Nifedipine

 Risk Factor: CM
 Class: CARDIOVASCULAR DRUGS / Calcium Channel Blockers

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

The use of nifedipine, a calcium channel-blocking agent, during pregnancy is controversial. Studies in pregnant sheep with IV infusions of the drug indicate that a progressive decrease in mean maternal arterial blood pressure occurs without a significant alteration of uterine vascular resistance (1). The hypotensive effect of nifedipine resulted in a decrease in uterine blood flow and fetal arterial oxygen content. Other investigators have reported similar results in animals with other calcium channel blockers (2). Although these studies indicated the potential problems with nifedipine, the investigators cautioned that their findings were preliminary and needed to be confirmed in humans (1,3).

Reproduction studies with nifedipine have been conducted in mice, rats, and rabbits (4). The drug was teratogenic (digital anomalies similar to those reported with phenytoin) in rats and rabbits, an effect that might have resulted from compromised uterine blood flow. Other toxicities were noted in the embryos and fetuses of mice, rats, and rabbits at doses 3.5 to 42 times the maximum recommended human dose (MRHD) on a weight basis, or doses higher or lower than the MRHD on a mg/m2 basis (4). These toxicities included stunted fetuses (mice, rats, rabbits), rib deformities (mice), cleft palate (mice), embryo and fetal deaths (mice, rats, rabbits), and prolonged pregnancy and decreased neonatal survival (rats; not evaluated in other species) (4). Small placentas and underdeveloped chorionic villi were observed in monkeys at doses equivalent to or less than the MRHD on a mg/m2 basis (4).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 37 newborns had been exposed to nifedipine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Two (5.4%) major birth defects were observed (two expected), one of which was a cardiovascular defect (0.5 expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.

A human study was reported in 1988 in which nine hypertensive pregnant women in the 3rd trimester were treated with 5 mg of nifedipine sublingually and compared with nine hypertensive women treated with placebo (5). The women were randomly assigned to the two groups but treatment was not blinded. Both maternal arterial blood pressure and uterine artery perfusion pressure were significantly lowered by nifedipine, but no apparent reduction in uteroplacental blood flow was detected. The investigators interpreted their findings as suggestive of a relative uterine vasodilation and a relative decrease in uterine vascular resistance that was proportional to the decrease in blood pressure.

Nifedipine has been used during the 2nd and 3rd trimesters for the treatment of severe hypertension (6). No fetal heart rate changes were observed after reduction of maternal blood pressure, nor were other adverse effects noted in the fetus or newborn. In a 1987 study, 23 women with severe hypertension of various causes (4 gestational, 17 essential, 1 renal, and 1 systemic lupus erythematosus) who either failed to respond to first-line therapy (atenolol, methyldopa, or hydralazine) had slow-release nifedipine, 40120 mg/day, added to their regimens (N=22) or nifedipine, 40 mg/day, was used as initial therapy (N=1) (7). Good blood pressure control was obtained in 20 women. The mean duration of therapy was 8.75 weeks (range 124 weeks). There were three perinatal deaths (rate 130/1000), but none could be attributed to drug therapy. The mean gestational age at delivery was 35 weeks (range 2939 weeks), and 15 (71%) of the 21 liveborn infants were delivered by cesarean section. A high percentage of the 22 infants with accessible data were growth retarded, 9 (41%) had birth weights at or below the 3rd percentile, and 20 (91%) were at or below the 10th percentile for body weight. The investigators could not determine whether this outcome was caused by the severe maternal disease, drug therapy, or a combination of both (7).

Nifedipine has been used as a tocolytic agent. An in vitro study using pregnant human myometrium found that nifedipine caused a dose-related decrease in contraction strength and lengthened the period of contraction in a nondose-related manner (8). In three studies totaling 31 women, nifedipine was used for this purpose (9,10 and 11) . In one patient, nifedipine, 20 mg 3 times daily combined with terbutaline, was given for a total of 55 days (10). A study involving 60 women in presumed early labor was reported in 1986 (11). Women were included in this open trial if they had a singleton pregnancy and intact membranes, were between 20 and 35 weeks' gestation, and were contracting at least once every 10 minutes, and if their cervix was less than 4 cm dilated. Included among the various exclusions were a history of midtrimester abortion or previous preterm delivery. The women were equally divided into three groups: nifedipine, ritodrine, and no treatment. Nifedipine dosage was 30 mg orally followed by 20 mg every 8 hours for 3 days. Ritodrine was initially administered as a standard IV infusion followed by 48 hours of oral therapy. The days from presentation to delivery in the nifedipine, ritodrine, and no treatment groups were 36.3, 25.1, and 19.3 days (p<0.001 nifedipine compared with the other two groups), respectively (11). No complications of the therapy were found in any of the infants from the three studies. Two of the studies (9,10) conducted follow-up examinations of the infants at 512 months of age and all were alive and well.

Two apparently clinically significant drug interactions when nifedipine and magnesium were used concurrently have been reported (12,13). A woman, at 32 weeks' gestation in premature labor, was treated with 60 mg of nifedipine orally for 3 hours followed by 20 mg every 8 hours. Uterine contractions returned 12 hours later and IV magnesium sulfate was started followed by the onset of pronounced muscle weakness after 500 mg had been administered. Her symptoms consisted of jerky movements of the extremities, difficulty in swallowing, paradoxical respirations, and an inability to raise her head from the pillow (12). The muscle weakness resolved 25 minutes after the magnesium was stopped. The effects were attributed to nifedipine potentiation of the neuromuscular blocking action of magnesium. In a second report, two women were hospitalized for hypertension at 30 and 32 weeks' gestation (13). In both cases, oral methyldopa 2 g and IV magnesium sulfate 20 g daily were ineffective in lowering the mother's blood pressure. Oral nifedipine 10 mg was given, and a marked hypotensive response occurred 45 minutes later. The blood pressures before nifedipine were 150/110 and 140/105 mm Hg, respectively, then decreased to 80/50 and 90/60 mm Hg, respectively, after administration of the calcium channel blocker. The blood pressures returned to the previous levels 2530 minutes later. Both infants were delivered following the hypotensive episodes, but only one survived.

