Calcium channel blockers for inhibiting preterm ... - Wiley Online Library

Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 192– 198

Systematic Review

Blackwell Publishing Ltd.

Nifedipine for preterm labour

Calcium channel blockers for inhibiting preterm labour; a systematic review of the evidence and a protocol for administration of nifedipine James F. KING,1 Vicki FLENADY,2 Dimitri PAPATSONIS,3 Gustaaf DEKKER4 and Bruno CARBONNE5 1

Department of Perinatal Medicine, Royal Women’s Hospital, Melbourne, 2Centre for Clinical Studies,Women’s and Children’s Health, Mater Misericordiae Health Services, Brisbane, 3Consultant Obstetrician and Gynaecologist, Department of Obstetrics and Gynaecology, Amphia Hospital, Breda, The Netherlands, 4Department of Obstetrics and Gynaecology, Lyell McEwin Hospital, University of Adelaide, South Australia, Australia and 5Department of Obstetrics and Gynaecology, Hospital Saint Antoine, Paris, France

Abstract Objective: To assess the effects on maternal, fetal and neonatal outcomes of nifedipine (and other calcium channel blockers) administered as a tocolytic agent to women in preterm labour. Methods: Standard methods of the Cochrane Collaboration and its Pregnancy and Childbirth Review Group were used. All published and unpublished randomised trials in which calcium channel blockers were used for tocolysis for women in preterm labour between 20 and 36 weeks’ gestation, were considered. Main results: The systematic review includes 12 randomised controlled trials with a total of 1029 participating women. No trials were identified in which calcium channel blockers were compared with a placebo or no alternative tocolytic treatment. Calcium channel blockers appear to be more effective than betamimetic agents in prolonging pregnancy for 7 days or longer, are much less likely to cause maternal side-effects and are associated with reduced neonatal morbidity. Conclusion: Calcium channel blockers (especially nifedipine) can be considered safer and more effective tocolytic agents than betamimetics. Key words: Calcium channel blockers, meta-analysis, tocolytic.

Introduction Preterm birth is a major contributor to perinatal mortality and morbidity and affects approximately 6–7 per cent of births in developed countries.1 No progress has been made over the last two decades in reducing the incidence of preterm birth in developed countries but some benefits have been identified from prolongation of pregnancy by enabling corticosteroids to be administered to hasten fetal lung maturation2 and to effect transfer to a centre with neonatal intensive care facilities.3 A range of tocolytic agents has been used to inhibit preterm labour in order to allow time for such cointerventions to occur. The tocolytics which have been most widely tested are the betamimetics ritodrine, salbutamol and terbutaline. Betamimetics have been shown to be effective in delaying delivery by up to 7 days, although no impact has yet been shown on perinatal mortality.4,5 Betamimetics have a high frequency of unpleasant, sometimes severe maternal side-effects including tachycardia, hypotension, tremulousness and a range of biochemical disturbances. Furthermore, betamimetics have been associated with at least 25 192

maternal deaths mainly from pulmonary oedema.6 There is a need therefore for an effective tocolytic agent with less sideeffects than the betamimetics. Calcium channel blockers (CCB) are non-specific smooth muscle relaxants, predominantly used for the treatment of hypertension in adults. They exert their tocolytic effect by preventing the influx of extracellular calcium ions into the myometrial cells. They have been demonstrated in vitro to have potent relaxant effect on human myometrium.7 The most widely used and studied CCB is nifedipine which (like nicardipine) belongs to the dihydropiridine group. Nifedipine was first reported in 1980 in an observational study to be an effective tocolytic agent with minimal side-effects.8 There is anecdotal evidence that nifedipine is gradually replacing betamimetics as the preferred tocolytic agent in clinical practice.

Correspondence: James F. King, Department of Perinatal Medicine, Royal Women’s Hospital, Carlton, Victoria 3053, Australia. Email: [email protected] Received 29 January 2003; accepted 26 February 2003.


Earlier reports from animal studies9 expressed concerns that nifedipine may have adverse effects on the fetal and placental circulation, and although there have been subsequent studies which failed to confirm this,10 it is necessary to review the evidence for the safety and efficacy of this treatment. We conducted a Cochrane systematic review of the randomised controlled trials in which CCB were compared to placebo, no treatment, or an alternative tocolytic treatment.11

Methods We adopted the standard Cochrane methodology for this review.12 We identified all published and unpublished randomised trials in which CCB were used for tocolysis for women in labour between 20 and 36 weeks’ gestation. We prespecified a range of relevant maternal and perinatal outcomes. Additional information was sought to enable assessment of methodology and to conduct intention-to-treat analyses. Analyses were conducted using a fixed effects model, or a random effects model when statistically significant heterogeneity was detected. Statistical heterogeneity between trials was assessed using the χ2 test for heterogeneity. Results are presented using relative risk (RR) for categorical data and weighted mean difference for variables measured on a continuous scale, and include 95% confidence intervals (CI). Results are also expressed using numbers needed to treat (NNT) where appropriate.

