Are there any known risks of administering sugammadex to a pregnant female (in any trimester) related to progesterone, baby development, or other mechanism?

Comment by InpharmD Researcher

Currently, there is limited data on the safety of administering sugammadex in pregnant females. A case series reported adverse events of preterm labor, preterm premature rupture of membranes, neonatal loss, new fetal anomalies, and developmental delay in the baby after receiving sugammadex for surgical fetal interventions, abdominal cerclage (AC), or nonobstetric surgery during antenatal period. These adverse events were determined to not be directly related to administration of sugammadex. There is data on administration of sugammadex 2 or 4mg/kg after cesarean delivery and the agent has been successful in reversal of rocuronium without significant side effects; although, one case reported hypersensitivity and anaphylactic reactions determined to be related to the use of sugammadex. Animal studies from the manufacturer, Merck, show there was no evidence of malformations in rats or rabbits following daily intravenous administration of sugammadex at doses up to six to eight times the recommended human dose. An additional animal study showed that sugammadex does not appear to affect the progesterone levels in pregnant rats in the first trimester.

  

PubMed: Sugammadex [Mesh] AND pregnant[Mesh] or pregnancy [Mesh]=13 articles

Background

A recent review article suggests that sugammadex is the preferred alternative to neostigmine for use in pregnant women due to the lack of maternal and fetal problems.[1] In pregnant patients that have airway management issues, guidance from the Obstetric Anaesthetists’ Association recommend high-dose rocuronium (1.0–1.2 mg/kg) as an alternative to succinylcholine for rapid sequence induction and tracheal intubation. If intubation failed and spontaneous ventilation is required, there is an advantage of quicker recovery of full reversal of NMB after high-dose sugammadex administration as compared to spontaneous offset of succinylcholine with the use of multiple vials of sugammadex during this emergency.[2]

In terms of maternal-fetal placental transfer, it is not expected for the drug to be transferred through the placenta due to its large molecular size and polarization in aqueous solution. The potential effects of sugammadex on the developing human fetus under varying conditions of potential anesthetic exposure are unknown at this time.[1] The manufacturer reports no evidence of teratogenicity after daily exposure in pregnant rats and rabbits at levels above the maximum recommended human dose. [3]

References:

[1] Richardson MG, Raymond BL. Sugammadex Administration in Pregnant Women and in Women of Reproductive Potential: A Narrative Review. Anesth Analg. 2020;130(6):1628-1637. doi:10.1213/ANE.0000000000004305
[2] Mushambi MC, Kinsella SM, Popat M, et al; Obstetric Anaesthetists’ Association; Difficult Airway Society. Obstetric Anaesthetists’ Association and Difficult Airway Society guidelines for the management of difficult and failed tracheal intubation in obstetrics. Anaesthesia. 2015;70:1286–1306.
[3] Merck & Co, Inc. Bridion (Sugammadex) Prescribing Information. Revised December 2018. Available at: https://www.merck.com/product/usa/pi_circulars/b/bridion/bridion_pi.pdf. Accessed June 14, 2019.
Relevant Prescribing Information

Risk Summary

There are no clinical trial data on BRIDION use in pregnant women to inform any drug-associated risks. The available data from the pharmacovigilance safety database and published literature on BRIDION use in pregnant women are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, there was no evidence of malformations following daily intravenous administration of sugammadex to rats and rabbits during organogenesis at exposures of up to 6 and 8 times, respectively, the maximum recommended human dose (MRHD) of 16 mg/kg. However, there was an increase in the incidence of incomplete ossification of the sternebra and reduced fetal body weights in the rabbit study at 8 times the MRHD, which is a dose level in which maternal toxicity was also observed. In a pre- and postnatal development study, sugammadex treatment resulted in an increase in early postnatal loss, which correlated with maternal behavior (increased incidence of pup cannibalism), at exposures equivalent to the MRHD and higher (see DATA). The background risk of major birth defects and miscarriage for the indicated population are unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data

Animal Data

In an embryofetal development study in rats, pregnant animals received daily intravenous administration of sugammadex at 0, 20, 100, and 500 mg/kg (0.2, 1, and 6 times the MRHD of 16 mg/kg/day, respectively, based on AUC comparison) during organogenesis (Gestational Days 6-17). No treatment-related maternal and embryofetal changes were observed.

