The data available to inform pregnant and lactating women about drug safety and efficacy are woefully inadequate. This lack of information encompasses every aspect of pharmaceutics, including limited human data about the embryonic risk, limited pharmacokinetic and pharmacodynamic information during and after pregnancy to ensure proper dosing, and a dearth of new medications to treat obstetrical and lactation disorders. This state of affairs has been longstanding and can be attributed to several realities, most of which have withstood any efforts to modify them. The first reality is the disinterest of the pharmaceutical industry to undertake pregnancy and lactation studies because of the considerable disincentives to undertake such studies. The medicolegal risks and the limited opportunity for financial gain are significant barriers to their participation. The US Food and Drug Administration has not mandated that new drugs or drugs “on patent” must include studies in pregnant women. Regulatory constrains that have defined pregnant women as a vulnerable class have greatly limited pharmacologic studies. Another contributing factor to this lack of information is the lack of researchers skilled in pharmacology with an interest in the pregnant woman. In addition, although difficult to measure, there is the hesitancy of pregnant and lactating women to participate in pharmacology research either for fear of fetal risk or an inability to commit the time required for such studies. Research in obstetrical and lactation pharmacology lags far behind that of pediatric pharmacology. Through the efforts of many, research in that field is highly funded and very productive in providing new information on medications used in children who, like pregnant women, have differing pharmacologic needs based on age (chronology for children and gestational age for pregnant women). Recently, the deficiencies and possible remedies for this embarrassing state of affairs in obstetrical and lactation pharmacology have been addressed by the federal government, which led to 15 recommendations from the Task Force on Research Specific to Pregnant Women and Lactating Women. In this article, we address the challenges in providing meaningful information about specific medications used by the mother and how these problems have evolved. We also suggest specific strategies to start the process of remediation.
Overview
An increasing number of pregnant women are using prescription and over-the-counter medications, dietary supplements, and herbal products during pregnancy. , A review of medication use from 1976 to 2008 demonstrated that in 2006 to 2008 as many as 50% of pregnant women took 4 or more medications at some time during their pregnancy and that 27% took ≥4 medications during the first trimester, the period of organogenesis. The majority of these medications were prescription medications. A pregnant woman may require medications for obstetrical disorders such as nausea and vomiting of pregnancy, gestational diabetes, gestational hypertension, preterm labor, and labor and delivery management. However, many pregnant women require medications for conditions that predate pregnancy such as depression, type 2 diabetes, HIV, epilepsy, chronic hypertension, rheumatologic diseases, and numerous other disorders that plague both men and women. These medical disorders are more common in the older parturient, and, because delayed childbirth is a reality in the contemporary society, the number of pregnant women using prescribed medications will continue to increase.
During pregnancy, the mother expects that the medications that are prescribed are safe and effective for her and safe for the baby. However, at the time when the most precise information is needed, drug safety data are embarrassingly scant and generally insufficient to inform the mother’s decision about a specific drug’s safety and/or efficacy. In this article we address the challenges in providing meaningful information about specific medications to the mother and how these problems have evolved. We also suggest specific solutions to start the process of remediation.
