With both the increased utilization of regional anesthesia and routine availability of supraglottic devices and video laryngoscopy, life-threatening airway failures in obstetric anesthesia are becoming increasingly rare. In a cohort of 14,000 patients receiving general anesthesia for cesarean delivery, the incidence of difficult and failed tracheal intubation was higher among pregnant compared to nonpregnant patients.1 While there were no airway-related deaths in this cohort, the incidence of maternal mortality from failed intubation has been estimated at 2.3 per 100,000 general anesthetics for cesarean delivery, or 1 death for every 90 failed intubations.2 Emergence from anesthesia, extubation, and the immediate postanesthetic period are also vulnerable periods for pregnant and nonpregnant patients alike. In a retrospective study of anesthesia-related mortality in pregnant patients from the state of Michigan between 1985 and 2003, 8 anesthesia-related deaths were reported. All deaths occurred during emergence or recovery from general anesthesia and were attributed to airway obstruction or hypoventilation.3 Incomplete neuromuscular blockade antagonism is a known risk factor for postoperative respiratory failure and need for tracheal reintubation among nonpregnant patients.4,5 The same risk likely holds true for pregnant patients, with the fundamental difference being the potentially catastrophic sequelae of hypoxia and hypercarbia on the developing fetus. Following pharmacologic neuromuscular blockade antagonism with neostigmine, the incidence of residual blockade and coinciding weakness has been reported to be as high as 60%.6 Sugammadex (Bridion, Merck), is a novel reversal alternative that results in rapid and effective reversal of aminosteroid-induced paralysis independent of blockade depth at the time of reversal.7 Implementation of sugammadex for paralytic reversal in nonpregnant adult patients has led to a 30% reduction in major postoperative pulmonary complications.8 The same may be assumed for pregnant patients, despite a lack of evidence in this population. Following its 2015 approval by the US Food and Drug Administration (FDA), sugammadex has rapidly gained acceptance as a safe and superior agent for antagonism of aminosteroid paralytic agents. Yet, there remain concerns regarding its use in pregnancy. A simulation-based pharmacokinetic/pharmacodynamic model cited in the 2008 product monograph by Merck Pharmaceutical describes an interaction between 4 mg/kg of sugammadex and progestogen that could lead to a decrease in progestogen levels by 34%, akin to taking an oral contraceptive 12 hours late.9 The results of that computer-generated model about the purported progestogen binding capability of sugammadex have subsequently been assumed to pose a theoretical risk of inducing preterm labor (PTL). On April 22, 2019, the Society for Obstetric Anesthesia and Perinatology (SOAP) published an ad hoc task force statement regarding the use of sugammadex during pregnancy, citing the aforementioned study, to avoid its use in early pregnancy as “in vitro studies indicate sugammadex binds to and encapsulates progesterone.”10 The admonitions against sugammadex use in pregnant patients put forth by Merck, SOAP, and the lack of FDA approval carry substantial weight from both a medical and medicolegal standpoint. Despite this, a growing number of case reports are being published regarding the use of sugammadex in pregnant patients remote from delivery.11–13 A 2021 series described 6 cases of nonobstetric surgery under general anesthesia in pregnant women between 8 and 24 weeks gestation, all of whom received sugammadex for reversal. Five of the 6 patients subsequently delivered at term. While 1 patient was admitted at 35 weeks 6 days gestation, she was induced in the setting of preeclampsia with severe features. No adverse maternal or fetal outcomes were reported in any of the 6 cases.11 Another 2021 series described obstetric and fetal outcomes for 25 pregnant patients requiring general anesthesia who received antenatal sugammadex between 4 and 27 weeks gestation. Although 12 of the patients experienced PTL, the onset of PTL was >2 weeks from the date of sugammadex administration, and all operations were fetal surgeries where the risk of PTL was already notably increased.14 Two additional cases in the recent literature involved the inadvertent maternal administration of rocuronium during an ambulatory fetal intrauterine transfusion procedure and a transesophageal echo preceding electrical cardioversion for persistent, symptomatic atrial fibrillation. The patient’s gestational ages were 29 and 34 weeks, respectively, and they both received sugammadex without periprocedural complications or reported PTL.12,13 It is possible that more anesthesiologists would choose to use sugammadex if