Tocolytic
Tocolytic | |
---|---|
Specialty | OB/GYN |
Tocolytics (also called anti-contraction medications or labor suppressants) are medications used to suppress
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
Types of agents
There is no clear
Various types of agents are used, with varying success rates and side effects. Some medications are not specifically approved by the
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]
Drug | Mechanism of action | Description | Possible contraindications |
Maternal side effects | Fetal 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] | cardiovascular collapse[28]
|
Calcium channel blockers have the fewest neonatal adverse effects[5] |
Atosiban | Oxytocin receptor antagonist | Safer 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 contraindications | No 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 inhibitor | Probably 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. 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.
Contraindications to tocolytics
In addition to drug-specific contraindications,[41] several general factors may contraindicate delaying childbirth with the use of tocolytic medications.
- Fetus is older than 34 weeks gestation[49]
- Fetus weighs less than 2.5 kg, or has intrauterine growth restriction (IUGR)[49] or placental insufficiency[49]
- Lethal congenital or chromosomal abnormalities[49]
- Cervical dilation is greater than 4 centimeters[49]
- Chorioamnionitis or intrauterine infection is present[49]
- Pregnant woman has severe
- Maternal hemodynamic instability with bleeding[41]
- Intrauterine fetal demise, lethal fetal anomaly, or non-reassuring fetal status[41]
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
See also
References
- ^ S2CID 5537988.
- PMID 32965883, retrieved 29 July 2021
- ISBN 9781444323030.
- PMID 26740166.
- ^ S2CID 58563849.
- ^ PMID 16645683.
- PMID 19264820.
- ^ PMID 35947046.
- ^ Why do doctors still use terbutaline to delay preterm labor despite its major health risks? Retrieved on October 20th, 2020
- PMID 10546776.
- PMID 22363704.
- ^ "Drugs@FDA: FDA-Approved Drugs". www.accessdata.fda.gov.
- PMID 9614414.
- ^ ISBN 978-1-4511-7782-4.
- ^ "Fenoterol drug information | DrugsUpdate India". www.drugsupdate.com. Retrieved 2 August 2021.
- PMID 24500892.
- S2CID 6900277.
- )
- PMID 11336775.
- PMID 29489143, retrieved 2 August 2021
- ^ Spirlet, Marina de; Treluyer, Jean-Marc; Chevret, Sylvie; Rey, Elisabeth; Tournaire, Michel; Cabrol, Dominique; Pons, Gérard (2004). Fundamental & Clinical Pharmacology. Oxford, UK: Blackwell Science Ltd. pp. 207–217.
- ^ S2CID 89620227.
- ^ "Gynipral (hexoprenaline) Full Prescribing Information". Russian State Register of Medicinal Products (in Russian). Nycomed Austria GmbH. St. Peter-Straße 25, A-4020, Linz, Austria. Retrieved 19 March 2016.
- ^ a b "Gynipral (hexoprenaline) Tablets 0.5 mg, Solution for Intravenous Infusion 5 μg/mL (0.0005%)". "RLS" (РЛС): Russian Register of Medical Products (in Russian). Retrieved 19 March 2016.
- ^ Welcome to the Women's – The Royal Women's Hospital Victoria Australia
- ^ "Nifedipine Monograph for Professionals - Drugs.com". 2015. Archived from the original on 25 December 2015.
- PMID 15284796.
- PMID 9061722.
- S2CID 1012738.
- PMID 24903678.
- S2CID 35984198.
- ^ S2CID 946463.
- PMID 9369826.
- ^ PMID 12972011.
- ^ "Indomethacin Side Effects: Common, Severe, Long Term". Drugs.com. Retrieved 30 July 2021.
- )
- PMID 7631682.
- PMID 15242723.
- PMID 23137151.
- ^ PMID 25126773.
- ^ PMID 28318214.
- ^ PMID 20148502.
- S2CID 22685586.
- ^ S2CID 205474115.
- ^
Iams JD, Romero R, Culhane JF, Goldenberg RL (2008). "Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth". S2CID 8204299.
- ^ PMID 23048010.
- ^
Simhan HN, Caritis SN (2007). "Prevention of Preterm Delivery". PMID 17671256.
- PMID 24297389.
- ^ ISBN 978-0-323-01399-4.
- PMID 22175022.
- PMID 15134284.