Preterm Labor: Diagnosis and Treatment

BEVERLY A. VON DER POOL

BEVERLY A. VON DER POOL, M.D.

Am Fam Physician. 1998;57(10):2457-2464

A more recent article on preterm labor is available.

Preterm labor and delivery are among the most challenging obstetric complications encountered by the family physician. In the United States, preterm delivery affects approximately one in 10 births and is the cause of at least 75 percent of neonatal deaths, excluding those related to congenital malformations. Although the cause of preterm labor is unknown, family physicians who provide obstetric care should familiarize themselves and their patients with the predisposing risk factors. Preconception counseling should emphasize family planning, nutrition, “safe sex techniques,” treatment of sexually transmitted diseases, and avoidance of cigarettes, alcohol, abusive drugs and harmful work conditions. The rate of fetal morbidity can be reduced with the early and accurate diagnosis of preterm labor, intervention to delay preterm delivery, administration of corticosteroids and provision of neonatal care. Research into biochemical markers such as fetal fibronectin, possible infectious etiologies such as bacterial vaginosis, and the use of more selective tocolytic therapy offers hope that new therapeutic approaches may increase rates of fetal survival.

Unfortunately, the incidence of premature birth has not decreased during the past 40 years. In the United States, preterm delivery affects approximately one in 10 births and is the cause of at least 75 percent of neonatal deaths, excluding those related to congenital malformations.¹

Preterm labor is defined as labor that occurs before completion of the 37th week of gestation. Currently, physicians must diagnose and manage preterm labor amid substantial controversy over the effectiveness of preventive and therapeutic modalities. This article proposes an approach to the diagnosis and treatment of preterm labor that concurs with the guidelines recently established by the American College of Obstetricians and Gynecologists (ACOG).²

Etiology and Epidemiology

In most cases, the cause of preterm labor is not diagnosed, and the etiology is likely to be multifactorial. The clinical factors associated with preterm labor are listed in Table 1. In 25 percent of preterm births, labor is induced for various maternal and fetal medical indications; approximately 30 percent of preterm births are associated with premature rupture of the membranes (PROM). Preterm birth can potentially be prevented in less than one half of the mothers who present in labor earlier than 37 weeks of gestation.³ Consequently, family physicians should identify all women in early preterm labor or at risk for preterm labor.

Maternal factors
	Low socioeconomic status
	Nonwhite race
	Maternal age ≤18 or ≥40 years
	Low prepregnancy weight
	Smoking
	Substance abuse
Maternal history
	Previous history of preterm delivery
	Previous history of a second-trimester abortion
Uterine factors
	Uterine volume increased
	Uterine anomalies
	Trauma
Infection

Because family physicians often have the advantage of seeing a patient before conception, they may be able to influence some of the maternal factors associated with preterm labor. All women, especially those under 18 or over 40 years of age, should be offered education and/or intervention for family planning, smoking, substance abuse, poor nutrition, sexually transmitted diseases and adverse work conditions that could harm a fetus. Prenatal care should also be provided in underserved rural and urban areas to women at high risk for preterm birth. Furthermore, pregnancy outcome can be optimized by the treatment of preexisting medical conditions, such as hypertension and diabetes.

Uterine malformations that predispose a patient to preterm labor include a bicornate or unicorn uterus, and uterine fibroids, particularly submucosal and subplacental fibroids. Women who are diagnosed with uterine malformations before conception may be given the option of birth control or surgery, if applicable. Cervical incompetence from trauma or exposure to diethylstilbestrol can lead to painless cervical dilation and preterm labor. Both of these conditions may respond to the placement of a cerclage; however, no controlled trials have been conducted to support this approach.

Infections of the genitourinary tract are an important and treatable factor associated with preterm labor. Women with Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, Trichomonas vaginalis, Gardnerella vaginalis or group B streptococci infections have higher rates of preterm births. Although cause and effect have not yet been conclusively defined, diagnosis and treatment of these infections are necessary to prevent perinatal transmission.⁴

A maternal history of one or more second-trimester abortions or a previous history of preterm labor also increases the risk of subsequent preterm labor. Women with such a history should be given the option of effective family planning.

