Continuing Education Activity

Tocolysis is an obstetrical procedure to prolong gestation in patients, some of which are experiencing preterm labor. This is achieved through various medications that work to inhibit contractions of uterine smooth muscle. The main medications used are beta-adrenergic agonist receptors, calcium channel blockers, cyclooxygenase inhibitors, and magnesium sulfate. This activity reviews and evaluates tocolysis and highlights the role of the interprofessional team in evaluating and managing tocolysis.

Objectives:

• Identify the indications for tocolysis.
• Summarize the different medications used for tocolysis.
• Review the risk factors for specific tocolysis medications.

Introduction

Tocolysis is an obstetrical procedure carried out with the use of medications with the purpose of delaying the delivery of a fetus in women presenting preterm contractions. These medications are administered with the hope of decreasing fetal morbidity and mortality. Tocolysis is intended to prolong gestation for two to seven days and works by creating a quiescent environment in the uterus. This is important to allow transportation to a higher care facility, to administer a fetal lung maturity scheme with antenatal corticosteroids, and the additional time is also used to determine the group B streptococcus (GBS) status of the pregnant woman, and provide prophylaxis if she is either positive or the GBS culture status is unknown. 

Tocolysis is not intended to increase gestation of the fetus to term but is focused on providing a window of time to support treatments that have been shown to improve outcomes for delivery. Currently, there are no United States Food & Drug Administration (FDA) approved medications for tocolysis. All medications are administered as off-label indications. However, these medications are still effective and should be used when clinically indicated. Historically, ritodrine and terbutaline had been approved for maintenance tocolysis. Ritodrine had been approved in 1977 but was removed by the FDA due to increased maternal mortality due to cardiovascular complications, is still used as a tocolytic internationally but has been associated with pulmonary edema.[1] Terbutaline was suggested in 1987 as a continuous infusion pump for maintenance tocolysis as well but was removed in 2011 and changed from a Pregnancy Class B to a Class C drug.[2]

Anatomy and Physiology

Tocolysis is effective because it focuses on both delaying and weakening uterine contractions. The pharmacology targets the activity of the myometrium. The myometrium is the smooth muscle in the uterus. 

From a physiologic perspective, the myometrium is responsible for the contractional effort of childbirth. Like all smooth muscle, this process is calcium-mediated. The start of a contraction does not require any nerve input nor hormonal stimulus. It begins with a spontaneous depolarization of the cell surface, which opens voltage-gated calcium channels.[3] The influx of calcium into the cells binds to intracellular calmodulin. This new complex activates myosin light chain kinase, an enzyme that phosphorylates myosin light chains, which are located on a critical portion of the myosin heads. The phosphorylation and dephosphorylation of the myosin head cause the continual bridging to actin filaments. This repetitive process results in the myometrium of contraction.

Though the average gestation age for women to go into the labor is 40 weeks, some conditions will result in labor starting earlier. It´s believed that this switch to a contractional uterus is caused by an equilibrium change of proinflammatory and anti-inflammatory cytokines.[4] Initiators of preterm labor include uterine overdistention, stress, infection, vascular complications, and decidual senescence. If contractions begin too early, the fetus has minimal chance of survival.

Indications

Tocolysis is used in the setting of preterm labor. Preterm birth is delivery before 37 weeks gestation and after 20 weeks. To diagnose preterm labor, continued contractions happen during the gestational age range mentioned previously to produce cervical changes. Continued contractions are defined as greater than or equal to 4 contractions over 20 minutes. It is difficult to determine which patients undergoing preterm labor will progress to preterm delivery.[5] Tocolysis is beneficial in patients having preterm labor before 34 weeks gestation. It, however, isn´t recommended to use tocolytic medications as prophylaxis, as it hasn´t been shown to reduce neonatal morbidity.[6]

Tocolysis has also been used in the setting of external cephalic version, uterine tachysystole, and suspected fetal distress. For the external cephalic version, betamimetics are the most successful at increasing the rate of cephalic presentation and reducing the frequency of cesarean section.[7] A dose of 0.25 mg of terbutaline is given subcutaneously or intravenously 30 minutes before the attempted procedure. There is no difference between subcutaneous and intravenous administration of terbutaline.

