Peer Review: Contraception Care

NAVIGATING THE MURKY WATERS SURROUNDING CONTRACEPTION CARE

AUTHORS

Morgan Herring, PharmD, BCPS, FAPhA Sara Wiedenfeld, PharmD, BCPS, BCACP Nicole Hanna, PharmD Candidate 2023 Emily Steimel, PharmD Candidate 2023

On June 24, 2022, the United States Supreme Court overturned the historical precedent of Roe v. Wade. This 1973 legislation protected the constitutional right to a legal abortion (within certain limits). When Roe was overturned, this automatically turned legal authority on abortions over to individual states. Since this change, there has been a lot of confusion in the healthcare landscape regarding if and when new state laws are violated. What treatments and at what doses are now considered abortive? Where are the legal boundaries for fault if a pharmacist were to fill a prescription that ended up being used for abortion? How will patients get access to legal abortive medications often used for other purposes or for procedures that if left untreated could endanger the life of the mother, like ectopic pregnancy or an incomplete spontaneous abortion (“miscarriage”)?

This caused the American Medical Association, American Pharmacists Association, National Community Pharmacists Association, and American Society of Health-System Pharmacists to put out a joint statement conveying the need to provide clarity to avoid loss of access by patients to necessary therapies.1 As a profession, pharmacists pride themselves, especially in Iowa, on providing access to our patients. To prevent access issues—often inadvertent—it is important to know all the current data.

Iowa’s Current Legal Stance on Abortion

Iowa laws on access to abortive medications and procedures are in flux. The current Iowa statute, as of the writing of this article, is Iowa Code 707.7, et seq.2 New code that is currently under judicial review was approved by Governor Reynolds and discussed as “The Fetal Heartbeat Bill” or Senate File 359.3 An injunction was placed on the bill by a district court judge in 2018. With the overturn of Roe v. Wade, Governor Reynolds is reviewing the legal options in hopes of having this bill considered a pre-existing law. Several other states have similar pre-existing laws that were considered “trigger laws.” Trigger laws are pre-existing laws that were deemed unconstitutional by the 1973 enaction of Roe v. Wade. By overturning Roe v. Wade, they can again be considered legal. A comparison of the two bills can be seen in Table 1.

The current position of these laws does not provide fault on the pharmacist for dispensing the medications that may be used for an illegal abortion but do bring to light some gray areas where potential civil litigation or penalty assessment could occur. This puts into question how pharmacists are to continue to provide access to patients while following state legal guidelines. Easy answers to these questions start with being informed on the data behind these therapies and providing the best counseling for patients on contraception efficacy, emergency contraception and abortive therapies. Table 1.

Code Section Iowa Code 707.7, et seq. Feticide2

Statutory Definition of Illegal Abortion “Feticide”: Intentional termination of human pregnancy after end of second trimester.

Statutory Definition of Legal Abortion “Abortion”: Termination of a human pregnancy with the intent other than to produce a live birth or remove a dead fetus.

“Partial Birth Equivalent”: A person who intentionally kills a viable fetus aborted alive shall be guilty of a Class B felony. Necessary to preserve life or health of mother or fetus; after end of second trimester with every reasonable effort made to preserve life of viable fetus

Penalty for Unlawful Abortion Class C felony (attempted feticide-Class D felony)

Consent Requirements –

Waiting Period Senate File 3593

“Abortion”: Termination of a human pregnancy with the intent other than to produce a live birth or remove a dead fetus.

“Unborn Child”: Individual organism of the species homo sapiens from fertilization to live birth.

“Fetal Heartbeat” means cardiac activity, the steady and repetitive rhythmic contraction of the fetal heart within the gestational sac. Typically at 6 weeks gestation.

An abortion performed in a medical emergency (a situation in which an abortion is needed to preserve the life of a pregnant woman) Conditions included: • Pregnancy as a result of rape if reported within 45 days of the incident.* • Pregnancy as a result of incest and must be reported within 140 days after incident.* • A spontaneous abortion (miscarriage), if not all the products of conception are expelled. • An attending physician has certified that the fetus has a fetal abnormality that is incompatible with life.