In another embryofetal development study, pregnant New Zealand white rabbits received daily intravenous administration of sugammadex at 0, 20, 65, 200 mg/kg (0.6, 2, and 8 times the MRHD, respectively, based on AUC comparison) during organogenesis (Gestational Days 6-18). Fetal body weight decreases (10 and 14%, respectively) were observed in the offspring at maternal doses of 65 mg/kg and 200 mg/kg. In addition, incomplete ossification of sternebra, and unossified 1st metacarpal were noted at a maternal dose of 200 mg/kg/day. Maternal toxicity was also observed at 200 mg/kg. Considering the observed effects of sugammadex on bone [see NONCLINICAL TOXICOLOGY (13.2)], it is possible that these findings may be attributable to drug. There was no evidence of malformations at any dose.

In a prenatal and postnatal development study, pregnant rats were administered sugammadex intravenously at 0, 30, 120, and 500 mg/kg (0.3, 1, and 6 times the MRHD, respectively, based on AUC comparison) from Gestational Day (GD) 6 to Postnatal Day (PND) 21 (corresponding to the beginning of organogenesis through parturition and subsequent pup weaning). Postnatal loss during PND 1-4 was noted across control litters and treated litters from dams receiving sugammadex as a result of pup cannibalization by dams. Overall incidence of affected litters was 2, 1, 4, and 3 litters, respectively, at 0, 30, 120, or 500 mg/kg/day. The reason for the increased cannibalization is not known. An effect of sugammadex on steroidal hormones and/or pheromones cannot be ruled out. In addition, there were no drug-related effects on parturition in rats during evaluations for prenatal or postnatal development.

References:

Bridion (sugammadex) injection [prescribing information]. Whitehouse Station, NJ: Merck and Co., Inc.: 2021.

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Are there any known risks of administering sugammadex to a pregnant female (in any trimester) related to progesterone, baby development, or other mechanism?

Please see Tables 1-3 for your response.

Case series and Case reports

[1]Case Series

Singh et al. (2021)

 Twenty five obstetric patients, from 21 to 36 years of age, received sugammadex during surgical fetal interventions, abdominal cerclage (AC), or nonobstetric surgery during antenatal period. Doses of sugammadex administered ranged from 140mg to 460mg. 

No obstetric complications directly attributable to sugammadex administration were identified.

Preterm labor occurred in 12 patients, preterm premature rupture of membranes occurred in 8 patients, unplanned cesarean delivery occurred in 14 (out of 19) patients, neonatal loss occurred in one patient, new fetal anomalies occurred in one patient, and developmental delay in baby occurred in three patients. 

[2]Case report

Yilmaz et al. (2019)

 A 36-year-old, multiparous 38-week pregnant woman with multiple sclerosis was admitted to the operating room after 8 h of fasting for a cesarean delivery. The patient was administered 2 mg kg−1 sugammadex intravenously

At the end of the operation, sugammadex was preferred because of the persistence of the deep neuromuscular block, and a smooth course of extubation was achieved.

No other safety related issues were reported.

[3]Case report

Moriwaki et al. (2019)

 A 37-year-old woman at 34 weeks gestation, weighing 42.5 kg, underwent a cesarean section under general anesthesia for abruptio placentae. Postoperatively, sugammadex 4.7 mg/kg was administered at post-tetanic count 2, 163 min after rocuronium administration. The patient was also administered magnesium and nifedipine The patient experienced a prolonged neuromuscular bloackade due to to the treatment with magnesium or combination of magnesium sulfate with a calcium antagonist.  No other safety related issues were reported. 

[4]Case series

Mahmut et al. (2019)

15 pregnant patients underwent the ECT procedure who did not benefit from medical treatment or who did not want medical treatment. All of the patients received 1 mg/kg propofol with 0.6 mg/kg rocuronium. Eight mg/kg sugammadex was used to terminate the effects of the non-depolarizing neuromuscular blocking agents. 

The patients received a total of 95 ECT treatments.

Spontaneous abortion occurred in four patients, six patients gave birth by spontaneous vaginal delivery, and five patients delivered by cesarean section. Neonatal respiratory distress developed in only one fetus. 

