Tocolytic

Tocolytics also called anti-contraction medications or labor suppressants, are medications that are given to women in preterm labor to prolong pregnancy to suppress premature labor (from the Greek tokos, childbirth, and lytic, capable of dissolving) for at least 48 hours to enable administration of antenatal corticosteroids, magnesium sulfate, or buy a bit more time for maternal transport to a hospital with a neonatal intensive care unit (also called a NICU). This is the nursery in a hospital where newborns get medical care. Tocolytics are given when delivery would result in premature birth. Tocolytics have been shown to improve infant morbidity and mortality rates.

Tocolytics therapy buys time for the administration of betamethasone, a glucocorticoid drug which greatly accelerate fetal lung maturity, but takes one to two days to work. Although tocolytics have not been shown to improve neonatal outcomes, they can delay preterm delivery long enough for antenatal corticosteroids to be administered or for the mother to be transported to a tertiary care facility ¹. In premature neonates, antenatal corticosteroids reduce morbidity and mortality ². Tocolytic therapy may therefore have an important role in improving outcomes from preterm delivery. With over 500 000 preterm births in the United States alone (12.3% of all births in 2008) ³ and 29% of these being less than 34 weeks’ gestation, preterm delivery is an important public health issue.

The suppression of contractions is often only partial and tocolytics can only be relied on to delay birth for several days. Depending on the tocolytic used the mother or fetus may require monitoring, as for instance blood pressure monitoring when nifedipine is used as it reduces blood pressure. In any case the risk of preterm labor alone justifies hospitalization.

If your labor does not stop and it looks like you will give birth to your baby early, you and the baby usually will be cared for by a team of health care professionals. The team may include a neonatologist, a doctor who specializes in treating problems in newborns. The care your baby needs depends on how early he or she is born. High-level neonatal intensive care units (NICUs) provide this specialized care for preterm infants.

The most common tocolytic agents used for the treatment of preterm labor are magnesium sulfate (MgSO4), indomethacin, and nifedipine ⁴. In the past, beta-mimetic agents, such as terbutaline or ritodrine, were the agents of choice, but in recent years their use has been significantly curtailed due to maternal and fetal side effects, such as maternal tachycardia, hyperglycemia, and palpitations The use of these agents can lead to pulmonary edema, myocardial ischemia, and cardiac arrhythmia.

In February 2011, the US Food and Drug Administration (FDA) required the addition of a new Black Box Warning and contraindication to the terbutaline prescribing information to warn about the risk of use for preterm labor. The decision was based on reports of death and serious adverse reactions, including tachycardia, transient hyperglycemia, hypokalemia, arrhythmias, pulmonary edema, and myocardial ischemia following prolonged administration of oral or injectable terbutaline to pregnant women. The FDA concluded that the risk of serious adverse events outweighs any potential benefit to pregnant women receiving prolonged treatment with terbutaline injection (>48-72 hours) or acute or prolonged treatment with oral terbutaline.

Terbutaline a short-acting beta-2 agonist was one of the most commonly used tocolytic agents in the cessation of labor contractions. Through an action on beta-2 receptors, terbutaline increases cyclic AMP, which decreases intracellular calcium levels, thereby decreasing myometrial contractility (the myometrium is the middle layer of the uterine wall and is responsible for inducing uterine contractions). Terbutaline should not be used to treat premature labor that has already lasted more than 48 to 72 hours. And if you have a health condition, like a heart problem or severe preeclampsia, terbutaline may not be safe for you. Benefits of terbutaline must also be weighed up against its risks, as serious and sometimes fatal side effects have been reported after the use of terbutaline in pregnant women.

