Sedative
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The human pregnancy experience with dexmedetomidine is limited to short-term use immediately before or during delivery in three women. The drug crosses the human placenta at term. A 2009 editorial concluded that off-label use of dexmedetomidine might be beneficial in providing pain relief for laboring women unwilling or unable to receive neuraxial analgesia (1). However, newborn toxicity, such as hypotension and sedation, is a potential concern. Moreover, dexmedetomidine may increase uterine contractions and this property should be considered if the drug is used during pregnancy.
FETAL RISK SUMMARY
Dexmedetomidine, a relatively selective α2-adrenergic agonist with sedative properties, is given as an IV infusion. It is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting and for sedation of nonintubated patients before and/or during surgical and other procedures. At recommended doses, dexmedetomidine does not cause respiratory depression. The drug undergoes nearly complete metabolism to inactive metabolites. Plasma protein binding is 94% and the terminal elimination half-life is about 2 hours (2).
Reproduction studies have been conducted in rats and rabbits. In rats, dexmedetomidine crossed the placenta. No teratogenicity was observed in rats given SC doses during organogenesis (gestation day 5–16) up to about the maximum recommended human IV dose (MRHD) based on BSA (MRHD-BSA). However, at the highest dose, postimplantation losses and a reduced number of live pups were observed. The no-observed-effect-level (NOEL) was less than the MRHD-BSA. In another rat study that used SC doses less than the MRHD-BSA from gestation day 16 through weaning, lower offspring weights were observed. Moreover, when offspring were allowed to mate, elevated fetal and embryocidal toxicity and delayed motor development were observed in second-generation offspring. No teratogenicity was noted in rabbits during organogenesis (day 6–18) given IV doses up to about 0.5 times the exposure at the MRHD based on AUC (2).
A study using pregnant rats evaluated the effects of chronic vs. acute exposure on fetal development and postnatal behavior (3). The rats were given either daily SC doses (gestation days 7–19) or a single SC dose on day 19. No structural anomalies were observed and there were no differences between the groups in terms of pup postnatal weight gain or behavioral performance (3). Extrapolating from the aforementioned information, all of the doses appeared to be less than the MRHD-BSA.
Studies for carcinogenicity have not been conducted. Assays for mutagenicity were negative but the drug was clastogenic in some tests. Fertility in male and female rats was not affected by SC doses that were less than the MRHD-BSA (2).
The relatively low molecular weight (about 201 for the free base) suggests that dexmedetomidine will cross the human placenta, but the plasma protein binding and short terminal elimination half-life might limit the exposure of the embryo and/or fetus, at least early in gestation. The manufacturer reported that the drug crossed the human placenta in an in vitro study but provided no other details (2). Term placentas were used in a single placental cotyledon study to measure the amount of dexmedetomidine compared with clonidine that crossed to the fetal circulation over a 2-hour period (4). Dexmedetomidine disappeared faster than clonidine from the maternal circulation, but the amount of drug appearing in the fetal circulation at 2 hours was less (12.5% vs. 22.1%). The difference was explained by greater placental retention of dexmedetomidine (48.1% vs. 11.3%). The fetal: maternal concentration ratio at 2 hours was 0.77 (4).
The sedative, analgesic, and hemodynamic controlling properties of dexmedetomidine have been reported in three pregnant women in labor (5–7). A 35-year-old woman with spinal muscular atrophy presented for cesarean section at 35 weeks’ gestation (5). She was given an IV infusion of dexmedetomidine with a total dose of 1.84 mcg/kg over 38 minutes, followed by general anesthesia. A male infant (weight not specified) was delivered 68 minutes after discontinuation of the infusion. Apgar scores were 6 and 8 at 1 and 5 minutes, respectively. The initially oxygen saturation in the newborn was 88% but with treatment improved to 95% at 5 minutes. At delivery, the umbilical arterial and maternal venous concentrations were 540 and 710 pg/mL, respectively, a ratio of 0.76. The initial low Apgar score was thought to be secondary to a combination of gestational age and residual inhalational anesthetic. However, a contribution from dexmedetomidine could not be excluded. The healthy infant was discharged home with his mother 1 week later (5).
