PRETERM LABORPRETERM LABOR

Solt Ido MDSolt Ido MD

Sources: ACOG Technical Bulletin,1995, No. 206; National Vital Statistics Report 2000;48(3).St John EB et al. Am J Obstet Gynecol. 2000;182:170-175.

Preterm Labor and Delivery (<37 Weeks)

Preterm Labor

800,000 (1 in 5) pregnant women exhibit signs and symptoms of preterm labor

70% of women identified as “high risk” deliver at term

Preterm Delivery

>452,000 (11%) of all pregnancies result in preterm birth

Single largest cause of perinatal mortality and morbidity

$4 to $6 billion annual acute care costs

9.8 10.0 10.2 10.2 10.6 10.6 10.8 10.7 11.0 11.0 11.0 11.0 11.4

0

5

10

15

20

Preterm Births United States, 1985-1998

Per

cen

t

All Races White Black

1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997

Note: Preterm is less than 37 weeks gestation.

Source: National Center for Health Statistics, final natality data. Prepared by March of Dimes Perinatal Data Center, 2000.

11.6

1998

Patient Characteristics

Predisposing Factors

Low socioeconomic status

Nonwhite race

Maternal age <18 or >40 years

Low prepregnancy weight

Multiple gestation

Smoking

Cause unknown for most cases

Previous preterm birth

Previous abortion

Substance abuse

No prenatal care

PROM

Source: ACOG Technical Bulletin. 1995; No. 206.

Source: ACOG Technical Bulletin. 1995; No. 206.

Etiologies of Preterm Labor

Uterine Causes

Cervical incompetence

Uterine anomalies

Uterine stretch

Infectious Causes

Association with chorioamnionitis

Clinical Characteristics of PTL

Regular or irregular contractions

Nonspecific symptoms

Backache

Pelvic pressure

Increased vaginal discharge

Bleeding

Cervical exam not always informative

Source: Cunningham FG et al, eds. Williams Obstetrics. 20th ed. Stamford, Conn: Appleton & Lange; 1997.

Current Approach

Clinical history

Clinical scoring systems

Risk classification

High Risk Previous PTD Multiple gestation pregnancy Diabetes Hypertension disorders

Patient presentation

Nulliparity—Risks not established

Source: Cunningham FG et al, eds. Williams Obstetrics. 20th ed. Stamford, Conn: Appleton & Lange; 1997.

Su

rviv

al, %

Dis

trib

uti

on

of

Bir

ths,

%

Gestational Age (weeks)

100

90

80

70

60

50

40

30

20

10

0

24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

0

5

10

15

20

25

30

Survival According to Gestational Age

Source: St John EB et al. Am J Obstet Gynecol. 2000;182:170-175.

Survived

Frequency of Birth

Ten Leading Causes of Infant MortalityUnited States, 1997

10.8

11.6

19.7

20.0

24.7

32.1

33.5

77.1

101.1

159.2

0 20 40 60 80 100 120 140 160 180

Pneumonia/Influenza

Hypoxia/Birth Asphyxia

Accidents

Infections

Placenta, Cord Comp.

Maternal Preg. Comp.

RDS

SIDS

Preterm/LBW

Birth Defects

Rate per 100,000 live births

Source: National Center for Health Statistics, final mortality data. Prepared by March of Dimes Perinatal Data Center, 2000.

Commonly Used Interventions

Culture/treatment for infection

Bed rest on left side

Hydration

Tocolytic agents

Lifestyle changes:

Stress reduction

Pelvic rest

Relaxation techniques

Cerclage

Home uterine monitoring

Maternal transport

Improve nutrition

No tobacco/alcohol

Work modification

Source: Cunningham FG et al, eds. Williams Obstetrics. 20th ed. Stamford, Conn: Appleton & Lange; 1997.

Potential Benefits of Risk Assessment Markers

More accurately identify women at risk

Avoid unnecessary treatment

Develop effective ongoing surveillance programs

Avoid unnecessary expense

Risk Assessment Markers

Biophysical markers

Measurement of cervical length

Biochemical markers

Fetal fibronectin (fFN)

Salivary estriol (E3)

Corticotropin-releasing hormone (CRH)

Interleukin-6 (IL-6)

Etiology

Most cases are idiopathic

Low socioeconomic status

Nonwhite

Young or advanced maternal age

Low prepregnancy weight

Previous preterm delivery (16-37%)

Smoking, cocaine

Multiple second-trimester losses

Etiology

Preterm rupture of membranes

Has its own set of etiologies

Results in preterm labor in >80% of cases

Racial / Ethnic groups

White patients more likely to present with preterm labor

Non-white more likely to present with preterm rupture of the membranes

Etiology

Uterine Abnormalities

Unicornate or bicornate uterus

Submucosal myomata

Cervical incompetence

Painless cervical dilation

May lead to preterm labor or PPROM

DES exposure

Infection?