Markers of Preterm Labor and Delivery

A number of studies have attempted to identify clinical and biochemical markers of pre-term labor and delivery associated with overall poor predictive values (Tables 2 and 3).^5–17 The most promising of these markers is the presence of fetal fibronectin in cervicovaginal secretions, which, if positive (defined as greater than 50 ng per mL) after 20 weeks of gestation, indicates decidual disruption.¹⁴ In 1995, the U.S. Food and Drug Administration labeled fetal fibronectin enzymatic immunoassay for use as a screening test for preterm labor. In symptomatic patients, fetal fibronectin has an excellent sensitivity (69 to 93 percent)^14–17 and a negative predictive value as high as 99.7 percent (or, in other words, a one in 333 chance of delivery within one week of a negative test result).¹⁵ The positive predictive value (PPV), that is, the ability to predict that a patient with a positive test result will have a preterm delivery, is as high as 83 percent in symptomatic patients. In the future, the greatest value of the test may be to identify a symptomatic patient with a negative test result who may then be followed without drug intervention.

Marker	Test	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
Fibronectin	Cervical or vaginal^14–17	69 to 93	72 to 86	13 to 83	81 to 99
Cytokine (Interleukin-6)	Serum^5,16	50	73 to 85	47 to 57	67 to 86
Cytokine (Interleukin-6)	Amniotic fluid¹⁵	52	100	100	79
Estradiol-17β	Serum⁶	12	71 to 76	12 to 14	—
Estriol	Salivary⁷	71	77	27	77
Progesterone	Serum⁶	6 to 35	67 to 69	7 to 32	—

Marker	Test	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
Risk scoring systems	Risk factors^8,9	88 to 92	23 to 30	94 to 98	41 to 76
Assessment of cervical length	Manual examination^10,15,17	8 to 64	68 to 96	7 to 32	89 to 94
Assessment of cervical length	Ultrasound examination^11,12	76 to 100	55 to 59	55-75	93 to 100
Monitoring of uterine activity	Patient-perceived¹³	NS	NS	NS	NS
Monitoring of uterine activity	Tocodynamometry^10,15,17	18 to 58	45 to 94	7 to 20	82 to 94
Vaginal bleeding	Pelvic examination^15,17	8 to 36	89 to 95	21 to 82	82 to 97

Fetal fibronectin is not a useful screening test in unselected populations (PPV: 13 to 36 percent).¹⁸ At the present time, general use of the test cannot be recommended because of its cost (approximately $215), a lack of accessible laboratories performing the test and insufficient data to justify a clinical advantage.

Prevention of Preterm Delivery

Although prospective, randomized studies conducted in the United States have not shown that educating patients at high risk for preterm labor and health care personnel caring for them decreases the incidence of preterm births, studies in France have shown a decrease in preterm births following implementation of an education program for preterm labor.¹⁹ Until further studies resolve the discord, family physicians who provide obstetric care should include risk identification and education regarding the signs and symptoms of preterm labor in routine pre-natal care. Although bed rest and decreased activity have not been shown to decrease the rate of preterm birth in high-risk pregnancies, decreased activity is reasonable if the woman experiences increased uterine contractions with activity. Because the data do not clearly show benefits of monitoring uterine activity at home, it is not recommended at this time for the prevention of preterm delivery.²⁰

Documenting an accurate gestational age as early as possible is of paramount importance in the diagnosis and management of preterm labor. Documentation of gestational age should include a record of the last menstrual period (LMP) in order to calculate Nägele's rule (LMP + 7 days − 3 months), the onset of quickening, the first fetal heart tones audible by Doppler ultrasound examination, and the first heart tones audible by fetoscope. In addition, an early pelvic examination and a second-trimester ultrasound examination should be performed, when appropriate.