Uterine tachysystole is defined as more than 5 contractions over 10 minutes averaged for 30 minutes.[8] Betamimetics, like terbutaline, are effective at aborting uterine contractions in this emergent setting.[9][10]

Contraindications

The contraindications for the procedure have been laid out in ACOG Practice Bulletin 171 in Box 1 and are the following:[11]

• A gestational age above 34 weeks
• Intrauterine fetal demise
• Lethal fetal anomaly
• Nonreassuring fetal status
• Severe preeclampsia or eclampsia
• Maternal bleeding with hemodynamic instability
• Chorioamnionitis
• Preterm premature rupture of membranes (except when there are no signs of maternal infection and there is a need for transportation, steroid administration, or both)
• Specific contraindications to tocolytic agents

Relative contraindications also include if there´s already advanced cervical dilation over 5 cm, maternal heart disease, hyperthyroidism, uncontrolled diabetes, mild abruptio placentae, stable placenta previa, and intrauterine growth restriction. Studies have shown that there is no beneficial delay in delivery with tocolytics for patients with symptomatic abnormal placentation.[12] Another considered contraindication is small for gestational age. While this can vary on an individual level, smaller infants will tend to need to be ventilated upon delivery.

Equipment

Tocolysis is achieved through different processes, all with the same eventual goal of quelling the smooth muscle activity in the uterus. Different tocolytic agents are preferred based on maternal medical history, current gestational age, and cost. There is no definitive first-line tocolytic agent by the American College of Obstetrics and Gynecology (ACOG) but nifedipine and indomethacin are most commonly used. Furthermore, combination tocolytic therapy might be more effective than using a single tocolytic agent.[13] Repeat tocolytic therapy is not recommended. The different medications currently used are:

• Beta-Adrenergic receptor agonists
• Calcium channel blockers
• Magnesium Sulfate
• Nonsteroidal antiinflammatories
• Oxytocin inhibitors

Beta-Adrenergic receptor agonists specifically work on the beta-2 receptor. Activation of the beta-2 receptors causes an increase in cyclic AMP (cAMP) which is associated with increased smooth muscle relaxation. The most common medication in this class is terbutaline. Hexoprenaline, a beta-2 receptor agonist, is used in many countries but has yet to be approved by the US Food and Drug Administration. Ritodrine is also another medication in the category that is used internationally for tocolysis but is not approved in the United States. There has been a black box warning issued by the US Food and Drug Administration against the use of injectable terbutaline in the setting of prolonged preterm labor-management (over 72 hours) due to maternal cardiac complications. These complications are suggested from terbutaline's activity at beta-1 receptors, which are located in cardiac muscle. Studies have suggested the tocolytic agents in this family might confer a risk of the development of childhood asthma.[14] Maternal risks include but are not limited to cardiac arrhythmias, tachycardia, hypotension, nausea, and vomiting. Fetal risks include but are not limited to tachycardia.

Calcium channel blockers specifically work on T-type calcium channels by inhibiting the entry of calcium into the uterine smooth muscle.[15] The lack of free calcium directly affects the ability of the calcium-calmodulin activation of myosin light chain kinases. The most common medication in this class is nifedipine. The two routes available for this medication are oral and sublingual. Recent literature has shown sublingual nifedipine achieved faster tocolysis.[16] Maternal risks include but aren´t limited to flushing headache, dizziness, nausea, and hypotension. Studies have shown no fetal risks with nifedipine use for the management of preterm labor. Women who have documented hypotension and other cardiac conditions should use nifedipine with great caution. Recent literature has suggested that nifedipine is the best tocolytic agent because of better neonatal outcomes and fewer side effects.[17]

Magnesium sulfate has an unresolved mechanism of action regarding uterine contractions, but it has been described to inhibit the entry of calcium into the uterine smooth muscle.[18] It also has vasodilatory effects on uterine blood vessels. The magnesium sulfate is used for neuroprotection and studies have failed to demonstrate its effectiveness in pregnancy prolongation in the setting of preterm labor.[19][20][6] It´s not advised to use magnesium sulfate in conjunction with calcium channel blockers, unless for neuroprotection, due to the risk of maternal respiratory depression. Its sole route of administration is intravenously and cleared by the kidneys. There are risks of magnesium toxicity and the side effects include flushing, nausea, reduced deep tendon reflexes, blurred vision, and reduced cardiac contractility. Calcium gluconate and fluids are used to manage the side effects of magnesium toxicity. 

