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Maternal Epidural Fentanyl Administered for Labor Analgesia Is Found in Neonatal Urine 24 Hours After Birth

Authors:
Correspondence
Maternal Epidural Fentanyl Administered
for Labor Analgesia Is Found
in Neonatal Urine 24 Hours After Birth
Albert Moore, Aly el-Bahrawy, Roupen Hatzakorzian, and William Li-Pi-Shan
Dear Editor:
Fentanyl is an opioid medication that is given epidu-
rally for labor analgesia. Although fentanyl is commonly
used, there are reports of it interfering with breastfeeding
success.
1
We could find no information on whether fentanyl
would be found in a neonate more than 24 hours after delivery
and so decided to present this case.
The patient gave consent, and the research ethics board gave
approval for this study. A 34-year-old, 39-week gravida 1 para
0 woman presented in spontaneous labor. She was 162 cm tall,
weighed 75 kg, was healthy, took no medication other than
prenatal vitamins, and had enjoyed an uneventful pregnancy.
She requested and received an epidural at 4:45 h the day of her
admission. The epidural catheter placement was uncompli-
cated, and adequate analgesia was provided using a pump that
infused 0.06% bupivacaine with 2 lg/mL fentanyl at 10 mL/
hour with a patient-controlled 5-mL demand bolus and a
lockout time of 10 minutes. Throughout her labor the patient
received six extra boluses of this solution.
A 3,780-g baby boy was born at 14:08 h, with Apgar scores
of 9 and 9 at 1 and 5 minutes, respectively, and an umbilical
artery pH of 7.19. The epidural pump was stopped soon after
birth, with the patient receiving 140 mL of the epidural so-
lution (280 lg of fentanyl over 11 hours =25 lg/hour). The
patient recovered and was discharged to the postpartum ward
where she was assessed by us the next day. At that time she
had used no medications for pain.
The baby-dependent items on the LATCH score were as-
sessed, and the latching ability and audible swallowing were
rated at 2 (normal). Urine samples were collected from the
mother at 14:00 h. At the same time, a clean sponge was
placed in a new diaper, which provided a neonatal urine
sample that was collected at 17:00 h. The samples were sent
to a toxicology laboratory, where it was determined that the
maternal urinary fentanyl level was 2.0 ng/mL, whereas the
neonatal level was 2.4 ng/mL.
Although it is known that epidurally administered fentanyl
crosses the placenta, it is thought that this leads to clinically
unimportant levels in the neonate.
2
The measured half-life of
fentanyl administered intravenously to infants 1 day or less of age
is highly variable and ranges from 75 to 441 minutes,
3
making
the duration it would remain in the neonate unclear. Our case
demonstrates that fentanyl can persist in the neonate for at least
24 hours after delivery, at amounts that may have clinical effects.
The minimum effective analgesic level of fentanyl in plasma for
adults is 0.63 ng/mL.
4
Although the corresponding level is un-
known in neonates, a level of 1.1 ng/mL has necessitated pro-
longed intubation in neonates.
3
The urinary concentration seems
to have some correlation with fentanyl dosage and levels.
5
Although fentanyl is transferred in breastmilk, it is virtu-
ally undetectable in colostrum 10 hours after it has been given
maternally.
6
In addition, fentanyl’s limited oral bioavail-
ability makes us believe the majority of neonatal fentanyl was
from placental transfer and not through breastmilk. Although
our LATCH score was reported as normal, more subtle
markers of breastfeeding difficulty may have been found if
we had assessed the Widstrom stages of neonatal breast-
feeding,
7
or more severe problems may have occurred if the
patient had required higher fentanyl doses. Adequate initia-
tion is essential for the continued success of breastfeeding,
and it is possible that the presence of neonatal fentanyl could
interfere in the important first days of life.
In conclusion, we provide evidence that fentanyl admin-
istered through an epidural for less than 12 hours will remain
in the mother and neonate, even 24 hours after cessation of
the epidural infusion. The clinical implications of this should
be further investigated.
References
1. Beilin Y, Bodian CA, Weiser J, et al. Effect of labor epidural
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2. Gambling DR, Huber CJ, Berkowitz J, et al. Patient-
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3. Koehntop DE, Rodman JH, Brundage DM, et al. Pharma-
cokinetics of fentanyl in neonates. Anesth Analg 1986;65:
227–232.
4. Gourlay GK, Kowalski SR, Plummer JL, et al. Fentanyl blood
concentration-analgesic response relationship in the treatment
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5. Van Nimmen NF, Poels KL, Menten JJ, et al. Fentanyl trans-
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BREASTFEEDING MEDICINE
Volume 11, Number 1, 2016
ªMary Ann Liebert, Inc.
