Acute Tocolysis – a Critical Analysis of Evidence-Based Data

Abstract

Tocolysis is among the most common obstetric measures. The objective is to prolong the pregnancy by at least 48 hours to complete foetal lung maturation and for the in-utero transfer of the pregnant woman to a perinatal centre. The indication for tocolysis is regular, premature contractions (≥ 4/20 min) and a dynamic shortening of the cervical length/cervical opening between 22 + 0 to 33 + 6 weeks of pregnancy. In this connection, the cervical length measured on ultrasound and the determination of biomarkers in the cervicovaginal secretions can be important decision-making aids. Beta sympathomimetics should no longer be used due to the high rate of severe maternal adverse effects. Given controversial data, magnesium sulphate is no longer recommended for tocolysis in current guidelines. Atosiban is as effective for prolonging pregnancy as beta sympathomimetics and nifedipine, has the lowest rate of maternal adverse effects, but also the highest drug costs. Nifedipine and indomethacin are recommended in international guidelines for acute tocolysis, however there are indications of increased neonatal morbidity following indomethacin. Current problems are, above all, the lack of randomised, controlled comparative and placebo-controlled studies, the data which are controversial to some extent, and the insufficient evidence of tocolytics to significantly improve the neonatal outcome.

Key words

preterm contractions - tocolysis - indication and objectives - tocolytics - evidence - safety profile

