Preterm Birth

Yinka Oyelese, MD, MRCOGAssociate Professor, Maternal Fetal MedicineUTHSC

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

Infants born preterm are at increased risk of:

•Respiratory Distress syndrome

•Chronic lung disease

•Intraventricular hemorrhage

•Necrotizing enterocolitis

•Retinopathy of prematurity

•Severe brain injury

Newborn morbidity

50% of long term major morbidity among non-anomalous fetuses:

•Cerebral palsy

•Mental retardation

•Blindness

•Deafness

•Sensory deficits

•Developmental delay

Long term consequences

The High Cost of Preterm Birth

Estimated annual societal economic burden in theUnited States

>$26.2 billion ($51,600 for every infant born preterm)

Average hospital length of stay

Average first-year medical costs, including both inpatientand outpatient care

13 daysPreterm infant

1.5 daysTerm infant

$32,325Preterm infant

$3325Term infant

1.

The High Cost of Preterm Birth

Estimated annual societal economic burden in theUnited States

>$26.2 billion ($51,600 for every infant born preterm)

Average hospital length of stay

Average first-year medical costs, including both inpatientand outpatient care

13 daysPreterm infant

1.5 daysTerm infant

$32,325Preterm infant

$3325Term infant

1.

Costs affect insurance rates, taxes, and PAY CHECKS!

Sources of preterm birth, United States 2000

Overall (%)

Singletons(%)

Twins(%)

Spontaneous 60 69 44

Medically indicated

40 31 56

Ananth et al, Obstet Gynecol, 2006

0

1

2

3

4

5

6

7

8

9

10

11

89 90 91 92 93 94 95 96 97 98 99 00

Pre

term

bir

th rate

(%

)Preterm births in the United States

0

1

2

3

4

5

6

7

89 90 91 92 93 94 95 96 97 98 99 00

Pre

term

bir

th rate

(%

)

Spontaneous PTB

Medically indicated PTB

Preterm PROM

SPB

Source of Preterm Birth

Spontaneous 30-50%

Preterm PROM

30-40%

Indicated 20-30%

Tucker et al. Obstet Gynecol 1991

-40

-30

-20

-10

0

10

20

30

40

50

60

89 90 91 92 93 94 95 96 97 98 99 00

Rel

ativ

e ch

ange

(%) in

pre

term

bir

th rat

e si

nce

198

9 Medically indicated

Spontaneous

Overall

SROM

Whites Blacks

All PTB 14% 15%

Spont PTB

3% 27%

Med-ind 55% 32%

PNM 30% 25%

Preterm Birth

Changes between 1989-00, US

Preterm Birth Trends

Whites (%) Blacks (%)89 00 Δ% 89 00 Δ%

Total PTB

8.3 9.4 14 18.5

16.2

-15

pPROM

1.1 0.8 -23 2.3 1.5 -37

Med-ind 2.3 3.6 55 4.1 5.6 32Spt labor 4.9 5.0 3 12.

19.1 -27

Indicated Preterm Birth

Singletons

Twins

Preeclampsia

43% 44%

FGR/fet dist 37% 33%

Abruption 7% 9%

Fetal death 7% 7%Tucker et al. 1991Meis et al. 1986

Among…Ischemic

placental disease present in

Term births 1 in 10 births

Preterm births 1 in 4 births

Indicated preterm births

≥1 in 2 births

Ananth and Vintzileos AJOG 2006

Ischemic Placental Disease

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 socio-

economic 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

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

•1405 preterm mothers

•2781 term mothers

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 father’s GA

- 1.22 days for each additional week in the mother’s GA

Lie et al. Obstet Gynecol 2006

Recurrence of preterm birth

Recurrence of preterm birth

0

5

10

15

20

25

30

35

40

22 24 26 28 30 32 34 36 38 40 42 44

Gestational age at first birth (weeks)

Proportion o

f second b

irth

s d

elivered p

rete

rm

(%

)

Second births at <37 weeks

Second births at <35 weeks

Second births at <32 weeks

<37 wks

<34 wks

<32 wks

US Preterm Birth Rate:Highest Among African Americans

0.0

5.0

10.0

15.0

20.0

All races Non-HispanicWhite

Hispanic Non-HispanicBlack

12.7%11.7% 12.1%

18.4%

ÒLow socioeconomic status alone does not explain theincrease in preterm births among African Americanscompared to the white non-Hispanic populationÓ2

1. Hamilton BE et al. National Center for Health Statistics. Available at:http://www.cdc.gov/nchs/products/pubs/pubd/hestats/prelimbirths05/prelimbirths05.htm

2. IOM. Preterm Birth: Causes, Consequences, and Prevention. 2006. Available at: http://www.iom.edu/CMS/3740/25471/35813.aspx.

