Drug Therapy Considerations in Pregnancy and Lactation PDF

Drug Therapy Considerations in Pregnancy and Lactation By Stephen M. Small, Pharm.D., BCPS, BCPPS, BCCCP, CNSC Reviewed by Laura Esposito, Pharm.D., BCPS, MSCP; Nicole Hahn, Pharm.D., BCACP; and Sherra Gardner, Pharm.D., BCACP LEARNING OBJECTIVES 1. Distinguish the regulatory responsibilities...

Drug Therapy Considerations in Pregnancy and Lactation By Stephen M. Small, Pharm.D., BCPS, BCPPS, BCCCP, CNSC Reviewed by Laura Esposito, Pharm.D., BCPS, MSCP; Nicole Hahn, Pharm.D., BCACP; and Sherra Gardner, Pharm.D., BCACP LEARNING OBJECTIVES 1. Distinguish the regulatory responsibilities between drug manufacturers and pharmacists regarding medication use in pregnancy and lactation. 2. Classify the physiologic phases of pregnancy and lactation to predict potential impacts on drug pharmacokinetics and pharmacodynamics. 3. Assess a drug’s potential for teratogenicity based on fetal physiology and the drug’s pharmacokinetic properties. 4. Design an appropriate regimen and monitoring plan for a drug prescribed to a lactating parent based on patient factors and drug characteristics. 5. Judge the fetal safety of a therapeutic regimen in a pregnant patient using drug information from different resources. INTRODUCTION ABBREVIATIONS IN THIS CHAPTER In 2021, there were over 3.5 million recorded births in the United States CO Cardiac output (Osterman 2023). Each pregnancy is a complex episode in a patient’s PLLR Pregnancy and Lactation Labeling Rule life during which bodily changes and adaptations affect both preg- REMS Risk evaluation and mitigation nant parent and fetus. Medications add to this complexity because strategies their pharmacodynamics, pharmacokinetics, benefits, and risks can RID Relative infant dose change from one trimester to the next. In addition, medications con- T4 Tetraiodothyronine tinue to have an impact in the medically complex postpartum period when a lactating parent’s necessary medication therapy may poten- Table of other common abbreviations. tially affect the newborn through breastfeeding. Nine in 10 women report using at least one medication during pregnancy, and the number of medications used per pregnancy has increased over 60% between the 1970s and 2000s (Haas 2018; Mitchell 2011). During that time, the medical and pharmacy profes- sions’ understanding of medications in pregnancy and lactation has increased, at least partially because of better study methods and with some lessons learned from cases of fetal harm. Pharmacists can encounter pregnant and lactating populations in almost every clinical specialty; therefore, pharmacists must view them as com- mon patients requiring utmost care to prevent harm and improve outcomes. Current State of Obstetric Clinical Pharmacy Obstetric pharmacy as a specialty is, at best, in its infancy. As of November 2023, there are no formal U.S. obstetric programs reg- istered in the American Society of Health-System Pharmacists’ residency database. There are also no pharmacy-specific obstetric certifications offered by organizations such as the Board of Pharmacy Specialties (Small 2023). However, interested pharmacists may join professional organizations such as the American College of Obstetrics ACSAP 2024 Book 2 Women’s and Men’s Health 7 Drug Therapy Considerations in Pregnancy and Lactation and Gynecologists, the Organization of Teratology Information mortality, adverse mental health outcomes from unwanted Specialists, and special interest groups to network and gain pregnancies, and increased birth defect incidence from fetal knowledge. Although pharmacists may practice in specialized teratogen exposure are only some of many potential conse- obstetric settings, currently no surveys estimate the extent quences (Berg 2023; Weatherspoon 2023). of their practice. Regardless, in any pharmacy specialty and Pharmacists play an important role in medication manage- practice, pharmacists encounter patients who are pregnant, ment and safety for this complex population, and clinicians postpartum, or planning to conceive. should have a solid understanding of pregnancy and lacta- The U.S. obstetric population has experienced increas- tion concepts. ingly poor outcomes over time and has the worst maternal outcomes in the developed world. Black women have a Challenges in Obstetric Pharmacology 2.6-fold higher risk of maternal mortality compared with There are few pharmacology data to apply in obstetric and non-Hispanic White