Magnesium sulfate is used as a tocolytic during pre-term labor but it shouldn’t be used for more than 5 to 7 days. Using magnesium sulfate for a longer time may lead to low levels of calcium and bone problems in your baby. Magnesium stimulates calcium reuptake by the sarcoplasmic reticulum, which promotes relaxation of muscle and vasodilation. For pre-term labor, magnesium decreases the calcium within the uterine muscle ⁵. Intravenously delivered magnesium sulfate may also reduce the risk of cerebral palsy if the child is born early ⁶. Magnesium side effects are associated with magnesium’s effect on the neuromuscular and cardiovascular system. Side effects can include flushing, hypotension, vasodilation, and hypermagnesemia ⁷.

The tocolytic agents currently used to treat preterm labor appear to be equally efficacious in delaying delivery for at least 48 hours. While magnesium sulfate (MgSO4) is associated with more maternal toxicity, indomethacin is associated with more fetal and neonatal toxicity.

Haas et al ⁸ analyzed randomized controlled trials of tocolysis to determine the optimal first-line tocolytic agent for treatment of premature labor. Fifty-eight studies satisfied the inclusion criteria. A random-effects meta-analysis showed that all tocolytic agents were superior to placebo or control groups at delaying delivery both for at least 48 hours (53% for placebo compared with 75-93% for tocolytics) and 7 days (39% for placebo compared with 61-78% for tocolytics). No statistically significant differences were found for the other outcomes, including the neonatal outcomes of respiratory distress and neonatal survival. The decision model demonstrated that prostaglandin inhibitors provided the best combination of tolerance and delayed delivery ⁸.

Table 1. Commonly used tocolytic drug classes

Drug class	Individual drugs in the class commonly used or studied	Major side effects	Comments
Betamimetics 9	Ritodrine, terbutaline, hexoprenaline, salbutamol	Cardiac arrhythmias (tachycardia), hypotension, hyperglycemia, pulmonary edema	Long-term use recently given an FDA “black box” warning
Calcium channel blockers 10	Nifedipine, nicardipine	Maternal hypotension, dizziness	Initial loading dose common
Magnesium sulfate 11	Magnesium sulfate	Flushing, respiratory suppression, cardiac arrest	Currently utilized for neuroprotection protocols
Oxytocin receptor blockers 12	Atosiban, barusiban	Gastrointestinal upset	Not utilized in the USA
Prostaglandin inhibitors 13	Indomethacin, sulindac, celecoxib	Maternal gastrointestinal disturbance, oligohydramnios, premature constriction of the ductus	Concern about ductal constriction limits use generally to <32 weeks’ gestation
Nitrates and others 14	Nitroglycerin, nitric oxide	Headache, flushing, maternal hypotension, tachycardia	Currently limited to research trials

[Source ¹⁵ ]

Tocolytic drugs

Many different classes of drugs have been used for tocolytic therapy, with varying success rates and side effects ¹⁶. These include beta mimetics such as ritodrine and terbutaline; magnesium sulfate; prostaglandin inhibitors (for example, indomethacin, ketorolac); calcium channel blockers such as nifedipine; nitrates (for example, nitroglycerine); oxytocin receptor blockers (for example, atosiban), and others ¹⁷. Each tocolytic has a unique mechanism of action, side effects, and degree of complexity to administer ¹⁸. Several Cochrane reviews have compared individual tocolytic drugs with placebo or other tocolytics ¹⁹. A recent pooled meta-analysis and decision analysis of trials on tocolytics showed that to delay delivery for 48 hours and seven days, prostaglandin inhibitors were the best first line tocolytic ¹. A standard pairwise meta-analysis, however, can only compare two treatments (or classes) that have been directly compared in head to head trials (direct evidence). Consequently, trials comparing two treatments from the same class are often excluded from class level meta-analyses. In the absence of a single high quality, randomized controlled trial comparing all tocolytic therapies, uncertainty remains about which is the most effective at delaying preterm delivery ²⁰.

Some medications are not specifically FDA approved for use in stopping uterine contractions in preterm labor, instead being used off label. Nifedipine is one of the most commonly used tocolytic agents.