The pharmacokinetics of nifedipine in pregnant women have been studied (14).

A prospective, multicenter cohort study of 78 women (81 outcomes; 3 sets of twins) who had 1st-trimester exposure to calcium channel blockers, including 44% to nifedipine, was reported in 1996 (15). Compared with controls, no increase in the risk of major congenital malformations was found.

In summary, the experience with nifedipine in human pregnancy is limited, although the agent has been used for tocolysis and as an antihypertensive agent in pregnant women. The agent does not appear to be a major human teratogen based on the results of one study. Severe adverse reactions, however, have occurred when the drug was combined with IV magnesium sulfate. Moreover, IV nifedipine in pregnant rhesus monkeys has been associated with fetal hypoxemia and acidosis (16). As a consequence of this and other animal studies, nifedipine should probably be reserved for women with severe hypertension who are unresponsive to standard therapy or in controlled trials until this toxicity has been studied more carefully.

Breast Feeding Summary

Nifedipine is excreted into human breast milk (17). A woman with persistent hypertension after premature delivery at 26 weeks' gestation was treated with nifedipine 30 mg every 8 hours for 48 hours, then 20 mg every 8 hours for 48 hours, then 10 mg every 8 hours for 36 hours. Concentrations of the drug in milk were related to dosage and the time interval between the dose and milk collection. Peak concentrations and time of occurrence were 53.35 ng/mL 30 minutes after 30 mg, 16.35 ng/mL 1 hour after 20 mg, and 12.89 ng/mL 30 minutes after 10 mg. The estimated milk half-lives after the three doses were 2.4 hours (30 mg), 3.1 hours (20 mg), and 1.4 hours (10 mg). In comparison with controls, nifedipine had no effect on milk composition. The authors concluded that these amounts, representing less than 5% of a therapeutic dose, posed little risk to a nursing infant. If desired, delaying breast feeding by 34 hours after a dose would significantly decrease the amount of drug ingested by the infant (17). The American Academy of Pediatrics considers nifedipine to be compatible with breast feeding (18).

References

1. Harake B, Gilbert RD, Ashwal S, Power GG. Nifedipine: effects on fetal and maternal hemodynamics in pregnant sheep. Am J Obstet Gynecol 1987;157:10038.
2. Holbrook RH Jr. Effects of calcium antagonists during pregnancy. Am J Obstet Gynecol 1989;160:1018.
3. Gilbert RD. Effects of calcium antagonists during pregnancy (reply). Am J Obstet Gynecol 1989;160:10189.
4. Product information. Procardia. Pfizer, 2000.
5. Lindow SW, Davies N, Davey DA, Smith JA. The effect of sublingual nifedipine on uteroplacental blood flow in hypertensive pregnancy. Br J Obstet Gynaecol 1988;95:127681.
6. Walters BNJ, Redman CWG. Treatment of severe pregnancy-associated hypertension with the calcium antagonist nifedipine. Br J Obstet Gynaecol 1984;91:3306.
7. Constantine G, Beevers DG, Reynolds AL, Luesley DM. Nifedipine as a second line antihypertensive drug in pregnancy. Br J Obstet Gynaecol 1987;94;113642.
8. Bird LM, Anderson NC Jr, Chandler ML, Young RC. The effects of aminophylline and nifedipine on contractility of isolated pregnant human myometrium. Am J Obstet Gynecol 1987;157:1717.
9. Ulmsten U, Andersson K-E, Wingerup L. Treatment of premature labor with the calcium antagonist nifedipine. Arch Gynecol 1980;229:15.
10. Kaul AF, Osathanondh R, Safon LE, Frigoletto FD Jr, Friedman PA. The management of preterm labor with the calcium channel-blocking agent nifedipine combined with the b-mimetic terbutaline. Drug Intell Clin Pharm 1985;19:36971.
11. Read MD, Wellby DE. The use of a calcium antagonist (nifedipine) to suppress preterm labour. Br J Obstet Gynaecol 1986;93:9337.
12. Snyder SW, Cardwell MS. Neuromuscular blockade with magnesium sulfate and nifedipine. Am J Obstet Gynecol 1989;161:356.
13. Waisman GD, Mayorga LM, Camera MI, Vignolo CA, Martinotti A. Magnesium plus nifedipine: potentiation of hypotensive effect in preeclampsia? Am J Obstet Gynecol 1988;159:3089.
14. O'Neill S, Osathanondh R, Kaul AF, Scavone JM, Bromley BS, Malin MA. The pharmacokinetics of nifedipine in pregnant women (abstract). Drug Intell Clin Pharm 1986;20:4601.
15. Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B, Cook L, McElhatton PR, Schmidt MA, Koren G. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol 1996;174:8238.
16. Ducsay CA, Cook MJ, Veille JC, Novy MJ. Nifedipine tocolysis in pregnant rhesus monkeys: maternal and fetal cardiorespiratory effects. Abstract No. 79, Society of Perinatal Obstetricians Annual Meeting, Las Vegas, Nevada, February, 1985.
17. Ehrenkranz RA, Ackerman BA, Hulse JD. Nifedipine transfer into human milk. J Pediatr 1989;114:47880.
18. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.