Teratogenicity study in rats of commonly used calcium channel blockers
Keywords:CCBs, Teratogenicity, Rats
Background: Calcium channel blockers (CCBs) are popular medicines used to treat hypertension, tachyarrhythmias or angina during pregnancy. Lack of adequate safety data has however created an uncertainty in the use of CCBs in pregnancy. Nifedipine has been reportedly associated with a variety of embryotoxic and fetotoxic effects in animals. Therefore, this study was undertaken to establish whether or not the commonly used CCBs (nifedipine and amlodipine) would produce teratogenic effects in rats.
Methods: Twenty pregnant rats were randomly assigned to each of the treatment and control groups. Nifedipine and amlodipine were used in three dose levels of 5, 10, 20 mg/kg and 0.5, 1, 2 mg/kg body weight respectively to test its teratogenic effects. The maximum dose of the test drugs used in our study was ten times the maximum recommended human dose. The drugs were administered to the pregnant rats using nasogastric tubes from day 6 through day 15 of pregnancy. The number of live births, stillbirths, litter sizes, crown-rump lengths, birth weights and gross abnormalities of the pups delivered were observed and recorded. Skeletal changes and soft tissue changes were also observed in the pups delivered to treated pregnant rats.
Results: It was found that nifedipine and amlodipine did not produce any teratogenic effects in rats at doses 2.5 to 10 times the recommended human dose. None of the pups showed any gross morphological, skeletal or visceral defects.
Conclusions: Nifedipine and amlodipine appear to be safe during pregnancy in therapeutic doses.
Product Monograph Procardia. Nifedipine. Pfizer Products Inc.
Product Monograph Norvasc. Amlodipine besylate. Pfizer Products Inc.
Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 10th ed. Philadelphia: Lippincott Williams and Wilkins; 2015.
Khan K, Zamora J, Lamont RF, Van Geijn H, Svare J, Santos-Jorge C, 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 Maternal Fetal Neonatal Med. 2010;23(9):1030-8.
Sorensen HT, Czeizel AE, Rockenbauer M, Steffensen FH, Olsen J. The risk of limb deficiencies and other congenital abnormalities in children exposed in utero to calcium channel blockers. Acta Obstet Gynecol Scand. 2001;80(5):397-401.
Ministry of Health and Family Welfare. Schedule Y - The Drugs and Cosmetics Acts and Rules, 1945. India: Governmentt of India; 2016.
Animal Welfare Division, Ministry of Environment and Forest, and Climate Change. Compendium of Committee for the Purpose of Control, Supervision of Experiments on Animals. India: Government of India; 2018.
Dawson AB. A note on the staining of the skeleton of cleared specimens with alizarin red S. Stain Technol. 1926;1(4):123-4.
Wilson JG. Experimental studies on congenital malformations. J Chronic Dis. 1959;10(2):111-30.
Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik C, Hernández-Díaz S, et al. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol 2011;205(1):51.
ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019;133(1):e1-e25.
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-20.
Eschenhagen T. Treatment of hypertension. In: Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw-Hill Education; 2018: 507-526.
Koren G. Special Aspects of Perinatal and Pediatric Pharmacology. In: Katzung BG, editor. Basic and Clinical Pharmacology. 14th ed. New York: McGraw-Hill Education; 2018: 1047-1057.
Ridings JE, Palmer AK, Davidson EJ, Baldwin JA. Prenatal toxicity studies in rats and rabbits with the calcium channel blocker diproteverine. Reprod Toxicol. 1996;10(1):43-9.
Richichi J, Vasilenko P. The effects of nifedipine on pregnancy outcome and morphology of the placenta, uterus, and cervix during late pregnancy in the rat. Am J Obstetric Gynecol. 1992;167(3):797-803.
Brucker MC, King TL. The 2015 US Food and Drug Administration pregnancy and lactation labeling rule. J Midwifery Women's Health. 2017;62(3):308-16.
18. Malha L, August P. Safety of antihypertensive medications in pregnancy: living with uncertainty. J Am Heart Assoc. 2019;8(15):e013495.
Kernaghan D, Duncan AC, McKay GA. Hypertension in pregnancy: a review of therapeutic options. Obstetric Med. 2012;5:44-9.
Papatsonis DN, Lok CA, Bos JM, van Geijn HP, Dekker GA. Calcium channel blockers in the management of preterm labor and hypertension in pregnancy. Eur J Obstetrics Gynecol Reprod Biol. 2001;97(2):122-40.
Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B, Cook L, et al. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol. 1996;174(3):823-8.
Houtzager BA, Hogendoorn SM, Papatsonis DN, Samsom JF, Van Geijn HP, Bleker OP, et al. Long‐term follow up of children exposed in utero to nifedipine or ritodrine for the management of preterm labour. BJOG. 2006;113(3):324-31.
Rizzo G, Arduini D, Mancuso S, Romanini C. Effects of nifedipine on umbilical artery velocity waveforms in healthy human fetuses. Gynecol Obstet Invest. 1987;24(3):151-4.
Moretti MM, Fairlie FM, Akl S, Khoury AD, Sibai BM. The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia remote from term. Am J Obstet Gynecol. 1990;163(6):1844-8.
Mito A, Murashima A, Wada Y, Miyasato‐Isoda M, Kamiya CA, Waguri M, et al. Safety of amlodipine in early pregnancy. J Am Heart Assoc. 2019;8(15):e012093.
Davis RL, Eastman D, McPhillips H, Raebel MA, Andrade SE, Smith D, et al. Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta‐blockers during pregnancy. Pharmacoepidemiol Drug Saf. 2011;20(2):138-45.
Weber-Schoendorfer C, Hannemann D, Meister R, Eléfant E, Cuppers-Maarschalkerweerd B, Arnon J, et al. The safety of calcium channel blockers during pregnancy: a prospective, multicenter, observational study. Reprod Toxicol. 2008;26(1):24-30.
Lennestål R, Olausson PO, Källén B. Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants. Eur J Clin Pharmacol. 2009;65(6):615-25.