Class C felony (attempted feticide-Class D felony)

Consent from mother that she received fetal heartbeat attestation (i.e.- there was no heartbeat)

*Incidents must be formally reported to law enforcement or to a private or public healthcare agency which may include a family physician

Contraception Efficacy

With the legal changes in Iowa, there is a potential to have additional questions from patients looking to avoid pregnancy. Pharmacist accessibility and medication knowledge make them the ideal candidate to have this discussion with patients. It is important when discussing contraceptive options with patients to understand that not all methods

are equivalent, even in ideal use situations. The World Health Organization ranks contraceptive efficacy based on both perfect and typical use situations.4 Even defining some options as “least effective,” these would be options that allow for 20% or greater chance of pregnancy in typical or imperfect use (Table 2). One of which is considered less effective is the progesterone-only pill (“mini-pill”) norethindrone 0.35mg.5 It is typically used in patients that are breast feeding or would like to avoid complications from estrogen containing contraceptive products but has an extremely tight compliance qualification. Each dose must be taken at the same time each day, with a 3-hour deviation from the time of usual dose considered a missed dose.5 This leads to an efficacy rate that could be lower than combined oral contraceptive pills which have a 24–48-hour window for missed doses due to extended duration of action.

Table 2.

Method

Surgical Sterilization Copper IUD (intrauterine devices) Hormonal IUD

Implant (Nexplanon) Injection (Depo-Provera) Combined Contraceptives pill Progesterone-only pill (“mini-pill”) Patch

Hormonal Vaginal Contraceptive Ring Male Condom

Sponge

Cervical Cap Diaphragm Female Condom

Spermicide Withdrawal

Fertility Based Awareness Typical Use Effectiveness8,9

99%

99%

99%

99%

96%

93%

93%

93%

93%

87%

Nulliparous: 86%, Multiparous: 73% 84%

83%

79%

79%

78%

77-98%

Of note, the progesterone-only pill with norgestrel is currently being considered by the FDA (Food and Drug Administration) for use as the first over-the-counter option for contraception; it has the same consideration for a missed dose as the norethindrone and would require two days of secondary protection until the norgestrel can get back to steady state concentrations.6,7

The most effective contraceptive options do not require adherence or effort from the patient. These methods include surgical sterilization and the long-acting reversible contraception options, implants and intrauterine devices. With the variety of contraception options available, choosing the right option should be patient specific, considering patient preference, effectiveness, comorbidities, desire for return to fertility and adverse effects.

Emergency Contraception vs. Abortive Therapies

Misinformation is common with emergency contraception and abortive agents. Pharmacists need to be prepared to dispel myths and discuss medications honestly and compassionately with patients. Distinguishing medication abortion from emergency contraception is important.

Medication Abortion/Medical Abortion

Medications related to abortion include misoprostol, mifepristone, and methotrexate.

The most common medication abortion regimen in the United States involves the use of two different medications: mifepristone and misoprostol. This drug combination can be used for medication abortion up to 70 days of gestation. Misoprostol is a prostaglandin E1 analogue that has multiple uses. Misoprostol causes cervical softening and uterine contractions. It is FDA approved for prevention of gastric ulcers in individuals who take anti-inflammatory drugs. Misoprostol is also used for treatment of early pregnancy loss, IUD insertion, induction of labor and post-partum hemorrhage. Misoprostol can be used orally, buccally, vaginally, and sublingually.10

Mifepristone is a selective progesterone receptor modulator that binds to the progesterone receptor with an affinity greater than progesterone itself but does not activate the receptor, thereby acting as an antiprogestin. Mifepristone’s actions on a uterus during pregnancy include decidual necrosis, cervical softening, increased uterine contractility and prostaglandin sensitivity. Mifepristone is taken orally.10 The FDA currently restricts mifepristone access under the REMS (Risk Evaluation and Mitigation Strategy) program. The REMS program requires that pharmacies that dispense mifepristone be certified. Mifepristone must be prescribed by or under the supervision of a certified healthcare provider who meets certain qualifications. In December 2021, FDA announced modifications to the REMS program removing the in-person dispensing requirement. Removing the in-person dispensing requirement allows dispensing of mifepristone by mail via certified prescribers or pharmacies, in addition to in-person dispensing in clinics, medical offices, and hospitals as currently outlined in the Mifepristone REMS program.11 Cramping and vaginal bleeding are expected effects of the regimen. Patients should be instructed to call their clinician if heavy bleeding occurs (more than two pads per hour for two consecutive hours or blood clots larger than a lemon) or if fever or chills are experienced for more than four hours. Patients can use NSAIDs for management of pain and cramping.10 US Attorney General Merrick Garland has stated publicly that states cannot ban mifepristone based on disagreement with the federal government on its safety and efficacy.

