During pregnancy, significant physiological changes occur owing to increased estrogen and progesterone levels, beginning in the first trimester, peaking at term and labor, and gradually reversing a few weeks postpartum [9]. Pregnancy-related physiological changes involve most organs and affect the pharmacokinetic profile of medications [10,11]. Decreased gastrointestinal motility and increased gastric pH affect drug absorption. Increased total body water, plasma volume, and capillary hydrostatic pressure lead to a significantly increased volume of distribution. Decreased concentrations of drug-binding proteins increase the bioactivity of certain drugs. Increased cardiac output induces greater hepatic and renal blood flow, resulting in the increased clearance of some medications.

However, information regarding pharmacokinetic changes or dosage requirements is lacking for most drugs used during pregnancy [12]. Moreover, it is often unclear whether altered pharmacokinetics lead to changes in drug efficacy or to adverse effects. Unfortunately, the use of sugammadex during pregnancy is not exempt. As sugammadex has no affinity for plasma proteins when administered intravenously, it immediately encapsulates rocuronium in a 1:1 molar ratio [13,14]. This leads to a concentration gradient that shifts rocuronium from the peripheral compartment (neuromuscular junction) to the central compartment (plasma), where it is encapsulated by sugammadex [15]. The sugammadex-rocuronium complex is highly soluble, and urinary excretion is the major route for its elimination without being metabolized by the liver [13].

Considering the physiological changes in pregnant women and pharmacokinetic properties of sugammadex, several analogies can be made. First, an increase in total body water increases the volume of distribution of the hydrophilic drug, which lowers the plasma concentration. The glomerular filtration rate (GFR) increases during pregnancy, and for drugs excreted by glomerular filtration, renal clearance parallels the changes in GFR during pregnancy [16]. However, the extent to which volume distribution increases and whether the dose of hydrophilic drugs should be increased remain unclear. Unlike the uniform increase in the GFR during pregnancy, the effect of renal tubular transport on renal clearance varies among drugs. Therefore, there are limitations in theoretically estimating the efficacy and safety of sugammadex during pregnancy.

Sugammadex is a modified γ-cyclodextrin with a lipophilic core and hydrophilic periphery and a molecular weight of 2,178 daltons. The addition of eight side chains extended the cavity size to achieve a better fit for steroidal NMBA [17]. In addition, negatively charged carboxyl groups were added at the ends of the eight side chains to maintain structural integrity and enhance electrostatic binding to the positively charged quaternary nitrogen of rocuronium [6]. Theoretically, it is difficult for sugammadex to pass through the placenta owing to its large molecular size and negatively charged characteristics [18].

Preclinical studies by Merck have reported conflicting results [19]. In an embryo-fetal development study, pregnant rats received daily intravenous administration of sugammadex up to six times the maximum recommended human dose (MRHD). No treatment-related maternal or embryo-fetal changes were observed. In another embryo-fetal development study, pregnant New Zealand white rabbits received daily intravenous administration of sugammadex up to eight times the MRHD. A decrease in fetal body weight was observed in the offspring at maternal doses of 65 and 200 mg/kg. Moreover, incomplete ossification of the sternum and an unossified first metacarpal were found in the offspring at a maternal dose of 200 mg/kg/day. Furthermore, maternal toxicity was observed at 200 mg/kg. Considering that bone retention of sugammadex occurred in rats after intravenous injection with a mean half-life of 172 days, these findings may be attributed to the drug [19]. No evidence of malformation was observed at any dose. In a prenatal and postnatal development study, pregnant rats were intravenously administered sugammadex at concentrations up to six times the MRHD dose. There were no drug-related effects on rat parturition during prenatal or postnatal development. However, there was postnatal loss due to pup cannibalization. Therefore, effects of sugammadex on steroidal hormones and pheromones should not be excluded.