Nonsteroidal anti-inflammatories work through inhibiting cyclooxygenases (COX).[21] These enzymes are responsible for the production of prostaglandins from arachidonic acid. The most common medication in this class is a non-selective COX inhibitor, indomethacin. The route of administration for indomethacin is orally or rectally. This medication has renal effects by vasoconstriction through the lack of prostaglandins being produced at the site of the afferent arteriole. Indomethacin also has gastrointestinal effects by increasing the rate of ulcer formation. The lack of prostaglandin production in the stomach increases the prevalence of mucosal injury and gastrointestinal bleeding. It is contraindicated in women who have a history of bleeding disorders, gastritis, aspirin hypersensitivity, and hepatic impairment. Indomethacin is also contraindicated after 32 weeks of gestational age because of premature closure of the ductus arteriosus. [22] Other fetal effects from indomethacin include oligohydramnios, gastric perforation, and pulmonary hypertension.

Oxytocin inhibitors work by competitively acting at the oxytocin receptor site. Oxytocin acts to increase the intracellular levels of inositol triphosphate. The medications currently in this class are atosiban and retosiban.[23] This group of tocolytics currently is not approved in the United States but was approved in Europe in 2000.[24] The medication is delivered intravenously. Maternal nor fetal side effects have not been described for this tocolytic.

In addition to the above tocolytic agents, nitroglycerine has also been tested for effectiveness with preterm labor. Nitroglycerine works by inducing myometrial guanylyl cyclase to produce cyclic GMP (cGMP). Increases in cGMP inhibit the ability of intracellular calcium levels to rise. Furthermore, cGMP is also used to dephosphorylate myosin heads which halts the ability for contractions to proceed. The two routes for nitroglycerine are intravenous and transdermal. Though the side effect profile is better when compared to beta-adrenergic receptor agonists, transdermal nitroglycerine isn´t recommended for tocolysis.[25] This competes with other literature that shows that transdermal nitroglycerine is more effective at delaying birth compared with nifedipine.[26]

Technique or Treatment

Maintenance tocolysis is the procedure of providing tocolysis beyond 48 hours. Typically 48 hours of medication is sufficient to bridge the patient through the steroid window and transport her to a tertiary care center. There is no official stance by ACOG on the status of maintenance tocolysis. Evidence does not suggest that beta-adrenergic receptor agonists, calcium channel blockers, COX inhibitors, or magnesium sulfate are sufficient for maintenance tocolysis. Progesterone and hydroxyprogesterone caproate have limited data that might suggest they might be beneficial for maintenance tocolysis. They may be used in patients with a history of preterm labor but are not considered tocolytic agents.[27]

Complications

Complications from tocolysis are primarily medication specific. These agents are not guaranteed to prolong labor so medications might have to be substituted to achieve uterine quiescence.

Clinical Significance

Tocolysis is clinically significant because it increases the amount of time to perform neonatal interventions. The WHO has shown that it is beneficial to delay delivery by up to 48 hours, allowing for antenatal corticosteroids to help fetal lung maturity in premature neonates.[28] There have been publications that have questioned if tocolytics have benefits on major neonatal morbidity.[29][30]

Enhancing Healthcare Team Outcomes

Tocolysis is an emergent procedure indicated to prolong gestation to decrease fetal morbidity and mortality. In 2006, preterm birth was associated with over 36% of the neonate deaths.[31] Accurate knowledge and understanding of the patient's medical history are crucial in deciding the best manage. Allergies and health conditions will determine which tocolytic agent is best suited for the patient. Appreciating the side effects from the different tocolytics will let providers known what to assess during the treatment duration. A patient that is suspected to be experiencing preterm labor should be evaluated by providers at Labor and Delivery within a hospital. If the patient currently is receiving primary, secondary, or community care, tocolysis is important to allow for additional time to be transferred to a tertiary care center. This requires coordination from different care settings and with transportation services. The tertiary care centers will have better access to specialists as well as resources for handling the delivery of preterm infants.

When a patient presents potentially needing tocolysis or is already receiving tocolytic medication, the high-risk obstetrical team should be notified of the patient's presence. Neonatal and anesthesia teams should also be informed so they can be aware of an upcoming preterm delivery. It has been shown that nurses play a crucial role in the care of obstetric patients that are experiencing obstetrical emergencies.[32]