Suspected Organisms

BV (Gardnerella)

Chlamydia

Ureaplasma

Trichomonas

Weak associations, no benefit of antibiotics in preventing PTL or PTD

Assessing Risk

Several methods advocated

Cervical length studies

Digital exams

2 cm dilation at 28 weeks showed increased risk in one study

1 cm dilation in early third trimester associated with increased risk

Large study found 7% at 28 weeks and 32% at 32 weeks with dilation and no increased PTL or PTD

Assessing Risk

No screening test or “score” successful in predicting PTL with any significant positive predictive value

FFN has a “useful” negative predictive value, but is NOT recommended by ACOG as a screening tool

Vaginal pH, uterine monitoring; jury is out

Prevention

Uterine monitoring

Randomized trials with conflicting data

Patients benefit from the nurse visit not necessarily the uterine monitor

More useful in patients with multiple gestation

May be useful in patients with a history of PTL/PTD or at high risk

Prevention

Oral Tocolytics

No benefit shown in randomized, placebo controlled trials

Bed rest

Most common treatment

Studies show no benefit

Prevention

17-P Therapy

17 alpha hydroxyprogesterone caproate

Shows 37% reduction in PTL / PTD in patients with previous PTL / PTD in two large, randomized, placebo-controlled trials

Start weekly injections at 16 weeks and continue until 36 weeks

Not for tocolysis or adjunct therapy

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

Preterm Delivery <35 Weeks

Risk of PTD by Cervical Length

Pro

bab

ilit

y o

f P

rete

rm D

eliv

ery 0.5

0.4

0.3

0.2

0.1

0.0

0 20 40 60 80

Cervical Length (mm)

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

Preterm Delivery <35 Weeks

Risk of PTD by Cervical Length

Pro

bab

ilit

y o

f P

rete

rm D

eliv

ery 0.5

0.4

0.3

0.2

0.1

0.0

0 20 40 60 80

Cervical Length (mm)

Fetal Fibronectin

A glycoprotein secreted by fetal membranes that is found in the choriodecidual junction

Responsible for cellular adhesiveness

Level in cervicovaginal secretions is highly associated with preterm labor (potential or existing) and preterm delivery

Source: Lockwood CJ et al. N Engl J Med. 1991;325:669-674.

Amnion

Chorion

FetalFibronectin

Decidua

Fetal Fibronectin

Fetal Fibronectin vs Gestational AgeF

etal

Fib

ron

ecti

n (

ng

/mL

)

0 5 10 15 20 25 30 35 40

Gestational Age (weeks)

Clinically Relevant Time Frame

(22-35 weeks)

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

0

500

1000

1500

2000

2500

3000

3500

4000

4500

50 ng/mLCutoff Level

Conclusions

NPV 99.7% before 28w

NPV 96.3% before 35w

PPV 31.7% at 24w

Tocolysis

Goals

Transport to tertiary care center

Administer corticosteroids

Prolong pregnancy

More effective when started prior to 3 cm dilation

No data suggest that tocolysis improves any index of long-term prenatal or perinatal morbidity or mortality beyond steroid adminstration

? Placement of cervical cerclage

Tocolysis

Indications

Less than 35 weeks gestation (morbidity and mortality is within 1% of term infants after 34 weeks gestation)

No evidence of infection

Viable

No life-threatening maternal complications

Tocolysis

Contraindications

Acute fetal distress

Chorioamnionitis

Severe Preeclampsia

Fetal demise

Maturity

Maternal hemodynamic instability

Tocolysis

Magnesium Sulfate

Most commonly used in tertiary centers

Low incidence of maternal side effects

Decreases smooth muscle contractility by interfering with calcium transportation (theory)

No better than other tocolytics but easier to control (drip) and fewer side effects

Magnesium Sulfate

Dosing

Try to maintain levels of 5.5-7 mg/dl

Usual dose is 6g loading dose followed by 3g/hour infusion

Magnesium levels can be monitored to check for theraputic range or if soft signs of toxicity are present

May increase dosage if no signs of toxicity

Magnesium Sulfate

Contraindications

Myasthenia Gravis

Myasthenia Gravis

MYASTHENIA GRAVIS!!!!

