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| [[Atosiban]]
| [[Atosiban]]
| [[Oxytocin receptor]] antagonist
| [[Oxytocin receptor]] antagonist
| Safer than both nifedipine and beta agonists; As effective as nifedipine and more effective than beta agonists.<ref>{{Cite journal|last=Lyndrup|first=Jens|last2=Lamont|first2=Ronald F|date=June 2007|title=The choice of a tocolytic for the treatment of preterm labor: a critical evaluation of nifedipine versus atosiban|url=http://www.tandfonline.com/doi/full/10.1517/13543784.16.6.843|journal=Expert Opinion on Investigational Drugs|language=en|volume=16|issue=6|pages=843–853|doi=10.1517/13543784.16.6.843|issn=1354-3784}}</ref> Fewer side effects than β<sub>2</sub> agonists{{citation needed|date=March 2016}}
| Safer than both nifedipine and beta agonists; As effective as nifedipine and more effective than beta agonists.<ref>{{Cite journal|last=Lyndrup|first=Jens|last2=Lamont|first2=Ronald F|date=June 2007|title=The choice of a tocolytic for the treatment of preterm labor: a critical evaluation of nifedipine versus atosiban|url=http://www.tandfonline.com/doi/full/10.1517/13543784.16.6.843|journal=Expert Opinion on Investigational Drugs|language=en|volume=16|issue=6|pages=843–853|doi=10.1517/13543784.16.6.843|issn=1354-3784}}</ref> Fewer side effects than β<sub>2</sub> agonists<ref>{{Cite journal|last=Flenady|first=Vicki|last2=Reinebrant|first2=Hanna E|last3=Liley|first3=Helen G|last4=Tambimuttu|first4=Eashan G|last5=Papatsonis|first5=Dimitri NM|date=2014-06-06|editor-last=Cochrane Pregnancy and Childbirth Group|title=Oxytocin receptor antagonists for inhibiting preterm labour|url=https://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004452.pub3|journal=Cochrane Database of Systematic Reviews|language=en|doi=10.1002/14651858.CD004452.pub3}}</ref>
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Revision as of 16:27, 30 July 2021

Tocolytic
SpecialtyOB/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"). 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 take one to two days before their effects are seen.

Tocolytic medications that are commonly used are β2 agonists, calcium channel blockers, NSAIDs, and magnesium sulfate. They can help delay delivery by suppressing uterine muscle contractions and aim to reduce fetal morbidity and mortality in preterm birth.[1] 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 (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.

Types of agents

There is no clear first-line tocolytic agent.[2][3]

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.

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[4] Cardiac tachyarrhythmias, poorly controlled diabetes mellitus, hyperthyroidism, prolonged tocolysis(>48 to 72 hours)[5] Tachycardia, palpitations, hypotension, dyspnea, chest pain, hypokalemia, hyperglycemia, lipolysis, pulmonary edema, myocardial ischemia [6] Fetal tachycardia, hyperinsulinemia, hypoglycemia, myocardial and septal hypertrophy, myocardial ischemia[7]
Ritodrine (Yutopar) β2 agonist No longer FDA approved[8] Poorly controlled thyroid disease, hypertension, and diabetes[9] Metabolic hyperglycemia, hyperinsulinemia, hypokalemia, antidiuresis, altered thyroid function, physiologic tremor, palpitations, nervousness, nausea or vomiting, fever, hallucinations[10] Neonatal tachycardia, hypoglycemia, hypocalcemia, hyperbilirubinemia, hypotension, intraventricular hemorrhage[10]
Fenoterol β2 agonist Not approved for tocolysis by FDA Diabetes palpitations, tachycardia, and chest pain[11] tachycardia,[12] impaired carbohydrate tolerance, hyperinsulinaemia[13]
Salbutamol (INN) or albuterol (USAN) β2 agonist Shown to be less effective than nifedipine for tocolysis regarding neonatal outcome[14] Diabetes, cardiovascular disease, glaucoma, hyperthyroidism, hypokalemia, seizures headache, palpitations, tachycardia, tremor, sweating, and shortness of breath[15] fetal tachycardia, hypoglycemia, hyperinsulinaemia[15]
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[16][17] Vertigo, anxiety, tremor, hyperhidrosis, tachycardia, hypotension, hyperglycemia, edema Hypoglycemia, bronchospasm, anaphylactic shock[17]
Nifedipine (Procardia, Adalat) Ca2+ channel blocker Is one of the most commonly used tocolytic agents.[18] Hypotension, preload-dependent cardiac disease.[19] It should not be used concomitantly with magnesium sulfate[20] 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[21] Calcium channel blockers have the fewest neonatal adverse effects[22]
Atosiban Oxytocin receptor antagonist Safer than both nifedipine and beta agonists; As effective as nifedipine and more effective than beta agonists.[23] Fewer side effects than β2 agonists[24]
Indomethacin NSAID Shown to effectively delay premature birth, studies show that it is safer and more effective for mothers that are <= 32 weeks of gestation [25] Late pregnancy (ductus arteriosus), significant renal or hepatic impairment Nausea, heartburn[26] Constriction of ductus arteriosus, pulmonary hypertension, reversible decrease in renal function with oligohydramnios, intraventricular hemorrhage, hyperbilirubinemia, necrotizing enterocolitis[27]
Sulindac NSAID Coagulation disorders or thrombocytopenia, NSAID-sensitive asthma, other sensitivity to NSAIDs[citation needed] GI complications such as nausea, vomiting and stomach pain due to COX inhibition NSAIDs have been shown to be associated with constriction of the ductus arteriousus and oligohydramnios
Magnesium sulfate[28] Myosin light chain inhibitor Shown to be ineffective for delaying birth or stopping early birth.[28] Meta-analyses have failed to support it as a tocolytic agent[28][29][30] Absolute contraindication: myasthenia gravis.[31] Use as a tocolytic agent may result in death of the fetus or infant.[28] Flushing, lethargy, headache, muscle weakness, diplopia, dry mouth, pulmonary edema, cardiac arrest[31] Lethargy, hypotonia, respiratory depression, demineralization with prolonged use[31]
Ethanol GABAA receptor PAM Shown to be ineffective: no better than placebo.[15] Was a frequently used tocolytic in the mid-20th century, but later double-blind studies[32] found it was not effective. Pregnancy: no amount of ethanol is safe to the fetus[33] Intoxication, withdrawal[15] Fetal alcohol syndrome: ethanol is a teratogen and can harm fetus[33]