Results Thirty-two studies were identified as potentially eligible for inclusion. Eight trials were excluded on methodological grounds and a further 12 studies10,13–21 were unable to be included until additional information is provided by the authors. Therefore, this review includes 12 randomised trials testing the effects of CCB for tocolysis in preterm labour. A total of 1029 women participated in the 12 trials.22–33 There were no placebo controlled trials identified. There were no trials in which a CCB was compared with no tocolytic agent. The 12 included trials all compared results of tocolysis by a CCB (mainly nifedipine) with an alternative tocolytic (mainly ritodrine).

Methodological quality of included studies The included trials were considered to be of reasonable quality. Ten of the included trials reported concealed random allocation to treatment. In two trials the precise method of random allocation to treatment was not described.27,29 Blinding of the intervention was not carried out in any of the included trials, nor was there blinded assessment of outcomes. In the present review, an attempt was made to conduct an intention-to-treat analysis for all outcomes. Although some trials had postrandomisation exclusions, the rate of exclusions was generally low and not considered to be a threat to validity.

Participants The characteristics of the participants included in these trials were clinically similar. The minimum gestational age at inclusion ranged from 20 to 26 weeks, and the maximum from 33.5 to 36 weeks. The mean gestational age at entry, when described, was between 28 and 32 weeks’ gestation. Preterm labour was reasonably consistently defined across the trials, most excluding those women with a cervical dilatation of greater than 4 cm. Four trials included women in preterm labour with ruptured membranes23,26,28,31 and three trials included twin pregnancies.27,29,30 The standard contraindications for tocolysis were reported as exclusion criteria in the majority of included trials; fetal distress, chorioamnionitis, severe pre-eclampsia/eclampsia and abruptio placentae.

Tocolysis regimens Ten trials compared oral nifedipine with other tocolytic agents.22–26,28,29,31–33 Eight of these trials used ritodrine as the other tocolytic. Initial tocolytic therapy with nifedipine was administered orally or sublingually, as either capsules or tablets (whole, or crushed and dissolved in water). Dosage varied from 30 mg/day to 160 mg/day until uterine contractions stopped. The largest trial used a higher dose of nifedipine than most of the included trials (up to 40 mg in the first hour).31 All 10 trials continued oral nifedipine after the initial treatment but three did not report the total duration of treatment.22–24 Ritodrine was usually started at 50 µg/min. Two trials used nicardipine as the CCB, one trial compared intravenous nicardipine with salbutamol27 and the other oral nicardipine with magnesium sulphate.30 Most trials used oral maintenance in both treatment groups until 34–37 weeks’ gestation.

Maternal outcomes When compared with any other tocolytic agent, the use of CCB resulted in a statistically significant decrease in the number of women giving birth within 7 days of initiation of treatment (RR, 0.76; 95% CI 0.60, 0.97) (Fig. 1) and prior to 34 weeks’ gestation (RR, 0.83; 95% CI 0.69, 0.99) (Fig. 2). The NNT for benefit for the outcome of birth within 7 days is 11 (95% CI 6, 100). This means that, on average, for every 11 women treated with CCB instead of any other tocolytic drug, one less birth occurs within this time period. Maternal adverse drug reaction was reduced with CCB (RR, 0.32; 95% CI 0.24, 0.41) and cessation of treatment for maternal drug reaction was markedly reduced (RR, 0.14; 95% CI 0.05, 0.36) (Fig. 3). The NNT for benefit against maternal adverse drug reaction was three (95% CI 3, 4) and for drug reaction requiring cessation of treatment was 14 (95% CI 10, 25). A trend toward superior tocolytic benefit was apparent in the outcomes of birth prior to 37 weeks’ gestation (RR, 0.95; 95% CI 0.83, 1.09), within 48 h of initiation of treatment (RR, 0.80; 95% CI 0.61, 1.05) and for pregnancy prolongation (interval from treatment to delivery) (weighted mean difference (WMD) 3.83 days; 95% CI −3.04, 10.70). For the outcome of pregnancy prolongation, a


193

J. F. King et al.

Figure 1 Birth within 7 days of treatment. CI, confidence interval; RR, relative risk.