women (Hoyert 2023; Douthard 2021). lactating populations. Only 1.3% of pharmacokinetic studies This pattern is possibly caused by many interplaying factors, published until 2013 included pregnant subjects (McCormack including women giving birth later in life, when chronic dis- 2014). This makes clinical decision-making difficult, theoreti- eases are more prevalent and may complicate care. Other cal, and fraught with potential error. possible reasons include socioeconomic factors and racial In 1994, the Institute of Medicine highlighted the need disparities in health care (Vilda 2019). The changing state-by- for more medication trials to include pregnant and lactating state legal status of abortion and other reproductive health populations (Mastroianni 1994). Ethical hurdles in obtaining care elements added a new dimension to these risks after study data include the potential for exposing pregnant women the U.S. Supreme Court’s decision issued in Dobbs v. Jackson and their unborn children to medications with unknown and Women’s Health Organization in 2022, which overturned complex risks. Difficulty recruiting sufficient subjects can Roe v. Wade. Evolving geographic disparities in maternal also decrease research statistical power. The 21st Century Cures Act in 2016 created the Task Force on Research Specific to Pregnant and Lactating Women (PRGLAC) to advise the U.S. Secretary of Health & Human Services on BASELINE KNOWLEDGE STATEMENTS medications requiring more pregnancy and lactation data. To increase trial participation, the task force’s recommen- Readers of this chapter are presumed to be familiar dations include removing pregnant patients as a “vulnerable with the following: population” in the Common Rule defining ethical study con- General elements and requirements of REMS duct. This removal from the Common Rule occurred in 2018, programs but the rule’s additional protections for pregnant patients still Stages of childbirth apply (Department of Homeland Security 2017). Other rec- Table of common laboratory reference values ommendations include implementing liability mitigation for investigators and financial incentives for conducting studies ADDITIONAL READINGS while still applying safeguards (PRGLAC 2018). Although clinicians are awaiting more information The following free resources have additional back- regarding medication benefits and risks in this population, ground information on this topic: pharmacists have tools to inform their recommendations, U.S. Food and Drug Administration (FDA). which will be discussed throughout this chapter. Approved Risk Evaluation and Mitigation Strategies (REMS). Updated 2023. Available at www.access- data.fda.gov/scripts/cder/rems/index.cfm. DRUG REGULATION IN PREGNANCY LactMed: Drugs and Lactation Database [database AND LACTATION on the internet]. National Institute of Child Health Historic Examples of Fetal Harm and Human Development. Available at https:// www.ncbi.nlm.nih.gov/books/NBK501922/. Many regulations and laws guiding current health care prac- MotherToBaby [homepage on the internet]. The tice resulted from recent tragedies in which pharmaceuticals Organization of Teratology Information Specialists. caused patient harm and death. Notable cases of fetal harm Available at https://mothertobaby.org. shaped some of our country’s most important drug legisla- U.S. Food and Drug Administration (FDA). List of tion. The following is a brief review of such examples from pregnancy exposure registries. Updated 2023. the recent past. Available at https://www.fda.gov/consumers/ pregnancy-exposure-registries/list-pregnancy-­ Thalidomide exposure-registries. Thalidomide, a sedative marketed in Europe and Canada for morning sickness in the 1960s, is the prototype of a fetotoxic ACSAP 2024 Book 2 Women’s and Men’s Health 8 Drug Therapy Considerations in Pregnancy and Lactation medication that led to regulatory changes. When it was devel- Contemporary Regulations and Surveillance oped, pregnancy studies for medications were rare. In 1961, it Inspired by the cases of harm discussed, U.S. regulations was discovered that thalidomide exposure in utero increased surrounding pregnancy and lactation explain some of the the risk of newborn phocomelia, a permanent shortening of challenges that persist today with insufficient medication arm and leg bones. This toxicity may be caused by its inhi- safety data in pregnancy and lactation, but improvements bition of fetal angiogenesis affecting limb