Current use of methotrexate related to pregnancy is in a patient diagnosed with an ectopic pregnancy. An ectopic pregnancy is a pregnancy that occurs outside of the uterine cavity, most commonly in the fallopian tube. Medical management with methotrexate is preferred over surgery in most cases to preserve future fertility. Methotrexate is a folate antagonist that binds to dihydrofolate reductase, which interrupts the synthesis of purine nucleotides and the amino acids serine and methionine, thereby inhibiting DNA synthesis and cell replication. Methotrexate affects actively proliferating tissues, such as bone marrow, buccal and intestinal mucosa, respiratory epithelium, malignant cells, and trophoblastic tissue. Methotrexate has many other therapeutic uses including in the treatment of rheumatoid arthritis and cancer.12

Emergency Contraception

Emergency contraception (EC) is used to prevent pregnancy after unprotected or inadequately protected sexual intercourse. The most used form of EC is the levonorgestrel tablet that can be purchased over the counter. Labeling recommends use up to 72-hours after unprotected sex but is most effective if used as soon as possible. Levonorgestrel delays follicle development when taken before ovulation. Ulipristal, which requires a prescription, is a selective progesterone receptor modulator and can be taken up to five days after unprotected sex. Ulipristal inhib-

its the rupture of the follicle even after luteinizing hormone has started to increase. The copper IUD can also be used for EC as an off-label indication. It is highly effective if placed within five days of unprotected sex. The copper IUD prevents fertilization by affecting sperm function and viability. EC is only effective before a pregnancy is established and unlikely to prevent implantation of a fertilized egg. Studies have not shown risk to an established pregnancy. Access to EC has significantly increased since it was approved for OTC (over-the-counter) use for any age in 2013, however significant barriers remain.16

Pharmacists’ Role in Contraception

Pharmacists can play many roles in contraception. As of September 1, 2022, twenty-one states have protocols for pharmacist prescribing of contraception.17 With the potential approval of an OTC contraceptive pill in the near future, pharmacists will further need to have expertise in this area. A recent review in the Journal of Managed Care and Specialty Pharmacy also found that a patient will visit a pharmacy one and a half to two times more than their primary care provider or other qualified health professional.18 This reinforces the need of pharmacists to be at the forefront for providing education and access to necessary medications.

A major barrier to contraception is access. A 2016 study reported that twenty nine percent of women had issues obtaining contraceptives. This included barriers from getting an appointment with a provider to accessing a pharmacy.19 Often the “conscience clause” is cited as a reason to avoid filling medications on moral or religious grounds.20 In order to provide access for patients that either require or prefer legally appropriate medications filled, it is recommended to have an alternative pharmacist at your pharmacy to provide timely dispensing or another local pharmacy that can provide the prescribed therapies. As the laws in Iowa evolve, it is important to know that recent changes have unearthed confusion and apprehension for prescribers, pharmacists, and patients alike. This situation is difficult to navigate, and it is important to have some grace with each other and provide clear communication on what the legal standards say. It is helpful for providers to be reminded to include a diagnosis code on a prescription, especially ones related to recent changes. Often in the electronic health record, the diagnosis is attached when prescribers enter the prescription, but it can be variable whether that information is transmitted to the pharmacy. Clear communication and documentation of standards when talking with prescribers is essential. Asking thoughtful questions and avoiding assumptions can help calm the nerves of all involved by allowing productive conversation.

