Tocolytic

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Tocolytic
Specialty OB/GYN

Tocolytics (also called anti-contraction medications or labor suppressants) are medications used to suppress premature labor (from Greek τόκος tókos, "childbirth", and λύσις lúsis, "loosening"). Preterm birth accounts for 70% of neonatal deaths. [1] Therefore, tocolytic therapy is provided when delivery would result in premature birth, postponing delivery long enough for the administration of glucocorticoids, which accelerate fetal lung maturity but may require one to two days to take effect.

Contents

Commonly used tocolytic medications include β2 agonists, calcium channel blockers, NSAIDs, and magnesium sulfate. These can assist in delaying preterm delivery by suppressing uterine muscle contractions and their use is intended to reduce fetal morbidity and mortality associated with preterm birth. [2] The suppression of contractions is often only partial and tocolytics can only be relied on to delay birth for a matter of days. Depending on the tocolytic used, the pregnant woman or fetus may require monitoring (e.g., blood pressure monitoring when nifedipine is used as it reduces blood pressure; cardiotocography to assess fetal well-being). In any case, the risk of preterm labor alone justifies hospitalization.

Indications

Tocolytics are used in preterm labor, which refers to when a baby is born too early before 37 weeks of pregnancy. As preterm birth represents one of the leading causes of neonatal morbidity and mortality, the goal is to prevent neonatal morbidity and mortality through delaying delivery and increasing gestational age by gaining more time for other management strategies like corticosteroids therapy that may help with fetus lung maturity. [3] [4] Tocolytics are considered for women with confirmed preterm labor between 24 and 34 weeks of gestation age and used in conjunction with other therapies that may include corticosteroids administration, fetus neuroprotection, and safe transfer to facilities. [5]

Types of agents

There is no clear first-line tocolytic agent. [6] [7] Current evidence suggests that first line treatment with β2 agonists, calcium channel blockers, or NSAIDs to prolong pregnancy for up to 48 hours is the best course of action to allow time for glucocorticoid administration. [1]

Various types of agents are used, with varying success rates and side effects. Some medications are not specifically approved by the U.S. Food and Drug Administration (FDA) for use in stopping uterine contractions in preterm labor, instead being used off-label.[ citation needed ]

According to a 2022 Cochrane review, the most effective tocolytics for delaying preterm birth by 48 hours, and 7 days were the nitric oxide donors, calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics. [8]

