Share to: share facebook share twitter share wa share telegram print page

 

Tocolytic

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"). 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.[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]

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] 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 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.[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

References

  1. ^ a b c American College of Obstetricians Gynecologists' Committee on Practice Bulletins—Obstetrics (2016). "Practice Bulletin No. 171: Management of Preterm Labor". Obstetrics & Gynecology. 128 (4): e155–e164. doi:10.1097/AOG.0000000000001711. ISSN 0029-7844. PMID 27661654. S2CID 5537988.
  2. ^ Mayer, Christopher; Apodaca-Ramos, Irasema (2021), "Tocolysis", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32965883, retrieved 29 July 2021
  3. ^ Ouzounian, Joseph G; Goodwin, T. Murphy; Paulson, Richard J; Montoro, Martin N; Muderspach, Laila I; Roy, Subir (2010). Management of Common Problems in Obstetrics and Gynecology. Blackwell Publishing Ltd. pp. 9–11. ISBN 9781444323030.
  4. ^ Harrison, Margo S.; Goldenberg, Robert L. (2016). "Global burden of prematurity". Seminars in Fetal & Neonatal Medicine. 21 (2): 74–79. doi:10.1016/j.siny.2015.12.007. ISSN 1878-0946. PMID 26740166.
  5. ^ a b 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. doi:10.1097/OGX.0000000000000635. ISSN 1533-9866. PMID 30648727. S2CID 58563849.
  6. ^ 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.
  7. ^ 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.
  8. ^ a b 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 (10 August 2022). "Tocolytics for delaying preterm birth: a network meta-analysis (0924)". Cochrane Database of Systematic Reviews. 2022 (8): CD014978. doi:10.1002/14651858.CD014978.pub2. PMC 9364967. PMID 35947046.
  9. ^ Why do doctors still use terbutaline to delay preterm labor despite its major health risks? Retrieved on October 20th, 2020
  10. ^ Gyetvai, K.; Hannah, M. E.; Hodnett, E. D.; Ohlsson, A. (1999). "Tocolytics for preterm labor: A systematic review". Obstetrics and Gynecology. 94 (5 Pt 2): 869–877. doi:10.1016/s0029-7844(99)00329-4. PMID 10546776.
  11. ^ 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. Bibcode:2012PLoSO...731679G. doi:10.1371/journal.pone.0031679. ISSN 1932-6203. PMC 3283660. PMID 22363704.
  12. ^ "Drugs@FDA: FDA-Approved Drugs". www.accessdata.fda.gov.
  13. ^ Pool, Beverly A. Von Der (1998). "Preterm Labor: Diagnosis and Treatment". American Family Physician. 57 (10): 2457–2464. ISSN 0002-838X. PMID 9614414.
  14. ^ a b Modak, Raj K. (2013). Anesthesiology Keywords Review. Lippincott Williams & Wilkins. ISBN 978-1-4511-7782-4.
  15. ^ "Fenoterol drug information | DrugsUpdate India". www.drugsupdate.com. Retrieved 2 August 2021.
  16. ^ 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. PMC 10603219. PMID 24500892.
  17. ^ 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. doi:10.1080/14767058.2016.1249844. ISSN 1476-4954. PMID 27756155. S2CID 6900277.
  18. ^ 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)
  19. ^ 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. PMID 11336775.
  20. ^ Johnson, Donavon B.; Merrell, Brigham J.; Bounds, Connor G. (2021), "Albuterol", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 29489143, retrieved 2 August 2021
  21. ^ 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.
  22. ^ 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. S2CID 89620227.
  23. ^ "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.
  24. ^ 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.
  25. ^ Welcome to the Women's – The Royal Women's Hospital Victoria Australia