growth. Most have occurred and are ongoing. This section describes some countries immediately withdrew the drug from their markets of the regulatory history and its current framework in this (Rehman 2011). area. In 1962, thalidomide inspired the passage of the Kefauver- Food & Drug Administration Labeling Harris Amendment. This law forced manufacturers to FDA drug regulation in pregnancy evolved during the era demonstrate safety and efficacy by drug trial data submitted of iatrogenic fetal harm between the 1960s and 1970s to the FDA before approval and marketing. This law had no (Figure 1). In the 1950s, pregnant subjects could not partici- direct requirements for manufacturers to obtain pregnancy pate in any clinical drug trials per the era’s ethical standards. and lactation safety data. Thalidomide is still currently in use for treating multi- ple myeloma, leprosy, and other diseases. It has significant restrictions enforced by way of a risk evaluation and mitiga- 1962 tion strategies (REMS) program to ensure patients prevent Thalidomide disaster leads to Kefauver-Harris Amendment requiring animal studies for approval, providing some fetal pregnancy during therapy. risk data Diethylstilbesterol Diethylstilbesterol (DES) was introduced in the 1940s as a 1977 synthetic estrogen analog to prevent premature labor and FDA reiterates stance that reproductive-age women, miscarriage. It was later used until the 1970s for lactation regardless of pregnancy status, be excluded from drug studies on ethical grounds suppression and treating menopause symptoms. In 1970, epidemiologists discovered that female fetus exposure to DES in utero was associated with an increased risk of clear 1979 cell carcinoma, by almost 40-fold, together with breast and Partly in response to DES disaster, FDA introduces new pancreatic cancers (Reed 2013). DES was taken off the U.S. pregnancy risk categorization requirement for medication labeling market for use as a synthetic estrogen by the late 1970s. Many believe that the history of fetal defects from DES even- tually inspired the FDA’s 1979 requirement for manufacturers 1993 to list pregnancy risk categories and lactation information in NIH Revitalization Act ensures women and minority groups are included in NIH-funded research, but does not all prescription medication labeling. necessarily impact all drug studies Isotretinoin Isotretinoin is an oral retinoid indicated for severe acne 2014 vulgaris since 1982. Animal studies showing birth defects FDA publishes new Pregnancy and Lactation Labeling Rule replacing letter risk categorizations with detailed risk led to its category X designation, contraindicating use in narratives pregnancy. By the mid-1980s, there were multiple reports for cases of ear, palate, cardiac, and brain malformations together with spontaneous abortions. In 1988, the pat- 2020 Deadline per Pregnancy and Lactation Labeling Rule to ent holder created the Pregnancy Prevention Program remove all pregnancy risk categories from labeling, but with based on recommendations from FDA hearings. This pro- varying compliance gram included patient educational materials and provider reimbursement for contraceptive counseling. A volun- tary referral to an isotretinoin exposure registry was also Figure 1. Landmarks in pregnancy labeling for medications (1962–present). offered. About 900 pregnancies in this registry had isotretinoin Information from: U.S. Food and Drug Administration exposures by 1998 (CDC 2000). Isotretinoin’s Pregnancy (FDA). Gender studies in product development: historical overview. Updated 2018. Available at www.accessdata.fda. Prevention Program later evolved into the iPledge program in gov/scripts/cder/rems/index.cfm; Pernia A, DeMaagd G. 2006 and then its current REMS program in 2010. After 2011, The new pregnancy and lactation labeling rule. around 300 women each year reported taking isotretinoin P T 2016;41:713-5. during pregnancy despite this program (Tkachenko 2019). ACSAP 2024 Book 2 Women’s and Men’s Health 9 Drug Therapy Considerations in Pregnancy and Lactation  Table 1. Pregnancy Risk Category System (1979–2014) Risk Category Description A Adequate, well-controlled studies in pregnant women failed to demonstrate a risk to the fetus in the first trimester, and there is no evidence of risk in later trimesters B Animal reproduction studies fail to demonstrate fetal risk and there are no adequate and well-controlled studies in pregnant women OR Animal reproduction studies show