DrugMechanism of actionDescriptionPossible
contraindications		Maternal side effectsFetal and neonatal side effects
Terbutaline (Brethine) β2 agonist Off-label use, FDA has advised that injectable terbutaline should only be used in urgent situations, and that the oral form of the drug should never be used [9] Cardiac tachyarrhythmias, poorly controlled diabetes mellitus, hyperthyroidism, prolonged tocolysis(>48 to 72 hours) [1] Tachycardia, palpitations, hypotension, dyspnea, chest pain, hypokalemia, hyperglycemia, lipolysis, pulmonary edema, myocardial ischemia [10] Fetal tachycardia, hyperinsulinemia, hypoglycemia, myocardial and septal hypertrophy, myocardial ischemia [11]
Ritodrine (Yutopar) β2 agonist No longer FDA approved [12] Poorly controlled thyroid disease, hypertension, and diabetes [13] Metabolic hyperglycemia, hyperinsulinemia, hypokalemia, antidiuresis, altered thyroid function, physiologic tremor, palpitations, nervousness, nausea or vomiting, fever, hallucinations [14] Neonatal tachycardia, hypoglycemia, hypocalcemia, hyperbilirubinemia, hypotension, intraventricular hemorrhage [14]
Fenoterol β2 agonist Not approved for tocolysis by FDA Diabetes, tachyarrhythmia, hypertrophic obstructive cardiomyopathy, hypersensitivity to fenoterol [15] Palpitations, tachycardia, and chest pain [16] Tachycardia, [17] impaired carbohydrate tolerance, hyperinsulinaemia [18]
Salbutamol (INN) or albuterol (USAN) β2 agonist Shown to be less effective than nifedipine for tocolysis regarding neonatal outcome [19] Diabetes, ischemic cardiopathy, cardiac arrhythmia, placenta praevia, hyperthyroidism, hypersensitivity to salbutamol (albuterol) [20] [21] Headache, palpitations, tachycardia, tremor, sweating, and shortness of breath [22] Fetal tachycardia, hypoglycemia, hyperinsulinaemia [22]
Hexoprenaline (Gynipral) β2 agonist Not FDA approved Hyperthyroidism, cardiovascular diseases, glaucoma, placental abruption, vaginal bleeding, inflammatory diseases of internal genitalia, 1st trimester of pregnancy, breastfeeding [23] [24] Vertigo, anxiety, tremor, hyperhidrosis, tachycardia, hypotension, hyperglycemia, edema Hypoglycemia, bronchospasm, anaphylactic shock [24]
Nifedipine (Procardia, Adalat) Ca2+ channel blocker Is one of the most commonly used tocolytic agents. [25] Hypotension, preload-dependent cardiac disease. [26] It should not be used concomitantly with magnesium sulfate [27] Flushing, headache, dizziness, nausea, transient hypotension. Administration of calcium channel blockers should be used with care in patients with renal disease and hypotension. Concomitant use of calcium channel blockers and magnesium sulfate may result in cardiovascular collapse [28] Calcium channel blockers have the fewest neonatal adverse effects [5]
Atosiban Oxytocin receptor antagonistSafer than both nifedipine and beta agonists; As effective as nifedipine and more effective than beta agonists. [29] Fewer side effects than β2 agonists. [30] Although not FDA approved in the US, atosiban was developed specifically to delay preterm labor. [31] No current contraindicationsNo maternal adverse effects [32] No adverse effects to the baseline fetal heart rate. No significant difference in neonatal side effect compared to other treatments [32]
Indomethacin NSAID Shown to effectively delay premature birth, studies show that it is safer and more effective for pregnant women that are <= 32 weeks of gestation [33] Late pregnancy (ductus arteriosus), significant renal or hepatic impairment [34] Nausea, heartburn [35] Constriction of ductus arteriosus, pulmonary hypertension, reversible decrease in renal function with oligohydramnios, intraventricular hemorrhage, hyperbilirubinemia, necrotizing enterocolitis [36]
Sulindac NSAID Studies show that it has similar efficacy to that of indomethacin and has a milder effect on the fetal ductus arteriousus [37] Coagulation disorders or thrombocytopenia, NSAID-sensitive asthma, other sensitivity to NSAID [38] GI complications such as nausea, vomiting and stomach pain due to COX inhibition [39] NSAIDs have been shown to be associated with constriction of the ductus arteriousus and oligohydramnios [34]
Magnesium sulfate [40] Myosin light chain inhibitorProbably effective in delaying preterm birth by 48 hours. [8] It is used for its neuro-protective effects since it is shown to decrease the risk of cerebral palsy in infants. [41] Absolute contraindication: myasthenia gravis. [42] Use as a tocolytic agent may result in death of the fetus or infant. [40] Flushing, lethargy, headache, muscle weakness, diplopia, dry mouth, pulmonary edema, cardiac arrest [42] Lethargy, hypotonia, respiratory depression, demineralization with prolonged use [42]
Ethanol GABAA receptor PAM Shown to be ineffective: no better than placebo. [22] Source revision needed Was a frequently used tocolytic in the mid-20th century, but later double-blind studies [43] found it was not effective.Pregnancy: no amount of ethanol is safe to the fetus [44] Intoxication, withdrawal [22] Fetal alcohol syndrome: ethanol is a teratogen and can harm fetus [44]

Calcium-channel blockers (such as nifedipine) and oxytocin antagonists (such as atosiban) may delay delivery by 2 to 7 days, depending on how quickly the medication is administered. [45] NSAIDs (such as indomethacin) and calcium channel blockers (such as nifedipine) are the most likely to delay delivery for 48 hours, with the least amount of maternal and neonatal side effects. [46] Otherwise, tocolysis is rarely successful beyond 24 to 48 hours because current medications do not alter the fundamentals of labor activation. [47] However, postponing premature delivery by 48 hours appears sufficient to allow pregnant women to be transferred to a center specialized for management of preterm deliveries, and thus administer corticosteroids for the possibility to reduce neonatal organ immaturity. [46]

The efficacy of β-adrenergic agonists, atosiban, and indomethacin is a decreased odds ratio (OR) of delivery within 24 hours of 0.54 (95% confidence interval (CI): 0.32-0.91) and 0.47 within 48 hours (OR 0.47, 95% CI: 0.30-0.75). [6]

Antibiotics were thought to delay delivery, but no studies have shown any evidence that using antibiotics during preterm labor effectively delays delivery or reduces neonatal morbidity. [41] Antibiotics are used in people with premature rupture of membranes, but this is not characterized as tocolysis. [48]

Contraindications to tocolytics

In addition to drug-specific contraindications, [41] several general factors may contraindicate delaying childbirth with the use of tocolytic medications.