The effect of drugs on fetal neuronal development is an emerging issue. Palanca et al. [20] reported that sugammadex alone promoted neural apoptosis in primary cultures. Neural apoptosis was further promoted when sugammadex was used alone rather than in combination with steroidal NMBA in primary cultures [21]. It was concluded that sugammadex caused depletion of neuronal cell cholesterol, resulting in oxidative stress and neuronal apoptosis. However, this does not occur in vivo because the mature blood-brain barrier (BBB) prevents the passage of sugammadex. Thus, sugammadex may pass through a compromised BBB, such as an immature or damaged one. The potential of anesthetics to cause neuroapoptosis and other neurodegenerative changes in the developing brain has become evident in animal studies over the past 20 years [22,23]. One study postulated that the co-administration of sugammadex with neonatal sevoflurane may exacerbate neuronal apoptosis due to changes in BBB integrity [24]. Neonatal mice exposed to 2% sevoflurane for 6 h developed BBB ultrastructural abnormalities. The co-administration of sugammadex with sevoflurane in neonatal mice further increased neuroapoptosis in the brain compared to 2% sevoflurane alone, whereas sugammadex alone did not induce apoptosis. This possibility should be considered when administering sugammadex with inhaled anesthetics in pregnant women. However, further studies are required to confirm these findings.

As sugammadex encapsulates steroidal NMBA, it may also bind to other appropriately sized steroidal substances. Progesterone is such a substance and in vitro binding studies suggest that progesterone levels may decrease by approximately 34% when exposed to sugammadex [19]. Decreased progesterone levels can lead to two serious adverse effects. One is failure to maintain early pregnancy, and the other is hormonal contraceptive failure.

Two animal studies that investigated the effect of sugammadex on progesterone levels in pregnant animals have been conducted [25,26]. Pregnant rats were randomly assigned to three groups and injected under sedation on the 7th day of gestation: control, sugammadex 30 mg/kg, and rocuronium 3.5 mg/kg + sugammadex 30 mg/kg [25]. Blood samples were obtained 35 min after injection to determine progesterone levels. Progesterone levels were not significantly different between the groups, and successful completion of pregnancy and absence of stillbirths or miscarriages were reported. Pregnant rabbits were randomly divided into three groups: control, rocuronium administered at the onset of general anesthesia (GI group), and rocuronium + sugammadex administered 60 min after general anesthesia (GII group) [26]. In the GII group, progesterone levels at 60 and 90 min after general anesthesia were significantly lower than the baseline progesterone levels. In addition, the progesterone levels at 60 and 90 min after general anesthesia were significantly lower in the GII group than those in the GI group. However, all pregnancies were successful without early birth or stillbirth. Because studies are still lacking and the results are inconclusive, it cannot definitely be concluded that sugammadex affects pregnancy by lowering progesterone levels.

Generally, low plasma protein binding, low molecular weight, and highly lipophilic and cationic drugs favor increased drug excretion into breast milk [27]. In contrast, sugammadex is large, hydrophilic, and has a half-life of 2 h and pKa of 2.82 [6]. Therefore, it is appropriate to predict minimal excretion of sugammadex into breast milk. Moreover, the oral absorption of sugammadex is thought to be low; therefore, it can be assumed that the amount of sugammadex delivered to breastfed infants is negligible. In a milk excretion study in rats, 20 mg/kg sugammadex was injected intravenously on postnatal day 9 and the maximum drug level was achieved at approximately 30 min [19]. The oral administration of sugammadex via milk did not induce adverse effects on survival, body weight, or physical or behavioral development in rats. However, there is no published evidence to support this.