Anesthesia management during ECT can be provided safely by using propofol and rocuronium-sugammadex in pregnancy in the postoperative period. However, there is a risk of abortion and neonatal respiratory distress in the use of ECT, especially in the first trimester period.

 [5] Case report

Soyoral et al. (2017)

 A 28-year-old 76 kg woman with myasthenia gravis was admitted at 39 weeks of gestation for a cesarean section.  Sugammadex was used (2 mg/kg) at the end of the surgery and was extubated without problem in 2 min after sugammadex.  No safety related adverse events associated with sugammadex were reported. 

 [6] Case report

Yamaoka et al. (2017)

 A 36-year-old primigravida (body weight, 65 kg; height, 167 cm) with no history of drug allergy or surgery underwent an elective cesarean section because of placenta previa.  The patient woke up approximately 10 min after the completion of the operation, and extubation was performed immediately following infusion of 200 mg sugammadex. An anaphylactic shock occurred following a single dose of sugammadex immediately after cesarean section.

 [7] Case report

Sengul et al. (2016)

  A 23-year-old, pregnant patient who was 75kg and 160cm, was diagnosed with Wolff-Parkinson-White Syndrome in the 22nd week of her pregnancy.  The patient was administered sugammadex 2mg/kg after the cesarean delivery.   There was no ECG change after administration of sugammadex. 

 [8] Case report

Kosinova et al. (2016)

 

 A 27-year-old woman was diagnosed with Becker type myotonia congenita at the age of 22. The patient underwent a schedule cesarean section at the gestational age of 39 weeks.  Sugammadex 4 mg/ kg IV was administered at the end of hte surgery.  No respiratory problems, no signs of residual neuromuscular blockade or worsening of pain were reported; however, the patient did report pain in the wound. 

[9] Case report

Garcia et al. (2012)

 A healthy 35-year-old 80 kg woman with myasthenia gravis was admitted at 34 weeks of gestation for worsening dyspnea and underwent a cesarean section. Rocuronium was reversed with sugammadex 200 mg (4 mg/kg of ideal body weight) Our patient still had persistent muscle weakness that prevented immediate tracheal extubation

 [10] Case report

 Puhringer et al. (2010)

 Seven pregnant patients ranging from 29 to 39 years of age received sugammadex 200mg to 300mg for reversal of rocuronium neuromuscular block after a cesarean section.   No adverse effects related to sugammadex or evidence of recurarization were observed in any patient.

[11] Case report

Weekes et al. (2010)

 A 38-year-old wheelchair-bound primigravida with transverse myelitis presented at 38 weeks of gestation for elective caesarean section.  Sugammadex 4 mg/kg was administered for complete reversal of blockade.  No safety related adverse events associated with sugammadex were reported. 
References:

