Narcotic Agonist Analgesic
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 3rd Trimester
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
The use of sufentanil during pregnancy with clinically used doses does not appear to present a significant risk to the fetus or newborn. Although no reports describing the use of the narcotic during the 1st trimester have been located, the lack of teratogenicity in animals and the general opinion that narcotic agents, in general, pose little risk of congenital malformations are reassuring. Sufentanil rapidly crosses the placenta to the fetus, even more so in the presence of fetal acidosis, and similar to all narcotics, dose-related depression of the fetus and newborn may occur. Both respiratory depression and adverse effects on neonatal neurobehavior are potential problems in the newborn. If sufentanil is used in pregnancy, healthcare professionals are encouraged to call the toll-free number (800-670-6126) for information about patient enrollment in the Motherisk study.
FETAL RISK SUMMARY
Sufentanil is a potent narcotic drug that is used as an analgesic adjunct to, or primary anesthetic agent during, general anesthesia and in combination with bupivacaine for epidural anesthesia during labor and vaginal delivery.
No evidence of teratogenicity has been observed in rats and rabbits, but the drug was embryocidal (most likely due to maternal toxicity) in both species when it was given for 10–30 days in a dose 2.5 times the upper human IV dose (1). No adverse reproductive (number of implantations and live fetuses, percent fetal wastage per litter, or mean fetal weight) or teratogenic effects (major or minor malformations) were observed in rats administered continuous infusions of sufentanil at doses of 10, 50, or 100 mcg/kg/day from day 5 through day 20 of pregnancy (2).
The placental transfer of sufentanil was studied in an experiment using the dual-perfused, single-cotyledon human placental model at doses of 1, 10, 20, and 100 ng/mL (3). Sufentanil was shown to rapidly cross the placenta by passive diffusion, but high maternal protein binding significantly reduced this transfer, whereas progressive fetal acidemia (reduction in pH from 7.4 to 6.8 in 0.2 increments) significantly increased transfer. Placental tissues appeared to bind sufentanil, but this accumulation apparently did not affect the overall net drug transfer to the fetus (i.e., the placenta accumulated sufentanil during periods of increasing maternal concentrations and then functioned as a source to sustain fetal drug levels when maternal concentrations declined) (3).
In another in vitro study, a single-pass (open) placental perfusion model was used to assess the placental transfer of sufentanil (1 and 100 ng/mL) and the effect of maternal plasma proteins, placental metabolism, and fetal pH (7.4–6.8) on the transfer (4). The conclusions of this study were identical to those of the study above, in that sufentanil rapidly crossed the placenta by passive diffusion, the placenta acted as a depot for the narcotic, maternal protein binding (not albumin) decreased transfer, and fetal acidosis increased the amount reaching the fetus (4). The authors also concluded that because of its low initial transfer (umbilical vein concentration only 2% of maternal concentration at 5 minutes), sufentanil may be the narcotic of choice if delivery is imminent (<45 minutes) (4).
Sufentanil crosses the placenta to the fetal circulation following maternal epidural anesthesia (5,6). In a 1991 double-blind study, 60 women undergoing elective cesarean section at term were randomized to receive epidural anesthesia consisting of 0.5% bupivacaine with epinephrine (1:200,000) alone (N = 20), sufentanil 20 mcg plus bupivacaine with epinephrine (N = 20), or sufentanil 30 mcg plus bupivacaine with epinephrine (N = 20) (6). The mean plasma concentrations of sufentanil in the mother and newborn in the 20-mcg group (14 subjects) were 0.030 and 0.025 ng/mL, respectively, whereas those in the 30-mcg group (15 subjects) were 0.056 and 0.042 ng/mL, respectively. The fetal:maternal ratios in the two groups were 0.83 and 0.75, respectively. To evaluate the safety of the epidural solutions for the newborn, the Neurological and Adaptive Capacity Score (NACS) was used to evaluate the infants at birth and between 1 and 2 hours. In each of the three groups, the percentage of neonates with a perfect score in each category of the NACS was statistically similar (6).