Figure 2 Birth prior to 34 weeks’ gestation. CI, confidence interval; RR, relative risk.

random effects model was used in the meta-analysis due to statistical heterogeneity.

Neonatal outcomes When compared with any other tocolytic agent, the use of CCB resulted in a statistically significant increase in gestation at birth (WMD 0.70 week; 95% CI 0.19, 1.20), and a reduction in neonatal respiratory distress syndrome (RDS) (RR, 0.63; 95% CI 0.46, 0.88) (Fig. 4), necrotising enterocolitis (RR, 0.21; 95% CI 0.05, 0.96) and intraventricular haemorrhage (RR, 0.59; 95% CI 0.36, 0.98) and admissions to a neonatal intensive care unit (NICU) (RR, 0.78; 95% CI 0.64, 0.95). The risk reduction for the outcome of RDS gives a NNT for benefit of 14 (95% CI 8, 50) and for intraventricular haemorrhage 13 (95% CI 7, 100). Less neonatal jaundice was also shown for infants of 194

women receiving CCB (RR, 0.73; 95% CI 0.57, 0.93). No statistically significant differences were shown in the outcomes of birthweight, admissions to neonatal intensive care unit, Apgar score < seven at 5 min, neonatal sepsis, or perinatal mortality. A number of clinically important outcomes were unable to be adequately assessed due to insufficient data, including fetal growth restriction which might be increased in the circumstance where delivery is suppressed by tocolytic treatment and the fetus retained in a possibly adverse intrauterine environment.

Discussion Based on the data included in this review, CCB are shown to be a more effective tocolytic agent than betamimetics (less births



Figure 3 Maternal adverse drug reaction requiring cessation of treatment. CI, confidence interval; RR, relative risk.

Figure 4 Respiratory distress syndrome. CI, confidence interval; RR, relative risk.

within 7 days of initiation of treatment and before 34 weeks’ gestation) with improvement in some clinically important neonatal outcomes (less RDS, intraventricular haemorrhage, necrotising enterocolitis, jaundice and admissions to NICU) and a marked reduction in adverse maternal side-effects.

There is a substantial amount of evidence from controlled trials (a further 12 trials) in which CCB have been compared to betamimetic agents, for which the data were not available in a format which allowed inclusion in the present review. However, in reviewing the information currently available


195

J. F. King et al.

NIFEDIPINE Nifedipine has been shown to be more effective than betamimetics (salbutamol, ritodrine, terbutaline) in prolonging pregnancy in the setting of preterm labour, with significantly fewer maternal side-effects. There is also evidence of improved neonatal outcomes with nifedipine compared to betamimetics. Nifedipine is therefore the drug of choice for use as a tocolytic.

Note: The combined cardiovascular effects of nifedipine and intravenous betamimetics are substantial. The two agents should not be used together under any circumstances. INDICATIONS Suppression of threatened or established preterm labour, in the absence of a contraindication to its use.

CONTRAINDICATIONS Suppression of labour is generally not indicated for: • • • • • • •

Gestation >34 weeks Fetal death-in-utero Fetal malformation where palliative care only is planned Suspected fetal compromise as determined by ultrasound or CTG warranting delivery Placental abruption Chorioamnionitis Pre-eclampsia

Contraindications to the use of nifedipine: • • • • • • •

Allergy to nifedipine Significant maternal cardiac disease Hypotension Hepatic dysfunction Concurrent use of IV betamimetics Concurrent use of transdermal nitrates (GTN) or antihypertensive medication Nifedipine and MgSO4: If women on high dose nifedipine (160 mg /day) require concomitant Rx with MgSO4, there is a risk of significant hypotension with the conventional 4– 6 g I/ V bolus. This risk is reduced by using a continuous infusion of MgSO4 1 g/ h. DOSAGE 20 mg orally stat followed by 20 mg orally after 30 min if contractions persist followed by 20 mg orally after 30 min if contractions persist followed by 20 mg orally 3–8 hourly for 48–72 h as indicated.