Renal failure

Severe hypocalcemia

Magnesium Sulfate

Side effects

Maternal “flushing” or warmth

Headache

Nausea

Dry mouth

Dizziness

Blurred vision

Magnesium Sulfate

Toxicity

Loss of deep tendon reflexes (serum concentration around 8mg/dl)

Mental status change / loss of consciousness

Respiratory depression

Pulmonary Edema

Profound Hypotension

Cardiac Arrhythmias

Magnesium Sulfate

Toxicity (continued)

Treat according to symptoms NOT levels

Calcium Gluconate

Comes in 10 ml vials

Each vial contains 4.5 mEq of Calcium Gluconate

Recommended dose is 4.5-7 mEq in adults

Can be given IM or in a 10% dilution IV

In respiratory depression or arrest, think of the ABC’s first, then give Calcium

Terbutaline

Β-agonist

Promotes smooth muscle relaxation

May be given IV or Sub-cutaneously

Rapid onset of action

No better than magnesium for PTL; higher incidence of maternal side effects

Terbutaline

Contraindications

Maternal cardiac rhythm disturbance

Cardiac disease

Poorly controlled diabetes

Thyrotoxicosis

Severe hypertension

Terbutaline

Side Effects / Toxicity

Maternal tachycardia

Fetal tachycardia

Hyperglycemia, hypokalemia

Hypotension

Cardiac insufficiency

Arrhythmias

Myocardial ischemia

Maternal death

Terbutaline

Other Uses

Asthma

P.O. tocolysis (not effective)

Subcutaneous pump (may be effective)

Uterine relaxation / fetal recussitation

Indomethacin

Powerful Anti-inflammatory

Inhibits prostaglandin synthesis

Readily crosses the placenta

Often used in conjunction with other tocolytic therapy (e.g., magnesium)

Shown effective in prolonging pregnancy 48-72 hours

Indomethacin

Contraindications

Asthma

Coronary artery disease

GI bleed

Oligohydramnios

Renal failure

Fetal cardiac lesion

Gestational age >32 weeks

Indomethacin

Side effects / toxicity

Rare maternal effects

GI bleeding (rare)

Mask fever (rare)

Fetal effects

May constrict ductus; most profound in patients >32 weeks

May cause oligohydramnios

May increase risk of IVH

Other Agents

Nifedipine

Calcium Channel blocker

Smooth muscle relaxer

Torodol

Anti-inflammatory

More GI side effects than Indomethacin

Ritodrine

Only FDA approved drug for PTL

Very rarely used; Β-agonist

Corticosteroids

For now, the ONLY evidence-based rational for tocolysis

Proper course of steroids within a 48-hour period reduced the risk of neonatal IVH by greater than 50% and RDS by 28%

Benefit seen prior to 34 weeks

Also reduces risk for NEC, ROP, and neonatal death

Corticosteroids

Dosing

Two IM doses of 12.5 mg Betamethasone, 24 hours apart

Full benefit is reached 24 hours AFTER the second dose

Also may give 6 mg Dexamethasone IM x 4 doses, 12 hours apart

Increased risk of cystic para-ventricular leukomalacia and cerebral palsy with Dex

Corticosteroids

Controversies

Multiple course administration

No evidence of harm to mother or fetus

No evidence of benefit over one course

“Accelerated” dosing

No evidence early course completion is better than single dose

May be a candidate for a new course if possible

Antibiotics

Used ONLY to prevent Group B β-streptococcus infection in the neonate

Fetus should receive two doses if possible

Dosing for PCN

5 million units loading dose

2.5 million units every 4 hours

May use ampicillin

Use clindamycin with PCN allergy

Antibiotics

Massive trials show antibiotics do not increase time to delivery in PTL

Culture-based use of antibiotics in pre-term labor is controversial

Use PCN if at all possible; most group B strep is sensitive

Summary for PTL

Does the patient have PTL?

Cervical exam

Document advanced dilation or change

Toco monitor

Is the patient a candidate for tocolysis?

<34 weeks

Viable

No contraindications

Summary for PTL

What method should be used?

Use magnesium if not contraindicated

Best tolerated

Easiest dosing to control

Indomethacin generally considered second line, then Terbutaline

What else should be given?

Steroids (ALWAYS)

Antibiotics

Summary for PTL

What other considerations?

Ultrasound for fetal weight

Neonatology consultation

What if the first line drug is not working?

Consider gestational age

Consider adding additional agent or re-bolus of current medication

Note interactions CAREFULLY

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