Risk Factor: CM
Class: Autonomics/ Skeletal muscle relaxants
Fetal Risk Summary
In obstetrics, the only documented use of dantrolene, a hydantoin derivative used as a direct-acting skeletal muscle relaxant, is to prevent or treat malignant hyperthermia. The syndrome of malignant hyperthermia is a potentially lethal complication of anesthesia induced with halogenated anesthetics and depolarizing skeletal muscle relaxants. References describing the use of dantrolene in pregnant patients for chronic spasticity or during the 1st or 2nd trimesters have not been located. The agent is embryocidal in animals and, in some species, produced minor skeletal variations at the highest dose tested (1,2 and 3).
Three studies have described the transfer of dantrolene across the human placenta to the fetus with cord:maternal serum ratios of 0.290.69 (4,5 and 6). Two women, who were considered to be malignant hyperthermia susceptible (MHS), were treated with oral doses of the drug prior to cesarean section (4). One woman received 100 mg twice daily for 3 days prior to elective induction of labor. The second patient received 150 mg on admission in labor and a second dose of 100 mg six hours later. Both women were delivered by cesarean section because of failure to progress in labor. Neither were exposed to malignant hyperthermia-triggering agents and neither developed the complication. The cord and maternal blood concentrations in the two cases were 0.40 and 1.38 g/mL (ratio 0.29), and 1.39 and 2.70 g/mL (ratio 0.51), respectively. The timing of the doses in relationship to delivery was not specified by the author. No adverse effects of the drug exposure were noted in the infants.
A second report described the prophylactic use of dantrolene, administered as a 1-hour IV infusion (2.2 mg/kg) 7.5 hours prior to vaginal delivery, under epidural anesthesia, of a healthy, vigorous infant (5). The mother had been confirmed to be MHS by previous muscle biopsy. At the time of delivery, the cord and maternal blood dantrolene concentrations were 2.1 and 4.3 g/mL, respectively, a ratio of 0.48. The mother did not experience malignant hyperthermia. No respiratory depression or muscle weakness was noted in the newborn.
A study published in 1988 treated 20 pregnant women diagnosed as MHS with oral dantrolene, 100 mg/day, for 5 days prior to delivery and for 3 days following delivery (6). Three of the patients were delivered by cesarean section. Known anesthetic malignant hyperthermia-triggering agents were avoided and no cases of the syndrome were observed. All fetuses had reactive nonstress tests and normal biophysical profiles before and after the onset of dantrolene administration. The mean maternal predelivery dantrolene serum concentration was 0.99 g/mL compared to a mean cord blood level of 0.68 g/mL, a ratio of 0.69. The mean serum half-life of dantrolene in the newborns was 20 hours (6). Extensive neonatal testing up to 3 days after delivery failed to discover any adverse effects of the drug.
Prophylactic dantrolene, 600 mg given as escalating oral doses over 3 days, was administered to a woman with biopsy-proven MHS 3 days prior to a repeat cesarean section (7). The woman had experienced malignant hyperthermia during her first cesarean section but did not during this surgery. No adverse effects were noted in the newborn.
Although no dantrolene-induced complications have been observed in fetuses or newborns exposed to the drug shortly before birth, some investigators do not recommend prophylactic use of the agent because safety in pregnancy has not been sufficiently documented, and the incidence of malignant hyperthermia in the anesthetized patient is very low (8,9 and 10). (A recent Reference cited incidences of 1:12,000 anesthesias in children and 1:40,000 in adults .) They recommend avoidance of those anesthetic agents that might trigger the syndrome, careful monitoring of the patient during delivery, and preparation to treat the complication if it occurs.
In summary, dantrolene has been used in a limited number of pregnant patients shortly before delivery. No fetal or newborn adverse effects have been observed, but a risk:benefit ratio has not yet been defined. Moreover, published 1st and 2nd trimester experience with this drug is completely lacking.
Breast Feeding Summary
Dantrolene is excreted into human breast milk. A 37-year-old woman undergoing an urgent cesarean section with general anesthesia (succinylcholine, thiopental, nitric oxide, oxygen, and isoflurane) developed tachycardia, respiratory acidosis, and hyperthermia (12). After delivery of the infant and cord clamping, IV dantrolene (160 mg) was administered. Over the next 3 days, she received decreasing total doses of IV dantrolene: 560 mg on day 1, 320 mg on day 2, and 80 mg on day 3. The infant was not allowed to nurse during this time. Seven breast milk samples were obtained (volume of milk samples and collection method not specified) over an 84-hour interval after the first dose. Milk concentrations of dantrolene ranged from a maximum of 1.2 g/mL (day 2; 36 hours after the first dose with a total dose of 720 mg at the time) to 0.05 g/mL on day 3 (total dose 1120 mg received at the time). The estimated elimination half-life from milk was 9.02 hours (12). Therefore, waiting 2 days after the last dantrolene dose to breast-feed would assure that the exposure of the nursing infant would be negligible.
- Nagaoka T, Osuka F, Hatano M. Reproductive studies of dantrolene. Teratogenicity study in rabbits. Clinical Report 1977;11:221217. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:549.
- Nagaoka T, Osuka F, Shigemura T, Hatano M. Reproductive test of dantrolene. Teratogenicity test on rats. Clinical Report 1977;11:221830. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:549.
- Product information. Dantrium. Norwich Eaton Pharmaceuticals, 1993.
- Morison DH. Placental transfer of dantrolene. Anesthesiology 1983;59:265.
- Glassenberg R, Cohen H. Intravenous dantrolene in a pregnant malignant hyperthermia susceptible (MHS) patient (Abstract). Anesthesiology 1984;61:A404.
- Shime J, Gare D, Andrews J, Britt B. Dantrolene in pregnancy: Lack of adverse effects on the fetus and newborn infant. Am J Obstet Gynecol 1988;159:8314.
- Cupryn JP, Kennedy A, Byrick RJ. Malignant hyperthermia in pregnancy. Am J Obstet Gynecol 1984;150:3278.
- Khalil SN, Williams JP, Bourke DL. Management of a malignant hyperthermia susceptible patient in labor with 2-chloroprocaine epidural anesthesia. Anesth Analg 1983;62:11921.
- Kaplan RF, Kellner KR. More on malignant hyperthermia during delivery. Am J Obstet Gynecol 1985;152:6089.
- Sorosky JI, Ingardia CJ, Botti JJ. Diagnosis and management of susceptibility to malignant hyperthermia in pregnancy. Am J Perinatol 1989;6:468.
- Sessler DI. Malignant hyperthermia. J Pediatr 1986;109:914.
- Fricker RM, Hoerauf KH, Drewe J, Kress HG. Secretion of dantrolene into breast milk after acute therapy of a suspected malignant hyperthermia crisis during cesarean section. Anesthesiology 1998;89:10235.