Author
Hyagriv Simhan, MD
Steve Caritis, MD / Section Editor
Charles J Lockwood, MD / Deputy Editor
Vanessa A Barss, MD
Last literature review version 16.1: January 2008 | This topic last updated: November 28, 2007 (More)
INTRODUCTION—Tocolytic therapy of an acute episode of idiopathic preterm labor (PTL) often abolishes contractions temporarily, but does not remove the underlying stimulus that initiated the process of parturition or reverse parturitional changes in the uterus. The net effect is that tocolytics are unlikely to prolong pregnancy by weeks or months. (See "Physiology of parturition").
The goals of treatment of PTL are to [1] :
· Delay delivery by at least 48 hours so that glucocorticoids given to the mother can achieve their maximum effect. Predelivery administration of glucocorticoids reduces the risk of neonatal death, respiratory distress syndrome, intraventricular hemorrhage, and necrotizing enterocolitis in premature neonates. (See "Antenatal use of glucocorticoids in women at risk for preterm delivery").
· Provide time for safe transport of the mother, if indicated, to a facility that can provide an appropriate level of neonatal care if the patient delivers preterm.
· Prolong pregnancy when there are underlying, self-limited conditions that can cause labor, such as pyelonephritis or abdominal surgery, and are unlikely to cause recurrent PTL.
Studies on the treatment of PTL are difficult to analyze because few placebo controlled trials exist and comparative trials are often poorly designed or underpowered. Many trials were at risk of selection, performance, attrition, and detection bias [2] . Others did not prospectively specify the outcomes to be evaluated and the plan for statistical analysis. Furthermore, glucocorticoids were not routinely administered; as a result, the neonatal benefits of delaying delivery for 48 hours were not fully realized.
The treatment of PTL will be reviewed here. Other issues related to PTL are discussed separately. (See "Pathogenesis of preterm birth" and see "Tests for prediction of preterm labor and delivery" and see "Prevention of spontaneous preterm birth" and see "Risk factors for preterm labor and delivery").
INITIAL EVALUATION—The initial evaluation of women suspected of PTL is discussed in detail separately. (See "Overview of preterm labor and delivery", sections on Diagnosis and Evaluation).
When to initiate treatment—There are no evidence based guidelines for when to initiate treatment of PTL, or universally agreed upon criteria for making this diagnosis [3] . Two general prerequisites for beginning labor inhibiting therapy are:
· Documentation of PTL — The diagnosis of PTL is generally based upon clinical criteria of regular, painful uterine contractions accompanied by cervical dilation and/or effacement. PTL is one of the most common reasons for hospitalization of pregnant women, but identifying women with preterm contractions who will deliver preterm is an inexact process. A systematic review noted that approximately 30 percent of PTL cases spontaneously resolved [4] . In subsequent studies, 50 percent of patients hospitalized for PTL deliver at term [5-7] .
Specific criteria for PTL used in research studies vary, but typically include persistent uterine contractions (eg, at least four every 20 minutes or eight every 60 minutes) with premature rupture of membranes or cervical dilation of 1 to 3 cm or effacement exceeding 50 percent or a change in cervical dilation or effacement detected by serial examinations [8,9] .
Sonography of the cervix and biochemical tests can be used, but PTL remains a clinical diagnosis. These procedures are discussed separately. (See "Prediction of prematurity by transvaginal ultrasound assessment of the cervix" and see "Tests for prediction of preterm labor and delivery").
· Lower and upper limits of gestational age — The lowest gestational age for which inhibition of PTL should be considered is controversial, and there are no definitive data from randomized trials on which to base a recommendation [10] . Fifteen weeks gestational age has been arbitrarily selected by many investigators, since it defines a point at which early pregnancy loss is less commonly attributable to karyotypic abnormality. Others use 20 weeks for the same reason and because delivery prior to this age is considered a spontaneous abortion rather than a preterm birth (PTB). (See "Spontaneous abortion: Risk factors, etiology, clinical manifestations, and diagnostic evaluation").
We feel that gestational age is not as relevant as the underlying etiology of PTL. As an example, inhibiting contractions after a self-limited event known to cause PTL, such as intraabdominal surgery, may be reasonable even at early gestational ages [11,12] .
There is greater consensus regarding the upper gestational age limit. Thirty-four weeks of gestation typically defines the threshold at which perinatal morbidity and mortality are felt to be too low to justify the potential maternal and fetal complications and costs associated with the inhibition of labor [10,13] .