[1] Singh S, Klumpner TT, Pancaro C, Rajala B, Kountanis JA. Sugammadex Administration in Pregnant Women: A Case Series of Maternal and Fetal Outcomes. A A Pract. 2021;15(2):e01407. Published 2021 Feb 24. doi:10.1213/XAA.0000000000001407
[2] Yılmaz R, Uzun ST, Reisli R. Sugammadex for Cesarean in a Patient with Multiple Sclerosis. Sisli Etfal Hastan Tip Bul. 2019;53(2):195-198. Published 2019 Jul 5. doi:10.14744/SEMB.2017.07108
[3] Moriwaki K, Kayashima K. Prolonged neuromuscular blockade and insufficient reversal after sugammadex administration in cesarean section under general anesthesia: a case report. JA Clin Rep. 2019;5(1):28. Published 2019 Apr 11. doi:10.1186/s40981-019-0248-8
[4] Karahan MA, Büyükfırat E, Binici O, et al. The Effects of Rocuronium-sugammadex on Fetomaternal Outcomes in Pregnancy Undergoing Electroconvulsive Therapy: A Retrospective Case Series and Literature Review. Cureus. 2019;11(6):e4820. Published 2019 Jun 3. doi:10.7759/cureus.4820
[5] Soyoral L, Goktas U, Cegin MB, Baydi V. Successful use of sugammadex for caesarean section in a patient with myasthenia gravis. Braz J Anesthesiol. 2017;67(2):221-222. doi:10.1016/j.bjane.2014.08.008
[6] Yamaoka M, Deguchi M, Ninomiya K, Kurasako T, Matsumoto M. A suspected case of rocuronium-sugammadex complex-induced anaphylactic shock after cesarean section. J Anesth. 2017;31(1):148-151. doi:10.1007/s00540-016-2280-4
[7] Sengul T, Saracoglu A, Sener S, Bezen O. The use of sugammadex in a pregnant patient with Wolff-Parkinson-White syndrome. J Clin Anesth. 2016;33:1-4. doi:10.1016/j.jclinane.2015.12.023
[8]Kosinova M, Stourac P, Harazim H, Janku P, Huser M, Vohanka S. Anaesthesia and orphan disease: rocuronium and sugammadex in the anaesthetic management of a parturient with Becker's myotonia congenita. Eur J Anaesthesiol. 2016;33(7):545-547. doi:10.1097/EJA.0000000000000442
[9] Garcia V, Diemunsch P, Boet S. Use of rocuronium and sugammadex for caesarean delivery in a patient with myasthenia gravis. Int J Obstet Anesth. 2012;21(3):286-287. doi:10.1016/j.ijoa.2012.02.006
[10] Pühringer FK, Kristen P, Rex C. Sugammadex reversal of rocuronium-induced neuromuscular block in Caesarean section patients: a series of seven cases. Br J Anaesth. 2010;105(5):657-660. doi:10.1093/bja/aeq227
[11] Weekes G, Hayes N, Bowen M. Reversal of prolonged rocuronium neuromuscular blockade with sugammadex in an obstetric patient with transverse myelitis. Int J Obstet Anesth. 2010;19(3):333-336. doi:10.1016/j.ijoa.2010.03.009

 

The Effects of Sugammadex on Progesterone Levels in Pregnant Rats

Design

Animal study

Objective

Evaluate the effects of sugammadex on progesterone levels in pregnant rats as well as on the physiological course of the pregnanc

Study Groups

Pregnant Winster Albino rats (n=26)

Group K, n=6 (control)

Group S, n=10 (sugammadex 30mg/kg)

Group SR, n=10 (sugammadex 30mg/kg and rocuronium) 

Methods

The drugs were administered in a double-blind fashion. The weight of the rats was measured using a precision balance.All rats underwent daily abdominal examination during their pregnancy. On the 7th day of pregnancy, the rats were monitored for 2 hours after the administration of sedatives and analgesic drugs, and blood samples were collected. All rats were assigned a unique number, and each pregnant rat was placed in a separate cage. On the 8th day of pregnancy, all rats underwent abdominal and vaginal examination.

Outcome Measures

Progesterone level, mean duration of pregnancy, and number of offspring. 

Results

 There was no significant difference between the groups in terms of mean weight measured on the 7th day of pregnancy, progesterone levels, duration of pregnancy, and the number of offspring (p>0.05).  

In all of the study groups, no stillbirth or miscarriage was observed in the rats. All of the offspring in the three groups appeared to be macroscopically normal without any deformity or malformation.

Study Author Conclusions

Sugammadex does not appear to affect the progesterone levels in pregnant rats in the first trimester and the clinical course. Successful completion of pregnancy and the absence of stillbirth or miscarriage will guide future studies about the use of sugammadex, particularly in the first trimester of the pregnancy.

InpharmD Researcher Critique

Note that this is an animal study; therefore, additional studies would need to be conducted to further evaluate the safety of sugammadex in pregnant females. 



References:

Et T, Topal A, Erol A, Tavlan A, Kılıçaslan A, Uzun ST. The Effects of Sugammadex on Progesterone Levels in Pregnant Rats. Balkan Med J. 2015;32(2):203-207. doi:10.5152/balkanmedj.2015.15502

 

Low-Dose or High-Dose Rocuronium Reversed with Neostigmine or Sugammadex for Cesarean Delivery Anesthesia: A Randomized Controlled Noninferiority Trial of Time to Tracheal Intubation and Extubation

Design

Randomized, parallel group, single-blinded, non-inferiority, controlled study; N= (240)

Objective

Determine whether rocuronium and sugammadex confer benefit in time to tracheal intubation and other neuromuscular blockade outcomes compared with succinylcholine, rocuronium, and neostigmine in women undergoing general anesthesia for cesarean delivery.