Note: Maximum dose is 160 mg/day. After 72 h if maintenance therapy is required, patients can be changed over to Adalat OROS (long acting) 30– 60 mg orally per day. In contrast to betamimetics, nifedipine does not induce tachyphylaxis, so maintenance therapy may be prescribed. SIDE-EFFECTS • • • • • • • •

Hypotension In normotensive patients the effects of nifedipine on blood pressure are minimal Care must be exercised in hypertensive patients, where blood pressure changes may be significant If significant hypotension occurs, treatment should be discontinued. IV rehydration with normal saline or Hartmann’s may be considered Tachycardia, palpitations Flushing Headaches, dizziness Nausea OBSERVATIONS

• • • • •

Continuous CTG while contracting 4 hourly temperatures 1/2 hourly pulse and blood pressure for the first hour, then Second hourly pulse and blood pressure for the first 24 h, then 4 hourly observations

Figure 5. Tocolysis for preterm labour using nifedipine. CTG, cardiotocography; GTN, glyceryl trinitate; IV, intravenous; MgSO4, magnesium sulfate.

196



from these trials awaiting assessment, it does not appear that as a group, their results differ substantially or systematically from the trials included in the present review. This supports the conclusion that CCB should be preferred over betamimetics for those women who are considered likely to benefit from tocolytic treatment. An important clinical aspect to tocolysis, particularly if maternal transport to a tertiary centre is being planned, is speed of onset of action. Because in most of the trials of CCB the medication was administered as an oral preparation, and in the trials of betamimetics the agents were administered intravenously, there is the possibility that betamimetics might have a more rapid onset of action enabling a more expeditious transfer with less risk of delivery prior to arrival at the referral centre. Two trials assessed uterine quiescence at 2 h as an index of successful tocolysis, and no statistically significant difference was seen between the two agents.26,32

Protocol for administration of nifedipine for tocolysis Because nifedipine is not licensed for use as a tocolytic agent, it is recommended that institutions develop specific protocols for administration, including consideration of issues surrounding consent. A clinical protocol for administering nifedipine for tocolysis based on existing protocols in several Australian teaching hospitals is offered as a prototype (Fig. 5).

7

8

9

10 11

12

13

14

15

16

Acknowledgement We wish to thank Drs JA Garcia-Velasco, JE Ferguson, E Janky, CAM Koks, M Kupferminc, J Morrison, V Cararach, and A Chittacharoen who provided additional information for this review. We also thank Katie Welsh for assistance in the compilation of the manuscript.

References 1 Lumley J. Epidemiology of preterm birth. Balliere’s Clin Obstet 2

3

4

5

6

Gynaecol. 1993; 7: 477 – 498. Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review). In: The Cochrane Library, Issue 4. Oxford: Update Software, 2002. Powell SL, Holt VL, Hickok DE, Easterling T, Connell FA. Recent changes in delivery site of low-birth-weight infants in Washington: Impact on birth weight-specific mortality. Am J Obstet Gynecol. 1995; 173: 1585 – 1592. King JF, Grant A, Keirse MJ, Chalmers I. Beta-mimetics in preterm labour: an overview of the randomized controlled trials. Br J Obstet Gynaecol. 1988; 95: 211– 222. Gyetvai K, Hannah M, Hodnett ED, Ohlsson A. Tocolysis for preterm labor: a systematic review. Obstet Gynecol. 1999; 94: 869 – 877. Papatsonis DN, Lok CA, Bos JM, Geijn HP, Dekker GA. Calcium channel blockers in the management of preterm labor