Contraindications—Tocolysis is contraindicated when the maternal/fetal risks of prolonging pregnancy or the risks associated with these drugs are greater than the risks associated with PTB. Contraindications to labor inhibition include:
· Intrauterine fetal demise
· Lethal fetal anomaly
· Nonreassuring fetal status
· Severe fetal growth restriction (see "Fetal growth restriction: Evaluation and management")
· Severe preeclampsia or eclampsia (see "Management of preeclampsia")
· Maternal hemorrhage with hemodynamic instability
· Chorioamnionitis
Inhibition of PTL is not effective in the presence of intraamniotic infection [14] . Although there is universal agreement that tocolysis is contraindicated in the presence of overt infection and may be harmful [15] , there is no consensus on whether women in PTL should be evaluated for subclinical infection. Moreover, the appropriate tests for diagnosis of subclinical infection have not been determined. This topic is discussed in detail separately. (See "Intraamniotic infection").
Known or suspected fetal pulmonary maturity is not an absolute contraindication to tocolysis as there are nonpulmonary morbidities associated with PTB. As an example, a 30-week fetus with a mature amniotic fluid test is still at risk for intraventricular hemorrhage, sepsis, hyperbilirubinemia, and other morbidities unrelated to respiratory distress syndrome. These fetuses could potentially benefit from prolongation of pregnancy and the nonpulmonary benefits of glucocorticoid therapy. (See "Premature infant").
Inhibition of PTL is less likely to be successful when cervical dilation is greater than 3 cm. Tocolysis can still be considered in these cases, especially when the goal is to administer antenatal glucocorticoids or safely transport the mother to a tertiary care center [3] .
Contraindications to use of specific agents are reviewed below in discussions of specific tocolytic drugs.
GENERAL COMMENTS ON TREATMENT OF PTL—The selection of an appropriate labor-inhibiting agent should be based upon efficacy and safety. Ideally, efficacy should be established in terms of significant clinical endpoints (eg, reduction in rate of respiratory distress or perinatal mortality) rather than surrogate endpoints (eg, prolongation of pregnancy by 48 hours or seven days). The drug should be safe for the mother, fetus, and neonate.
If the first tocolytic agent chosen does not successfully inhibit PTL, the clinician might consider discontinuing it and beginning therapy with a second agent. It is important to exclude intrauterine infection before beginning a second agent as amniotic fluid cultures are positive in almost 65 percent of women in whom tocolysis with a single agent is not successful [16] . The presence of clinical criteria for chorioamnionitis (maternal fever, fundal tenderness, maternal leukocytosis, maternal/fetal tachycardia) is a contraindication to further tocolytic therapy. In the absence of clear clinical criteria of infection, one might consider amniocentesis for gram stain, glucose, and culture in women with single agent tocolytic failure to help exclude occult intraamniotic infection before switching to a second agent [17] . (See "Intraamniotic infection").
Concurrent use of multiple tocolytic agents should be undertaken with caution [3] . A study of the concurrent use of ritodrine and magnesium reported significantly more cardiovascular effects in women who received ritodrine plus magnesium sulfate (11/24) than in those who received ritodrine alone (1/17) [18] . The predominant side effect was chest pain, frequently associated with electrocardiogram changes indicative of myocardial ischemia. In addition, there was no improvement in efficacy with concurrent administration of magnesium and ritodrine therapy. We recommend that clinicians not administer magnesium sulfate, calcium channel blockers, and beta-adrenergic agonists simultaneously. Others have described limited success using a combination of atosiban, terbutaline, sulindac, and broad spectrum antibiotics in a small series of women with very early gestations (23 to 25 weeks) [19] .
There are no data on the role of repeated courses of tocolytics for treatment of recurrent PTL. (See "Antenatal use of glucocorticoids in women at risk for preterm delivery", section on Repeated courses of therapy).
BEDREST, HYDRATION, AND SEDATION—There is no high quality evidence of the efficacy of bedrest for prevention or treatment of PTL in singleton pregnancy. The following findings have addressed the effect of bedrest on PTB in different groups of women.
· Women at risk of PTB — A review from the Cochrane database that evaluated bedrest versus no intervention for preventing PTB included a single randomized trial (n = 1266 women [20] ) [21] . There was no evidence of benefit or harm from use of bed rest at home or in hospital versus usual activity to prevent PTB (RR 0.92, 95% CI 0.62-1.37).
· Women with twin pregnancies — Routine hospitalization of women with twin pregnancies for bedrest does not prolong gestation. Another Cochrane review found that the risk of PTB less than 34 weeks of gestation was actually increased in women prophylactically hospitalized for bedrest compared to ambulatory women with twins who were hospitalized when pregnancy complications developed (OR 1.84; 95% CI 1.01-3.34) [22] .