DOI: 10.1089/bfm.2015.0173
40
patients undergoing palliative care. J Clin Pharmacol
2010;50:667–678.
6. Steer PL, Biddle CJ, Marley WS, et al. Concentration of
fentanyl in colostrum after an analgesic dose. Can J Anaesth
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7. Brimdyr K, Cadwell K, Widstrom AM, et al. The association
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[Epub ahead of print]. doi: 10.1111/birt.12186.
Address correspondence to:
Albert Moore, MD
Department of Anesthesia
Royal Victoria Hospital
1001 Decaire Boulevard
Montreal, QC, H4A 3J1, Canada
E-mail: moore_albert@hotmail.com
CORRESPONDENCE 41
... The fentanyl concentration required for 50% inhibition (IC 50 ) for the G-protein-coupled µ-opioid receptor needed for analgesic effect was reported to be 0.4 ng/ml [9]. Also, the fentanyl minimum effective (MEC) concentration for analgesic effect in infant plasma was reported to be 1.1 ng/ml [10]. The maternal fentanyl dose can be transferred transplacentally during labor to their newborns [11,12] and can cause neonatal side effects including bradycardia, lower adaptive capacity [13,14], and respiratory depression [15]. ...
... Fentanyl expresses moderate binding to α-1-acid glycoprotein (AAG) in plasma [46]. Maternal fentanyl can cross the mother's placenta [10,47]. ...
... Also, the fentanyl PBPK model in adults was scaled to pregnancy during the third trimester and verified using measured fentanyl concentrations in the pregnant mother's umbilical vein and systemic venous plasma after epidural and intravenous administration [11,65,66]. Furthermore, the model was used to simulate the urine, saliva, plasma, and bECF levels in infants after the transplacental transfer of fentanyl from a parturient mother receiving epidural fentanyl [10,47]. The fentanyl PBPK model built herein (Fig. 1a) accounted for the fentanyl binding to plasma AAG; metabolism by CYP3A4 and CYP3A7; efflux via P-gp in the intestine, liver, kidneys, and blood-brain barrier (BBB); renal elimination via glomerular filtration; and an additional undefined hepatic plasma clearance [46]. ...
Article
Background and Objective Fentanyl can mitigate the mother and newborn complications resulting from labor pain. However, fentanyl shows a narrow therapeutic index between its respiratory depressive and analgesic effects. Thus, prenatally acquired high fentanyl levels in the newborn brain extracellular fluid (bECF) may induce respiratory depression which requires therapeutic drug monitoring (TDM). TDM using saliva and urine in newborns can reduce the possibility of infections and distress associated with TDM using blood. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict fentanyl concentrations in different newborn tissues due to intrauterine exposure.MethodsA fentanyl PBPK model in adults after intravenous and epidural administration was built, validated, and scaled to pregnancy and newborn populations. The dose that the newborn received transplacentally at birth was calculated using the pregnancy model. Then, the newborn bECF, saliva, plasma, and urine concentrations after such a dose were predicted using the newborn PBPK model.ResultsAfter a maternal epidural dose of fentanyl 245 µg, the predicted newborn plasma and bECF levels were below the toxicity thresholds. Furthermore, the salivary threshold levels in newborns for fentanyl analgesic and respiratory depression effects were estimated to be 0.39 and 14.7–18.2 ng/ml, respectively.Conclusion The salivary TDM of fentanyl in newborns can be useful in newborns exposed to intrauterine exposure from parturient females dosed with epidural fentanyl. However, newborn-specific values of µ-opioid receptors IC50 for respiratory depression are needed.Graphical Abstract
... They found that all three drugs can be detected in maternal and umbilical venous plasma at the time of delivery. In a case reported by Moore et al, [30] a 39week pregnant woman received epidural analgesia with a mixture of 0.06% bupivacaine and 2 mg/mL fentanyl for 11 h (280 mg fentanyl given). At 24 h after delivery, fentanyl could still be detected in the urine of both mother (2.0 ng/mL) and neonate (2.4 ng/mL). ...
... At 24 h after delivery, fentanyl could still be detected in the urine of both mother (2.0 ng/mL) and neonate (2.4 ng/mL). [30] Therefore, both local anesthetics and opioids administered for ELA can arrive neonates and produce effects. ...
