
(SECONDARY ANALYSIS)
Women with CL <28 mm had
a) less PTBs (0% vs, 30%); and
b) less NICU admissions (16% vs. 52

%)

Speculation
It is possible that progesterone
administration in women with history of
SPTB may benefit only those with a short
cervix in the current pregnancy

Use of Progesterone to Reduce Preterm

Birth
(ACOG Committee Opinion, Number 419, October 2008)

It should be offered to women with a singleton

pregnancy and a history of spontaneous
preterm birth < 37 weeks gestation
Progesterone supplementation for
asymptomatic women with an incidentally
identified very short cervical length (< 15 mm)
may be considered; however, routine cervical
length screening is not recommended