The placental transfer of sufentanil, fentanyl, and bupivacaine was studied in a double-blind, randomized trial involving 36 women at term who received epidural anesthesia during labor prior to vaginal delivery (6). Patients received a 12-mL bolus of (a) bupivacaine 0.25% alone (N = 13), (b) bupivacaine 0.125% plus sufentanil 15 mcg (N = 9), or (c) bupivacaine 0.125% plus fentanyl 75 mcg (N = 14), followed by a 10 mL/hr infusion of bupivacaine 0.125% alone, bupivacaine 0.125% plus sufentanil 0.25 mcg/mL, or bupivacaine 0.125% plus fentanyl 1.5 mcg/mL. The mean umbilical vein:maternal vein (UV:MV) ratios for bupivacaine in the three groups were 0.29, 0.43, and 0.33, respectively. The mean UV concentrations of the narcotics for sufentanil and fentanyl were 0.016 and 0.18 ng/mL, respectively, whereas the mean MV concentrations were 0.019 and 0.52 ng/mL, respectively. The UV:MV ratios for sufentanil and fentanyl were 0.81 and 0.37, respectively. The NACS was used to assess the newborns in each group at delivery, 2 hours of age, and 24 hours of age (6). No statistical differences among the three groups were observed at delivery or at 2 hours of age, but at 24 hours, the bupivacaine-fentanyl group’s NACS was significantly lower than that of the bupivacaine-sufentanil group, a result thought to reflect the continued presence of fentanyl in the neonate (6).
Intrathecal sufentanil (10 mcg), followed at least 1 hour later with bupivacaine epidural analgesia (N = 65), was compared with bupivacaine epidural analgesia alone (N = 64) in a 1996 report comparing the effects of the two analgesic regimens on fetal heart rate changes during labor (7). No statistical differences were observed between the groups in the incidence of clinically significant fetal heart rate tracing abnormalities (recurrent late decelerations and/or bradycardia) or in maternal hypotension within the 1st hour of administration (7). In addition, there were no differences between the groups in arterial or venous cord pH or the number of 5-minute Apgar scores <7. No abnormal fetal heart rate patterns were observed in an earlier study that compared intrathecal sufentanil (10 mcg) either alone (N = 20) or with 0.2 mg epinephrine (N = 20) (8). Epinephrine did not prolong analgesia but did increase the incidence of vomiting while decreasing the incidence and severity of pruritus. In a 1993 report, abnormal fetal heart rate changes were observed in 15% (11 of 73 tracings that were acceptable for analysis) among 108 women who received intrathecal sufentanil (10 mcg) during active labor (9). Of the 11 abnormal tracings, 5 were of moderate but transient variable decelerations, 4 were of mild nonrepetitive late decelerations, 1 was of a single episode of bradycardia, and 1 was of an episode of decreased variability. None of the 11 affected pregnancies required intervention for fetal compromise.
A number of studies have reported the successful use of sufentanil to produce adequate labor analgesia without fetal or newborn harm (10–19). A 1992 reference concluded that 10 mcg of sufentanil administered intrathecally produced faster and superior analgesia to that observed with epidural or IV administration of the same dose (10). Intermittent injections of intrathecal sufentanil (5 mcg) were compared with intermittent injections of intrathecal fentanyl (10 mcg) or meperidine (10 mg) in another 1992 report (11). In this study, meperidine provided better maternal analgesia once cervical dilation had progressed beyond 6 cm (11). No intergroup differences were observed in umbilical cord blood gases and none of the newborns had a 5-minute Apgar score <7. No significant differences were observed in Apgar scores, umbilical cord blood pH levels, or NACS at 2 and 24 hours in a study comparing epidural sufentanil plus bupivacaine (N = 30) to epidural fentanyl plus bupivacaine (N = 30) (12). During labor, the patients received epidural infusions at 12 mL/hr of either sufentanil (0.25 mcg/mL) or fentanyl (2.5 mcg/mL), both in 0.0625% bupivacaine. The total narcotic doses of sufentanil or fentanyl were 15.9 and 139.8 mcg, respectively. In seven other studies, spinal sufentanil either alone or combined with other various agents compared favorably with controls in efficacy and fetal and newborn safety (13–19).
A case of maternal respiratory depression following a 15-mcg dose of intrathecal sufentanil during labor was described in 1994 (20). A marked decrease (to 89%) in the patient’s hemoglobin oxygen saturation was noted that was treated with tactile stimulation and oxygen via face mask. A healthy, 3905-g male infant was delivered 2.5 hours later with Apgar scores of 7 and 8 at 1 and 5 minutes, respectively. No adverse effects were observed in the neonate during routine hospital follow-up.
BREASTFEEDING SUMMARY
The use of sufentanil during lactation is unlikely because of its clinical indications. It is not surprising, therefore, that no reports describing the use of this agent during lactation have been located. The molecular weight (about 579) of sufentanil citrate, the commercial form of the drug, is low enough that passage into milk should be expected. The effects, if any, of this exposure on a nursing infant are unknown.