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.[34] 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.[35] Otherwise, tocolysis is rarely successful beyond 24 to 48 hours because current medications do not alter the fundamentals of labor activation.[29] 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.[35]

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).[2]

Antibiotics may also delay the onset of labor in women with premature rupture of membranes, but this is not usually characterized as tocolysis.[36]

Contraindications to tocolytics

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

See also

References

  1. ^ Mayer, Christopher; Apodaca-Ramos, Irasema (2021), "Tocolysis", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32965883, retrieved 29 July 2021
  2. ^ a b Tan TC, Devendra K, Tan LK, Tan HK (May 2006). "Tocolytic treatment for the management of preterm labour: a systematic review". Singapore Med J. 47 (5): 361–6. PMID 16645683.
  3. ^ de Heus R, Mol BW, Erwich JJ, et al. (2009). "Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study". BMJ. 338: b744. doi:10.1136/bmj.b744. PMC 2654772. PMID 19264820.
  4. ^ Why do doctors still use terbutaline to delay preterm labor despite its major health risks? Retrieved on October 20th, 2020
  5. ^ American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. Practice Bulletin No. 171: Management of Preterm Labor. Obstet Gynecol. 2016 Oct;128(4):e155-64. doi: 10.1097/AOG.0000000000001711. PMID 27661654.
  6. ^ Gyetvai K, Hannah ME, Hodnett ED, Ohlsson A. Tocolytics for preterm labor: a systematic review. Obstet Gynecol. 1999 Nov;94(5 Pt 2):869-77. doi: 10.1016/s0029-7844(99)00329-4. PMID 10546776.
  7. ^ 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). doi:10.1371/journal.pone.0031679. ISSN 1932-6203. PMC 3283660. PMID 22363704.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ "Drugs@fda:fda approved drug products. (n.d.)".
  9. ^ Pool, Beverly A. Von Der (1998). "Preterm Labor: Diagnosis and Treatment". American Family Physician. 57 (10): 2457. ISSN 0002-838X.
  10. ^ a b Modak, Raj K. (2013). Anesthesiology Keywords Review. Lippincott Williams & Wilkins. ISBN 978-1-4511-7782-4.
  11. ^ Neilson, James P.; West, Helen M.; Dowswell, Therese (5 February 2014). "Betamimetics for inhibiting preterm labour". The Cochrane Database of Systematic Reviews (2): CD004352. doi:10.1002/14651858.CD004352.pub3. ISSN 1469-493X. PMID 24500892.
  12. ^ 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: The Official Journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 30 (20): 2387–2394. doi:10.1080/14767058.2016.1249844. ISSN 1476-4954. PMID 27756155.
  13. ^ Drugs during pregnancy and lactation : treatment options and risk assessment. Christof Schaefer, P. W. J. Peters, Richard K. Miller (Third ed.). London, UK. 2015. ISBN 978-0-12-407901-4. OCLC 892869035.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link)
  14. ^ Tsatsaris, V (2001). "Tocolysis with nifedipine or beta-adrenergic agonists: a meta-analysis1". Obstetrics & Gynecology. 97 (5): 840–847. doi:10.1016/S0029-7844(00)01212-6.
  15. ^ a b c d 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. doi:10.2174/1381612825666190329124214. ISSN 1873-4286. PMID 30931850. Cite error: The named reference ":2" was defined multiple times with different content (see the help page).
  16. ^ "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.
  17. ^ 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.
  18. ^ Welcome to the Women's - The Royal Women's Hospital Victoria Australia
  19. ^ "Nifedipine". The American Society of Health-System Pharmacists. Archived from the original on 25 December 2015. Retrieved 19 December 2015.