  26. ^ "Nifedipine Monograph for Professionals - Drugs.com". 2015. Archived from the original on 25 December 2015.
  27. ^ 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. doi:10.1016/j.ajog.2004.02.050. ISSN 0002-9378. PMID 15284796.
  28. ^ 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.
  29. ^ 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. 16 (6): 843–853. doi:10.1517/13543784.16.6.843. ISSN 1354-3784. PMID 17501696. S2CID 1012738.
  30. ^ Flenady, Vicki; Reinebrant, Hanna E; Liley, Helen G; Tambimuttu, Eashan G; Papatsonis, Dimitri NM (2014). Cochrane Pregnancy and Childbirth Group (ed.). "Oxytocin receptor antagonists for inhibiting preterm labour". Cochrane Database of Systematic Reviews (6): CD004452. doi:10.1002/14651858.CD004452.pub3. PMC 11086629. PMID 24903678.
  31. ^ Neilson, J. P. (2007). "Oxytocin Receptor Antagonists for Inhibiting Preterm Labour". Obstetrics & Gynecology. 110 (1): 180–181. doi:10.1097/01.AOG.0000269669.34758.4e. ISSN 0029-7844. PMID 17601917. S2CID 35984198.
  32. ^ a b Tsatsaris, Vassilis; Carbonne, Bruno; Cabrol, Dominique (2004). "Atosiban for Preterm Labour". Drugs. 64 (4): 375–382. doi:10.2165/00003495-200464040-00003. ISSN 0012-6667. PMID 14969573. S2CID 946463.
  33. ^ 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. PMID 9369826.
  34. ^ a b 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. doi:10.1016/s1521-6934(03)00047-6. ISSN 1521-6934. PMID 12972011.
  35. ^ "Indomethacin Side Effects: Common, Severe, Long Term". Drugs.com. Retrieved 30 July 2021.
  36. ^ 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)
  37. ^ 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. doi:10.1016/0002-9378(95)90163-9. ISSN 0002-9378. PMID 7631682.
  38. ^ Stevenson, Donald D. (2004). "Aspirin and NSAID sensitivity". Immunology and Allergy Clinics of North America. 24 (3): 491–505, vii. doi:10.1016/j.iac.2004.03.001. ISSN 0889-8561. PMID 15242723.
  39. ^ 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 (1 December 2012). "Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project)". Drug Safety. 35 (12): 1127–1146. doi:10.2165/11633470-000000000-00000. ISSN 1179-1942. PMC 3714137. PMID 23137151.
  40. ^ a b 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. PMC 10838393. PMID 25126773.
  41. ^ a b c d e f Rundell, Kristen; Panchal, Bethany (2017). "Preterm Labor: Prevention and Management". American Family Physician. 95 (6): 366–372. ISSN 0002-838X. PMID 28318214.
  42. ^ a b c William G. Sayres, Jr (2010). "Preterm Labor". American Family Physician. 81 (4): 477–484. ISSN 0002-838X. PMID 20148502.
  43. ^ 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.
  44. ^ 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. S2CID 205474115.
  45. ^ 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.
  46. ^ 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: e6226. doi:10.1136/bmj.e6226. ISSN 0959-8138. PMC 4688428. PMID 23048010.
  47. ^ Simhan HN, Caritis SN (2007). "Prevention of Preterm Delivery". New England Journal of Medicine. 357 (5): 477–487. doi:10.1056/NEJMra050435. PMID 17671256.
  48. ^ 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. PMC 11297390. PMID 24297389.
  49. ^ a b c d e f g h i j k Wong, D. L.; Perry, S. E.; Hockenberry, M. J.; Lowdermilk, D. L. (2002). Maternal Child Nursing Care. Mosby. ISBN 978-0-323-01399-4.
  50. ^ Hubinont, C.; Debieve, F. (2011). "Prevention of Preterm Labour: 2011 Update on Tocolysis". Journal of Pregnancy. 2011: 941057. doi:10.1155/2011/941057. ISSN 2090-2727. PMC 3228310. PMID 22175022.
  51. ^ Cole, Stephen; Smith, Roger; Giles, Warwick (2004). "Tocolysis: current controversies, future directions". Current Opinion in Investigational Drugs. 5 (4): 424–429. ISSN 1472-4472. PMID 15134284.
Kembali kehalaman sebelumnya