Awareness that fetal viability is directly related to gestational age will enhance patient care. At some institutions, the fetal survival rate approaches 90 percent at 24 to 27 weeks of gestation and 98 percent at 28 to 31 weeks of gestation in patients in preterm labor who are treated with tocolysis.²¹ Physicians who provide obstetric care should know the percentiles of fetal viability for their institution and should refer patients at risk for preterm labor to an institution that provides this critical care. Office personnel, as well as emergency department and labor and delivery nurses, should also know the triage protocol for patients at risk for preterm labor.

Diagnosis

Identification of the symptoms of preterm labor will help ensure that the patient can be evaluated, diagnosed and treated appropriately. The signs and symptoms that appear to predict preterm labor include frequent contractions (more than four per hour), cramping, pelvic pressure, excessive vaginal discharge, backache and low back pain. Because the symptoms of preterm labor may be non-specific, family physicians at the University of Alabama at Birmingham use the Creasy and Herron criteria of preterm labor.²² A diagnosis of preterm labor should be made in a patient between 20 weeks and 36 weeks, six days of gestation if uterine contractions occur at a frequency of four per 20 minutes or eight per 60 minutes, and are accompanied by one of the following: PROM, cervical dilation greater than 2 cm, effacement exceeding 50 percent, or a change in cervical dilation or effacement detected by serial examinations.

Management of Preterm Labor

Once the diagnosis of preterm labor is suspected, a complete history should be taken, including the patient's present symptoms, expected date of delivery, past medical history, medication use and allergies. Before the physical examination, a clean-catch or catheterized urine specimen should be obtained for urinalysis and culture. A general physical examination, including a vaginal examination using a sterile speculum, can then be performed.

Vaginal discharge or pooled fluid should be checked for ferning, and nitrazine testing can be performed if PROM is suspected. A wet preparation and a potassium hydroxide (KOH) preparation should be obtained, as bacterial vaginosis is strongly associated with preterm labor.^23,24 In addition, cervical cultures for C. trachomatis and N. gonorrhoeae are recommended because of their association with preterm labor. A rectovaginal culture for group B streptococcus should also be obtained. If preterm premature rupture of membranes (PPROM) is documented, digital examination should not be performed. Dilation and effacement of the cervix can be estimated during the vaginal examination. If there is no evidence of PPROM, a careful, gentle digital examination may be performed.

After the pelvic examination is completed, the patient should be placed in the lateral recumbent position and externally monitored for fetal heart tones and contractions. If uterine contractions are present at least every 15 minutes, an intravenous bolus of 500 mL of normal saline or Ringer's lactate can be administered. This rapid intravascular expansion can diminish the contractions of an irritable uterus and help the physician differentiate this condition from preterm labor. The rate of intravenous fluid replacement can then be adjusted to 100 mL per hour. If contractions persist, a single dose of terbutaline sulfate (Brethine, Bricanyl), 0.25 mg, can be given subcutaneously to allow time to discuss treatment options, to transfer the patient or to differentiate preterm labor from an irritable uterus.

If available, an ultrasound examination may be performed to determine the gestational age, presentation, placental location and presence of fetal anomalies. If an amniocentesis is performed, amniotic fluid can be sent to obtain a Gram stain, glucose level, lecithin/sphingomyelin ratio, and culture and sensitivity testing.²⁵

The patient's history, physical examination, and laboratory and ultrasound findings must be thoroughly evaluated to determine whether she meets the criteria for preterm labor or is a candidate for parenteral tocolytic therapy. Several absolute and relative contraindications must be considered before initiating therapy (Table 4).² The literature clearly supports the efficacy of parenteral tocolytic agents in delaying delivery for 24 to 48 hours.^26–28 Such a delay increases the time that may be required for the beneficial effects of adjunctive corticosteroid therapy or for transfer to a tertiary treatment center capable of handling a preterm delivery and a premature infant. Input from the patient and her family, once they have considered the benefits and risks, is vital in the decision to initiate therapy.

