Tocolytic Explained

Tocolytic
Specialty:	OB/GYN
Synonyms:	Labor suppressants

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.

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. 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.^{[2] [3]} 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.^[4]

Types of agents

There is no clear first-line tocolytic agent.^{[5] [6]} 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.

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.

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.^[7]

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^[8]	Cardiac tachyarrhythmias, poorly controlled diabetes mellitus, hyperthyroidism, prolonged tocolysis(>48 to 72 hours)	Tachycardia, palpitations, hypotension, dyspnea, chest pain, hypokalemia, hyperglycemia, lipolysis, pulmonary edema, myocardial ischemia^[9]	Fetal tachycardia, hyperinsulinemia, hypoglycemia, myocardial and septal hypertrophy, myocardial ischemia^[10]
Ritodrine (Yutopar)	β2 agonist	No longer FDA approved^[11]	Poorly controlled thyroid disease, hypertension, and diabetes^[12]	Metabolic hyperglycemia, hyperinsulinemia, hypokalemia, antidiuresis, altered thyroid function, physiologic tremor, palpitations, nervousness, nausea or vomiting, fever, hallucinations^[13]	Neonatal tachycardia, hypoglycemia, hypocalcemia, hyperbilirubinemia, hypotension, intraventricular hemorrhage
Fenoterol	β2 agonist	Not approved for tocolysis by FDA	Diabetes, tachyarrhythmia, hypertrophic obstructive cardiomyopathy, hypersensitivity to fenoterol^[14]	Palpitations, tachycardia, and chest pain^[15]	Tachycardia,^[16] impaired carbohydrate tolerance, hyperinsulinaemia^[17]
Salbutamol (INN) or albuterol (USAN)	β2 agonist	Shown to be less effective than nifedipine for tocolysis regarding neonatal outcome^[18]	Diabetes, ischemic cardiopathy, cardiac arrhythmia, placenta praevia, hyperthyroidism, hypersensitivity to salbutamol (albuterol) ^[19]	Headache, palpitations, tachycardia, tremor, sweating, and shortness of breath^[20]	Fetal tachycardia, hypoglycemia, hyperinsulinaemia
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^[21] ^[22]	Vertigo, anxiety, tremor, hyperhidrosis, tachycardia, hypotension, hyperglycemia, edema	Hypoglycemia, bronchospasm, anaphylactic shock
Nifedipine (Procardia, Adalat)	Ca^2+ channel blocker	Is one of the most commonly used tocolytic agents.^[23]	Hypotension, preload-dependent cardiac disease.^[24] It should not be used concomitantly with magnesium sulfate^[25]	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^[26]	Calcium channel blockers have the fewest neonatal adverse effects
Atosiban	Oxytocin receptor antagonist	Safer than both nifedipine and beta agonists; As effective as nifedipine and more effective than beta agonists.^[27] Fewer side effects than β2 agonists.^[28] Although not FDA approved in the US, atosiban was developed specifically to delay preterm labor.^[29]	No current contraindications	No maternal adverse effects^[30]	No adverse effects to the baseline fetal heart rate. No significant difference in neonatal side effect compared to other treatments
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 ^[31]	Late pregnancy (ductus arteriosus), significant renal or hepatic impairment^[32]	Nausea, heartburn^[33]	Constriction of ductus arteriosus, pulmonary hypertension, reversible decrease in renal function with oligohydramnios, intraventricular hemorrhage, hyperbilirubinemia, necrotizing enterocolitis^[34]
Sulindac	NSAID	Studies show that it has similar efficacy to that of indomethacin and has a milder effect on the fetal ductus arteriousus ^[35]	Coagulation disorders or thrombocytopenia, NSAID-sensitive asthma, other sensitivity to NSAID^[36]	GI complications such as nausea, vomiting and stomach pain due to COX inhibition^[37]	NSAIDs have been shown to be associated with constriction of the ductus arteriousus and oligohydramnios
Magnesium sulfate^[38]	Myosin light chain inhibitor	Probably effective in delaying preterm birth by 48 hours. It is used for its neuro-protective effects since it is shown to decrease the risk of cerebral palsy in infants.	Absolute contraindication: myasthenia gravis.^[39] Use as a tocolytic agent may result in death of the fetus or infant.	Flushing, lethargy, headache, muscle weakness, diplopia, dry mouth, pulmonary edema, cardiac arrest	Lethargy, hypotonia, respiratory depression, demineralization with prolonged use
Ethanol	GABAA receptor PAM	Shown to be ineffective: no better than placebo.Source revision needed Was a frequently used tocolytic in the mid-20th century, but later double-blind studies^[40] found it was not effective.	Pregnancy: no amount of ethanol is safe to the fetus^[41]	Intoxication, withdrawal	Fetal alcohol syndrome ethanol is a teratogen and can harm fetus