· Women with arrested PTL in index pregnancy — In one trial, the women were assigned to hospitalization or decreased activity at home: the rate of PTB was similar in the two groups (29 and 28 percent, respectively) [23] . In the second trial, the women were assigned to activity restriction or no activity restriction after successful tocolysis: the PTB rates were not significantly different (44 and 35 percent, respectively) [24] . However, both trials were underpowered to detect a small difference in outcome.
Neither intravenous hydration nor sedation reduced the rate of PTB in women with PTL in randomized trials [25-27] .
BETA-ADRENERGIC RECEPTOR AGONISTS—The beta-adrenergic receptor agonists ritodrine and terbutaline have been studied in several randomized, placebo-controlled trials. Salbutamol and hexoprenaline have also been evaluated, but data are more limited [28] . Although it remains the only drug approved by the FDA for the treatment of PTL, ritodrine hydrochloride is no longer manufactured in the United States.
Mechanism of action—The beta-adrenergic receptor agonists cause myometrial relaxation by binding with beta-2 adrenergic receptors and increasing intracellular adenyl cyclase. An increase in intracellular cyclic AMP activates protein kinase and results in the phosphorylation of intracellular proteins. The resultant drop in intracellular free calcium interferes with the activity of myosin light-chain kinase. Interference with myosin light-chain kinase inhibits the interaction between actin and myosin and, thus, myometrial contractility is diminished. (See "Physiology of parturition").
Target cells eventually become desensitized to the effect of beta-adrenergic receptor agonists, thereby limiting efficacy [29,30] . The reduction in response over time is known as tachyphylaxis.
Efficacy—The efficacy of beta-adrenergic tocolytic therapy has been evaluated in multiple trials, most of which used ritodrine as the beta-adrenergic receptor agonist.
A Cochrane review including 1332 patients enrolled in 11 randomized, placebo-controlled trials found beta-adrenergic receptor agonists decreased the number of women giving birth within 48 hours (RR 0.63, 95% CI 0.53-0.75) and possibly within seven days (RR 0.67, 95% CI 0.48-1.01) [31] . There was also a trend toward reduction in respiratory distress syndrome that was not statistically significant (RR 0.87, 95% CI 0.71-1.08), and no effect on the neonatal death rate (RR 1.00, 95% CI 0.48-2.09).
These trends, with the upper limit of the confidence interval just crossing the threshold of no effect, suggest that relative risk reductions of the order of 30 percent in respiratory distress syndrome are plausible, and may be demonstrated by trials with a larger total sample size, improved identification of patients with true PTL, and exclusion of pregnancies over 34 weeks of gestation. A limitation of many of the trials included in the meta-analysis is that glucocorticoids were not routinely administered. Thus, the neonatal benefits of delaying delivery for 48 hours were not fully realized.
Comparative data are discussed below (see "Calcium channel blockers" below).
Maternal side effects—Many of the maternal side effects of beta-adrenergic receptor agonists are related to activation of beta-1 adrenergic receptors. Stimulation of these receptors increases maternal heart rate and stroke volume. On the other hand, stimulation of the beta-2 adrenergic receptors causes peripheral vasodilation, diastolic hypotension, and bronchial relaxation. The combination of these two cardiovascular effects leads to tachycardia, palpitations, and lower blood pressure.
Common symptoms associated with use of these drugs include tremor (39 versus 4 percent with placebo), palpitations (18 versus 4 percent with placebo), shortness of breath (15 versus 1 percent with placebo), and chest discomfort (10 versus 1 percent with placebo) [32] .
Pulmonary edema is uncommon, occurring in 0.3 percent of patients [33,34] . Pulmonary edema probably results from several additive factors including fluid overload, decreased diastolic filling time duration with increased heart rate, and the increased plasma volume of pregnancy. Alternatively, pulmonary edema may be unrelated to the beta-adrenergic receptor agonists, being due to increased vascular permeability due to infection, inflammation, or preeclampsia [34,35] . (See "Critical illness during pregnancy and peripartum", section on Tocolytic-induced pulmonary edema, and see "Pulmonary pearls: A 24 year-old woman with pulmonary edema after labor and delivery").
Beta-adrenergic receptor agonists have important metabolic effects, including hypokalemia (39 versus 6 percent with placebo), hyperglycemia (30 versus 10 percent with placebo), and lipolysis. Myocardial ischemia is a rare complication.
Fetal side effects—Beta-adrenergic receptor agonists cross the placenta into the fetal compartment. Fetal effects, such as fetal tachycardia, are analogous to the maternal effects noted above. Neonatal hypoglycemia may result from fetal hyperinsulinemia due to prolonged maternal hyperglycemia. Fetal acid/base status and neonatal well-being are not compromised by these agents [36] .