Deficiency of Pharmacologic Data for Women During Pregnancy and Lactation
The embryo, fetus, newborn, and child
The pregnant and lactating woman presents unique pharmacologic challenges that must be addressed before she can consider taking a prescribed medication. The most obvious concern is the effect of the medication on the fetus who is the passive (in most cases) recipient of any medication taken by the mother. Medications may adversely impact fetal organogenesis, organ maturation, or organ function. The newborn is also the passive recipient of medications taken by the lactating woman because many maternal medications can be found in breast milk. Thus, the most common question pregnant and lactating women ask about medications is whether that medication is safe for their fetus or newborn. Unfortunately, data in humans are lacking. Of the 272 drugs approved by the United States Food and Drug Administration (FDA) from 2000 to 2010, the teratogenic risks could not be ascertained for 97.7 % of those drugs and 73% had no human data. Congress has passed legislative initiatives to address drug safety and efficacy over the last several decades. Particularly relevant to fetal risk is the FDA’s effort to quantify the fetal risk for patients and their providers. In 1979, the FDA established 5-letter risk categories––A, B, C, D, or X––to indicate the potential of a drug to cause birth defects or harms if used during pregnancy. The labeling was changed in 2015 with the Pregnancy and Lactation Labeling Rule (PLLR). It was generally believed that the old, 5-letter system was not informative and that it led to false assumptions about the drug risk profile. The new system was expected to enable better, patient-specific counseling and informed decision-making for pregnant women and their providers. The A, B, C, D, or X risk categories were replaced with narrative sections, which were to provide information about the dosing, potential risks to the developing fetus, and pregnancy registry information. The lactation subsection was intended to provide a listing of drugs that should not be used during breastfeeding and other information to help the lactating mother decide if her milk may be harmful to her infant. Pharmacokinetic (PK) data were also to be provided. According to the PLLR, different requirements are applied for prescription drugs that sought FDA approval after the ruling went into effect in 2015 and the prescription drugs approved after or before 2001. Importantly, medications approved before 2001 and generic drugs are not subject to the PLLR rule. The PLLR requirements for a new drug sponsor do not mandate that new studies must include human trials but rather that the sponsor must summarize the extant information about the specific medication. A recent review of new drugs introduced since the PLLR came into effect indicates that only a few studies have included human data. Table 1 includes a list of 8 of the 53 new drugs approved in 2020 that might be used by pregnant women. The table details the specific areas in which information is lacking. The other 45 approved drugs were for the treatment of diseases uncommon during pregnancy. This lack of human data may be why the PLLR is not widely recognized or utilized. It seems, therefore, that the PLLR is not achieving its objectives because of the limited safety information generated during drug development for the use of the medications by pregnant and lactating women.
| Drug name, indication | Available data on safety, efficacy, fetal effects, and breast milk | Drug name, indication | Available data on safety, efficacy, fetal effects, and breast milk |
|---|---|---|---|
| Oliceridine (Olinvyk), | Safety in pregnancy: no data | Ozanimod (Zeposia), multiple sclerosis | Safety in pregnancy: no data |
| acute pain | Efficacy in pregnancy: no data | Efficacy in pregnancy: no data | |
| Fetal developmental risk: no data | Fetal developmental risk: no data | ||
| Exposure in mother: no data | Exposure in mother: no data | ||
| Exposure to fetus: no data | Exposure to fetus: no data | ||
| Exposure through human milk: no data | Exposure through human milk: no data | ||
| RID: N/A | RID: N/A | ||
| Effect on breast ed infants: no data | Effect on breastfed infants: no data | ||
| Milk production: no data | Milk production: no data | ||
| Eptinezumab (Vyepti), | Safety in pregnancy: no data | Vibegron (Gemtesa), overactive bladder | Safety in pregnancy: no data |
| migraine | Efficacy in pregnancy: no data | Efficacy in pregnancy: no data | |
| Fetal developmental risk: no data | Fetal developmental risk: no data | ||
| Exposure in mother: no data | Exposure in mother: no data | ||
| Exposure to fetus: no data | Exposure to fetus: no data | ||
| Exposure through human milk: no data | Exposure through human milk: no data | ||
| RID: N/A | RID: N/A | ||
| Effect on breastfed infants: no data | Effect on breastfed infants: no data | ||