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.^[42] 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.^[43] Otherwise, tocolysis is rarely successful beyond 24 to 48 hours because current medications do not alter the fundamentals of labor activation.^[44] 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.^[43]

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).^[5]

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. Antibiotics are used in people with premature rupture of membranes, but this is not characterized as tocolysis.^[45]

Contraindications to tocolytics

In addition to drug-specific contraindications,^[46] several general factors may contraindicate delaying childbirth with the use of tocolytic medications.

• Fetus is older than 34 weeks gestation^[47]
• Fetus weighs less than 2.5 kg, or has intrauterine growth restriction (IUGR)^[47] or placental insufficiency
• Lethal congenital or chromosomal abnormalities^[47]
• Cervical dilation is greater than 4 centimeters^[47]
• Chorioamnionitis or intrauterine infection is present^[47]
• Pregnant woman has severe pregnancy-induced hypertension,^[47] severe eclampsia^[47] /preeclampsia, active vaginal bleeding,^[47] placental abruption, a cardiac disease,^[47] or another condition which indicates that the pregnancy should not continue.^[47]
• Maternal hemodynamic instability with bleeding
• Intrauterine fetal demise, lethal fetal anomaly, or non-reassuring fetal status

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.^[48] More studies on the use of multiple tocolytics must be directed to research overall health outcomes rather than solely pregnancy prolongation.^[49]