Average length of gestation by plurality

•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 (isn’t 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 glycoproteinÒglueÓ at the maternal-fetal interface

Presence incervicovaginalsecretions highlyassociated with risk ofpreterm 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

Cervicovaginal Presence of Fetal Fibronectinfrom 22 to 35 Weeks Is Abnormal

Fet

al F

ibro

nect

in (

ng/m

L)

0 5 10 15 20 25 30 35 40

Gestational Age (Weeks)

Clinically Relevant Time Frame

(22 to 35 weeks)

0

500

1000

1500

2000

2500

3000

3500

4000

4500

50 ng/mLCutoff Level

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

Comparison of Risk Factors

Rel

ativ

e R

isk

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

14.1

7.77.1

2.72.61.5

0

2

4

6

8

10

12

14

16

AfricanAmerican

BMI <19.8 (+) BV PreviousSPTB

CL ² 25 mm (+) fFN

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

Spontaneous Preterm Birth < 32 Weeks

Qui ckTi me™ and a decompressor

are needed to see thi s pi cture.

NPV for delivery within:7 days = 99.5%14 days = 99.2% <37 weeks = 84.5%

N = 763Mean gestational age at fFN testing= 30.3±3.0 weeksMean gestational age at delivery=38.4±2.6 weeks

Benefits of aNegative Test¥Less intervention

¥Avoid hospitalizations

¥Physician and patientreassurance

fFN in Symptomatic Patients:

High NPV

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

Benefits of aPositive Test¥Identify group that can be

targeted for intervention

¥Opportunity for antenatalsteroids

¥Preparation for optimalneonatal care

fFN in Symptomatic Patients:

Helpful PPV

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.

Q ui ckTi me™ and a decompressor

are needed to see thi s pi cture.

PPV for delivery within:7 days = 12.7%14 days = 16.7% <37 weeks = 44.7%

N = 763Mean gestational age at fFN testing = 30.3±3.0 weeksMean gestational age at delivery = 38.4±2.6 weeks

NICHD Preterm Prediction Study:Asymptomatic Patients

59.263<28 weeks

39.954<30 weeks

8.921² 34 weeks

21.238<32 weeks

Relative RiskSensitivityDelivery

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.

If fFN positive at 22 to 24 weeks:

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 & NICHD MFMU Network, 1996)

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

Conspiracy?

Cervical Length: Ultrasound Marker forRisk Assessment

Cervical Length (mm)

Pro

babi

lity

of P

rete

rm D

eliv

ery

(%)

50

40

30

20

10

0

0 20 40 60 80

Cervical length was measured at 24 weeks.

Iams JD et al. N Engl J Med. 1996;334:567-572.

Preterm Delivery <35 Weeks

Cervical Length as a Marker for RiskAssessment in Asymptomatic Women

What is "short"?Ğ In the medical literature, defined as 1.5 to 3.0 cm 1

Ğ ² 2.5 cm seems to have the best predictive accuracy

For SPTB before 35 weeks, cervical lengthof less than 2.5 cm from 16 to 24 weeks:2

Ğ Sensitivity 69%

Ğ Specificity 80%

Ğ PPV 55%

Ğ 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:

Ğ Cervical length of less than 1.5 cm was associated witha 37%-47% chance of delivering within 7 days 1,2

Ğ With a cervical length of greater than 3 cm, pretermbirth is highly unlikely3

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.

Changes in Cervical Morphology

Normal Cervix Short and Funneled Cervix

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

Transvaginal sonographic cervical assessment

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 RCT’s

• Rust-2000 Unselected No benefit• Althuisius-2001 High-risk Benefit* • To-2004 Unselected No benefit• Berghella-2004 Unselected No benefit

AUTHOR-YEAR POPULATION OUTCOME

*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)

• Prolongation (wks) 8.8 3.1• Mean BW (g) 2,101 739• Live birth 86% 41%• Neon survival 96% 57%• PTB <32 wks 31% 94%• NICU admission 28% 86%

Cerclage

(n=29)

No Cerclage

(n=17)

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)

SPB <35 weeks No cerclage 39/101 (39%) Cerclage (for CL <25 mm) 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)

Reduction in PTB < 35 wks in cerclage patients

OR (95% CI)If CL < 15 mm 0.23 (0.08, 0.66)If CL 16-24 mm 0.84 (0.49, 1.40)

P=0.05

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

19.6

30.7

54.9

11.4

20.6

36.3

0

20

40

60

80

<32 Weeks <35 Weeks <37 Weeks

Pre

term

Bir

th (

%)

42%

33%

34%

NICHD 17P Study: Rate of RecurrentPreterm Birth Substantially Reduced

NICHD=National Institute of Child Health and Human Development

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

Placebo Placebo Placebo17P 17P 17P

Progesterone for the reduction of risk of preterm birth

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 (O’Brien et al Ultrasound Obstet Gynecol 2007;30:687 DeFranco et al Ultrasound Obstet Gynecol 2007;30:697)

• 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%)

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

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

Speculation

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