| Milk production: no data | Milk production: no data | ||
| Amisulpride (Barhemsys), | Safety in pregnancy: insufficient data | Remdesivir (Veklury), | Safety in pregnancy: no data |
| nausea, antipsychotic, and vomiting | Efficacy in pregnancy: no data | COVID-19 | Efficacy in pregnancy: no data |
| Fetal developmental risk: insufficient data | Fetal developmental risk: no data | ||
| Exposure in mother: available | Exposure in mother: no data | ||
| Exposure to fetus: no data | Exposure to fetus: no data | ||
| Exposure through human milk: M/P ratio = 11:20 | Exposure through human milk: limited, likely because it is not well-absorbed orally | ||
| RID: 11% | RID: N/A | ||
| Effect on breastfed infants: no data | Effect on breastfed infants: no data | ||
| Milk production: no data | Milk production: no data | ||
| Rimegepant (Nurtec ODT), | Safety in pregnancy: no data | Fostemsavir (Rukobia), HIV | Safety in pregnancy: no data |
| Migraines | Efficacy in pregnancy: no data | Efficacy in pregnancy: no data | |
| Fetal developmental risk: no data | Fetal developmental risk: no data | ||
| Exposure in mother: no data | Exposure in mother: no data | ||
| Exposure to fetus: no data | Exposure to fetus: no data | ||
| Exposure through human milk: expected to be limited based on related drugs | Exposure through human milk: no data | ||
| RID: <1% based on related drugs | RID: N/A | ||
| Effect on breastfed infants: no data | Effect on breastfed infants: no data | ||
| Milk production: no data | Milk production: no data |
Much of the attention about the fetal safety of medication used by pregnant women has been focused on the risk of fetal malformations or perceptible injury to the fetus or infant. This is critically important, however, the endpoints according to which fetal safety is defined are crude and imprecise and far too insensitive because they are limited to observed malformations or organ injury or dysfunction. The potential long-term effects of medications on a child’s organ function or its neuroanatomy and neurodevelopment are not assessed. Once a newborn is discharged from the nursery after birth, the ascertainment of harms from in utero exposure to a medication is considered complete. Drug safety can be evaluated best by long-term follow-ups of children exposed to potentially harmful medication in utero. In particular, those drugs that impact the maternal brain, such as opioids and selective serotonin reuptake inhibitors (SSRIs), may also affect the fetal brain and, indeed, recent magnetic resonance imaging (MRI) studies do suggest that maternal opioid and SSRI use may lead to adverse changes in neonatal brain volumes and connectivity.
The pregnant woman
The vast majority of medications used by pregnant women have not been approved for use during pregnancy. These medications were approved by the FDA based on the efficacy, safety, PK, and pharmacodynamic (PD) studies in men and nonpregnant women. Safety and efficacy during pregnancy were not evaluated in pregnant women. Consequently, these drugs are used “off-label” when administered to pregnant women. Generally, the dosing regimen prescribed for pregnant women is that which was approved by the FDA for nonpregnant women and men. Pregnancy is characterized by dramatic changes in the maternal physiology and pharmacology. Every aspect of pharmacology is affected during pregnancy including drug absorption, distribution, metabolism, and elimination, and these changes differ from trimester to trimester. , These pharmacologic changes can lead to either excessive drug concentrations with increased side effects or inadequate drug concentrations that lead to ineffective drug usage. Several Obstetric-Fetal Pharmacology Research Units (OPRU)– or Obstetrical-Fetal Pharmacology Research Centers (OPRC)–sponsored studies have demonstrated the differences in the PKs and PDs for several medications commonly used during pregnancy ( Table 2 ). The area under the plasma concentration-time curve (AUC) is a standard and convenient way to demonstrate the gestational differences in drug. Decreased exposure is typically seen in most cases for drugs that are cleared renally and those cleared by specific enzymes in the liver. Some drugs require a higher dose or dosing frequency during pregnancy because of the decreased exposure (as determined by the AUC). The glyburide dose-adjusted AUC during pregnancy is 53% lower than in the nonpregnant or postpartum woman. Likewise, the dose-adjusted AUC for buprenorphine and oseltamivir during pregnancy is dramatically lower than in the postpartum or nonpregnant woman ( Table 2 ).
| AUC | Glyburide a dose normalized (ng × h/mL) | Buprenorphine b dose normalized (ng × h/mL) | Oseltamivir carboxylate c popPK analysis (ng × h/mL) |
|---|---|---|---|
| Pregnant | 72±27 | 1.9±1.4 | 2653±928 |
| Nonpregnant | 153±69 | 4.0±2.5 | 3507±992 |
| Difference | 53% | 53% | 24% |
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