Calcium Channel Blocker
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Nimodipine is teratogenic and toxic in experimental animals. However, human data early in gestation are insufficient to assess the risk to the embryo or fetus. Only a few of the 10 calcium channel blockers have any human data on exposure during early gestation. Based on this very limited information, these agents do not appear to be major human teratogens. However, more information is required before any conclusion can be reached as to the potential teratogenic risk of these agents.
FETAL RISK SUMMARY
Nimodipine is a dihydropyridine calcium channel blocker used to reduce the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage after rupture of congenital aneurysms. Nimodipine shares similar hemodynamic effects with other calcium channel blockers, but does not usually produce a marked lowering of blood pressure. In clinical studies involving nonpregnant patients, only about 5% of the subjects experienced a marked lowering of blood pressure (1).
In studies with male and female rats, nimodipine had no effect on fertility or reproductive performance at doses up to about four times the equivalent human dose of 60 mg every 4 hours in a 50-kg patient (EHD) (1). Reproduction studies have been conducted in rats and rabbits. Nimodipine was teratogenic in rabbits, producing an increase in the incidence of malformations and stunted fetuses at oral doses of 1–10 mg/kg/day (1). In rats, nimodipine dosing during organogenesis was embryotoxic, causing resorptions and stunted fetal growth, but except for skeletal variations, caused no malformations (1). The dose used in rats was about 12 times the EHD. Oral doses about 4 times the EHD administered late in organogenesis and continued to nearly the end of gestation or for 21 days after delivery were associated with an increase in skeletal variations, stunted fetuses, and stillbirths but no malformations (1).
The placental transfer of nimodipine early in human gestation has apparently not been studied. Consistent with its molecular weight (about 418), nimodipine crosses the human placenta at term.
An abstract and later full report described the use of nimodipine for the management of preeclampsia (2,3). Ten women at about 38 weeks’ gestation with preeclampsia were treated with nimodipine, 30 mg orally every 4 hours. Delivery occurred within 24 hours of starting nimodipine and continued for 24 hours after delivery. Both systolic and diastolic blood pressures were significantly reduced after nimodipine administration without evidence of fetal distress. At delivery, the median nimodipine concentrations in the maternal and umbilical cord serum were 7.32 and 2.6 ng/mL, respectively (fetal:maternal ratio 0.36). In four patients who were delivered by cesarean section within 2 hours of the first dose, the maternal and cord serum levels were 9.68 and 3.46 ng/mL, respectively (fetal:maternal ratio 0.36). The median Apgar scores were 8 (range 6–10) and 9 (range 8–10) at 1 and 5 minutes, respectively. No adverse effects of the drug treatment were observed in the newborns and all were doing well at 6-week follow-up (3). One newborn was excluded from the above data because the mother suffered a ruptured uterus. Although severely depressed at birth (Apgar scores 1 and 5 at 1 and 5 minutes, respectively), the infant was successfully resuscitated and was developing normally at 6 weeks of age (3).
A prospective, multicenter, cohort study of 78 women (81 outcomes; 3 sets of twins) who had 1st trimester exposure to calcium channel blockers, including 11% to nimodipine, was reported in 1996 (4). Compared with controls, the women experienced no increase in major congenital malformations.
Nimodipine also has been used for its cerebral vasodilator characteristics in the treatment of eclampsia complicated by cerebral vasospasm and edema (5–7). In the first two cases, delivery of the fetus had occurred before initiation of therapy (5,6). The use of nimodipine in combination with magnesium sulfate was not recommended because of the risk for maternal heart block (6). In the third report, seizures in four pregnant patients were halted with IV clonazepam (average dose 3 mg, range 1–5 mg), followed by IV nimodipine (1 mg/hr for 20 minutes, then 2 mg/hr) to control blood pressure (mean dose 1.83 mg) (7). The four liveborn infants were delivered by cesarean section once maternal blood pressure was controlled. The mean birth weight was 1822 g (range 1460–2800 g). Individual Apgar scores were not provided, but two infants had 5-minute Apgar scores <7. One mother died of severe postpartum complications, and another developed multiorgan disease secondary to severe preeclampsia/eclampsia (7).