A 37-year-old woman at 38 weeks’ gestation with diabetes and preeclampsia presented in labor (6). Because she refused epidural analgesia, an IV infusion of dexmedetomidine was started. Three hours later, a cesarean section under general anesthesia was conducted because of persistent late decelerations in the fetal heart rate. A healthy, 3.7-kg female infant was delivered with Apgar scores of 8 and 9. The mother and infant were doing well and discharged home after 7 days (6).
In another 2009 report, a morbidly obese 31-year-old woman with spina bifida occulta and a tethered spinal cord at L5-S1 presented at 40 weeks’ for elective induction of labor (7). Patient-controlled analgesia with IV fentanyl was started but was unsuccessful in controlling pain from her contractions. An IV infusion of dexmedetomidine was added, which immediately resulted in a marked decrease in her pain. Because of prolonged labor and the diagnosis of chorioamnionitis, a cesarean section was conducted under general anesthesia. The dexmedetomidine infusion was continued during the procedure. A healthy male infant (weight not specified) was delivered with Apgar scores of 7 and 8. The infant did well and was discharged 4 days later (7).
A 2005 in vitro study described the effects of dexmedetomidine on human myometrium (8). At simulated clinical plasma concentrations, the drug enhanced the frequency and amplitude of contractions.
BREASTFEEDING SUMMARY
No reports describing the use of dexmedetomidine during human lactation have been located.
The relatively low molecular weight (about 201 for the free base) suggests that the drug will be excreted into breast milk, but the plasma protein binding (94%) and short terminal elimination half-life (2 hours) should limit the amount in milk. However, as with other weak bases, accumulation in the relatively acidic milk may occur. The oral absorption of the drug is unknown, as is the effect, if any, of exposure in a nursing infant. Nevertheless, the sedative properties of the drug in the mother will limit the opportunities for breastfeeding.
References
1.Sia AT, Sng BL. Editorial. Intravenous dexmedetomidine for obstetric anaesthesia and analgesia: converting a challenge into an opportunity? Int J Obstet Anesth 2009;18:204–6.
2.Product information. Precedex. Hospira, 2010.
3.Tariq M, Cerny V, Elfaki I, Ahmad Khan H. Effects of subchronic versus acute in utero exposure to dexmedetomidine on foetal developments in rats. Basic Clin Pharmacol Toxicol 2008;103:180–5.
4.Ala-Kokko TI, Pienimäki P, Lampela E, Hollmén AI, Pelkonen O, Vahakangas K. Transfer of clonidine and dexmedetomidine across the isolated perfused human placenta. Acta Anaesthesiol Scand 1997;41:313–9.
5.Neumann MM, Davio MB, Macknet MR, Applegate II RL. Dexmedetomidine for awake fiberoptic intubation in a parturient with spinal muscular atrophy type III for cesarean delivery. Int J Obstet Anesth 2009;18:403–7.
6.Abu-Halaweh SA, Al Oweidi AKS, Abu-Malooh H, Zabalawi M, Alkazaleh F, Abu-Ali H, Ramsay MAE. Intravenous dexmedetomidine infusion for labour analgesia in patient with preeclampsia. Eur J Anaesthesiol 2009;26:86–7.
7.Palanisamy A, Klickovich RJ, Ramsay M, Ouyang DW, Tsen LC. Intravenous dexmedetomidine as an adjunct for labor analgesia and cesarean delivery anesthesia in a parturient with a tethered spinal cord. Int J Obstet Anesth 2009;18:258–61.
8.Sia AT, Kwek K, Yeo GS. The in vitro effects of clonidine and dexmedetomidine on human myometrium. Int J Obstet Anesth 2005;14:104–7.