Journal Issue: Low Birth Weight Volume 5 Number 1 Spring 1995
Tocolytics: Drugs to Suppress Preterm Labor
The physiological trigger for labor both at term and preterm remains a mystery (see the article by Nathanielsz in this journal issue). At term, judging whether or not labor has started depends on the frequency of contractions and cervical dilation. Judging whether or not preterm labor has started is more difficult because contractions may occur without cervical dilation, and waiting for the cervix to dilate may lead to stronger contractions, which are more difficult to stop. Successful inhibition of preterm labor depends upon early diagnosis, but the diagnosis of preterm labor is erroneous up to 80% of the time.9 As a result, preterm labor is widely overdiagnosed so as not to miss those minority of cases of true preterm labor. Over the years, a wide variety of drugs—called tocolytics—have been used in attempts to suppress preterm contractions. The effectiveness of several of these drugs is discussed below.
Betamimetic agents are used more extensively than any other agents. All of these drugs are chemically and pharmacologically related to the catecholamines, compounds in the body that control involuntary muscles such as the heart and uterus. These drugs stimulate receptors in the uterus which cause the uterus to relax, thus stopping uterine contractions. Data on the effect of betamimetic drugs in controlled trials of preterm labor shows that they are successful in delaying delivery for up to two days. However, there is no associated decrease in the incidence of perinatal mortality or morbidity with the use of these drugs.10,11 One of the major benefits of using tocolytic drugs is to delay delivery long enough to give prenatal corticosteroids a chance to enhance the maturation of fetal lungs.11 One may conclude that, conversely, little benefit may be reaped if glucocorticoids are not used.
Recent attention has been focused on a new way to administer the betamimetic drugs which uses a pump implanted under the skin to inject the drugs. The pump delivers small doses of the drug in short pulses, a method that is thought to maximize the effect of each small dose. Pregnancy was prolonged an average of nine weeks in a small group of women who failed oral betamimetic therapy, but used the pump.12 Further studies are needed to validate this potentially promising approach.
Inhibitors of Prostaglandin Synthesis
There is substantial evidence that prostaglandins are of critical importance in the initiation and maintenance of human labor (see the article by Nathanielsz in this journal issue). Suppression of the body's ability to produce prostaglandins is, therefore, a logical approach to the prevention of preterm labor. The most widely used inhibitor of prostaglandin synthesis in preterm labor is indomethacin. Two small studies found that the prostaglandin-inhibiting drugs may be effective in preventing preterm labor.13,14 Compared with betamimetic drugs, indomethacin is more effective in delaying delivery for up to two days. In addition, indomethacin delayed delivery slightly longer (7 to 10 days) than betamimetic drugs, and decreased the overall incidence of preterm delivery and low birth weight.15,16
One of the major reasons prostaglandin inhibitors are not more widely used is that they are not innocuous drugs. In the mother, side effects such as stomach ulcers, gastrointestinal and other bleeding, and allergic reactions occur but are very rare. In the fetus, indomethecin has been associated with a severe interruption in the blood circulation between the baby's heart and lungs, and other serious side effects.
Magnesium sulfate is a commonly used tocolytic, and in many institutions is the first-line therapy for preterm labor. The ability of magnesium to decrease uterine contractility has long been recognized, but the mechanism by which it does so is not known. In one trial, magnesium was found to have no significant effect on duration of gestation, birth weight, neonatal morbidity, and perinatal mortality.17 Compared with the other drugs, magnesium sulfate appears to be no better than other tocolytics.18-20 The combination of ritodrine (a commonly used betamimetic drug) and magnesium sulfate resulted in a higher incidence of serious side effects with no greater benefit than ritodrine alone. There are no convincing data that magnesium sulfate delays delivery beyond two days, nor are there data to show a decrease in preterm delivery or an improvement in neonatal outcomes beyond that gained by glucocorticoid administration.
Over the past 10 years, calcium channel blockers have emerged as major agents for the control of preterm labor and for the treatment of hypertension in pregnancy. Because calcium is required to produce muscle contractions, agents that block the uptake of calcium in muscle cells will decrease the ability of the muscles to contract. In all studies, nifedipine, the most commonly used calcium blocker, has been as successful as betamimetics in delaying preterm labor.21,22 As with the betamimetics, magnesium sulfate, and indomethacin, there has been no real evidence for decreased perinatal morbidity and mortality with the use of calcium antagonists.
As all tocolytics have significant failure rates, especially in the face of advanced preterm labor, several groups have asked whether combination therapy may offer advantages. One randomized trial compared ritodrine alone with ritodrine and magnesium sulfate and found improved pregnancy prolongation with the combination therapy. Unfortunately, in two studies, one-half of the women receiving combination therapy developed severe side effects (cardiovascular symptoms or very fast heart rates).20,23 Most clinicians are reluctant to accept this high level of side effects given the small benefit that even single-agent therapy has shown. A combination that may have more benefit in the future is that of betamimetics and calcium channel blockers, which is currently under study.
Recently, an oxytocin analogue which also blocks uterine contractility has been introduced.24 Oxytocin is a compound that the body produces to stimulate uterine contractions. Oxytocin analogues may be used to prevent the action of oxytocin and thus prevent contractions. Further studies are needed to determine the efficacy of these promising drugs.
There is currently no evidence that the use of tocolytic drugs is effective in preventing preterm birth. Moreover, the use of these drugs is associated with many potentially severe side effects. There is strong evidence that tocolytic agents work to delay delivery for up to two days. This short delay is important as it can be used to allow time for corticosteroids to take effect and enhance fetal lung maturity, or to allow the mother to be transferred to a hospital with high-level neonatal intensive care facilities. The scientific evidence of efficacy available for all of these drugs is surprisingly scarce given the frequency of their use. There are few data to support using tocolytics without prenatal corticosteroid therapy to achieve a measurable decrease in perinatal morbidity and mortality.
Despite the availability of tocolytic agents and their extensive use, there has been no reduction in the overall incidence of low birth weight (less than 2,500 grams, or 5 pounds, 8 ounces) since the introduction of these drugs. In many instances of preterm labor, the use of tocolytic drugs is contraindicated, such as with uterine infections, bleeding, or severe maternal disease and, therefore, these drugs cannot be used. Thus, despite the short-term efficacy of tocolytic drugs, this technology has not made an impact on reducing overall low birth rate.25