Hidden Perioperative Risk for Contraceptive Failure

Case Report

A 24-year-old woman presents for cholecystectomy under general anesthesia. She reports no prior medical conditions, denies tobacco use, drinks socially, and denies illicit drug use. She is currently sexually active and uses a combined oral contraceptive (COC) as her primary method of birth control. She had one prior anesthetic with significant postoperative nausea and vomiting (PONV).

Question

Use of which of the following medications perioperatively will require counseling on the need for an additional method of birth control postoperatively?

Discussion

Hormonal contraceptives are common in the United States, with ∼14% of American women taking COCs for pregnancy prevention. ¹ Combined hormonal contraceptives, usually consisting of ethinyl estradiol and synthetic progestin, work systemically to halt ovulation by reducing luteinizing hormone and increasing the circulating levels of sex hormone-binding globulin. ² The systemic effectiveness of COCs is dependent on estrogens and synthetic progestins circulating in the blood and acting on the hypothalamus–pituitary–ovary axis to prevent ovulation. ³ Oral contraceptives undergo first-pass metabolism in the liver by cytochrome P450, namely CYP3A4 and CYP2C9. ⁴

Other hormonal contraceptive methods, including patches, rings, injections, hormonal intrauterine devices (IUDs), and implants, release hormones into surrounding tissue or the circulation to suppress ovulation. Drugs that disrupt the metabolism or circulation of sex steroid hormones contained in oral contraceptives and other delivery systems could result in ovulation and potentially unexpected pregnancy. ⁵ For this reason, it is essential for practitioners and patients to be cognizant of possible drug–drug interactions that negate the effects of oral contraceptives. Medications important to consider perioperatively are sugammadex, aprepitant, and it's prodrug, fosaprepitant.

Neuromuscular blocking agents are routinely used in anesthesia to facilitate endotracheal intubation and muscle relaxation. Rocuronium and vecuronium are commonly used nondepolarizing neuromuscular blocking agents. Approved by the Food and Drug Administration (FDA) in 2015, sugammadex is an altered gamma-cyclodextrin given to reverse the effects of rocuronium and vecuronium. It is increasingly used as the drug of choice for reversal of neuromuscular blockade induced by these agents. Sugammadex selectively binds to the lipophilic core of rocuronium and vecuronium, making them unable to bind at the neuromuscular junction thus restoring muscle activity. ⁶ Sugammadex binds progesterone with high affinity and may potentially bind estrogens and progestins used in hormonal contraceptives, thereby lowering the free plasma concentration of these hormones and reducing their effectiveness. ⁷

The administration of sugammadex approximates one or more missed doses of an oral contraceptive and thus a backup method of contraception is recommended after its use. ⁸ In addition, the reduced circulating hormone levels may decrease the effectiveness of other nonoral hormonal contraceptives, including patches, rings, injections, hormonal IUDs, and implants. The FDA and Society for Obstetric Anesthesia and Perinatology (SOAP) both endorse the use of barrier contraception for 7 days after administration of sugammadex for patients using hormonal contraceptives, including combined oral, transdermal, intrauterine, and vaginal as well as progestin-only forms. ^{9 –11}

Aprepitant is an antiemetic and acts as a selective competitive antagonist of G-protein coupled neurokinin-1 receptors, and are used perioperatively to prevent PONV. ¹² Aprepitant attenuates the emetic reflex by acting in both the central and peripheral nervous system. Aprepitant reduces the effectiveness of all hormonal contraceptives, including birth control pills, patches, rings, injections, hormonal IUDs, and implants, through its effect on ethinyl estradiol and norethindrone. ^13,14 Although the exact mechanism of drug interaction is unclear, aprepitant has shown to be a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4.

Aprepitant is also an inducer of CYP2C9. ¹⁵ Induction of CYP3A4 and CYP2C9 can increase the rate of metabolism of contraceptives, effectively reducing the concentration of circulating hormones. ¹⁶ The overall consequence is similar to sugammadex but lasts for a longer duration. For that reason, nonhormonal methods of contraception or abstinence are advised for 28 days–2 months after administration of aprepitant. ¹⁵

Despite these recommendations, counseling is not always provided regarding the need for alternate birth control with sugammadex and aprepitant use. In fact, one study found only 1 of 134 women using hormonal contraceptives were counseled perioperatively. ⁷ Although electronic medical records have enabled individual institutions to create alerts and educational content, there is still a need for in-person counseling and informed consent. Health care providers should discuss possible drug interactions with the patient both preoperatively and postoperatively.

Anesthesia providers could also opt to use medications that do not have interactions with hormonal contraceptives, while considering the risks and benefits of these alternative medications (Table 1). For example, although neostigmine and glycopyrrolate can be used for reversal of muscle relaxants, sugammadex has advantages over neostigmine, including prompt and complete ability to antagonize profound neuromuscular blockade, hemodynamic stability, and rare adverse effects. Although there are many antiemetic alternatives to aprepitant, including ondansetron, granisetron, promethazine, olanzapine, and droperidol, these choices may have undesirable side effects that may limit their use.

Anesthesiologists, proceduralists, and surgeons must consider the consequences of drugs interacting with hormonal contraceptives when administering and prescribing medications perioperatively. Although anesthesiologists select and administer most perioperative medications, many other physicians interact with patients during this period and should be aware that these medications may have lasting effects. Often primary care physicians, surgeons, and proceduralists see patients before surgery and have an essential role of setting expectations and introducing potential perioperative issues. In addition, aprepitant is used to treat nausea by physicians outside of the operative setting.

This medication interaction is relevant and important to those who prescribe them such as primary care physicians, hematologists, oncologists, and gastroenterologists among others. When administering these medications, physicians should clearly communicate the need for alternative contraceptive methods after drug administration of sugammadex and aprepitant. Otherwise, patients may be unaware that they received these medications and the possible interactions with their contraceptive regimen. Currently, the potential for failure of hormonal contraceptives after receiving sugammadex or aprepitant is primarily addressed in the recovery room after the administration of these medications. ⁸

Anesthesiologists and perioperative physicians should consider discussing these risks with the patient before their administration so patients can provide input on the likelihood of using an alternative birth control method and the risk of an unintended pregnancy. Providers should consider an informed consent discussion preoperatively, counseling patients after the surgery, and the use of alternative medications shown to have similar effectiveness and outcomes without negating the effectiveness of hormonal contraceptives. Further research is needed to better understand the actual risks of hormonal failure after sugammadex and aprepitant administration, including but not limited to consequences such as menstrual cycle reinitiation, unintended pregnancy, interruption of gender affirming, and menopause hormone therapies.

Answer: (E) Both B (aprepitant) and D (sugammadex)