References
1.Product information. Sufenta. Janssen Pharmaceutica, 1998.
2.Fujinaga M, Mazze RI, Jackson EC, Baden JM. Reproductive and teratogenic effects of sufentanil and alfentanil in Sprague-Dawley rats. Anesth Analg 1988;67:166–9.
3.Johnson RF, Herman N, Arney TL, Johnson HV, Paschall RL, Downing JW. The placental transfer of sufentanil: effects of fetal pH, protein binding, and sufentanil concentration. Anesth Analg 1997;84:1262–8.
4.Krishna BR, Zakowski MI, Grant GJ. Sufentanil transfer in the human placenta during in vitro perfusion. Can J Anaesth 1997;44:996–1001.
5.Vertommen JD, Van Aken H, Vandermeulen E, Vangerven M, Devlieger H, Van Assche AF, Shnider SM. Maternal and neonatal effects of adding epidural sufentanil to 0.5% bupivacaine for cesarean delivery. J Clin Anesth 1991;3:371–6.
6.Loftus JR, Hill H, Cohen SE. Placental transfer and neonatal effects of epidural sufentanil and fentanyl administered with bupivacaine during labor. Anesthesiology 1995;83:300–8.
7.Nielsen PE, Erickson JR, Abouleish EI, Perriatt S, Sheppard C. Fetal heart rate changes after intrathecal sufentanil or epidural bupivicaine [sic] for labor analgesia: incidence and clinical significance. Anesth Analg 1996;83:742–60.
8.Camann WR, Minzter BH, Denney RA, Datta S. Intrathecal sufentanil for labor analgesia. Effects of added epinephrine. Anesthesiology 1993;78:870–4.
9.Cohen SE, Cherry CM, Holbrook RH Jr, El-Sayed YY, Gibson RN, Jaffe RA. Intrathecal sufentanil for labor analgesia—sensory changes, side effects, and fetal heart rate changes. Anesth Analg 1993;77:1155–60.
10.Camann WR, Denney RA, Holby ED, Datta S. A comparison of intrathecal, epidural, and intravenous sufentanil for labor analgesia. Anesthesiology 1992;77:884–7.
11.Honet JE, Arkoosh VA, Norris MC, Huffnagle HJ, Silverman NS, Leighton BL. Comparison among intrathecal fentanyl, meperidine, and sufentanil for labor analgesia. Anesth Analg 1992;75:734–9.
12.Russell R, Reynolds F. Epidural infusions for nulliparous women in labour. A randomised double-blind comparison of fentanyl/bupivacaine and sufentanil/bupivacaine. Anaesthesia 1993;48:856–61.
13.Phillips GH. Epidural sufentanil/bupivacaine combinations for analgesia during labor: effect of varying sufentanil doses. Anesthesiology 1987;67:835–8.
14.Van Steenberge A, Debroux HC, Noorduin H. Extradural bupivacaine with sufentanil for vaginal delivery. A double-blind trial. Br J Anaesth 1987;59:1518–22.
15.Le Polain B, De Kock M, Scholtes JL, Van Lierde M. Clonidine combined with sufentanil and bupivacaine with adrenaline for obstetric analgesia. Br J Anaesth 1993;71:657–60.
16.Grieco WM, Norris MC, Leighton BL, Arkoosh VA, Huffnagle HJ, Honet JE, Costello D. Intrathecal sufentanil labor analgesia: the effects of adding morphine or epinephrine. Anesth Anal 1993;77:1149–54.
17.D’Angelo R, Anderson MT, Philip J, Eisenach JC. Intrathecal sufentanil compared to epidural bupivacaine for labor analgesia. Anesthesiology 1994;80:1209–15.
18.Vertommen JD, Lemmens E, Van Aken H. Comparison of the addition of three different doses of sufentanil to 0.125% bupivacaine given epidurally during labour. Anaesthesia 1994;49:678–81.
19.Dahlgren G, Hultstrand C, Jakobsson J, Norman M, Eriksson EW, Martin H. Intrathecal sufentanil, fentanyl, or placebo added to bupivacaine for cesarean section. Anesth Analg 1997;85:1288–93.
20.Hays RL, Palmer CM. Respiratory depression after intrathecal sufentanil during labor. Anesthesiology 1994;81:511–2.