FDA Pregnancy Risk Categories: Old and New – What do we need to know?

September 6, 2018 Suzanne Konigsberg

Gopala Krishna, Principal Consultant, Doug Ross, Senior Consultant & Partha Roy, Vice President – Technical, PAREXEL® Consulting

For years, drug developers and the FDA have been using the letter grades/categories (A, B, C, D and X) for pregnancy risk. However, these did not explicitly state the comprehensive risk associated with the grades for the users and the prescribers and did not specify whether the drugs or metabolites are present in the breast milk. So, the new pregnancy rule called:  Pregnancy and Lactation Labelling Rule (PLLR) was introduced by the FDA in 2015 with new information and made them more user-friendly. Further, FDA made this change because: clinically, many women require drug treatment during pregnancy due to chronic conditions such as epilepsy, diabetes, hypertension, or asthma. To withhold drug treatment would be dangerous for both mother and baby. In addition, women are having babies at a later age, which can boost the number of women with chronic conditions. Accessible and understandable pregnancy and lactation information is important for women and their health care providers to assess risk versus benefit. The PLLR removes pregnancy letter categories, categorizes available information appropriately and requires the label to be updated when information becomes outdated.

Pregnancy Risk Categories as we knew previously (prior to 2015)

  • In 1979, FDA established five letter risk categories: A, B, C, D or X - to indicate potential of a drug to cause birth defects if used during pregnancy (gradations of “safe” to “not so safe”)
  • Categories were determined by assessing the reliability of documentation and the risk to benefit ratio
  • Categories did not take into account any risks from drugs or their metabolites in breast milk


New Pregnancy and Lactation Labelling Rule (PLLR): Effective 2015

Below is a comparison of the current (old) prescription drug labeling with the new PLLR labeling requirements (https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm)Prescription Drug Labeling Sections 8.1-8.3 described in content of the page

Pregnancy subsection in the United States Package Insert (USPI; 8.1, is under the Section 8: Use in Specific Populations) includes information for a pregnancy exposure registry for the drug when one is available:

  • Registries collect and maintain data on the effects of approved drugs that are prescribed to and used by pregnant women
  • Information about the existence of registries in drug labeling is mandatory now
  • Information in the Pregnancy subsection includes a Risk Summary, Clinical considerations, and Data
  • Information formerly found in the “Labor and Delivery” subsection is now included in the “Pregnancy” subsection.

Nursing mothers subsection is renamed, the Lactation subsection (8.2):

  • Provides information about using the drug while breastfeeding, such as the amount of drug in breast milk and potential effects on the breastfed infant

Females and Males of Reproductive Potential subsection (8.3), new to the labeling, includes:

  • Information, when necessary, about the need for pregnancy testing, contraception recommendations, and information about infertility as it relates to the drug


An Example of the New PLLR in the USPI (section 8):

  • In Section 8 of USPI (https://www.allergan.com/assets/pdf/viibryd_pi ) a listing of the new PLLR categories is shown, as applicable. Briefly, it includes pregnancy risk summary comprising data from animal reproductive studies, its relevance to maximum human recommended dose (MHRD), fold safety margins, clinical considerations such as disease-associated maternal and/or embryo/fetal risk, fetal/neonatal adverse reactions and available human and animal data. Lactation risk summary comprising data regarding the secretion of drug in the breast milk and potential adverse effects on the breastfed child or from the underlying maternal condition. This example did not have any information on the reproductive potential of females and males; however such information is included when relevant, needed and available.


PLLR Effective timeframes:

  • Labeling changes went into effect on June 30, 2015
  • Prescription drugs and biologics submitted after June 30, 2015, are using the new format
  • Labeling for prescription drugs approved on or after June 30, 2001, are being phased in gradually
  • Labeling for over-the-counter (OTC) medicines will not change; OTC drug products are not affected by the final rule


PAREXEL’s Regulatory Consulting team can provide key advice to companies developing therapies regarding the new PLLR.  Our subject matter experts help drug developers to summarize animal reproductive toxicology studies, search the public literature on the reproductive effects of a given therapy including clinical data and categorize such information in the new format. Further our experts can assist in creating drug registries and manage information appropriately and update the label (USPI) periodically, as needed and/or as new safety information becomes available. This helps in complying with the new PLLR requirement by the regulatory agencies.


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