See also

• Labor induction

Notes and References

1. 2016. Practice Bulletin No. 171: Management of Preterm Labor. Obstetrics & Gynecology. en-US. 128. 4. e155–e164. 10.1097/AOG.0000000000001711. 27661654. 0029-7844. American College of Obstetricians Gynecologists' Committee on Practice Bulletins—Obstetrics. 5537988.
2. Book: Ouzounian. Joseph G. Management of Common Problems in Obstetrics and Gynecology.. Goodwin. T. Murphy. Paulson. Richard J. Montoro. Martin N. Muderspach. Laila I. Roy. Subir. Blackwell Publishing Ltd. 2010. 9781444323030. 9–11.
3. Harrison. Margo S.. Goldenberg. Robert L.. 2016. Global burden of prematurity. Seminars in Fetal & Neonatal Medicine. 21. 2. 74–79. 10.1016/j.siny.2015.12.007. 1878-0946. 26740166.
4. Hanley. Margaret. Sayres. Lauren. Reiff. Emily S.. Wood. Amber. Grotegut. Chad A.. Kuller. Jeffrey A.. 2019. Tocolysis: A Review of the Literature. Obstetrical & Gynecological Survey. 74. 1. 50–55. 10.1097/OGX.0000000000000635. 1533-9866. 30648727. 58563849.
5. Tan TC, Devendra K, Tan LK, Tan HK . Tocolytic treatment for the management of preterm labour: a systematic review . Singapore Med J . 47 . 5 . 361–6 . May 2006 . 16645683 .
6. de Heus R, Mol BW, Erwich JJ, etal . Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study . BMJ . 338 . b744 . 2009 . 19264820 . 2654772 . 10.1136/bmj.b744.
7. Wilson . Amie . Hodgetts-Morton . Victoria A . Marson . Ella J . Markland . Alexandra D . Larkai . Eva . Papadopoulou . Argyro . Coomarasamy . Arri . Tobias . Aurelio . Chou . Doris . Oladapo . Olufemi T . Price . Malcolm J . Morris . Katie . Gallos . Ioannis D . Tocolytics for delaying preterm birth: a network meta-analysis (0924) . Cochrane Database of Systematic Reviews . 10 August 2022 . 2022 . 8 . CD014978 . 10.1002/14651858.CD014978.pub2. 35947046 . 9364967 .
8. https://www.nwhn.org/doctors-still-use-terbutaline-delay-preterm-labor-despite-major-health-risks Why do doctors still use terbutaline to delay preterm labor despite its major health risks?
9. 10546776. 1999. Gyetvai. K.. Hannah. M. E.. Hodnett. E. D.. Ohlsson. A.. Tocolytics for preterm labor: A systematic review. Obstetrics and Gynecology. 94. 5 Pt 2. 869–877. 10.1016/s0029-7844(99)00329-4.
10. Gaudet. Laura M.. Singh. Kavita. Weeks. Laura. Skidmore. Becky. Tsertsvadze. Alexander. Ansari. Mohammed T.. 2012. Effectiveness of Terbutaline Pump for the Prevention of Preterm Birth. A Systematic Review and Meta-Analysis. PLOS ONE. 7. 2. e31679. 10.1371/journal.pone.0031679. 1932-6203. 3283660. 22363704. 2012PLoSO...731679G. free.
11. Web site: Drugs@FDA: FDA-Approved Drugs. www.accessdata.fda.gov.
12. Pool. Beverly A. Von Der. 1998. Preterm Labor: Diagnosis and Treatment. American Family Physician. 57. 10. 2457–2464. 9614414. 0002-838X.
13. Book: Modak, Raj K.. Anesthesiology Keywords Review. 2013. Lippincott Williams & Wilkins. 978-1-4511-7782-4. en.
14. Web site: Fenoterol drug information DrugsUpdate India. 2021-08-02. www.drugsupdate.com.
15. Neilson. James P.. West. Helen M.. Dowswell. Therese. 2014-02-05. Betamimetics for inhibiting preterm labour. The Cochrane Database of Systematic Reviews. 2. CD004352. 10.1002/14651858.CD004352.pub3. 1469-493X. 24500892. 10603219.
16. Verdurmen. Kim M. J.. Hulsenboom. Alexandra D. J.. van Laar. Judith O. E. H.. Oei. S. Guid. 2017. Effect of tocolytic drugs on fetal heart rate variability: a systematic review. The Journal of Maternal-Fetal & Neonatal Medicine . 30. 20. 2387–2394. 10.1080/14767058.2016.1249844. 1476-4954. 27756155. 6900277.