adverse effect, but adequate well-controlled studies in pregnant women fail to demonstrate fetal risk C Animal studies show fetal adverse effect and there are no adequate and well-controlled studies in pregnant women, but the benefits may outweigh risks OR There are no available, adequate animal or human studies D There is evidence of fetal risk based on human study, investigational, or marketing data, but benefits may be acceptable compared with its risks X There is adequate evidence of fetal risk based on human study, investigational, or marketing data, and risks outweigh the benefits Information from: U.S. Food and Drug Administration (FDA); U.S. Department of Health and Human Services. Content and format of labeling for human prescription drug and biological products; requirements for pregnant and lactation labeling (73 FR 30831). Fed Regist 2008;73:30832-3. Animal studies were required instead after 1962 and became Women, regardless of pregnancy or lactation status, the sole source of pregnancy risk data through the 1970s. remained largely excluded from drug studies through the The FDA reiterated in 1977 that minors and premenopausal 1980s until the NIH Revitalization Act of 1993. Today, the FDA women capable of becoming pregnant could not participate still cannot force manufacturers to submit pregnancy and in phase I or II trials (FDA 2018). With these restrictions, pre- lactation data with applications, and most data are obtained scribing guidance was often left incomplete given that only by way of postmarketing studies and pregnancy registries data from animals and limited case reports were included, if instead. even available. The FDA published a new Pregnancy and Lactation Manufacturers were not required to include pregnancy or Labeling Rule (PLLR) in 2014. This phased out letter risk cate- lactation information in labeling until 1979. Subsequent label- gories and required new labeling with narratives of pregnancy ing was required to include a pregnancy section featuring A, and lactation safety data, clinical management, applicable B, C, D, X letter risk designations (Table 1). pregnancy exposure registries, and female and male repro- This initial system was especially helpful for A and X cate- ductive risks. Per the PLLR implementation timeline, former gory drugs with adequate safety data. However, these generic letter risk categories should have been removed from most risk categories are based only on the existence and quality U.S. medication labeling by 2020 (Pernia 2016). Full com- of a drug’s pregnancy safety data and can be misinterpreted pliance is still pending with roughly one-third of products as a grading system implying increasing risk from A to X. It approved between 2010 and 2015 not meeting requirements did not guide providers on how to weigh medication risks (Byrne 2020). based on patient conditions, especially when data and risks were more nuanced (i.e., categories B, C, and D). For example, The Joint Commission many antidepressants and antipsychotic medications listed In 2020, the Joint Commission published 13 pregnancy- and in categories C and D may initially give providers pause when postpartum-related performance measures when evaluating prescribing them. However, the maternal benefits of these organizations for accreditation (The Joint Commission 2019). medications often outweigh their risks. This system also did The majority pertain to inpatient labor, delivery, and postpar- not state data sources. This labeling was required only for tum care rather than ambulatory care. However, ambulatory systemically absorbed medications and could be omitted if care pharmacists could participate in some measures, such as no pregnancy risks were demonstrated. guideline development for severe hypertension management ACSAP 2024 Book 2 Women’s and Men’s Health 10 Drug Therapy Considerations in Pregnancy and Lactation (PC.06.03.01, EP1 and 2) and participating in annual severe The FDA was given the authority in 2007 to direct manu- hypertension and preeclampsia drills (PC.06.03.01, EP4). facturers to implement these programs and defined REMS In 2023, it also published recommendations to improve programs using former risk minimization action plan ele- maternal health and outcomes. These address racial dispari- ments. It is debatable whether REMS programs truly decrease ties in health systems and highlight treatments for behavioral medication harm. A 2013 government report found that 8 pro- health conditions