Tocolytic medication examples:

• Magnesium sulfate (injection): A drug used to treat convulsions during pregnancy, nephritis in children, magnesium deficiency, and tetany. Used for immediate control of life-threatening convulsions in the treatment of severe toxemias (pre-eclampsia and eclampsia) of pregnancy and in the treatment of acute nephritis in children. Also indicated for replacement therapy in magnesium deficiency, especially in acute hypomagnesemia accompanied by signs of tetany similar to those of hypocalcemia. Also used in uterine tetany as a myometriat relaxant.
• Orciprenaline: A beta-2 adrenergic agonist used to treat bronchospasm, asthma, and COPD.
• Hexoprenaline: Hexoprenaline is a stimulant of beta 2 adrenergic receptors. It is used as a bronchodilator, antiasthmatic, and tocolytic agent.
• Ritodrine (Yutopar): An adrenergic beta agonist used to treat premature labor.
• Fenoterol: A beta-2 adrenergic agonist and bronchodilator used for the symptomatic treatment of asthma.
• Nifedipine (Procardia, Adalat): A dihydropyridine calcium channel blocker indicated for the management of several subtypes of angina pectoris, and hypertension.
• Atosiban: An inhibitor of oxytocin and vasopressin used to delay imminent preterm birth in pregnant adult women displaying specific clinical observations.
• Salbutamol: A beta-2 adrenergic receptor agonist used to treat asthma, bronchitis, COPD, as well as prevent exercise induced bronchospasms.
• Indomethacin: A nonsteroidal anti-inflammatory (NSAID) used for symptomatic management of chronic musculoskeletal pain conditions and to induce closure of a hemodynamically significant patent ductus arteriosus in premature infants.
• Terbutaline (Brethine): A beta-2 adrenergic agonist used as a bronchodilator and to prevent premature labor.
• Nylidrin: A vasodilator used to treat patients with peripheral vascular disorders, and elderly patients with symptoms associated with organic mental disorders.
• Isoxsuprine: A beta-adrenergic agonist used in the symptomatic treatment of cerebrovascular insufficiency, peripheral vascular disease of arteriosclerosis obliterans, thromboangiitis obliterans (Buerger’s disease) and Raynaud’s disease.

Magnesium sulfate tocolytic

Magnesium sulfate is widely used as the primary tocolytic agent because it has similar efficacy to terbutaline with far better tolerance. Common maternal side effects include flushing, nausea, headache, drowsiness, and blurred vision. The mother should be monitored for toxic effects, such as respiratory depression or even cardiac arrest, that can occur at supratherapeutic levels. In addition, magnesium sulfate readily crosses the placenta and may lead to respiratory and motor depression of the neonate.

Although magnesium sulfate is approved to prevent seizures in preeclampsia and for control of seizures in eclampsia, its use for preterm labor is off-label. In 2013, the FDA issued a safety alert warning not to exceed 5-7 days of continuous IV magnesium sulfate when the agent is used for preterm labor ²¹. Longer treatment duration may lead to hypocalcemia in the developing fetus and result in neonates with skeletal abnormalities related to osteopenia. Hypermagnesemia causes hypocalcemia as a result of a decrease in the secretion of parathyroid hormone ²².

Several observational studies have reported an association of antenatal treatment with magnesium sulfate for preterm labor or preeclampsia with a decreased risk of cerebral palsy in low birth weight or preterm infants ²³. While the use of magnesium sulfate for the prevention of cerebral palsy in preterm infants has been recently suggested, it has yet to receive universal acceptance.

Antenatal magnesium sulfate should be considered for use in women at high risk of delivery before 34 weeks’ gestation, mainly in those with premature rupture of membranes, active labor, and planned delivery within 24 hours. Loading and maintenance doses, and the duration of the treatment specifically for neuroprotection should not normally exceed 6 g, 1-2 g/h, and 24 hours, respectively.

The use of magnesium sulfate usually requires baseline maternal laboratory evaluation, including complete blood count (CBC count) and serum creatinine level, urine output greater than 30 mL/h, normal vital signs, and appropriate maternal mentation. The initial recommended loading dose is 4-6 g IV over 20 minutes, followed by a maintenance dose of 1-4 g/h depending on urine output and persistence of uterine contractions.

