Preterm birth is one of the major health problems in the United States. Approximately 11-12% of all births occur preterm (as defined as < 37 weeks gestation) and the rate has increased by approximately 19% since 1990 (1). The concern with preterm labor and birth is its outcome; it accounts for approximately 70% of all neonatal deaths and 50% of the long-term neurological disabilities (2). Tocolysis has been a prominent component of efforts to prevent preterm labor and delivery. It is hoped that medications will reduce uterine contractions and allow more time in utero for the fetus. The literature supports that only a minority of patients benefit from tocolytic agents.
Beta-mimetic Agents: The beta-mimetic agents, such as terbutaline and ritodrine (FDA approved), work by relaxing the myometrial smooth muscle by a reduction in intracellular calcium. Maternal side effects include hypokalemia, hyperglycemia, tachycardia, decreased systemic vascular resistance, and increased risk of pulmonary edema. Beta-mimetics have been linked to at least 25 maternal deaths from pulmonary edema (3). In 2003, the American College of Obstetricians and Gynecologists concluded, “It would appear, on the basis of currently available evidence, very difficult to support the use of beta-mimetics, which have a high incidence of side effects. Although these drugs do delay delivery in the short term, there is no demonstrable benefit for the newborn (4).”
Magnesium: The use of magnesium sulfate as a tocolytic varies by location. It is rarely used in Europe but is widely used in the United States, where it continues to be used because of its high safety profile. Magnesium sulfate results in blurry vision and maternal weakness. It potentiates the nondepolarizing muscle relaxants, necessitating a major reduction in dose of these medications. A 2004 review found no benefit of magnesium for short- or long-term delay in delivery (5).
Calcium Channel Blockers: Calcium channel blockers relax the myometrium. A study of 1024 patients found that calcium channel blockers were more effective than beta-mimetic agents in prolonging pregnancy for 7 days or longer, were much less likely to cause maternal side effects, and were associated with reduced neonatal morbidity(6). The most commonly used drug of this class is nifedipine. These drugs should not be used in women with cardiovascular disease or those who are hemodynamically unstable.
Prostaglandin Synthetase Inhibitors: The discovery that prostaglandins play a role in the initiation of labor led to the study of prostaglandin synthetase inhibitors as agents for treating preterm labor. Studies suggest that indomethacin is more effective than placebo in prolonging pregnancy (7). The concern with the use of indomethacin is its fetal effects. Premature closure of the ductus arteriosus and oligohydramnios have been associated with maternal administration of indomethacin.
Atosiban: Oxytocin antagonists have been developed. Labor is accompanied by an increase in oxytocin receptors. Atosiban is the only oxytocin antagonist that has undergone extensive study. Atosiban has several advantages in that it is a specific inhibitor of myometrial contractility with little transplacental passage. A multicenter trial compared atosiban to placebo in 501 women with preterm labor. No difference in length of labor or neonatal outcome was noted (8).
Conclusion: Multiple studies have failed to show a benefit to maintenance of tocolysis for preventing the recurrence of preterm labor. Because of its high neonatal mortality, physicians feel obligated to do something when a parturient presents in preterm labor. At present, most interventions fail to demonstrate benefits. The safest agent currently used for tocolysis appears to be nifedipine, although the American College of Obstetricians and Gynecologists has not identified a tocolytic of choice.
1. Martin JA, Hamilton BE, Sutton PD, et al. Births: Final data for 2002: National Vital Statistics Reports, Vol 52, No 10, Hyattsville, MD: National Center for Health Statistics, 2003.
2. Hack M, Fanaroff AA. Outcomes of extremely immature infants: A perinatal dilemma. NEJM 1993; 329: 1649.
3. MIngemarrson I, Lamon RF. An update on the controversies of tocolytic therapy for the prevention of preterm birth. Acta Obstet Gynaecol Scand 2003; 82:1.
4. ACOG Practice Bulletin No 43: Management of preterm labor. Obstet Gynecol 2003;101:1039.
5. Crowther CA, Hiller JE, Doyle WW. Magnesium sulphate for preventing preterm birth in preterm labour. The Cochrane Library 2004; Issue 3: Chichester, UK. John Wiley & Sons, 2004.
6. King TF, Flenady V, Papatsonsis D, et al. Calcium channel blockers for inhibiting preterm labour: A systematic review of the evidence and a protocol for administration of nifedipine. Aust N Z J Obstet Gynaecol 2003; 43: 192.
7. Moise KJ. The effect of advancing gestational age on the frequency of ductal constriction secondary to maternal indomethacin use. Am J Obstet Gynecol 1993; 168: 1350.
8. Romero R, Bibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: A randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 000; 182: 1173.
Robert R. Gaiser, M.D.
Robert Gaiser is Professor of Anesthesiology and Critical Care at the Hospital of the University of Pennsylvania