• References/Literatur

• 1 De Renzo GC, Roura LC, Facchinetti F. et al. Preterm labor and birth management: Recommendations from the European Association of Perinatal Medicine. J Matern Fetal Neonatal Med 2017; 30: 2011-2030
• 2 IQTIG. Institut für Qualitätssicherung und Transparenz im Gesundheitswesen 2018. Basisauswertung zum Erfassungsjahr 2017: Geburtshilfe. Online: https://iqtig.org/downloads/auswertung/2017/16n1gebh/QSKH_16n1-GEBH_2017_BUAW_V02_2018-08-01.pdf last access: 01.08.2018
• 3 ACOG. Practice Bulletin No. 171. Management of preterm labour. Obstet Gynecol 2016; 128: e155-e164
• 4 Hackney DN, Olson-Chen C, Thomberg LL. What do we know above the natural outcomes of preterm labour? A systematic review and meta-analysis of women without tocolysis in preterm labour. Paediatr Perinat Epidemiol 2013; 27: 452-460
• 5 Nijman TAJ, van Vliet EOG, Koullali B. et al. Antepartum and intrapartum interventions to prevent preterm birth and its sequelae. Semin Fetal Neonatal Med 2016; 21: 121-128
• 6 Onderoglu LS. Digital examination and transperineal ultrasonographic measurement of cervical length to assess risk of preterm delivery. Int J Gynaecol Obstet 1997; 59: 223-228
• 7 Gomez R, Romero R, Medina L. et al. Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes. Am J Obstet Gynecol 2005; 192: 350-359
• 8 Melchor JC, Khalil A, Wing D. et al. Prediction of preterm delivery in symptomatic women using PAMG-1, fetal fibronectin and phIGFBP-1 tests: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2018;
• 9 De Franco EA, Lewis DF, Odibo AO. Improving the screening accuracy for preterm labour: is the combination of fetal fibronectin and cervical length in symptomatic patients a useful predictor of preterm birth? A systematic review. Am J Obstet Gynecol 2013; 208: 233.e1-233.e6
• 10 van Baaren GJ, Vis JY, Wilms FF. et al. Predictive value of cervical length measurement and fibronectin testing in threatened preterm labor. Obstet Gynecol 2014; 123: 1185-1192
• 11 Vis JY, van Baaren GJ, Wilms FF. et al. Randomized comparison of Nifedipine and placebo in fibronectin-negative women with symptoms of preterm labor and a short cervix (APOSTEL-I Trial). Am J Perinatol 2015; 32: 451-460
• 12 van Baaren GJ, Vis JY, Grobman WA. et al. Cost-effectiveness analysis of cervical length measurement and fibronectin testing in women with threatened labor. Am J Obstet Gynecol 2013; 209: 436.e1-436.e8
• 13 Lange TS, Roos C, Bloemenkamp KW. et al. Impact of a randomized trial on maintenance tocolysis on length of hospital admission of women with threatened preterm labor in the Netherlands. Eur J Obstet Gynecol Reprod Biol 2015; 186: 8-11
• 14 Berghella V, Saccone G. Fetal fibronectin testing for prevention of preterm birth in singleton pregnancies with threatened preterm labor: a systematic review and metaanalysis of randomized controlled trials. Am J Obstet Gynecol 2016; 215: 431-438
• 15 Son M, Miller ES. Predicting preterm birth: Cervical length and fetal fibronectin. Semin Perinatol 2017; 41: 445-451
• 16 McIntosh J, Feltovich H, Berghella V. et al. Society for Maternal-Fetal Medicine (SMFM). The role of routine cervical length screening in selected high- and low-risk women with preterm birth prevention. Am J Obstet Gynecol 2016; 215: B2-B7
• 17 Navathe R, Berghella V. Tocolysis for acute preterm labour: Where have we been, where are we now, and where are we going?. Am J Perinatol 2016; 33: 229-235
• 18 NICE. Preterm labour and birth. NICE guideline [NG25]. 2015. Online: http://www.nice.org.uk/guidance/ng25 last access: 31.03.2018
• 19 Kiefer DG, Vintzileos AM. The utility of fetal fibronectin in the prediction and prevention of spontaneous preterm births. Rev Obstet Gynaecol 2008; 1: 106-112
• 20 Gyetvai K, Hannah ME, Hodnett ED. et al. Tocolytics for preterm labor: a systematic review. Obstet Gynecol 1999; 94: 869-877
• 21 Anotayanonth S, Subhedar NV, Neilson JP, Harigopal S. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2004; (04) CD004352
• 22 Sentilhes L, Sénat MV, Ancel PY. et al. Prevention of spontaneous preterm birth: Guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol 2017; 210: 217-224
• 23 RCOG. Green-top Guideline No. 1b. Tocolysis for women in preterm labour. 02/2011 Online: http://www.wisdom.wales.nhs.uk/opendoc/296835 last access: 31.03.2018
• 24 Vogel JP, Oladapo OT, Manu A. et al. New WHO recommendations to improve the outcomes of preterm birth. Lancet Glob Health 2015; 3: e589-e590
• 25 Haas DM, Imperiale TF, Kirkpatrick PR. et al. Tocolytic therapy: a meta-analysis and decision analysis. Obstet Gynecol 2009; 113: 585-594
• 26 Haas DM, Caldwell DM, Kirkpatrick PR. et al. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ 2012; 345: e6226
• 27 Neilson JP, West HM, Dowswell T. Betamimetics for inhibiting preterm labour. Cochrane Database Syst Rev 2014; (02) CD004352
• 28 Petousis S, Margioula-Sierkon M, Kalogeannidis I. Effectiveness of tocolytic agents on prevention of preterm delivery, neonatal morbidity, and mortality: Is there a consensus? A Review of the literature. Obstet Gynecol Surv 2016; 71: 243-252
• 29 Yamasmit W, Chaithongwongwatthana S, Tolosa JE. et al. Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy. Cochrane Database Syst Rev 2012; (09) CD004733 doi:10.1002/14651858.CD004733
• 30 Dodd JM, Crowther CA, Middleton P. Oral betamimetics for maintenance therapy after threatened preterm labour. Cochrane Database Syst Rev 2012; (12) CD003927 doi:10.1002/14651858.CD003927
• 31 de Heus R, Mol BW, Erwich JJ. et al. Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study. BMJ 2009; 338: b744