Maintenance of magnesium sulfate therapy requires careful assessment of maternal mentation, visual symptoms, deep tendon reflexes , and cardiac rate with discontinuation whenever evidence of toxicity exists. Urine output should be carefully monitored and ideally maintained at greater than 50 mL/h. Limiting intravenous intake to prevent pulmonary edema may be prudent. Oral intake can be maintained at the discretion of the provider. Serum magnesium levels may be obtained 1 hour after the loading dose and then every 6 hours and the maintenance dosage should be titrated to maintain a serum level of 4-8 mg/dL.

Since the primary therapeutic goal of tocolysis is to delay preterm delivery within 48 hours from the initiation of steroid prophylaxis, little evidence suggests that extended magnesium sulfate therapy is beneficial. The authors recommend discontinuing magnesium sulfate therapy after 48 hours in most patients unless the gestational age is less than 28 weeks when a gain of an additional 3-4 days may significantly reduce neonatal morbidity and mortality. Due to the risk of toxicity, consulting an maternal-fetal medicine specialist may be beneficial if magnesium sulfate is to be continued for more than 72 hours. Since no clinical evidence suggests that oral beta-mimetics, subcutaneous terbutaline pump, or oral magnesium compounds are effective in delaying preterm birth, alternative tocolysis is not currently recommended after the discontinuation of IV magnesium sulfate therapy.

When acute mild toxicity exists in the presence of normal urine output, magnesium sulfate should be temporarily discontinued until the serum magnesium level and deep tendon reflexes return to normal. If the toxicity symptoms are life threatening, administering 1 g of calcium gluconate by slow intravenous push and strongly considering not reinstituting magnesium sulfate despite the return to normal levels is recommended.

Indomethacin

Indomethacin is an appropriate first-line tocolytic for the pregnant patient in early preterm labor (< 30 weeks) or preterm labor associated with polyhydramnios. A more significant inflammatory response in the membranes and decidua is observed at gestational ages less than 30 weeks compared with 30-36 weeks. Indomethacin reduces prostaglandin synthesis from decidual macrophages. The fetal renal effects of indomethacin may be beneficial to reduce polyhydramnios.

Prostaglandin synthetase inhibitors, such as indomethacin, have been shown to have efficacy similar to that of terbutaline but are associated with infrequent maternal side effects. However, these agents readily cross the placenta and can cause oligohydramnios due to a decrease in fetal renal blood flow if used for more than 48 hours. The administration of indomethacin is often limited to 48 hours, and baseline labs, including CBC count and liver function tests (LFTs), should be ordered prior to initiation of therapy.

During treatment, urine output, maternal temperature, and amniotic fluid index (AFI) should be evaluated periodically. The initial recommended dose is 100 mg per rectum followed by 50 mg orally every 6 hours for 8 doses. If oligohydramnios occurs, the amniotic fluid usually reaccumulates when the indomethacin is stopped, but persistent fetal anuria, renal microcystic lesions, and neonatal death have been reported. Indomethacin can also cause premature closure or constriction of the ductus arteriosus. Since this effect is more common after 32 weeks’ gestation, indomethacin therapy is not usually recommended after 32 weeks.

Nifedipine

Nifedipine, a calcium channel blocker, is commonly used to treat high blood pressure and heart disease because of its ability to inhibit contractility in smooth muscle cells by reducing calcium influx into cells. Consequently, nifedipine has emerged as an effective and safe alternative tocolytic agent for the management of preterm labor. Despite its unlabeled status, several randomized studies have shown that the use of nifedipine in comparison with other tocolytics is associated with a more frequent successful prolongation of pregnancy, resulting in significantly fewer admissions of newborns to the neonatal intensive care unit, and may be associated with a lower incidence of respiratory distress syndrome, necrotizing enterocolitis, and intraventricular hemorrhage.