Study Groups

Rocoronium (rocuronium 1 mg/kg and reversed with sugammadex 2–4 mg/kg) n=120

Succhinylcholine (succinylcholine 1 mg/kg for induction, rocuronium 0.3 mg/kg for maintenance, and neostigmine 0.03 mg/kg for reversal of the neuromuscular blockade), n=120

Inclusion Criteria

All women aged 14 to 60 years admitted to the obstetric ward in Brno or Olomouc University Hospital for delivery were eligible to participate in the study. Inclusion criterion for enrollment was cesarean delivery scheduled under general anesthesia.

Exclusion Criteria

Indicated and performed neuraxial blockade, anesthesiologist or obstetrician opposition to patient inclusion, allergy or intolerance to ≥1 of the study drugs or known allergies or reactions to iodine, and patient refusal or no written informed consent.

Methods

The study took place at two different hospitals: University Hospital in Brno and University Hospital in Olomouc in the Czech Republic. 

 In the ROC group, sugammadex reversal was administered when the PTC was ≥1. Low-dose sugammadex (2 mg/kg) was administered if the TOF count was ≥1 and high-dose (4 mg/kg) was used for deeper neuromuscular blockade (PTC ≥1). 

Intubating conditions were assessed using resistance to laryngoscopy (none, slight, and severe), position of vocal cords (medial, paramedial, partially abducted, and fully abducted), laryngoscopic view (Cormack-Lehane), response to intubation attempt (none, cardiovascular-blood pressure and/or pulse increase of 20% from baseline, and movement of limbs). 

Complications during anesthesia and the perioperative period were recorded. Neonatal outcome was evaluated using Apgar scores at 1, 5, and 10 minutes assessed by an experienced neonatologist and umbilical artery blood gas analysis, 

Duration

Not provided

Outcome Measures

Primary endpoint was the time from induction of anesthesia to tracheal intubation

Secondary outcomes were differences in intubating conditions, incidence of intraoperative anesthesia complications, neonatal outcomes, and the time from the completion of surgical skin closure to tracheal extubation.

Baseline Characteristics

  

Rocoronium (n=120)

(Mean, SD)

Succhinylcholine (n=120)

(Mean, SD)

 

Age, years 

  31 (5) 31 (5) 

BMI at delivery (kg/m2)

  30 (6)  30 (6) 

Gestational age (wk)

 37(3) 38 (2) 

Type of cesarean delivery, intrapartum

 64  62 

 

Results

The mean time to tracheal intubation was 2.9 seconds longer in those receiving rocuronium compared with succinylcholine (95% CI, −5.3 to 11.2 seconds). 

 There were no differences between groups in the incidence of 10-minute Apgar score of ​<7; however, the incidene of low Apgar scores was greater in the rocoronium group than in the succhinycholine group at 1 and 5 minutes.  There were no significant differences in neonatal outcome among subjects underoing scheduled cesarean delivery.

In patients receiving rocuronium and sugammadex, the total procedure time was approximately 7 minutes longer than that in patients receiving succinylcholine, rocuronium, and neostigmine. 

Adverse Events

There were no differences in the incidence of intraoperative anesthesia complications or complications in the 24-hour follow up.

Study Author Conclusions

Rocuronium for rapid-sequence induction was found to be noninferior to succinylcholine with respect to the time to tracheal intubation but was accompanied by more frequent absence of laryngoscopy resistance and lower incidence of myalgia than succinylcholine for cesarean delivery under general anesthesia

InpharmD Researcher Critique

This study was not double-blinded which may have impacted the evaluation of complaints after the 24 hour post surgery period. In addition, the generalizability may limited to clinical practice in which protocols do not includ neuromusclar blockade with a nondepolirazing muscle relaxant after recovery from succinylcholine. 



References:

Stourac P, Adamus M, Seidlova D, et al. Low-Dose or High-Dose Rocuronium Reversed with Neostigmine or Sugammadex for Cesarean Delivery Anesthesia: A Randomized Controlled Noninferiority Trial of Time to Tracheal Intubation and Extubation. Anesth Analg. 2016;122(5):1536-1545. doi:10.1213/ANE.0000000000001197