17. Book: Drugs during pregnancy and lactation : treatment options and risk assessment. 2015. Christof Schaefer, P. W. J. Peters, Richard K. Miller. 978-0-12-407901-4. Third. London, UK. 892869035.
18. Tsatsaris. V. 2001. Tocolysis with nifedipine or beta-adrenergic agonists: a meta-analysis1. Obstetrics & Gynecology. en. 97. 5. 840–847. 10.1016/S0029-7844(00)01212-6. 11336775.
19. Book: Spirlet. Marina de. Fundamental & Clinical Pharmacology. Treluyer. Jean-Marc. Chevret. Sylvie. Rey. Elisabeth. Tournaire. Michel. Cabrol. Dominique. Pons. Gérard. Blackwell Science Ltd. 2004. Oxford, UK. 207–217.
20. Lamont. Ronald F.. Jørgensen. Jan S.. 2019. Safety and Efficacy of Tocolytics for the Treatment of Spontaneous Preterm Labour. Current Pharmaceutical Design. 25. 5. 577–592. 10.2174/1381612825666190329124214. 1873-4286. 30931850. 89620227.
21. Web site: Gynipral (hexoprenaline) Full Prescribing Information. Russian State Register of Medicinal Products. Nycomed Austria GmbH. St. Peter-Straße 25, A-4020, Linz, Austria. 19 March 2016. Russian.
22. Web site: Gynipral (hexoprenaline) Tablets 0.5 mg, Solution for Intravenous Infusion 5 μg/mL (0.0005%). "RLS" (РЛС): Russian Register of Medical Products. Russian. 19 March 2016.
23. http://www.rwh.org.au/rwhcpg/maternity.cfm?doc_id=1821 Welcome to the Women's – The Royal Women's Hospital Victoria Australia
24. Web site: 2015. Nifedipine Monograph for Professionals - Drugs.com. live. https://web.archive.org/web/20151225224837/http://www.drugs.com/monograph/nifedipine.html. 25 December 2015.
25. Koontz. Stephanie L.. Friedman. Steven A.. Schwartz. Martin L.. 2004. Symptomatic hypocalcemia after tocolytic therapy with magnesium sulfate and nifedipine. American Journal of Obstetrics and Gynecology. 190. 6. 1773–1776. 10.1016/j.ajog.2004.02.050. 0002-9378. 15284796.
26. Davis. W. B.. Wells. S. R.. Kuller. J. A.. Thorp. J. M.. March 1997. Analysis of the risks associated with calcium channel blockade: implications for the obstetrician-gynecologist. Obstetrical & Gynecological Survey. 52. 3. 198–201. 10.1097/00006254-199703000-00023. 0029-7828. 9061722.
27. Lyndrup. Jens. Lamont. Ronald F. 2007. The choice of a tocolytic for the treatment of preterm labor: a critical evaluation of nifedipine versus atosiban. Expert Opinion on Investigational Drugs. en. 16. 6. 843–853. 10.1517/13543784.16.6.843. 17501696. 1012738. 1354-3784.
28. Flenady. Vicki. Reinebrant. Hanna E. Liley. Helen G. Tambimuttu. Eashan G. Papatsonis. Dimitri NM. 2014. Cochrane Pregnancy and Childbirth Group. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database of Systematic Reviews. 6. CD004452. en. 10.1002/14651858.CD004452.pub3. 24903678. 11086629.
29. 2007. Oxytocin Receptor Antagonists for Inhibiting Preterm Labour. Obstetrics & Gynecology. en. 110. 1. 180–181. 10.1097/01.AOG.0000269669.34758.4e. 17601917. 0029-7844. Neilson. J. P.. 35984198.
30. Tsatsaris. Vassilis. Carbonne. Bruno. Cabrol. Dominique. 2004. Atosiban for Preterm Labour. Drugs. en. 64. 4. 375–382. 10.2165/00003495-200464040-00003. 14969573. 946463. 0012-6667.
31. Macones. George A.. Robinson. Charlah A.. 1997. Is there justification for using indomethacin in preterm labor? An analysis of neonatal risks and benefits. American Journal of Obstetrics and Gynecology. en. 177. 4. 819–824. 10.1016/S0002-9378(97)70275-8. 9369826.