In cesarean sections, neuraxial anesthesia is preferred over general anesthesia; however, general anesthesia is still administered under some conditions [28]. Because pregnancy-related physiological changes peak at term and delivery, the efficacy and safety profiles are of primary concern when using sugammadex after fetus delivery. A randomized controlled noninferiority trial was conducted to show that a high-dose of rocuronium can achieve intubation conditions comparable to those of succinylcholine for cesarean delivery [29]. In the rocuronium group, 2 mg/kg sugammadex was administered if the train of four (TOF) count was ≥ 1 and 4 mg/kg sugammadex was used if the post-tetanic count (PTC) was ≥ 1. Among the 120 patients, the time from neuromuscular blockade reversal to TOF ratio > 0.9 was 104 ± 63 (mean ± SD) s. In addition, no signs of residual blockade or side effects were observed. These findings are similar to those reported in other clinical studies [30,31].

The sugammadex doses required for the routine reversal of moderate or deep blocks during cesarean section appear to be sufficiently effective and safe at doses equivalent to adult doses (2-4 mg/kg). In emergencies, such as cannot intubate and cannot ventilate (CICV), a high-dose of sugammadex (16 mg/kg) must be administered for immediate reversal before fetal birth; however, these cases have not yet been reported. Recent large multicenter studies showed difficult intubation rates of 2.0-5.4% which is similar to the general surgical population (4.4%) [32-34]. In contrast, failed intubation rate is higher in pregnant women (0.12-0.53%) compared with that in the general surgical population (0.06%) [32,33,35]. In 2015, the Obstetric Anesthetists’ Association and Difficult Airway Society developed the first national obstetric guidelines for difficult airway management [36]. The guidelines recommend considering high-dose sugammadex administration for immediate reversal of CICV. Although there is no evidence for the efficacy and safety of high-dose sugammadex in pregnant women and fetuses, it is reasonable to consider sugammadex administration because the risks of exposure to severe hypoxia could be more harmful than the potential risk of using high doses of sugammadex.

Unlike cesarean sections, pregnant women undergoing non-obstetric surgery do not deliver a fetus and must continue their pregnancy. Therefore, few clinical studies have reported the use of sugammadex in such cases, and these have only recently been published in the form of case series [18,37-40]. Theoretically, the passage through the placenta or BBB is limited; however, animal experiments have shown worrisome results [19,24]. In 2019, an interesting case of sugammadex placental transfer was reported [37]. A woman at 29 weeks of gestation required an intrauterine transfusion for Rh (D) alloimmunization. During the intrauterine transfusion procedure, maternal respiratory distress occurred because of the intramyometrial injection of rocuronium, which was intended to be administered intramuscularly to the fetus. After the administration of sugammadex (100 mg), the patient’s respiratory distress resolved. After the patient had stabilized, additional rocuronium was administered to the fetal buttocks. Interestingly, adequate paralysis was achieved in the fetus without sustained paralysis induced by the maternal sugammadex injection, suggesting limited maternal-fetal placental transfer of sugammadex.

Recently, several case series and a multicenter retrospective study on maternal and fetal outcomes after sugammadex use in pregnant women have been published [18,38-40] (Table 2). In two case series, patients were at 4-26 gestational age and received 0.7-4.3 mg/kg sugammadex. Although preterm premature rupture of membranes (N = 8/25) and preterm labor (N = 12/25) occurred, none of these episodes occurred within 2 weeks of receiving sugammadex [18]. In another case series, only one patient experienced preterm labor; however, it was induced by severe preeclampsia and developed 12 weeks after sugammadex administration [38]. In a multicenter retrospective observational study with 73 patients who received sugammadex and 51 patients who did not [39], the gestational age was 15.0 ± 5.1 (mean ± SD) weeks and the median total dose of sugammadex was 200 mg. Miscarriages and preterm births within 4 weeks of sugammadex administration were not significantly different between the patients with and those without sugammadex exposure. In one study, a larger dose of sugammadex (8 mg/kg) was administered to 15 patients who underwent electroconvulsive therapy [40]. Spontaneous abortion occurred in one patient and one infant developed neonatal respiratory distress. Moreover, no patients experienced preterm delivery or labor induced by sugammadex administration. Although these studies did not show obvious detrimental effects of sugammadex on maternal and fetal outcomes, their retrospective nature and small sample size cannot confirm the safety concerns.

