PRETERM LABOR
Solt Ido MD
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
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 Births
United States, 1985-1998
20
Percent
15
10
5
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
11.6
0
1985 1986 1987 1988 1989 1990 1991
All Races
1992 1993 1994 1995 1996 1997 1998
White
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.
Black
Patient Characteristics


Predisposing Factors

Low socioeconomic status

Previous preterm birth

Nonwhite race

Previous abortion

Maternal age <18 or >40 years

Substance abuse

Low prepregnancy weight

No prenatal care

Multiple gestation

PROM

Smoking
Cause unknown for most cases
Source: ACOG Technical Bulletin. 1995; No. 206.
Etiologies of Preterm Labor


Uterine Causes

Cervical incompetence

Uterine anomalies

Uterine stretch
Infectious Causes

Association with chorioamnionitis
Source: ACOG Technical Bulletin. 1995; No. 206.
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.
Survival According to Gestational Age
100
90
25
Survival, %
80
70
20
60
50
15
40
10
30
20
5
10
0
Distribution of Births, %
30
0
24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
Gestational Age (weeks)
Survived
Frequency of Birth
Source: St John EB et al. Am J Obstet Gynecol. 2000;182:170-175.
Ten Leading Causes of Infant Mortality
United States, 1997
Rate per 100,000 live births
159.2
Birth Defects
101.1
Preterm/LBW
77.1
SIDS
33.5
RDS
32.1
Maternal Preg. Comp.
24.7
Placenta, Cord Comp.
20.0
Infections
19.7
Accidents
11.6
Hypoxia/Birth Asphyxia
10.8
Pneumonia/Influenza
0
20
40
60
80
Source: National Center for Health Statistics, final mortality data.
Prepared by March of Dimes Perinatal Data Center, 2000.
100
120
140
160
180
Commonly Used Interventions

Culture/treatment for infection

Bed rest on left side

Hydration

Tocolytic agents

Lifestyle changes:

Stress reduction

Improve nutrition

Pelvic rest

No tobacco/alcohol

Relaxation techniques

Work modification

Cerclage

Home uterine monitoring

Maternal transport
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, placebocontrolled trials
Start weekly injections at 16 weeks and continue until 36
weeks
Not for tocolysis or adjunct therapy
Risk of PTD by Cervical Length
Probability of Preterm Delivery
Preterm Delivery <35 Weeks
0.5
0.4
0.3
0.2
0.1
0.0
0
20
40
Cervical Length (mm)
Source: Iams JD et al. N Engl J Med. 1996;334:567-572.
60
80
Risk of PTD by Cervical Length
Probability of Preterm Delivery
Preterm Delivery <35 Weeks
0.5
0.4
0.3
0.2
0.1
0.0
0
20
40
Cervical Length (mm)
Source: Iams JD et al. N Engl J Med. 1996;334:567-572.
60
80
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.
Fetal Fibronectin
Amnion
Chorion
Fetal
Fibronectin
Decidua
Fetal Fibronectin (ng/mL)
Fetal Fibronectin vs Gestational Age
4500
Clinically Relevant Time Frame
(22-35 weeks)
4000
3500
3000
2500
2000
1500
1000
500
0
0
5
10
15
20
25
30
Gestational Age (weeks)
Source: Adapted from Garite TJ et al. Contemp Obstet Gynecol. 1996;41:77-93.
35
40
50 ng/mL
Cutoff 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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