they understood that the manufacturer’s FDA-approved package insert warning and SOAP recommendation stemmed from a potential misinterpretation and unsupported extrapolation of preclinical data regarding progesterone and progestogen.9 Progesterone is an endogenous sex hormone secreted initially by the ovaries and subsequently by the placenta during pregnancy and is vital for both the maturation of the uterus and the prevention of premature myometrial contractility.15 In contrast, progestogen, or progestin, refers to a synthetic form of progesterone. Progestogens have a different chemical structure and pharmacokinetic profile from endogenous progesterone.16 This subtle distinction has important, potentially substantial clinical implications that have been illustrated in a prior animal study. Pregnant, first-trimester Winster Albino rats (n = 26) were divided into 3 treatment groups and received an injection of either: 1.5 mL of physiologic serum (control), 30 mg/kg of sugammadex, or 30 mg/kg of sugammadex combined with 3.5 mg/kg of rocuronium. None of the rats in the study developed PTL, and no significant difference was found in the measured serum progesterone levels between groups, even at supratherapeutic human doses in the absence of a known binding substrate.17 Careful consideration of these distinctions and the evidence raises questions regarding the validity of the manufacturer’s warning and coinciding SOAP statement. Ideally, the theoretical risk of progesterone binding and PTL would be better elucidated in a clinical trial of sugammadex use in pregnant patients. However, this is infeasible as drug trials almost universally exclude pregnant patients due to concern for fetal teratogenicity and potential effects on organogenesis, growth, and lactation. As a result, these drugs are not approved by the FDA for use in the obstetric population, and their administration is considered off-label. For a drug manufacturer to legally market a drug in the United States, it must first be approved by the FDA. The process begins with an investigational new drug application (IND), which is required to test the product in human subjects, followed by a new drug application (NDA), which compiles the data analysis from the phased clinical trials (I–III). The NDA is then reviewed by the FDA for the safety and efficacy, appropriateness of proposed labeling, and identity, strength, quality, and purity of the drug. Upon FDA approval of an NDA, a drug can enter the US market with continual FDA oversight of its activity, including reporting of research and adverse events, surveillance, information dissemination, and off-label use.18 Given this onerous process, how are providers to determine if sugammadex is safe in pregnancy? Providers who are currently using sugammadex could, and should, publish large retrospective studies evaluating the incidence of PTL and other potential maternal and fetal complications. Additionally, a registry could be established to monitor the safety and efficacy of ongoing sugammadex administration. With the available evidence regarding sugammadex including superiority over neostigmine and concomitant decrease in postoperative pulmonary complications, and lack of evidence to suggest maternal or fetal harm, we urge consideration of sugammadex for aminosteroid neuromuscular blockade reversal for nonobstetric surgery independent of gestational age. In conjunction with the current available evidence from the pharmaceutical company, the FDA, and aligning societal guidelines, providers will need to weigh the risks and benefits of sugammadex use and decide how to counsel their patients should they choose to administer it. Establishing safety for a new drug with potential implications for the fetus is challenging. Our hope is that a careful reexamination of the available evidence along with prospective data collection will better help providers delineate the ideal reversal agent for both the pregnant patient and the fetus. DISCLOSURES Name: Ian N. Gaston, MD. Contribution: This author helped conceive, design, and format this article. Conflicts of Interest: None. Name: Elizabeth M. S. Lange, MD. Contribution: This author made substantial contributions to conception, content, design, and formatting of this article. Conflicts of Interest: None. Name: Jason R. Farrer, MD. Contribution: This author made substantial contributions to content, design, and formatting of this article. Conflicts of Interest: None. Name: Paloma Toledo, MD, MPH. Contribution: This author made substantial contributions to the conception, content, design, and formatting of this article. Conflicts of Interest: P. Toledo is a has received speaker fees from Pacira. This manuscript was handled by: Jill M. Mhyre, MD.
Search from 250 M+ research papersSearch from 250 M+ research papers
Feb 22, 2024
H. Corner + 2
Open Access