  20. ^ Koontz, Stephanie L.; Friedman, Steven A.; Schwartz, Martin L. (June 2004). "Symptomatic hypocalcemia after tocolytic therapy with magnesium sulfate and nifedipine". American Journal of Obstetrics and Gynecology. 190 (6): 1773–1776. doi:10.1016/j.ajog.2004.02.050. ISSN 0002-9378. PMID 15284796.
  21. ^ 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. doi:10.1097/00006254-199703000-00023. ISSN 0029-7828. PMID 9061722.
  22. ^ Hanley, Margaret; Sayres, Lauren; Reiff, Emily S.; Wood, Amber; Grotegut, Chad A.; Kuller, Jeffrey A. (January 2019). "Tocolysis: A Review of the Literature". Obstetrical & Gynecological Survey. 74 (1): 50–55. doi:10.1097/OGX.0000000000000635. ISSN 1533-9866.
  23. ^ Lyndrup, Jens; Lamont, Ronald F (June 2007). "The choice of a tocolytic for the treatment of preterm labor: a critical evaluation of nifedipine versus atosiban". Expert Opinion on Investigational Drugs. 16 (6): 843–853. doi:10.1517/13543784.16.6.843. ISSN 1354-3784.
  24. ^ Flenady, Vicki; Reinebrant, Hanna E; Liley, Helen G; Tambimuttu, Eashan G; Papatsonis, Dimitri NM (6 June 2014). Cochrane Pregnancy and Childbirth Group (ed.). "Oxytocin receptor antagonists for inhibiting preterm labour". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD004452.pub3.
  25. ^ 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. 177 (4): 819–824. doi:10.1016/S0002-9378(97)70275-8.
  26. ^ "Indomethacin Side Effects: Common, Severe, Long Term". Drugs.com. Retrieved 30 July 2021.
  27. ^ Management of high-risk pregnancy : a practical approach. S. S. Trivedi, Manju, MD Puri, Swati Agrawal (Second ed.). New Delhi. 2016. ISBN 978-93-5250-046-8. OCLC 946116669.{{cite book}}: CS1 maint: location missing publisher (link) CS1 maint: others (link)
  28. ^ a b c d 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. doi:10.1002/14651858.CD001060.pub2. PMID 25126773.
  29. ^ a b Simhan HN, Caritis SN (2007). "Prevention of Preterm Delivery". New England Journal of Medicine. 357 (5): 477–487. doi:10.1056/NEJMra050435. PMID 17671256.
  30. ^ Nanda, K; Grimes, DA (2006). "Magnesium sulfate tocolysis: Time to quit". Obstetrics and Gynecology. 108 (4): 986–989. doi:10.1097/01.AOG.0000236445.18265.93. PMID 17012463. S2CID 30014199.
  31. ^ a b c William G. Sayres, Jr (2010). "Preterm Labor". American Family Physician. 81 (4): 477–484. ISSN 0002-838X.
  32. ^ Castrén O, Gummerus M, Saarikoski S (1975). "Treatment of imminent premature labour". Acta Obstet Gynecol Scand. 54 (2): 95–100. doi:10.3109/00016347509156739. PMID 1094787. S2CID 22685586.
  33. ^ a b "Committee opinion no. 496: At-risk drinking and alcohol dependence: obstetric and gynecologic implications". Obstetrics and Gynecology. 118 (2 Pt 1): 383–388. 2011. doi:10.1097/AOG.0b013e31822c9906. ISSN 1873-233X. PMID 21775870.
  34. ^ Iams JD, Romero R, Culhane JF, Goldenberg RL (2008). "Primary, secondary, and tertiary interventions to reduce the morbidity and mortality of preterm birth". The Lancet. 371 (9607): 164–175. doi:10.1016/S0140-6736(08)60108-7. PMID 18191687. S2CID 8204299.
  35. ^ a b 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. doi:10.1136/bmj.e6226. ISSN 0959-8138. PMC 4688428. PMID 23048010.
  36. ^ Kenyon, Sara; Boulvain, Michel; Neilson, James P. (2 December 2013). "Antibiotics for preterm rupture of membranes". The Cochrane Database of Systematic Reviews (12): CD001058. doi:10.1002/14651858.CD001058.pub3. ISSN 1469-493X. PMID 24297389.
  37. ^ a b c d e f g h i j k Wong, Perry, and Hockenberry. Maternal Child Nursing Care. Mosby 2002.
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