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This review summarizes recent evidences regarding the potential influences of epidural labor analgesia (ELA) on the outcomes of neonates and children. Terms and relevant words including "ELA," "ELA and neonatal outcomes," "ELA and children's development," and "ELA and children's neurocognitive development" were used to search articles published in PubMed database up to October 2019.Original articles and reviews regarding potential influences of ELA on neonates and children were identified. Relevant references of the selected articles were also screened. The anesthetics used during ELA can be absorbed, enter the fetus, and produce neonatal depression; however, these effects are less severe than those during systematic opioid analgesia. The impact of anesthetic exposure during ELA on children's neurodevelopment has not been fully studied, but would be mild if any. ELA increases the risk of intrapartum maternal fever; the latter may be harmful to neonatal outcomes. The use of ELA may increase birth injury by increasing instrumental delivery, although long-term adverse events are rare. On the other hand, ELA may reduce maternal depression and, thus, produce favorable effects on neurocognitive development in childhood; but evidences are still lacking in this aspect. ELA may produce both favorable and unfavorable effects on neonates and children. These effects should be discussed with parturient women before making decisions. The potential harmful effects should be carefully managed. The overall impacts of ELA on neonatal and children's outcomes need to be studied further.
... Moore A. et al. (2016) described a case of EA in childbirth in wom an with gestation period of 39 weeks using combination of 0.06 % bupivacaine and 2 mcg/ml of fentanyl for 11 hours (280 mcg of fentanyl). 24 hours after delivery, fentanyl was still detected in the urine of both the mother (2.0 ng/ml) and the newborn (2.4 ng/ml) [24]. Thus, the authors of this study demonstrated that both LA and opioids injected into the epidural space circulate for a long time in the body not only of mother, but also of newborn, which can cause adverse effects. ...
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INTRODUCTION: When performing epidural analgesia in childbirth, if surgical delivery is necessary, the question arises about the choice of further tactics of regional anesthesia. The article discusses the peculiarities of the effect of local anesthetics on the condition of a newborn during the conversion of epidural analgesia into anesthesia when caesarean section is necessary, depending on the local anesthetic used. OBJECTIVE: To assess the condition of a newborn baby during the conversion of epidural analgesia in childbirth through the natural birth canal into anesthesia during cesarean section, depending on the local anesthetic used. MATERIALS AND METHODS: A prospective randomized study of 143 children born to mothers who underwent the conversion of epidural analgesia into anesthesia for operative delivery by caesarean section was conducted. Depending on the local anesthetic used, the patients were divided into three groups, in the first group 20.0 ml of 2 % lidocaine in combination with 0.1 mg of epinephrine was injected into the epidural space, in the second group — 20.0 ml of 0.5 % bupivacaine, in the third — 20.0 ml of 0.75 % ropivacaine. The assessment of the condition of newborns was carried out on the Apgar scale at the 1st and 5th minutes of life and on the NACS scale in the first 15 minutes, 2, 24 and 72 hours after birth. RESULTS: The assessment of newborns on the Apgar scale, regardless of the local anesthetic used during epidural anesthesia at the first and fifth minutes, corresponded to 7 or more points (p > 0.05). The neuropsychiatric state of newborns when assessed on the NACS scale did not differ statistically significantly in all groups and at all stages of the study. Within each group, between the study stages, the average values of the NACS scores increased statistically significantly compared to the previous one. CONCLUSIONS: The conversion of epidural analgesia in childbirth through the natural birth canal into anesthesia during cesarean section is safe for the fetus and newborn when using 20.0 ml of 2 % lidocaine in combination with 0.1 mg of epinephrine or 20.0 ml of 0.5 % bupivacaine, or 0.75 % ropivacaine in a volume of 20.0 ml.
... A systematic review found no relationship between use of epidural analgesia and neonatal morbidity [3]. However, despite the low anesthetics doses administered during epidural analgesia, they cross the placenta and enter the fetus [16,17]. Additionally, epidural analgesia during labor was also reported to be associated with morphological changes in neonatal brains [18]. ...
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... Historically maternal fentanyl analgesia has been identified in fetal blood. Recently, a case report noted the presence of fentanyl in neonatal urine and raised concern that drug levels associated with detectable urine fentanyl may have unknown clinical consequences (19). Urine screening is typically performed using a fentanyl homogenous enzyme immunoassay (20). ...
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... A placental transfer of 90% has been measured by Moises (61). Fentanyl has been measured in the newborn infant's urine for at least 24 hours postpartum (62). Fentanyl exposure can depress the newborn infant's behaviour during the first hours after birth, especially the suckling behaviour in a dose-dependent manner (29). ...