17

18

19

20 21 22

23

24

25

and hypertension in pregnancy. Eur J Obstet Gynecol Reprod Biol. 2001; 97: 122–140. Saade GR, Taskin O, Belfort MA, Erturan B, Moise KJ Jr. In vitro comparison of four tocolytic agents, alone and in combination. Obstet Gynecol. 1994; 84: 374–378. Ulmsten U, Andersson KE, Wingerup L. Treatment of premature labor with the calcium antagonist nifedipine. Arch Gynecol. 1980; 229: 1–5. Harake B, Gilbert RD, Ashwal S, Power GG. Nifedipine: Effects on fetal and maternal haemodynamics in pregnant sheep. Am J Obstet Gynecol. 1987; 157: 1003–1008. Meyer WR, Randall HW, Graves WL. Nifedipine vs. ritodrine for suppressing preterm labor. J Reprod Med. 1990; 35: 649–653. King JF, Flenady VJ, Papatsonis DNM, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour (Cochrane Review). In: The Cochrane Library, Issue 1. Oxford: Update Software, 2003. Clarke M, Oxman AD (eds). Cochrane Reviewers’ Handbook 411 [updated October 2001]. In: Review Manager (Revman) [Computer Program], Version 4.1. Oxford: The Cochrane Collaboration, 2001. Carr DB, Clark AL, Kernek K, Spinnato JA. Maintenance oral nifedipine for preterm labor: a randomised clinical trial. Am J Obstet Gynecol. 1999; 181: 822–827. El-Sayed YY, Holbrook RH Jr, Gibson R, Chitkara U, Druzin ML, Baba D. Diltiazem for maintenance tocolysis of preterm labor: comparison to nifedipine in a randomized trial. J Matern Fetal Med. 1998; 7: 217–221. Kose D, Karaosmanoglu S, Yeniguc CT, Yucesoy I, Ozben C, Baysal C. Efficacy and safety of nifedipine in the management of preterm labor. Jinekoloji ve Obstetrik Dergisi. 1995; 9: 164 –170. Rodriguez-Escudero FJ, Aranguren G, Benito JA. Verapamil to inhibit the cardiovascular side effects of ritodrine. Int J Gynecol Obstet. 1981; 19: 333–336. Smith CS, Woodland MB. Clinical comparison of oral nifedipine and subcutaneous terbutaline for initial tocolysis. Am J Perinatol. 1993; 10: 280–284. Breart G, Sureau C, Rumeau-Rouquette C. A study of the comparative efficiency of ifenprodil and ritodrine in the treatment of threatening premature labour [translation, in French]. J Gynecol Obstet Biol Reprod (Paris). 1979; 8: 261–263. Dubay P, Singhal D, Bhagoliwal A, Mishra AS. Assessment of new borns of mothers treated with nifedipine and isoxsuprine. J Obstet Gynecol India. 1992; 42: 778 – 780. Haghighi L. Prevention of preterm delivery: nifedipine or magnesium sulfate. Int J Gynecol Obstet. 1999; 66: 297 – 298. Roy UK, Pan S. Use of calcium antagonist (nifedipine) in premature labour. J Indian Med Assoc. 1993; 91: 8 – 10. Bracero LA, Leikin E, Kirshenbaum N, Tejani N. Comparison of nifedipine and ritodrine for the treatment of preterm labor. Am J Perinatol. 1991; 8: 365–369. Ferguson JE 2nd, Dyson DC, Schutz T, Stevenson DK. A comparison of tocolysis with nifedipine or ritodrine: analysis of efficacy and maternal, fetal, and neonatal outcome. Am J Obstet Gynecol. 1990; 163: 105 –111. Garcia-Velasco JA, Gonzalez Gonzalez A. A prospective, randomized trial of nifedipine vs. ritodrine in threatened preterm labor. Int J Gynaecol Obstet. 1998; 61: 239 – 244. Glock JL, Morales WJ. Efficacy and safety of nifedipine vs. magnesium sulfate in the management of preterm labor: a randomized study. Am J Obstet Gynecol. 1993; 169: 960 – 964.


197

J. F. King et al.

26 Janky E, Leng JJ, Cormier PH, Salamon R, Meynard J. A

30 Larmon J, Ross B, May W, Dickerson G, Fischer R, Morrison

randomized study of the treatment of threatened premature labor. Nifedipine versus ritodrine. J Gynecol Obstet Biol Reprod (Paris). 1990; 19: 478 – 482. 27 Jannet D, Abankwa A, Guyard B, Carbonne B, Marpeau L, Milliez J. Nicardipine versus salbutamol in the treatment of premature labor. A prospective randomized study. Eur J Obstet Gynecol Reprod Biol. 1997; 73: 11–16. 28 Koks CA, Brolmann HA, de Kleine MJ, Manger PA. A randomized comparison of nifedipine and ritodrine for suppression of preterm labor. Eur J Obstet Gynecol Reprod Biol. 1998; 77: 171 – 176. 29 Kupferminc M, Lessing JB, Yaron Y, Peyser MR. Nifedipine versus ritodrine for suppression of preterm labour. Br J Obstet Gynaecol. 1993; 100: 1090 –1094.

JC. Oral nicardipine versus intravenous magnesium sulfate for the treatment of pretem labor. Am J Obstet Gynecol. 1999; 181: 1432 – 1437. 31 Papatsonis DN, Van Geijn HP, Ader HJ, Lange FM, Bleker OP, Dekker GA. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol. 1997; 90: 230 – 234. 32 Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br J Obstet Gynaecol. 1986; 93: 933 – 937. 33 Weerakul W, Chittacharoen A, Suthutvoravut S. Nifedipine versus terbutaline in management of preterm labor. Int J Gynecol Obstet. 2002; 76: 311 – 313.

198
