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National Women’s Health Clinical Guideline / Recommended Best Practice Note: The electronic version of this guideline is the version currently in use. Any printed version can not be assumed to be current. Please remember to read our disclaimer. NIFEDIPINE TOCOLYSIS • • • Background Drug Protocol Monitoring • • Nifedipine Tocolysis Flowchart References Purpose The purpose of this document is to outline background information and protocol supporting the use of Nifedipine for women with pre term labour Scope Medical and midwifery staff in Women’s Assessment Unit, Labour & Birthing Suite/ Ward 96/98. Developed by: Authorised by: Nifedipine Tocolysis Clinical Director Maternal Fetal Med Clinical Director O&G Classification: Date Issued: NMP200/SSM/041 Updated October 2009 Page: 1 of 7 Background Why Nifedipine? Spontaneous preterm birth (<37 weeks) occurs in 5% of pregnancies in New Zealand (New Zealand mothers and babies HFA report), accounting for two thirds of normally formed perinatal deaths and is the leading cause of admission to neonatal intensive care units (Lockwood et al. 1999). Preterm labour is multifactorial and can result from a range of pathologies, eg infection, bleeding, multiple pregnancy. However in many cases there is no clinically obvious cause. If there is no reason to expedite the delivery and the gestation is <34 weeks, then current management is to administer a tocolytic drug to delay delivery while corticosteroids are given for lung maturation. Corticosteroids significantly reduce neonatal morbidity and mortality but take 48 hours to achieve the maximum effect (Liggins et al. 1972). Acute tocolytic treatment should be discontinued 48 hours after the first dose of steriods as the primary objective of acute tocolysis is not to prolong gestation, but prevent delivery until the corticosteroids can take effect. A number of tocolytics have been used for maintenance tocolysis (betamimetics, magnesium sulphate, prostaglandin synthetase inhibitors and oxytocin antagonists) (Sanchez-Ramos et al. 1999). None of these have been shown to be useful and all have significant side effects. Furthermore, these agents need to given intravenously (atosiban) or have the potential to cause maternal (betamimetics, magnesium sulphate) or fetal (indomethacin) side effects. Nifedipine is a calcium-channel blocker, which is administered orally with very few side effects. Evidence Nifedipine has been shown to be more effective for acute tocolysis when compared to the most commonly used agents- betamimetics (Papatonis et al. 1997). It is the only tocolytic yet described which has been reported to reduce neonatal morbidity (Papatonis et al. 2000). A recent metaanalysis (Tsatsaris et al. 2001) showed that nifedipine was more effective than betamimetics in delaying delivery at least 48 hours [OR 1.52, 95% CI 1.03-2.24], and was more likely to prolong pregnancy beyond 34 weeks [OR 1.87, 95% CI 1.11-3.15]. Treatment with nifedipine was associated with reduced neonatal respiratory distress syndrome [OR 0.57, 95% CI 0.37-0.89] and fewer admissions to neonatal intensive care [OR 0.65, 95% CI 0.43-0.97]. Nifedipine is the only tocolytic to date which has shown a benefit for the neonate. The authors of the meta-analysis concluded “nifedipine appears to be more effective than beta agonists for tocolysis, improves neonatal outcome and should be considered for use as a first-line tocolytic agent” (Tsatsaris et al. 2001). Side effects associated with nifedipine were uncommon and mild, including transient facial flushing and mild headache. Treatment was much less likely to be interrupted due to side effects with nifedipine [OR 0.12, 95% CI 0.05-0.29] compared to a betamimetic (Tsatsaris et al. 2001). To evaluate safety of nifedipine, Ferguson and colleagues conducted a randomised study of nifedipine versus ritodrine (Ferguson et al. 1989). They found that the cardiovascular and metabolic effects of nifedipine were minimal, unlike ritodrine (a betamimetic). Nifedipine is commonly used in pregnancy for the treatment of pre-eclampsia (elevated blood pressure), but normotensive women on nifedipine have a minimal drop in blood pressure. Developed by: Authorised by: Nifedipine Tocolysis Clinical Director Maternal Fetal Med Clinical Director O&G Classification: Date Issued: NMP200/SSM/041 Updated October 2009 Page: 2 of 7 Drug Protocol Trade Name Nyefax Retard Mechanism of Action Calcium Channel Blocker Indications Acute Tocolysis Threatened preterm labour at less than 34 weeks where the clinician decides tocolysis is warranted to achieve steroid administration. Indications Acute Tocolysis Threatened preterm labour at less than 34 weeks where the clinician decides tocolysis is warranted to achieve steroid administration. Contraindications / Indications for Tocolysis Maternal Absolute: • Suspected intrauterine infection • Suspected placental abruption • Hypotension • Shock • Previous allergic response to Nifedipine Relative: Use of a ß-blocker (risk hypotension) Use of magnesium sulfate (risk hypotension) • • Fetal: • Congenital anomalies of the fetus incompatible with normal life • Severe fetal growth restriction • Gestational age >34 weeks • Abnormal CTG Possible Adverse Effects The most common side effects are: transient palpitations (0-6%), headaches (5-6%), and facial flushing (5-18%) (Ferguson et al. 1990; Kupferminc et al. 1993). Other less common side effects are: constipation, dizziness, nausea, tachycardia, fatigue, peripheral