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Corticosteroid Therapy

Corticosteroid therapy is presently the only treatment shown to improve fetal survival when given to a woman in preterm labor between 24 and 34 weeks of gestation.²⁹ Studies have shown a decrease in intraventricular hemorrhage, respiratory distress syndrome and mortality even when treatment lasts for less than 24 hours, although optimal benefits begin 24 hours after therapy and last for seven days.²⁹ Corticosteroid therapy is also beneficial in pregnant women of less than 30 to 32 weeks of gestation with PPROM and no evidence of chorioamnionitis. Treatment regimens include betamethasone, in a dosage of 12 mg given intramuscularly every 24 hours for two days, or dexamethasone, in a dosage of 6 mg given intramuscularly every 12 hours for two days.

Parenteral Tocolytic Therapy

Drugs used for tocolysis include magnesium sulfate, ritodrine (Yutopar), terbutaline, nifedipine (Adalat, Procardia) and indomethacin (Indocin).³⁰ Recent studies have shown that antocin (Atosiban), an oxytocin receptor inhibitor (not labeled by the FDA for this purpose) may also be effective.^31,32

It is difficult to evaluate the efficacy of these drugs because of the inability to establish a definitive diagnosis of labor and the lack of consensus regarding the definition of successful treatment of preterm labor. However, it should be emphasized that tocolytic therapy has not been definitively shown to improve fetal outcome.

Magnesium Sulfate

Compared with beta-adrenergic agonists, magnesium sulfate is often used as a first-line therapy for tocolysis because it is highly effective and is associated with fewer side effects.^27,28 Magnesium sulfate acts centrally to decrease seizures and blocks neuromuscular transmission. The mechanism for preventing uterine contraction is unknown but may be related to calcium antagonist activity. A loading dose of 4 to 6 g should be given intravenously over 15 to 30 minutes. A continuous infusion of 1 to 4 g per hour is then administrated to maintain a magnesium level between 4 and 6 mEq. The infusion is continued until 12 to 24 hours of uterine quiescence is achieved. Commonly, terbutaline, in a dosage of 2.5 to 5.0 mg, is given orally 30 minutes before discontinuing the magnesium sulfate infusion, then every two to four hours thereafter to control contractions; however, a recent meta-analysis³³ does not support the role of oral therapy after resolution of an acute episode. The production of oral ritodrine was discontinued in 1995 because of issues concerning the dose and efficacy of the drug in women in preterm labor. Oral terbutaline is a more cost-effective alternative.

Complications associated with the use of magnesium sulfate are summarized in Table 5.² Maternal side effects include nausea, vomiting, hypotension, headache and the more severe effects of respiratory depression and pulmonary edema. Because magnesium sulfate crosses the placenta, fetal side effects include decreased muscle tone and lethargy. An immediate antidote to magnesium toxicity is an infusion of calcium gluconate.

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Beta-Mimetic Agents

The beta-mimetic drugs most commonly used in the United States are intravenous ritodrine and terbutaline, although ritodrine is the only drug labeled by the FDA for tocolysis.³⁴ Ritodrine and terbutaline stimulate the beta₂ receptors, resulting in relaxation of the uterine muscles and the smooth muscles of the lung with few effects on the beta₁ cardiac receptors. Intravenous ritodrine is administered in an initial dose of 0.05 to 0.1 mg per minute and increased at 15 minute intervals to 0.35 mg per minute. The usual dosage of terbutaline is 0.25 mg administered subcutaneously every one to six hours.

As previously noted, oral terbutaline, in a dosage of 2.5 to 5.0 mg, can be given every four hours, although a meta-analysis³³ of the literature failed to find significant benefit in oral tocolytic maintenance therapy over observation alone. The goal of oral maintenance therapy with beta-mimetic agents is to prevent uterine contractions that result in cervical change. The dosage is adjusted to minimize fetal contractions and to maintain the maternal heart rate between 90 and 105 beats per minute. If used, oral tocolytic therapy should be continued until 35 to 37 weeks of gestation.

