Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
In last month’s article, I described the kinds of studies that are conducted to evaluate the safety of medications during pregnancy and lactation. When physicians and nurses see patients, they must be able to understand and discuss how drugs are labeled with regard to pregnancy and lactation. In this article, the second of three parts, I describe the current and proposed U.S. Food and Drug Administration (FDA) classification system for pregnancy and lactation labeling. Next month, I will discuss some general principles and guidelines for prescribing medications during pregnancy and lactation.
Current FDA Pregnancy and Lactation Labeling System
The current standard for drug labeling information on pregnancy and lactation began in 1979. According to this standard, the risks of taking a drug during pregnancy are categorized under a five-letter system (Briggs, Freeman, & Yaffe, 2005). Using data from animal and human studies, the FDA classifies drug safety using the following categories:
- A: Controlled studies have shown no risk.
- B: No evidence of risk found in human beings.
- C: A risk cannot be ruled out.
- D: Positive evidence of risk exists.
- X: The drug is contraindicated in pregnancy.
For any drug, these classifications are included in the product labeling where clinicians and patients can review it (i.e., in the Physicians’ Desk Reference [PDR]). However, these categories may be misleading because they do not simply represent a linear increase in risk from category A to B to C to D to X. On the contrary, categories C, D, and X are based on risk weighed against benefit. The categories also do not always clearly distinguish between risks based on human versus animal data findings, or between differences in frequency, severity, and type of fetal developmental toxicities.
For lactation, there is no standard FDA classification system to categorize risk. One approach for categorizing lactation risk has been suggested by Hale (2004). These safety categories include L1 (safest), L2 (safer), L3 (moderately safe), L4 (possibly hazardous), and L5 (contraindicated). They are somewhat more arbitrary than the FDA classification for pregnancy, are based on fewer data, and are not included in product labeling (e.g., the PDR).
Proposed FDA Pregnancy and Lactation Labeling System
The current pregnancy labeling category system has been criticized as being confusing, too simplistic, and not conveying current knowledge based on newer studies. In addition, as noted above, there is no standard approach for classifying lactation risks. Because of these problems, the FDA has proposed a revision of the classification system for pregnancy and lactation labeling (FDA, 2008). The labeling would contain two subsections: one on pregnancy and one on lactation. Both the pregnancy and lactation subsections would have three principal components:
- A risk summary section.
- A clinical considerations section.
- A data section.
Proposed Pregnancy Labeling
The pregnancy Fetal Risk Summary section would characterize the likelihood that the drug increases the risk of four kinds of developmental abnormalities: structural anomalies, fetal and infant mortality, impaired physiological function, and alterations to growth. If there is a risk, the labeling would indicate whether this risk is based on information from animals or human beings. If there are only animal data, the fetal risk summary would contain only the risk conclusion. However, when there are human data, the risk conclusion would be followed by a paragraph describing the most important data about the effects of the drug on the fetus. To the extent possible, this summary narrative would include the specific developmental abnormality (e.g., neural tube defects); the incidence, seriousness, reversibility, and correctability of the abnormality; and the effect on the risk of dosage, duration of exposure, and gestational timing of exposure.
The pregnancy Clinical Considerations section would include information about inadvertent exposure to the drug, prescribing decisions for pregnant women taking the drug, and the drug effects during labor or delivery. The inadvertent exposure information would describe known or predicted risks to the fetus from exposure to the drug early in pregnancy before a woman knows she is pregnant, including data on the dosage, timing, and duration of exposure to the drug.
The information covering prescribing decisions for pregnant women would describe the following:
- Risk to the pregnant woman and the fetus from the disease the drug is indicated to treat.
- Necessary dosing adjustments with the drug during pregnancy.
- Adverse reactions unique to pregnancy associated with use of the drug.
- Any particular interventions that might be needed for using the drug during pregnancy.
- Any complications in the neonate associated with the use of the drug (including the severity and reversibility of the complications, as well as the interventions that might be needed to manage the complications).
The information about drug effects during labor or delivery would cover drugs with a recognized use during labor or delivery (whether or not the drug is indicated for that use). This information would describe the effect of the drug on the mother and the fetus/neonate, its effect on the duration of labor and delivery, and the possibility of complications (including any necessary interventions for the complications, as well as the effect of the complications on the later growth, development, and functional maturation of the child).
The pregnancy Data section would describe in more detail the available data regarding use of the drug in human beings and from animal studies, all of which were used to develop the information contained in the “Fetal Risk Summary” section. The information in this section would include the following:
- A description of the kinds of human and animal studies conducted.
- The animal species used.
- Dosage exposure information (including dosages from human studies, as well as human dosage equivalents from animal studies).
- The nature of any identified fetal developmental anomalies and other adverse events.
- For animal data, an explanation of what is known about the relationship between drug exposure and mechanism of action in animals versus human beings.
The pregnancy labeling section would also include information about whether there is a pregnancy exposure registry for the drug, with information about how to enroll. Finally, all drug labels would carry a general statement that all pregnancies have a background risk of birth defects, fetal loss, or other adverse pregnancy outcome regardless of drug exposure.
Proposed Lactation Labeling
The lactation (breastfeeding) section of prescription drug labeling would use the same format as the pregnancy section (i.e., a risk summary section, a clinical considerations section, and a data section). The lactation Risk Summary section would provide information about whether use of the drug is compatible with breastfeeding; the effects of the drug on milk production; whether the drug is present in human milk and if so, how much; and the effect of the drug on the breast-fed child. The lactation Clinical Considerations section would include information about ways to minimize exposure to the breast-fed child (e.g., timing or pumping and discarding milk), potential drug effects in the child (including recommendations for monitoring or responding to these effects), and dosing adjustment during lactation. Finally, the lactation Data section would provide an overview of data on which the risk summary and clinical considerations for lactation are based.
The proposed change to the FDA labeling system will provide more detailed, comprehensible, and practical information about the use and effects of drugs during pregnancy and lactation. However, rather than quickly glancing at a drug’s categorical classification in the PDR under the current system, the proposed system will require some effort by patients, physicians, and nurses to actually read the information to know and understand the effects of medication during pregnancy and lactation. Nurses should be familiar with the labeling information when they counsel patients about taking medication during pregnancy and breastfeeding.
- Briggs, G.G., Freeman, R.K. & Yaffe, S.J. (2005). Drugs in pregnancy and lactation (7th ed.). Philadelphia: Lippincott Williams & Wilkins.
- Hale, T.W. (2004). Medications and mothers’ milk. Amarillo, TX: Pharmasoft.
- U.S. Food and Drug Administration. (2008). Pregnancy and lactation labeling. Retrieved February 3, 2009, from http://www.fda.gov/cder/regulatory/pregnancy_labeling/default.htm