edema, and increased liver enzymes. Liver enzyme changes are not a concern with such limited use, but care should be taken in those with known liver disease Maximum Dose 160mg Nyefax Retard in 24 hours. Continued on next page Developed by: Authorised by: Nifedipine Tocolysis Clinical Director Maternal Fetal Med Clinical Director O&G Classification: Date Issued: NMP200/SSM/041 Updated October 2009 Page: 3 of 7 Drug Protocol, Continued Dose & Administration Initially 10mg orally (2x Nifedipine 5mg capsules) every 15 mins, up to 4 doses of Nifedipine to stop contractions. After this slow release nifedipine. It has been found that an 8 hourly dosage of 40mg – 20mg – 40mg Nyefax Retard is suitable for most women. On occasions a higher dose may be required up to the maximum below. Maximum nifedipine sustained release scheme: 60mg – 40mg 60mg Nyefax Retard. Minimum nifedipine sustained release scheme: 20mg – 20mg 20mg Nyefax Retard. The Nyefax Retard should be discontinued 24 hours after the last steroid dose. There is no data supporting continued use. Resource People Developed by: Authorised by: Nifedipine Tocolysis Dr Emma Parry, Associate Professor Lesley McCowan, Professor Peter Stone for further information and advice. Clinical Director Maternal Fetal Med Clinical Director O&G Classification: Date Issued: NMP200/SSM/041 Updated October 2009 Page: 4 of 7 Monitoring Maternal Pulse, blood pressure and temperature on admission. A speculum examination should be performed and swabs taken for infection and fetal fibronectin testing where indicated and available. If membranes are intact and cervix has not been visualized sufficiently; a digital examination should also be performed to check cervical dilatation. During the first hour, pulse and blood pressure should be checked every 30 minutes. After the first hour, pulse, blood pressure and temperature should be checked every hour for 2 hours, then QID if the uterine activity is diminishing. Once stable the woman can be transferred to the A/N ward. Fetal Baseline CTG must be normal before commencement of therapy. Also monitor with a CTG at the commencement of treatment. This should be continuous for the first hour at least and until contractions cease. CTG monitoring should then continue as clinically indicated. If there is a change in the clinical situation e.g. increase in maternal temperature or pulse rate or return/ increase in contractions, then CTG monitoring should be recommenced. Changing From Salbutamol to Nifedipine If a woman has already commenced salbutamol tocolysis, then the infusion should be stopped. Usual observations for salbutamol use should be continued until the maternal pulse drops below 100. At this stage the nifedipine protocol can commence with the 10mg quick release tablets as above if the woman is still contracting or a standard slow release protocol of 40-20-40mg if she is not. Observations & Documentation Please see flow chart below. Developed by: Authorised by: Nifedipine Tocolysis Clinical Director Maternal Fetal Med Clinical Director O&G Classification: Date Issued: NMP200/SSM/041 Updated October 2009 Page: 5 of 7 Nifedipine Tocolysis Flowchart Developed by: Authorised by: Nifedipine Tocolysis Clinical Director Maternal Fetal Med Clinical Director O&G Classification: Date Issued: NMP200/SSM/041 Updated October 2009 Page: 6 of 7 References • • • • • • • • • • Carr, D. B., A. L. Clark, K. Kernek and J. A. Spinnato (1999). “Maintenance oral nifedipine for preterm labor: A randomized clinical trial.” American Journal of Obstetrics and Gyneology 181: 822-827. Ferguson, J. E., M. D. Dyson, R. H. Holbrook, T. Schutz and D. K. Stevenson (1989). “Cardiovascular and metabolic effects associated with nifedipine and ritodrine tocolysis.” American Journal of Obstetrics and Gyneology 161: 788-795. Ferguson, J. E., M. D. Dyson, T. Schutz and D. K. Stevenson (1990). “A comparison of tocolysis with nifedipine or ritodrine: Analysis of efficacy and maternal, fetal, and neonatal outcome.” American Journal of Obstetrics and Gyneology 163: 105-111. Kupferminc, M., J. B. Lessing, Y. Yaron and M. R. Peyser (1993). “Nifedipine versus ritodrine for suppression of preterm labour.” British Journal of Obstetrics and Gynaecology 100: 10901094. Liggins, G. C. and R. N. Howie (1972). “A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants.” Pediatrics 50: 515525. Lockwood, C. J. and E. Kuczynski (1999). “Markers of risk for preterm delivery.” Journal of Perinatal Medicine 27(1): 5-20. Papatonis, D. N. M., J. H. Kok, H. P. Van Geijn, O. P. Bleker, H. J. Ader and G. A. Dekker (2000). “Neonatal effects of nifedipine and ritodrine for preterm labor.” Obstetrics & Gynecology 95(95): 477-481. Papatonis, D. N. M., H. P. Van Geijn, H. J. Ader, F. M. Lange, O. P. Bleker and G. A. Dekker (1997). “Nifedipine and Ritodrine in the Management of Preterm Labor: A Randomized Multicenter Trial.” Obstetrics & Gynecology 90(2): 230-234. Sanchez-Ramos, L., A. M. Kaunitz, F. L. Gaudier and L. Delke (1999). “Efficacy of maintenance therapy after acute tocolysis: A meta-analysis.” American Journal of Obstetrics and Gyneology 181: 484-490. Tsatsaris, V., D. Papatsonis, F. Goffinet, G. Dekker and B. Carbonne (2001). “Tocolysis with nifedipine or beta-adrenergic agonists: a meta-analysis.” Obstetrics and Gynecology 97: 840847 Developed by: Authorised by: Nifedipine Tocolysis Clinical Director Maternal Fetal Med Clinical Director O&G Classification: Date Issued: NMP200/SSM/041 Updated October 2009 Page: 7 of 7