Nifedipine trials: effectiveness and safety aspects

Professor Herman P. van Geijn
Department of Obstetrics and Gynaecology
Vrije Universiteit Medical Center, Amsterdam, The Netherlands

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Biography
Professor Herman van Geijn trained in Obstetrics and Gynaecology at the University of Nijmegen, The Netherlands. He then moved to Columbus, Ohio, USA, for a Fellowship in Maternal-Fetal Medicine at the Ohio State University. In 1980, he joined the Department of Obstetrics and Gynaecology at the Vrije Universiteit Medical Center (VUMC), Amsterdam. Since then, he has fulfilled various positions. Currently he is Head of the Department of Obstetrics and Gynaecology and Director of the Residency Training Programme. He is a also a member of the Dutch Society of Obstetrics and Gynaecology, the FIGO study group – Assessment of New Technologies in Obstetrics and Gynaecology - and on the Board of the International Society – The Fetus as a Patient. For 10 years, he was the Project Leader of European Concerted Actions on Fetal Surveillance. His research interests include perinatal medicine, fetal surveillance, preterm delivery and maternal vascular diseases and stress. He has published over 160 papers in international peer-review journals and a substantial number of book chapters. 

Abstract
Nifedipine (Adalat®) is marketed as an antihypertensive agent. It inhibits voltage dependent L-type calcium channels, which lead to vascular (and other) smooth muscle relaxation and negative inotropic and chronotropic effects in the heart. Vasodilatation followed by a baroreceptor-mediated increase in sympathetic tone then results in indirect cardio-stimulation¹.

Nifedipine was introduced as a tocolytic agent at a time when beta-agonists and magnesium sulphate dominated the arena for the prevention of preterm birth. The oral administration route, the availability of slow-release preparations, the low incidence of (mild) side effects and its limited cost explain the attraction to this medication from the obstetric field and, therefore, its rapid and widespread distribution.

Currently, over 40 studies have been published on nifedipine’s tocolytic effectiveness^2,3, including five meta-analyses⁴. The quality of the studies suffered particularly from performance bias since the majority of the trials failed to ensure blinding to treatment, both for providers and patients. Concerns about other methodological flaws include measurement, outcome assessment and attrition bias. In particular, the safety aspects of nifedipine for tocolysis have been under-assessed. The conclusion from the meta-analyses, favouring the use of nifedipine as a tocolytic agent, is not supported by solid data.

One should realise that the tocolytic effectiveness and safety of nifedipine has been primarily assessed in normal pregnancies. Based on its pharmacological properties, one should be cautious when administering nifedipine when the maternal cardiovascular condition is potentially compromised, such as intrauterine infection, twin pregnancy, maternal hypertension, cardiac disease, etc. Life-threatening pulmonary oedema and/or cardiac failure are definite risks and have been recently reported^5-7. Under such circumstances, the baroreceptor-mediated increase in sympathetic tone potentially cannot balance the cardiac depressant activity of nifedipine.

References

1. Scholz H. Pharmacologic aspects of calcium channel blockers. Cardiovasc Drugs Ther 1997; 10: 869–72.
2. Papatsonis DN, Kok JH, van Geijn HP, Bleker OP, Ader HJ, Dekker GA. Neonatal effects of nifedipine and ritodrine for preterm labor. Obstet Gynecol 2000; 95: 477–81.
3. 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: 230–34.
4. King JF, Flenady VJ, Papatsonis DN, Dekker GA, Cardonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev 2003; The Cochrane Library, Issue 3: Oxford Update Software.
5. Vaast P, Dubreucq-Fossaert S, Houfflin-Debarge V, et al. Acute pulmonary oedema during nicardipine therapy for premature labour: report of five cases. Eur J Obstet Gynecol Reprod Biol 2004;113:98–99.
6. Hodges R, Barkehall-Thomas A, Tippett C. Maternal hypoxia with nifedipine for threatened preterm labour. Br J Obstet Gynaecol 2004;111:380–381.
7. Verhaert D, Van Acker R. Acute myocardial infarction during pregnancy. Acta Cardiol 2004;59:331–339.