to help decrease risk of maternal death grams between 2008 and 2011 did not submit any REMS data (The Joint Commission 2023a, 2023b). These are only rec- to the FDA by their deadlines. Only 7 out of 49 REMS assess- ommendations and not regulations, but they advocate ments submitted by manufacturers met their performance increasing access to prenatal care for underserved popula- goals, and about half of the assessments were incomplete tions, address providers’ unconscious biases, and enhance (Levinson 2013). behavioral health screenings. Pregnancy Exposure Registries Risk Evaluation and Mitigation Strategies The estimated birth defect rate in the general population is There are 67 medications with active REMS programs (FDA about 3%, and about one-third of all pregnancies do not reach 2023a). Some programs relate to pregnancy and lactation term (Rossen 2023; CDC 2008). Determining fetal harm from risks (Table 2). For REMS with a pharmacy requirement, any medications is complex amid this backdrop of baseline preg- pharmacist involved in their dispensing must comply with nancy loss and defect rates. Although the FDA’s MedWatch the mandates, which can be complex. Noncompliance can program allows for reporting drug-associated fetal harm, it result in patient harm and regulatory repercussions for man- does not look at exposures without complications. Instead, ufacturers, and potentially for prescribers and pharmacies registries track exposures regardless of the maternal and as well. The FDA first published guidance for manufacturers fetal outcomes to help make an accurate assessment. in the 2000s for risk minimization action plans in labeling to Pregnancy exposure registries allow patient, pharmacist, and decrease harm from certain medications. provider participation in postmarketing surveillance. As of 2007, the FDA can require a manufacturer to imple- ment a pregnancy registry as a condition of a drug’s approval Table 2. REMS Programs Specific to Medication in certain scenarios (Box 1). The FDA can request companies Risks in Pregnancy complete preapproval or postapproval pregnancy risk stud- ies if there is concern. Establishing registries can provide one Initial REMS such method. Otherwise, the FDA can only recommend imple- Drug Approval Date menting postmarketing strategies to assess risk. The FDA Ambrisentan March 2019 does not oversee or endorse any registry. Instead, they are run by third-party organizations or research groups. Bosentan April 2019 Reporting patient exposures is largely voluntary outside Isotretinoin October 2016 of REMS-mandated registries. Registries may be specific to Lenalidomide May 2021 one medication or an entire medication class such as atypi- cal antipsychotics. The FDA’s website lists over 150 registries Macitentan April 2021 and their contact information (Box 2) (FDA 2023b). Some Mifepristone April 2019 registries may allow enrollment only through a provider. Mycophenolate September 2012 Pharmacists can educate patients and advocate enrollment in these registries. Phentermine/topiramate July 2012 Pomalidomide October 2020 PS-Mycophenolate June 2023 Box 1. Factors for Implementing Riociguat October 2013 Medication Pregnancy Exposure Registries Sparsentan February 2023 Indication for use during any phase of pregnancy or is a Thalidomide August 2010 chronic, long-term medication Clinical trial, animal study, or related data from similar drugs suggest embryo-fetal toxicity PS = parallel system; REMS = risk evaluation and mitigation Significant chance of accidental exposure during strategies. pregnancy in reproductive-age females Information from: U.S. Food and Drug Administration (FDA). Approved Risk Evaluation and Mitigation Strategies Information from: Gliklich RE, Dreyer NA, Leavy MB, eds. (REMS). Updated 2023. Available at www.accessdata.fda. Registries for Evaluating Patient Outcomes: A User’s Guide, 3rd gov/scripts/cder/rems/index.cfm. ed. Agency for Healthcare Research and Quality, 2014. ACSAP 2024 Book 2 Women’s and Men’s Health 11 Drug Therapy Considerations in Pregnancy and Lactation  Box 2. Examples of Contemporary Table 3. Pregnancy Trimester Definitions and Goal Pregnancy Exposure Registries Laboratory Values Antiepileptic Drug Pregnancy Registry Goal Laboratory Values Antiretroviral Pregnancy Registry Migraine Pregnancy Registry Trimester Weeks of Gestation Hgb (g/dL) Hct (%) TSH (mU/L)a Mycophenolate Pregnancy Registry National Pregnancy Registry for Antidepressants First 0–13 ≥ 11 ≥ 33