Future direction of tocolytics

Most tocolytics are currently being used off-label. The future direction of the development of tocolytics agents should be directed toward better efficacy in intentionally prolonging pregnancy. This will potentially result in less maternal, fetal, and neonatal adverse effects when delaying preterm childbirth. A few tocolytic alternatives worth pursuing include Barusiban, a last generation of oxytocin receptor antagonists, as well as COX-2 inhibitors. [50] More studies on the use of multiple tocolytics must be directed to research overall health outcomes rather than solely pregnancy prolongation. [51]

See also

Related Research Articles

<span class="mw-page-title-main">Childbirth</span> Expulsion of a fetus from the pregnant mothers uterus

Childbirth, also known as labour, parturition and delivery, is the completion of pregnancy where one or more babies exits the internal environment of the mother via vaginal delivery or caesarean section. In 2019, there were about 140.11 million human births globally. In the developed countries, most deliveries occur in hospitals, while in the developing countries most are home births.

<span class="mw-page-title-main">Terbutaline</span> Chemical compound

Terbutaline, sold under the brand names Bricanyl and Marex among others, is a β2 adrenergic receptor agonist, used as a "reliever" inhaler in the management of asthma symptoms and as a tocolytic to delay preterm labor for up to 48 hours. This time can then be used to administer steroid injections to the mother which help fetal lung maturity and reduce complications of prematurity. It should not be used to prevent preterm labor or delay labor more than 48–72 hours. In February 2011, the Food and Drug Administration began requiring a black box warning on the drug's label. Pregnant women should not be given injections of the drug terbutaline for the prevention of preterm labor or for long-term management of preterm labor, and should not be given oral terbutaline for any type of prevention or treatment of preterm labor "due to the potential for serious maternal heart problems and death."

<span class="mw-page-title-main">Preterm birth</span> Birth at less than a specified gestational age

Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is between 28 and 32 weeks, early preterm birth occurs between 32 and 34 weeks, late preterm birth is between 34 and 36 weeks' gestation. These babies are also known as premature babies or colloquially preemies or premmies. Symptoms of preterm labor include uterine contractions which occur more often than every ten minutes and/or the leaking of fluid from the vagina before 37 weeks. Premature infants are at greater risk for cerebral palsy, delays in development, hearing problems and problems with their vision. The earlier a baby is born, the greater these risks will be.

<span class="mw-page-title-main">Misoprostol</span> Medication to induce abortion and treat ulcers

Misoprostol is a synthetic prostaglandin medication used to prevent and treat stomach and duodenal ulcers, induce labor, cause an abortion, and treat postpartum bleeding due to poor contraction of the uterus. It is taken by mouth when used to prevent gastric ulcers in people taking nonsteroidal anti-inflammatory drugs (NSAID). For abortions it is used by itself or in conjunction with mifepristone or methotrexate. By itself, effectiveness for abortion is between 66% and 90%. For labor induction or abortion, it is taken by mouth, dissolved in the mouth, or placed in the vagina. For postpartum bleeding it may also be used rectally.

<span class="mw-page-title-main">External cephalic version</span> Process by which a breech baby can sometimes be turned from buttocks or foot first to head first

External cephalic version (ECV) is a process by which a breech baby can sometimes be turned from buttocks or foot first to head first. It is a manual procedure that is recommended by national guidelines for breech presentation of a pregnancy with a single baby, in order to enable vaginal delivery. It is usually performed late in pregnancy, that is, after 36 gestational weeks, preferably 37 weeks, and can even be performed in early labour.

Labor induction is the process or treatment that stimulates childbirth and delivery. Inducing (starting) labor can be accomplished with pharmaceutical or non-pharmaceutical methods. In Western countries, it is estimated that one-quarter of pregnant women have their labor medically induced with drug treatment. Inductions are most often performed either with prostaglandin drug treatment alone, or with a combination of prostaglandin and intravenous oxytocin treatment.

<span class="mw-page-title-main">Indometacin</span> Anti-inflammatory drug

Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.

<span class="mw-page-title-main">Atosiban</span> Chemical compound

Atosiban, sold under the brand name Tractocile among others, is an inhibitor of the hormones oxytocin and vasopressin. It is used as an intravenous medication as a labour repressant (tocolytic) to halt premature labor. It was developed by Ferring Pharmaceuticals in Sweden and first reported in the literature in 1985. Originally marketed by Ferring Pharmaceuticals, it is licensed in proprietary and generic forms for the delay of imminent preterm birth in pregnant adult women.

<span class="mw-page-title-main">Prelabor rupture of membranes</span> Medical condition

Prelabor rupture of membranes (PROM), previously known as premature rupture of membranes, is breakage of the amniotic sac before the onset of labor. Women usually experience a painless gush or a steady leakage of fluid from the vagina. Complications in the baby may include premature birth, cord compression, and infection. Complications in the mother may include placental abruption and postpartum endometritis.

