The long-standing letter-based pregnancy risk category system for prescription medications (A, B, C, D, and X) was officially phased out by the Federal Drug Administration (FDA) on June 30, 2015. In its place, the new Pregnancy and Lactation Labeling Rule (PLLR) has been implemented to provide a more consistent and comprehensive explanation of the risks associated with prescription drugs during pregnancy and lactation.
The previous standard pregnancy category system assigned each medication a letter category to denote safety of use during pregnancy and lactation. However, rather than separating drugs by severity or incidence of adverse effects, the categories reflected the amount and quality of available evidence regarding the risk of adverse effects to the fetus. Although relatively easy to interpret at surface level, the letter-based system was prone to oversimplification and misinterpretation. As an example, the categories were often viewed as a grading system, wherein each category was thought more harmful than the prior (as in, X is worse than D, and D is worse than C). However, this tendency led to oversimplified and occasionally erroneous interpretations regarding drug safety. For example, newer medications with fewer experimental trials, and thus fewer documented harmful effects, were labelled as safer— Category B— than better-studied drugs with some documented adverse effects— Category C. The lack of clarifying information regarding assignation of categories precluded evidence-based decision-making when attempting to prescribe medications during pregnancy and lactation.
The PLLR provides greater detail on the safety of prescription medication in order to better inform physician evidence-based decision making and counseling. Rather than assigning a letter, safety information is now described narrative-style in medication package inserts. Information on PLLR-compliant safety inserts is divided between three sections: “8.1 Pregnancy,” “8.2 Lactation,” and an entirely new section, “8.3 Females and Males of Reproductive Potential.” Notably, in the new section “Females and Males of Reproductive Potential,” the PLLR addresses the risks of prescription drug use with respect to fertility and provides recommendations for pregnancy testing and contraception while taking the drug.
Within each section, safety information falls into three main categories: summary of risk, clinical considerations, and available data. The pregnancy section also requires disclosure of pregnancy exposure registry data.
This section provides a general conclusion on the level of increased risk of fetal developmental abnormalities based on all available data on the medication.
This section provides information on the probable risk given inadvertent drug exposure while pregnant. It also states information about change in dosing in pregnancy, maternal adverse reactions unique to or increased in pregnancy, and potential harmful effects to the fetus.
Both human and animal studies are discussed here, including study structure, information about exposure, species involved, and adverse effects on fetal development observed.
For any drug that applies for FDA approval on or after June 30, 2015, the pregnancy and safety lactation information must be in compliance with the PLLR. Drugs approved prior to 2015 had either 3, 4, or 5 years to update their guidelines from the date of the PLLR implementation, depending on when they were approved. Any medication approved prior to June 2001 is only required to remove the pregnancy letter category, but not to provide any additional information.
With a constantly increasing number of pharmacological treatments on the market, including those beneficial for disease states during pregnancy, an appropriate understanding of the safety implications on the developing fetus is essential. The previous pregnancy category system was simplistic and lacked the appropriate level of clarity and detailed required to understand the fetal and maternal consequences of a particular medication (Murase). The PLLR seeks to remedy the shortcomings of the letter categories by providing a clear statement of the perceived risk to the fetus and mother, a concise yet comprehensive summary of clinically relevant information, and a summary of the available studies on the medication. While more time-intensive to interpret than a lettering system, the PLLR will hopefully provide clinicians with more confidence when counseling patients.
Figure 1. Sample package insert for Truvada following the new Pregnancy and Lactation Labelling Rule.