Fetal Risk Summary
Midazolam is a short-acting benzodiazepine used for anesthetic induction. Reproduction studies in rats and rabbits at 10 and 5 times the human dose, respectively, found no evidence of teratogenicity in either species or impairment of fertility in rats (1). No reports have been located that describe the use of midazolam in humans during the 1st or 2nd trimesters.
Midazolam crosses the human placenta, but this transfer, at least after oral and IM use, appears to be slower than that experienced with other benzodiazepines, such as diazepam, oxazepam, or lorazepam (2). In 13 patients given 15 mg of midazolam orally a mean of 11.4 hours (range 10.512.4 hours) before cesarean section, only 1 had measurable levels of the drug at the time of surgery: maternal venous level was 12 ng/mL and cord venous level was 7 ng/mL. No patient had detectable levels of the drug in the amniotic fluid. A second group of patients (N=11) were administered 15 mg of midazolam orally a mean of 34.3 minutes (1560 minutes) before cesarean section. The mean serum concentrations in maternal venous, umbilical venous, and umbilical arterial blood were 12.7, 8.4, and 5.7 ng/mL, respectively. The cord venous:maternal venous and cord arterial:maternal venous ratios were 0.74 and 0.45, respectively. Six patients in a third group were administered midazolam, 0.05 mg/kg IM, 1845 minutes (mean 30.5 minutes) before cesarean section. Drug levels from the same sampling sites and ratios obtained in the second group were measured in this group, with results of 40.0, 21.7, and 12.8 ng/mL, respectively, and 0.56 and 0.32, respectively. None of the 1- and 5-minute Apgar scores of the 30 infants was less than 7, and no adverse effects attributable to midazolam were observed in the newborns (2).
The placental transfer of midazolam and its metabolite, a-hydroxymidazolam, was described in a 1989 Reference (3). (See Reference 7 for the clinical and physiologic condition of the newborns.) Twenty women were given 0.03 mg/kg of midazolam IV for anesthesia induction before cesarean section. The mean concentrations of midazolam in the mothers’ serum and cord blood were 339 and 318 ng/mL (ratio 0.66), respectively. Similar measurements of the metabolite produced values of 22 and 5 (ratio 0.28), respectively. The elimination half-life of midazolam in the newborn infants was 6.3 hours (3).
Plasma levels of midazolam were measured at frequent intervals up to 2 hours after a 5-mg IV dose administered to two groups of pregnant patients in a study published in 1985 (4). Levels were significantly higher in 12 patients in early labor than in 8 women undergoing elective cesarean section. No reason was given for the significant difference. Data on the exposed newborns were not given.
Midazolam, 0.2 mg/kg (N=26), or thiopental, 3.5 mg/kg (N=26), was combined with succinylcholine for rapid-sequence IV induction before cesarean section in a study examining the effects of these agents on the newborn (5). Five of the newborns exposed to midazolam required tracheal intubation compared to one in the thiopental group, a significant difference (p
A 1989 study compared the effects of midazolam 0.3 mg/kg (N=20) with thiopental 4 mg/kg (N=20) in mothers undergoing induction of anesthesia before cesarean section (6). The only difference found between the groups was a significantly (p
Breast Feeding Summary
Midazolam is excreted in the breast milk of lactating women (8). In a study published in 1990, 12 women in the immediate postpartum period took 15 mg orally at night for 5 nights. No measurable concentrations of midazolam or the metabolite, hydroxymidazolam, were detected (
Two women were also studied at 23 months postpartum (8). In six paired milk and serum samples collected up to 6 hours after a 15-mg dose, the mean milk:plasma ratio was 0.15. Based on an average milk concentration of 10 nmol/L, the authors estimated a nursing infant would ingest 0.33 g of midazolam and 0.34 g of metabolite per 100 mL of milk if nursed within 46 hours of the maternal dose (8).
The American Academy of Pediatrics considers the effects of midazolam on the nursing infant to be unknown, but they may be of concern (9).
- Product information. Versed. Roche Laboratories, 1997.
- Kanto J, Sjovall S, Erkkola R, Himberg J-J, Kangas L. Placental transfer and maternal midazolam kinetics. Clin Pharmacol Ther 1983;33:78691.
- Bach V, Carl P, Ravlo O, Crawford ME, Jensen AG, Mikkelsen BO, Crevoisier C, Heizmann P, Fattinger K. A randomized comparison between midazolam and thiopental for elective cesarean section anesthesia. III. Placental transfer and elimination in neonates. Anesth Analg 1989;68:23842.
- Wilson CM, Dundee JW, Moore J, Collier PS, Mathews HLM, Thompson EM. A comparison of plasma midazolam levels in non-pregnant and pregnant women at parturition. Br J Clin Pharmacol 1985;20:256P7P.
- Bland BAR, Lawes EG, Duncan PW, Warnell I, Downing JW. Comparison of midazolam and thiopental for rapid sequence anesthetic induction for elective cesarean section. Anesth Analg 1987;66:11658.
- Crawford ME, Carl P, Bach V, Ravlo O, Mikkelsen BO, Werner M. A randomized comparison between midazolam and thiopental for elective cesarean section anesthesia. I. Mothers. Anesth Analg 1989;68:22933.
- Ravlo O, Carl P, Crawford ME, Bach V, Mikkelsen BO, Nielsen HK. A randomized comparison between midazolam and thiopental for elective cesarean section anesthesia: II. Neonates. Anesth Analg 1989;68:2347.
- Matheson I, Lunde PKM, Bredesen JE. Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects. Br J Clin Pharmac 1990;30:78793.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.