In 2015, the U.S. Food and Drug Administration (FDA) proposed major revisions to prescription drug labeling in order to provide more accurate and helpful information on the effects of medications used during pregnancy and breastfeeding. The system used by the FDA for the last 30 years classifies the reproductive safety of medications using five risk categories (A, B, C, D and X) based on data derived from human and animal studies. While widely used to make decisions regarding the use of medications during pregnancy, many have criticized this system of classification, indicating that this type of drug labeling is often not helpful and, even worse, may be misleading.

The Pregnancy and Lactation Labeling Rule or PLLR has abolished the letter categories and instead includes more comprehensive information discussing the potential risks and benefits to the mother and the fetus, and how these risks may change during the course of pregnancy. (You can find a PowerPoint presentation from the FDA describing the PLLR here.)

Instead of using an arbitrary lettering system, the PLLR provides detailed risk summaries and more comprehensive information derived from clinical experience (if available), animal data, and concerns related to the pharmacologic activity of the drug. In addition, the label includes information on the risks associated with untreated illness. This information helps to put the potential effects of the drug into perspective with the goal of providing a more individualized risk-benefit analysis. 

In addition, the PLLR will also reduce the “innocent until proven guilty” phenomenon, where newer, untested drugs with no known harmful side effects were perceived to be safer (Category B) than tested drugs with possible or known side effects (Category C).


Are Healthcare Providers Using the New System?

According to a cross-sectional study from 2020 including 290 medications approved between January 2010 to December 2019, all products submitted after June 20, 2015, were in compliance with the PLLR; however, of those submitted between 2010 and 2015, 32.6% were not in PLLR format. Human data on pregnancy and lactation were available in less than 20% of the new product labels. 

A study from 2020 queried 1500 allergists and immunologists about the PLLR.  This may not be the most representative sample, as only 184 (12%) who received the survey via email actually completed the survey.  However, the findings were concerning and worth noting.  Less than half (46%) of the respondents were aware that the pregnancy letter category system had been replaced with a narrative summary. After reading the example of the PLLR, most of the respondents (68%) felt that the narrative summary was too long.  Most of the respondents (95%) stated that they will continue to use the pregnancy letter category system to make prescribing decisions.

To the best of my knowledge, no other studies have assessed the use of the PLLR by obstetricians or other specialists.  While we cannot make meaningful conclusions about the use of the PLLR by all healthcare providers, experience in our clinic suggests that the PLLR is not widely used.  


Where Do You Find This Information?

Finding information on the reproductive safety of medication is not that straightforward.  Not so long ago, you could find the information continued within the product label in the Physician’s Desk Reference or PDR which was updated regularly and mailed to doctors’ offices every year.  Now we go to the internet and find all kinds of stuff, much of it outdated or misleading.   

Many commonly used and reputable websites, such as WebMD and the Mayo Clinic do not include the new information provided in the PLLR. And there are many other websites of variable quality that continue to use the old lettering system.

Even when you try to make sure the information comes from a reputable source, the information can be misleading.  For example, if you search for “lorazepam package insert”, the first listing is from the FDA, the governmental organization responsible for approving the language contained in package inserts.  It seemed legitimate but with a little bit of digging, I discovered that the document that came up first was outdated — from 2007.  

Don’t trust the internet.    


Updated Information on DailyMed

DailyMed is a useful website which is hosted by NIH and posts updated drug listings (package insert information) as submitted by the Food and Drug Administration (FDA).  It’s relatively easy to use; the PRECAUTIONS section outlines data on pregnancy and lactation safety.

While the information on the site is up-to-date, it feels a little sparse.  Certainly the narrative summary provides more information than a single letter, but will providers find that the information is detailed enough to inform and simplify decision-making in pregnant and breastfeeding women?  While it may help, I suspect that it is but one piece of information that women need to make informed decisions regarding their care.  As providers, it is our job to help our patients navigate this complex and often confusing body of information. 


Ruta Nonacs, MD PhD

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