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... По данным A. Moore и соавт. (2016), концентрация фентани- ла при его эпидуральном введении (280 мкг фен- танила = 25 мкг/ч) сохраняется у новорожденных в течение 24 часов послеродового периода в коли- честве, которое может давать клинические про- явления [23]. Однако в пилотном исследовании M. Kokki и соавт. ...
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The pharmacokinetics of fentanyl were studied in fourteen neonates undergoing major surgical procedures. Five patients were less than 1 day of age, seven were 1-4 days old, and two were 7-14 days old. Fentanyl was given intravenously, 10 micrograms/kg (n = 1), 25 micrograms/kg (n = 4), or 50 micrograms/kg (n = 9), and plasma concentrations measured at intervals of up to 18 hr. Average weight was 2.9 kg. The injection of 25 or 50 micrograms/kg of fentanyl over 1-3 min was hemodynamically well-tolerated by all patients. Four newborns without respiratory impairment secondary to surgery or disease needed ventilatory support for an average of 24 hr (range 11-40 hr). Plasma concentrations of fentanyl were most appropriately described by a two-compartment model. The mean +/- SEM values of selected model parameters were volume of the central compartment, 1.45 +/- 0.34 L/kg; volume of distribution at steady state, 5.1 +/- 1 L/kg; clearance, 17.94 +/- 4.38 ml X kg-1 X min-1; and terminal elimination half-life (t 1/2 beta), 317 +/- 70 min. In seven patients transient rebound in plasma fentanyl concentrations of 0.5 ng/ml or greater occurred. In three patients with markedly increased intraabdominal pressure, the t 1/2 beta was 1.5-3 times the population mean. Thus fentanyl disposition in neonates is highly variable, but the t 1/2 beta is predictably prolonged in the presence of increased abdominal pressure.
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The influence of labor epidural fentanyl on the neonate is controversial. The purpose of this study was to determine whether epidural fentanyl has an impact on breast-feeding. Women who previously breast-fed a child and who requested labor epidural analgesia were randomly assigned in a double-blinded manner to one of three groups: (1) no fentanyl group, (2) intermediate-dose fentanyl group (intent to administer between 1 and 150 microg epidural fentanyl), or (3) high-dose epidural fentanyl group (intent to administer > 150 microg epidural fentanyl). On postpartum day 1, the mother and a lactation consultant separately assessed whether the infant was experiencing difficulty breast-feeding, and a pediatrician assessed infant neurobehavior. All women were contacted 6 weeks postpartum to determine whether they were still breast-feeding. Sixty women were randomly assigned to receive no fentanyl, 59 were randomly assigned to receive an intermediate dose, and 58 were randomly assigned to receive high-dose fentanyl. On postpartum day 1, women who were randomly assigned to receive high-dose fentanyl reported difficulty breast-feeding (n = 12, 21%) more often than women who were randomly assigned to receive an intermediate fentanyl dose (n = 6, 10%), or no fentanyl (n = 6, 10%), although this did not reach statistical significance (P = 0.09). There was also no significant difference among groups in breast-feeding difficulty based on the lactation consultant's evaluation (40% difficulty in each group; P = 1.0). Neurobehavior scores were lowest in the infants of women who were randomly assigned to receive more than 150 microg fentanyl (P = 0.03). At 6 weeks postpartum, more women who were randomly assigned to high-dose epidural fentanyl were not breast-feeding (n = 10, 17%) than women who were randomly assigned to receive either an intermediate fentanyl dose (n = 3, 5%) or no fentanyl (n = 1, 2%) (P = 0.005). Among women who breast-fed previously, those who were randomly assigned to receive high-dose labor epidural fentanyl were more likely to have stopped breast-feeding 6 weeks postpartum than woman who were randomly assigned to receive less fentanyl or no fentanyl.
Fentanyl transdermal absorption linked to pharmacokinetic characteristics in Department of Anesthesia, Royal Victoria Hospital
  • N F Van Nimmen
  • K L Poels
  • J J Menten
Van Nimmen NF, Poels KL, Menten JJ, et al. Fentanyl transdermal absorption linked to pharmacokinetic characteristics in Department of Anesthesia, Royal Victoria Hospital, Montreal, Quebec, Canada. BREASTFEEDING MEDICINE Volume 11, Number 1, 2016
patients undergoing palliative care
  • Mary Ann Liebert
ª Mary Ann Liebert, Inc. DOI: 10.1089/bfm.2015.0173 patients undergoing palliative care. J Clin Pharmacol 2010;50:667-678.