Encourage communication and access for patients throughout the state. By providing education and collaboration with prescribers, myths about the use of these medications can be dispelled. Ideally, using this education on these common medications to continue conversations with health-systems and pharmacies will ensure these medications are accessible for proper legal use. Continue to tell patients' stories to help those that may not speak for themselves. Table 3. Medications that can be used for abortion and common uses and counseling points

Drug Indications Typical Dosing Schedule Comments

Misoprostol (Cytotec)13

Mifepristone (Mifeprex)14 FDA Approved: NSAID-induced gastric ulcer; Prophylaxis Off-label uses:

Cervical Ripening Procedure • Hysteroscopy • IUD placement • Induction of labor

Postpartum hemorrhage

Ulcer of Duodenum

Termination of Pregnancy

FDA Approved: Hyperglycemia: Idiopathic Cushing Syndrome Off-label uses: 200 mcg orally 4 times daily

Gel: 25 mcg vaginally every 4 hours (max 400 mcg) Insert: 200 mcg vaginally, leave in 24 hours or until active labor onset Tablet: 20 mcg to 25 mcg orally every 2 hours 600 to 1000 mcg orally, sublingually, or rectally one time

800 mcg/day in 2 or 4 divided doses for 4 weeks

800 mcg buccally taken a minimum of 24 hours after mifepristone 200 mg orally in a single dose. A repeat dose of misoprostol 800 mcg buccally may be taken for incomplete expulsion with pregnancy

300 mg to 1,200 mg daily

Endometriosis 5 to 10 mg daily Induction of Labor 200 mg or 400 mg once Miscarriage 200 mg orally followed by vagi-nal dose 24 hours later if <13 weeks' gestation Ovarian Cancer 200 mg daily Dilation of cervical canal Not specified Common Adverse Events: Gastrointestinal: Abdominal pain, diarrhea (including severe diarrhea), constipation, dyspepsia, flatulence, nausea, vomiting, headache

Common Adverse Events: hypertension, peripheral edema, hypokalemia, abdominal pain, decrease in appetite, diarrhea, nausea, vomiting, dizziness, headache, endometrial disorder, hypertrophy, fatigue

Methotrexate15 FDA Approved: Psoriasis, moderate to severe

Rheumatoid arthritis

Various oncology uses

Off-label uses:

Tubal ectopic preg-nancy, termination of intrauterine pregnancy Various autoimmune disorders

Various oncology uses 10 to 25 mg/ week

7.5 to 25 mg/ week

Varies

50 mg/m2 (max 100 mg) x 1-2 doses, intramuscular injection

Varies

Varies Common Adverse Events: Diarrhea, nausea, oral mucosal ulcers, vomiting, hepatic cirrhosis, hepatic toxicity, increased liver enzymes, renal toxicity, dizziness, fatigue, headache, cough The dosage form indicated for ectopic pregnancy and termination of intrauterine pregnancy is intramuscular only. The dosage form recommended for other indications varies between oral, subcutaneous, or intramuscular.

Table 4. Emergency Contraception Agents16

Type of Emergency Contraception Timing of use after un-protected intercourse Efficacy

Copper IUD (Para-Gard®) Up to 5 days Almost 100% effective

Ulipristal (Ella®) tablet

Levonorgestrel tablet (Plan-B®) Up to 5 days Less effective if over 195 pounds Up to 3 days Most effective if used ASAP Access

Requires office visit for insertion

Rx only

OTC

TAKE HOME POINTS:

• Legislation involving abortive therapies is complex and communication between all parties involved is important. • Pharmacists should dispel misinformation on abortive agents, hormonal contraception, and emergency contraception. • Common abortive therapies have other non-abortive uses that should be considered in the dispensing process. Pharmacists should be aware of counseling points related to their use. • Many contraception options are available. Pharmacists can help guide patient choice based on efficacy, past medical history, adverse effects, return to fertility, cost, ease of use, and adherence. • Pharmacists play a key role in optimizing contraceptive efficacy by counseling on missed doses and need for additional protection (back-up). • Access to legally prescribed medications is a barrier that pharmacists can help patients overcome. REFERENCES 1. American Medical Association (AMA), American Pharmacists Association (APhA), American Society of Health-System Pharmacists (ASHP) and the National Community Pharmacists Association (NCPA). press release. (September 9, 2022) AMA, APhA, ASHP, NCPA Statement on State Laws

Impacting Patient Access to Medically Necessary Medications. [Press Release] https://www.pharmacist.com/APhA-Press-Releases/ama-apha-ashp-ncpa-statement-on-state-laws-impacting-patient-access-to-medically-necessary-medications Accessed September 30, 2022. 2. Iowa Code § 707.7. https://www.legis.iowa.gov/docs/code/707.7.pdf Accessed

September 19, 2022. 3. Senate File 359. May 4, 2018. https://www.legis.iowa.gov/legislation/Bill-

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