A 1998 abstract described an ongoing international, multicenter, randomized, controlled trial comparing the effects of nimodipine and magnesium sulfate in the prevention of eclampsia (8). Another study involving 21 women with severe preeclampsia compared oral nimodipine with IV magnesium sulfate for the prevention of seizures (9). Neither report provided data on newborns.
Maternal hypotension caused by nimodipine is a potential, but yet unreported, complication that could jeopardize the fetus. An in vitro study has examined the potential use of nimodipine as a tocolytic agent (10). Thus, additional data on the potential for nimodipine-induced maternal hypotension may be forthcoming.
BREASTFEEDING SUMMARY
Nimodipine is excreted into breast milk. In a 1996 case report, a 36-year-old woman at 3 weeks postpartum experienced a transient clinical syndrome of paresthesias (arm and face) associated with motor dysphasia (11). The symptoms resolved, but perioral dysesthesia and motor dysphasia recurred after cerebral angiography. Because the symptoms were thought possibly to be vascular spasm secondary to angiographic examination, the woman was treated with IV nimodipine (formulation not available in the United States). Over a 24-hour interval, she received a total dose of 46 mg (1 mg/hr for 2 hours, then 2 mg/hr). Milk samples were collected (50–60 mL/collection) by the patient every 3–4 hours during nimodipine therapy and blood samples were drawn about every 6 hours. The infant was not allowed to nurse during this period. Nimodipine milk concentrations ranged from 0.42 ng/mL (0.5 hours) to 4.70 ng/mL (26 hours; 2 hours after the infusion ended), whereas the maternal serum concentrations ranged from 3.54 to 10.83 ng/mL. The milk:serum ratios at 0.5, 7.5, and 13.5 hours were 0.12, 0.06, and 0.15, respectively. Assuming a milk intake of 150 mL/kg/day, the authors estimated that the infant would have received 0.008% to 0.092% of the mother’s weight-adjusted dose. This exposure was thought to be clinically insignificant (11).
References
1.Product information. Nimotop. Bayer, 2002.
2.Belfort M, Saade G, Cruz A, Adam K, Kirshon B, Kramer W, Moise K Jr. Nimodipine as an alternative to magnesium sulfate in the management of severe preeclampsia: maternal and fetal effects (abstract). Am J Obstet Gynecol 1994;170:412.
3.Belfort MA, Saade GR, Moise KJ Jr, Cruz A, Adam K, Kramer W, Kirshon B. Nimodipine in the management of preeclampsia: maternal and fetal effects. Am J Obstet Gynecol 1994;171:417–24.
4.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;174:823–8.
5.Horn EH, Filshie M, Kerslake RW, Jaspan T, Worthington BS, Rubin PC. Widespread cerebral ischaemia treated with nimodipine in a patient with eclampsia. Br Med J 1990;301:794.
6.Belfort MA, Carpenter RJ Jr, Kirshon B, Saade GR, Moise KJ Jr. The use of nimodipine in a patient with eclampsia: color flow Doppler demonstration of retinal artery relaxation. Am J Obstet Gynecol 1993;169:204–6.
7.Anthony J, Mantel G, Johanson R, Dommisse J. The haemodynamic and respiratory effects of intravenous nimodipine used in the treatment of eclampsia. Br J Obstet Gynaecol 1996;103:518–22.
8.Belfort M, Anthony J, Saade G and the Nimodipine Study Group. Interim report of the nimodipine vs. magnesium sulfate for seizure prophylaxis in severe preeclampsia study: an international, randomized, controlled trial (abstract). Am J Obstet Gynecol 1998;178:S7.
9.Belfort MA, Saade GR, Yared M, Grunewald C, Herd JA, Varner MA, Nisell H. Change in estimated cerebral perfusion pressure after treatment with nimodipine or magnesium sulfate in patients with preeclampsia. Am J Obstet Gynecol 1999;181:402–7.
10.Kaya T, Cetin A, Cetin M, Sarioglu Y. Effects of endothelin-1 and calcium channel blockers on contractions in human myometrium. A study on myometrial strips from normal and diabetic pregnant women. J Reprod Med 1999;44:115–21.
11.Carcas AJ, Abad-Santos F, de Rosendo JM, Frias J. Nimodipine transfer into human breast milk and cerebrospinal fluid. Ann Pharmacother 1996;30:148–50.