A systemic review by Conde-Aqudelo ²⁴ found that nifedipine was associated with significantly fewer maternal adverse events than β2 -adrenergic-receptor agonists and magnesium sulfate for tocolysis in women with preterm labor.

A recommended initial dosage of nifedipine is 20 mg orally, followed by 20 mg orally after 30 minutes. If contractions persist, therapy can be continued with 20 mg orally every 3-8 hours for 48-72 hours with a maximum dose of 160 mg/d. After 72 hours, if maintenance is still required, long-acting nifedipine 30-60 mg daily can be used.

Contraindications of nifedipine therapy include allergy to nifedipine, hypotension, hepatic dysfunction, concurrent use of beta-mimetics or magnesium sulfate (MgSO4), transdermal nitrates, or other antihypertensive medication. Other commonly reported side effects of nifedipine are maternal tachycardia, palpitations, flushing, headaches, dizziness, and nausea. Continuous monitoring of the fetal heart rate is recommended as long as the patient has contractions; the patient’s pulse and blood pressure should be carefully monitored. Pregnant women with liver disease should not be prescribed nifedipine.

Tocolytic indications

Tocolytics are medications used to suppress premature labor (from the Greek tokos, childbirth, and lytic, capable of dissolving). They are given when delivery would result in premature birth. The therapy also buys time for the administration of betamethasone, a glucocorticoid drug which greatly accelerate fetal lung maturity, but takes one to two days to work.

The suppression of contractions is often only partial and tocolytics can only be relied on to delay birth for several days. Depending on the tocolytic used the mother or fetus may require monitoring, as for instance blood pressure monitoring when nifedipine is used as it reduces blood pressure. In any case the risk of preterm labor alone justifies hospitalization.

Tocolytic contraindications

Several factors may contraindicate delaying birth with the use of tocolytic medications.

• Fetus is older than 37 weeks gestation
• Fetus weighs more than 2500g or has intrauterine growth restriction (IUGR)
• Fetus is in acute distress or has passed (or has a fatal anomaly)
• Dilation is greater than 4 cm
• Chorioamnionitis or intrauterine infection is present
• Mother has severe pregnancy-induced hypertension, eclampsia, active vaginal bleeding, a cardiac disease, or another condition which indicates that the pregnancy should not continue.

Tocolytic side effects

Terbutaline side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• chest pain, fast heart rate;
• pounding heartbeats or fluttering in your chest;
• a light-headed feeling, like you might pass out;
• tremors; or
• worsening or no improvement in your symptoms.

Common side effects may include:

• nervousness;
• headache;
• dizziness, weakness, drowsiness;
• nausea, dry mouth;
• tired feeling; or
• sleep problems (insomnia).

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

Magnesium sulfate tocolytic side effects

Check with your doctor immediately if any of the following side effects occur while taking magnesium sulfate:

Incidence not known

• confusion
• dizziness or lightheadedness
• fast, slow, or irregular heartbeat
• low blood pressure
• muscle weakness
• skin infection after soaking
• sleepiness

Some side effects of magnesium sulfate may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Incidence not known

• diarrhea
• skin irritation after soaking

Fetal harm

Continuous administration of magnesium sulfate beyond 5 to 7 days to pregnant women can lead to hypocalcemia and bone abnormalities in the developing fetus. These bone abnormalities include skeletal demineralization and osteopenia. In addition, cases of neonatal fracture have been reported. The shortest duration of treatment that can lead to fetal harm is not known. Magnesium sulfate should be used during pregnancy only if clearly needed. If magnesium sulfate is given for treatment of preterm labor, the woman should be informed that the efficacy and safety of such use have not been established and that use of magnesium sulfate beyond 5 to 7 days may cause fetal abnormalities.

Aluminum toxicity

• This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
• Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
• Parenteral use in the presence of renal insufficiency may lead to magnesium intoxication. IV use in the eclampsia should be reserved for immediate control of life-threatening convulsions.

References

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