Few clinical studies have examined steroidal hormone levels after sugammadex injection [41,42]. One study investigated the hormonal profiles of 50 young male patients randomly divided into N (neostigmine) and S (sugammadex 4 mg/kg) groups [42]. Sugammadex showed no adverse effects on progesterone and cortisol levels, while it was associated with a temporary increase in aldosterone and testosterone levels. They explained that sugammadex has no effect on progesterone levels because of its relatively low affinity (120 to 700 times lower than that of rocuronium) and tight binding to plasma proteins. A more recent prospective observational study was conducted to investigate the effects of sugammadex on perioperative estrogen and progesterone levels in premenopausal women aged 18-50 years [41]. After 240 min of sugammadex administration, progesterone in patients taking oral contraceptives tended to decrease; however, it was non-significantly decreased within 20% below baseline, far less than the 34% expected pharmacokinetically. Nonetheless, they did not consider the menstrual cycle or surgical stress, which significantly affect hormonal levels. In addition, because endogenous progesterone is suppressed by oral contraceptives (exogenous progesterone), a small change in progesterone exaggerates the percentage change. Both authors suggested that statistically significant changes in hormonal levels were borderline or temporary and would be clinically insignificant.

However, investigating the association between unexpected pregnancies and sugammadex use is difficult. Lazorwitz et al. [43] reported a single case (0.7%; 95% CI: 0-4.1%) of unexpected pregnancy after sugammadex administration in 134 patients using hormonal contraceptives. Based on the ultrasound measurements, the estimated date of conception was 19 days after sugammadex administration. Although there are no clinical reports of unintended pregnancy due to sugammadex-progesterone interaction, the manufacturer advises seriously considering this interaction. They recommended that if an oral contraceptive is taken on the same day that sugammadex is administered or non-oral hormonal contraceptives are used, the patient must use an additional non-hormonal contraceptive method or a backup method of contraception for the next 7 days [19]. Unintended pregnancy can be personally, socially, and economically burdensome; therefore, patients should be informed and educated even if there is a slight possibility. However, several studies show that 78-94% of anesthesia providers are aware of the risk of oral contraceptive failure with sugammadex, whereas only 20 to 33% of anesthesia providers discuss this with their patients [44,45]. Appropriate education and policies are required to overcome discrepancies between knowledge and practice. Anesthesia providers must assess the risk of oral contraceptive failure induced by sugammadex preoperatively and screen women of childbearing age for oral contraceptive administration. If women are at risk of oral contraceptive failure, anesthesia providers should counsel about sugammadex and its alternatives (acetylcholinesterase inhibitors) and make decisions regarding the choice of NMB antagonists. After surgery, information should be provided through a take-home leaflet or letter to improve postoperative recall [46,47]. Along with these perioperative processes, education of relevant medical staff and feedback from audits are necessary.

Currently, there is no clinical evidence regarding the use of sugammadex during breastfeeding [48]. However, owing to the biochemical and pharmacokinetic characteristics of sugammadex and preclinical evidence, sugammadex is acceptable for use during breastfeeding [49]. In contrast, a statement published by the Society for Obstetric Anesthesia and Perinatology (SOAP) disagrees with immediate breastfeeding [8]. According to the World Health Organization recommendations, breastfeeding should be initiated within the first hour of birth [50]. If a mother who received sugammadex after cesarean section began breastfeeding within 1 h after delivery, she may have breastfed at the peak concentration of sugammadex. Moreover, in the early postpartum period, large gaps between mammary alveolar cells enhance the delivery of maternal proteins to breast milk and may allow sugammadex to pass through breast milk [51]. Immature metabolism and renal function delay sugammadex clearance in infants. Therefore, SOAP recommends the use of acetylcholine esterase inhibitors and, if not, pumping and discarding breast milk for the first 12-14 h after surgery [8].