<span class="mw-page-title-main">Cervical effacement</span>

Cervical effacement or cervical ripening refers to the thinning and shortening of the cervix. This process occurs during labor to prepare the cervix for dilation to allow the fetus to pass through the vagina. While this a normal, physiological process that occurs at the later end of pregnancy, it can also be induced through medications and procedures.

<span class="mw-page-title-main">Cervical cerclage</span> Obstetrics medical procedure

Cervical cerclage, also known as a cervical stitch, is a treatment for cervical weakness, when the cervix starts to shorten and open too early during a pregnancy causing either a late miscarriage or preterm birth. In women with a prior spontaneous preterm birth and who are pregnant with one baby, and have shortening of the cervical length less than 25 mm, a cerclage prevents a preterm birth and reduces death and illness in the baby.

Antenatal steroids, also known as antenatal corticosteroids, are medications administered to pregnant women expecting a preterm birth. When administered, these steroids accelerate the maturation of the fetus' lungs, which reduces the likelihood of infant respiratory distress syndrome and infant mortality. The effectiveness of this corticosteroid treatment on humans was first demonstrated in 1972 by Sir Graham Liggins and Ross Howie, during a randomized control trial using betamethasone.

Postterm pregnancy is when a woman has not yet delivered her baby after 42 weeks of gestation, two weeks beyond the typical 40-week duration of pregnancy. Postmature births carry risks for both the mother and the baby, including fetal malnutrition, meconium aspiration syndrome, and stillbirths. After the 42nd week of gestation, the placenta, which supplies the baby with nutrients and oxygen from the mother, starts aging and will eventually fail. Postterm pregnancy is a reason to induce labor.

<span class="mw-page-title-main">Uterine atony</span> Loss of tone in the uterine musculature

Uterine atony is the failure of the uterus to contract adequately following delivery. Contraction of the uterine muscles during labor compresses the blood vessels and slows flow, which helps prevent hemorrhage and facilitates coagulation. Therefore, a lack of uterine muscle contraction can lead to an acute hemorrhage, as the vasculature is not being sufficiently compressed. Uterine atony is the most common cause of postpartum hemorrhage, which is an emergency and potential cause of fatality. Across the globe, postpartum hemorrhage is among the top five causes of maternal death. Recognition of the warning signs of uterine atony in the setting of extensive postpartum bleeding should initiate interventions aimed at regaining stable uterine contraction.

<span class="mw-page-title-main">Postpartum bleeding</span> Loss of blood following childbirth

Postpartum bleeding or postpartum hemorrhage (PPH) is often defined as the loss of more than 500 ml or 1,000 ml of blood following childbirth. Some have added the requirement that there also be signs or symptoms of low blood volume for the condition to exist. Signs and symptoms may initially include: an increased heart rate, feeling faint upon standing, and an increased breathing rate. As more blood is lost, the patient may feel cold, blood pressure may drop, and they may become restless or unconscious. The condition can occur up to six weeks following delivery.

<span class="mw-page-title-main">Vaginal delivery</span> Delivery through the vagina

A vaginal delivery is the birth of offspring in mammals through the vagina. It is the most common method of childbirth worldwide. It is considered the preferred method of delivery, with lower morbidity and mortality than Caesarean sections (C-sections).

A uterotonic, also known as an oxytocic or ecbolic, is a type of medication used to induce contraction or greater tonicity of the uterus. Uterotonics are used both to induce labor and to reduce postpartum hemorrhage.

Amnioinfusion is a method in which isotonic fluid is instilled into the uterine cavity.

Uterine Tachysystole is a condition of excessively frequent uterine contractions during pregnancy. It is most often seen in induced or augmented labor, though it can also occur during spontaneous labor, and this may result in fetal hypoxia and acidosis. This may have serious effects on both the mother and the fetus including hemorrhaging and death. There are still major gaps in understanding treatment as well as clinical outcomes of this condition. Uterine tachysystole is defined as more than 5 contractions in 10 minutes, averaged over a 30-minute period.

<span class="mw-page-title-main">High-risk pregnancy</span> Medical condition

A high-risk pregnancy is one where the mother or the fetus has an increased risk of adverse outcomes compared to uncomplicated pregnancies. No concrete guidelines currently exist for distinguishing “high-risk” pregnancies from “low-risk” pregnancies; however, there are certain studied conditions that have been shown to put the mother or fetus at a higher risk of poor outcomes. These conditions can be classified into three main categories: health problems in the mother that occur before she becomes pregnant, health problems in the mother that occur during pregnancy, and certain health conditions with the fetus.

References

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