32. Loudon. Jenifer A. Z.. Groom. Kate M.. Bennett. Philip R.. 2003. Prostaglandin inhibitors in preterm labour. Best Practice & Research. Clinical Obstetrics & Gynaecology. 17. 5. 731–744. 10.1016/s1521-6934(03)00047-6. 1521-6934. 12972011.
33. Web site: Indomethacin Side Effects: Common, Severe, Long Term. 2021-07-30. Drugs.com. en.
34. Book: Management of high-risk pregnancy : a practical approach.. 2016. S. S. Trivedi, Manju, MD Puri, Swati Agrawal. 978-93-5250-046-8. Second. New Delhi. 946116669.
35. Räsänen. Juha. Jouppila. Pentti. 1995. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor: A randomized study. American Journal of Obstetrics and Gynecology. 173. 1. 20–25. 10.1016/0002-9378(95)90163-9. 7631682. 0002-9378.
36. Stevenson. Donald D.. 2004. Aspirin and NSAID sensitivity. Immunology and Allergy Clinics of North America. 24. 3. 491–505, vii. 10.1016/j.iac.2004.03.001. 0889-8561. 15242723.
37. Castellsague. Jordi. Riera-Guardia. Nuria. Calingaert. Brian. Varas-Lorenzo. Cristina. Fourrier-Reglat. Annie. Nicotra. Federica. Sturkenboom. Miriam. Perez-Gutthann. Susana. Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project. 2012-12-01. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Safety. 35. 12. 1127–1146. 10.2165/11633470-000000000-00000. 1179-1942. 3714137. 23137151.
38. Crowther. CA. Brown. J. McKinlay. CJ. Middleton. P. 2014. Magnesium sulphate for preventing preterm birth in threatened preterm labour.. The Cochrane Database of Systematic Reviews. 8. CD001060. 10.1002/14651858.CD001060.pub2. 25126773. free. 10838393.
39. William G. Sayres. Jr. 2010. Preterm Labor. American Family Physician. 81. 4. 477–484. 20148502. 0002-838X.
40. Castrén O, Gummerus M, Saarikoski S . Treatment of imminent premature labour . Acta Obstet Gynecol Scand . 54 . 2 . 95–100 . 1975 . 1094787 . 10.3109/00016347509156739. 22685586 .
41. 2011. Committee opinion no. 496: At-risk drinking and alcohol dependence: obstetric and gynecologic implications. Obstetrics and Gynecology. 118. 2 Pt 1. 383–388. 10.1097/AOG.0b013e31822c9906. 1873-233X. 21775870. 205474115 .
42. Iams JD, Romero R, Culhane JF, Goldenberg RL . 2008 . Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth . . 371 . 9607 . 164–175 . 18191687 . 10.1016/S0140-6736(08)60108-7. 8204299 .
43. Haas. David M. Caldwell. Deborah M. Kirkpatrick. Page. McIntosh. Jennifer J. Welton. Nicky J. 2012. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. The BMJ. 345. e6226. 10.1136/bmj.e6226. 0959-8138. 4688428. 23048010.
44. Simhan HN, Caritis SN . 2007 . Prevention of Preterm Delivery . . 357 . 477–487 . 17671256 . 10.1056/NEJMra050435 . 5.
45. Kenyon. Sara. Boulvain. Michel. Neilson. James P.. 2013-12-02. Antibiotics for preterm rupture of membranes. The Cochrane Database of Systematic Reviews. 12. CD001058. 10.1002/14651858.CD001058.pub3. 1469-493X. 24297389. 11297390.
46. Rundell. Kristen. Panchal. Bethany. 2017. Preterm Labor: Prevention and Management. American Family Physician. 95. 6. 366–372. 28318214. 0002-838X.
47. Book: Wong . D. L. . Perry . S. E. . Hockenberry . M. J. . Lowdermilk . D. L. . Maternal Child Nursing Care . Mosby . 2002 . 978-0-323-01399-4 .
48. Hubinont. C.. Debieve. F.. 2011. Prevention of Preterm Labour: 2011 Update on Tocolysis. Journal of Pregnancy. en. 2011. 941057. 10.1155/2011/941057. 22175022. 3228310. 2090-2727. free.
49. Cole. Stephen. Smith. Roger. Giles. Warwick. 2004. Tocolysis: current controversies, future directions. Current Opinion in Investigational Drugs . 5. 4. 424–429. 1472-4472. 15134284.