The complications caused by beta-mimetic therapy are listed in Table 5.² Because intravenous beta-mimetic drugs can cause severe hypotension and tachycardia, the patient's blood pressure should be monitored frequently. Myocardial ischemia is also associated with intravenous administration of ritodrine; therapy should be discontinued and an electrocardiogram should be obtained immediately if the patient has chest pain or develops an arrhythmia. Pulmonary edema can be avoided by limiting the sodium and total fluid load to a maximum of 2,500 to 3,000 mL per 24 hours. Fluid input and output, daily weight, hourly respiratory rate and signs of pulmonary fluid accumulation should be monitored. Because hyperglycemia and keto-acidosis have occurred in patients receiving beta-mimetic therapy, serum glucose should be measured at baseline and repeated at 12-hour intervals in a patient without diabetes and at two-hour intervals in a patient with diabetes who is receiving intravenous fluids. Metabolic alterations, hypoglycemia or cardiac arrhythmias, and hypokalemia should be treated appropriately.

Second-Line Agents for Tocolysis

Indomethacin and calcium channel blockers are second-line drugs for the treatment of preterm labor. Indomethacin, a prostaglandin inhibitor, acts by inhibiting the production of cytokines that may trigger labor. Studies^35,36 have demonstrated the ability of indomethacin to inhibit preterm labor for 48 hours in pregnancies of less than 32 weeks of gestation. A 100-mg dose of indomethacin can be given by rectum and repeated after one to two hours if contractions persist. An oral dose of 25 mg every four to six hours should not be continued for longer than 48 hours because of potential fetal side effects. The use of indomethacin in the treatment of preterm labor has been associated with oligohydramnios and transient constriction of the ductus arteriosus.

Calcium channel blockers, such as nifedipine, inhibit the contraction of smooth muscle, resulting in uterine relaxation. Several small studies have shown that the efficacy of nifedipine is similar to that of ritodrine.^30,37

In most protocols, nifedipine is administered orally in a loading dose of 30 mg, followed by 20 mg given every four to eight hours for 24 hours, and then a maintenance dose of 10 mg every eight hours until 35 to 37 weeks of gestation or delivery.³⁷ The potential complications of second-line drugs are listed in Table 5.²

Emerging Treatments

Oxytocin inhibitors offer a potential new therapeutic agent for the treatment of preterm labor. Although the exact mechanism of action is not known, uterine oxytocin receptors and/or oxytocin may have etiologic roles in uterine hyperactivity in women with preterm labor. Studies of the two oxytocin antagonists, antocin³² and an orally active nonpeptidyl oxytocin antagonist,³⁸ have suggested a high level of efficacy and few side effects (primarily nausea and vomiting). Phase III trials are currently being conducted to examine the effect of antocin on preterm uterine activity.

Antibiotic Therapy

Certain maternal infections, such as those previously noted, play a potential etiologic role in preterm labor. Therefore, women with sexually transmitted diseases, urinary tract infections, severe respiratory infections and vaginitis should be treated appropriately. Patients with intact amniotic membranes and a history of positive group B streptococcal culture are usually treated with intravenous penicillin. This approach is based on the rationale that treatment will prevent perinatal transmission, although this approach is not substantiated in the prevention of preterm labor. Pregnancy and delivery may be prolonged in women treated with erythromycin, ampicillin and clindamycin (Cleocin).³⁹

Final Comment

Although the diagnosis and treatment of preterm labor are fraught with controversy, there are areas of consensus. Preconception counseling and early prenatal care that identifies and treats risk conditions can optimize pregnancy outcome. The physician must try to accurately date a patient's pregnancy, attempt to diagnose preterm labor at an early stage and make the appropriate management decision for the patient. This decision may include transfer to a tertiary site or management with appropriate consultation. Fetal fibronectin, a biochemical marker, may be a useful diagnostic tool in the future, but there are insufficient outcome data to justify its use at present. Documented infections such as sexually transmitted diseases, urinary tract infections and vaginitis should be treated. Tocolytic therapy should be used to delay delivery in order to administer corticosteroids. At present, corticosteroid therapy is the only treatment shown to improve fetal survival and outcome. Further studies are needed to find a marker with a high positive predictive value for preterm labor. Intervention studies are also needed to evaluate outcomes.

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