• 32 Besinger RE, Jannucci TA. Tocolytic Therapy. In: Elder MG, Lamont RF, Romero R. eds. Preterm Labor. New York: Churchill Livingstone; 1997: 243-297
• 33 Herzog S, Cunze T, Martin M. et al. Pulsatile vs. continuous parenteral tocolysis: comparison of side effects. Eur J Obstet Gynecol Reprod Biol 1999; 85: 199-206
• 34 Conde-Agudelo A, Romero R. Transdermal nitroglycerin for the treatment of preterm labour: a systematic review and meta-analysis. Am J Obstet Gynecol 2013; 209: 551.e1-551.e18
• 35 Duckitt K, Thornton S, OʼDonnovan OP. et al. Nitric oxide donors for treating preterm labour. Cochrane Database Syst Rev 2014; (05) CD002860
• 36 Reinebrant HE, Pileggi-Castro C, Romero CLT. et al. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev 2015; (06) CD001992
• 37 Gordon MC, Samuels P. Indomethacin. Clin Obstet Gynecol 1995; 38: 697-711
• 38 Hendricks SK, Smith JR, Moore DE. et al. Oligohydramnios associated with prostaglandin synthetase inhibitors in preterm labour. Br J Obstet Gynaecol 1990; 97: 312-318
• 39 Sandrock JC, Grobman WA, Garbour SE. The effect of short-term indomethacin therapy on amniotic fluid volume. Am J Obstet Gynecol 2005; 192: 1443-1445
• 40 King J, Flenady V, Cole S. et al. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev 2005; (02) CD001992
• 41 Loe SM, Sanchez-Ramos L, Kaunitz AM. Assessing the neonatal safety of indomethacin tocolysis. A systematic review with meta-analysis. Obstet Gynecol 2005; 106: 173-179
• 42 Hammers AL, Sanchez-Romero L, Kaunitz AM. Antenatal exposure to indomethacin increased the risk of severe intraventricular haemorrhage, necrotizing enterocolitis, and periventricular leukomalacia: a systematic review with metaanalysis. Am J Obstet Gynecol 2015; 212: 505.e1-505.e13
• 43 Crowther CA, Brown J, McKinlay CJD. et al. Magnesium sulphate for preventing preterm birth in threatened labour. Cochrane Database Syst Rev 2014; (08) CD001060
• 44 Klauser CK, Briery CM, Keiser SD. et al. Effect of antenatal tocolytics on neonatal outcome. J Matern Fetal Neonatal Med 2012; 25: 2778-2781
• 45 Haram K, Mortensen JHS, Morrison JC. Tocolysis for acute preterm labor: does anything work. J Matern Fetal Neonatal Med 2015; 28: 371-378
• 46 Lewis DF. Magnesium sulfate: the first-line tocolytic. Obstet Gynecol Clin North Am 2005; 113: 485-500
• 47 Lyell DJ, Pullen K, Campbell L. et al. Magnesium sulphate compared with Nifedipine for acute tocolysis of preterm labor. Obstet Gynecol 2007; 110: 61-67
• 48 Xiao C, Gangal M, Abenhaim HA. Effect of magnesium sulfate and nifedipine on the risk of developing pulmonary edema in preterm births. J Perinatal Med 2014; 42: 585-588
• 49 McNamara HC, Crowther CA, Brown J. Different treatment regimens of magnesium sulphate for tocolysis in women in preterm labour. Cochrane Database Syst Rev 2015; (12) CD011200
• 50 Elliott JP, Lewis DF, Morrison JC. et al. In defense of magnesium sulfate. Obstet Gynecol 2009; 113: 1341-1348
• 51 Committee Opinion No. 652. Summary: Magnesium sulfate use in obstetrics. Obstet Gynecol 2016; 127: 195
• 52 Mercer BM, Merlino AA. for the Society for Maternal-Fetal Medicine. Magnesium sulfate for preterm labour and preterm birth. Obstet Gynecol 2009; 114: 650-667
• 53 Tsatsaris V, Carbonne B, Cabrol D. Atosiban for preterm labour. Drugs 2004; 64: 375-382
• 54 Flenady V, Reinebrant HE, Lieley HG. et al. Oxytocin receptor antagonists for inhibiting preterm labour. Cochrane Database Syst Rev 2014; (06) CD004452
• 55 Nonnenmacher A, Hopp H, Dudenhausen J. Wirksamkeit und Sicherheit von Atosiban vs. pulsatiler Applikation von Fenoterol bei der Behandlung vorzeitiger Wehen. Z Geburtsh Neonatol 2009; 213: 201-206
• 56 van Vliet EOG, Boormans EM, de Lange TS. et al. Preterm labor: current pharmacotherapy options to tocolysis. Expert Opin Pharmacother 2014; 15: 787-797
• 57 van Vliet EOG, Nijman TAJ, Schuit E. et al. Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): a multicentre, randomised controlled trial. Lancet 2016; 387: 2117-2124
• 58 van Veen AJ, Pelinek MJ, van Pampus MG. et al. Severe hypotension and fetal death due to tocolysis with Nifedipine. BJOG 2005; 112: 509-510
• 59 Papatsonis DN, Carbonne B, Dekker GH. et al. Severe hypotension and fetal death due to tocolysis with nifedipine. BJOG 2005; 112: 582-583
• 60 Stones W. Nifedipine for tocolysis. Lancet Glob Health 2016; 4: e24
• 61 Impey L. Severe hypotension and fetal distress following sublingual administration of nifedipine to a patient with severe pregnancy induced hypertension at 33 weeks. BJOG 1993; 100: 959-961
• 62 Khan K, Zamora J, Lamont RF. et al. Safety concerns for the use of calcium channel blockers in pregnancy for the treatment of spontaneous preterm labour and hypertension: a systematic review and meta-regression analysis. J Matern Fetal Neonatal Med 2010; 23: 1020-1038
• 63 Oei SG. Calcium channel blockers for tocolysis: A review of their role and safety following reports of serious adverse events. Eur J Obstet Gynecol Reprod Biol 2006; 126: 137-145
• 64 Lima MM, Souza ASR, Diniz C. et al. Doppler velocimetry of the uterine, umbilical and fetal cerebral arteries in pregnant women undergoing tocolysis with oral nifedipine. Ultrasound Obstet Gynecol 2009; 34: 311-315
• 65 Houtzager BA, Hogendoorn SM, Papatsonis DN. et al. Long-term follow up of children exposed in utero to nifedipine or ritodrine for the management of preterm labour. BJOG 2006; 113: 324-331
• 66 Conde-Agudelo A, Romero R, Kusanovic JP. Nifedipine in the management of preterm labor: a systematic review and metaanalysis. Am J Obstet Gynecol 2011; 204: 134.e1-134.e20
• 67 Flenady V, Wojcieszek AM, Papatsonis DNM. et al. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev 2014; (06) CD002255