ABSTRACT: On May 29, 2008, the FDA issued a proposed rule aimed at revising current regulations on the pregnancy,labor and delivery, and nursing mother sections of prescribing information. The aim of the new labeling format is to provide sufficient information to pregnant and breastfeeding patients and their healthcare providers when prescribing and counseling about medication. Following approval, the new regulations will eliminate the commonly known pregnancy letter categories and create pregnancy and lactation sections, each of which will contain fetal risk summary, clinical considerations, and data subsections.

On May 29, 2008, the FDA issued a proposed rule aimed at revising current regulations pertaining to the pregnancy, labor and delivery, and nursing mother sections of the prescribing information for prescription drugs and biologic products.1 Initiation of this amendment was prompted by the FDA’s goal to provide women and their healthcare providers with sufficient information when deciding which medications to prescribe in pregnant and breastfeeding patients.2 Improved regulations to ensure safe and effective medication use during pregnancy are essential, considering that about half of all pregnancies are unexpected, leading to unintended drug exposure.

Recent data indicate that about 90% of pregnant women take at least one medication and 70% take one or more prescription drugs, potentially putting the fetus at high risk for drug-induced developmental abnormalities.3 Many pregnant women may also be on medications to control chronic disease states such as hypertension or to manage acute conditions developed during pregnancy such as gestational diabetes.4

In addition, physiological changes to the cardiovascular, hepatic, and renal systems during pregnancy can alter the pharmacokinetics of medications. Therefore, appropriate dosage adjustments may be required to maintain therapeutic drug levels. Pregnant women have a 40% to 50% increase in blood volume, leading to larger volumes of distribution and potentially subtherapeutic levels of hydrophilic drugs at standard doses. Pregnancy is also associated with an increase in CYP3A4 activity, which contributes to the increased clearance of its substrates such as nifedipine and carbamazepine. Glomerular filtration rate increases 50% during pregnancy, increasing the elimination rate and decreasing the half-life for medications such as digoxin and piperacillin, which primarily undergo renal excretion. These changes in absorption, distribution, metabolism, and elimination must be considered to ensure therapeutic efficacy and safety when prescribing for pregnant women.5

Current Labeling

The original FDA regulations on pregnancy, labor and delivery, and lactation labeling for prescription drugs were formulated in 1979. According to these regulations, prescribing information must include risk evaluation on use during pregnancy under the “Use in Specific Populations” section for all drugs except those that are not absorbed systemically or those with insignificant data to demonstrate risk to the fetus.1

Currently, this risk assessment is presented in the commonly known form of pregnancy categories consisting of A, B, C, D, and X designations (TABLE 1).1 Categorical classification is based on whether or not data are available, whether the data come from animal or human studies, and the results from these studies. In addition, Categories D and X consider benefits versus risks of using the drug while pregnant. The purpose of these labeling regulations was to present adequate information to assist healthcare providers when prescribing for patients already identified as being pregnant, not to provide information following drug exposure during an unplanned pregnancy. Limitations of this system were quickly identified by professional societies such as the Teratology Society as well as by the FDA, which initiated public hearings in 1997 to evaluate this specific labeling regulation.4


Feedback from these hearings established that although healthcare providers strongly rely on the pregnancy categories to make pharmacotherapy decisions, the meaning of these categories is commonly misunderstood and inappropriately applied in practice. One concern is that oversimplification leads to a misinterpretation of the pregnancy categories for a rank order of risk in which Category A represents the lowest risk and Category X the highest. In addition, the risk and benefit considerations in Categories C, D, and X are commonly overlooked.4 For example, warfarin is a Category X drug contraindicated during pregnancy because of its teratogenic effects in humans.6 Hormonal contraceptives are also Category X drugs, but their designation is based on the fact that they lack efficacy for their FDA labeled indication of preventing pregnancy in already pregnant women, as well as on findings of congenital disorders in animal studies.4

Another limitation of the current pregnancy categories is the assumption that drugs within the same category share the same extent of risk for congenital disorders, including similar clinical presentation, degree of severity, and rate of occurrence. This point is supported by the finding that 65% to 70% of all prescription drugs are assigned to Pregnancy Category C yet have drastically different sets of supporting evidence and risks.4 According to the FDA, drugs are classified as Category C “if animal reproduction studies have shown an adverse effect on the fetus, if there are no adequate and well-controlled studies in humans, and if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.”1 As an example, oseltamivir is Category C because animal studies have shown some degree of skeletal abnormality; however, the rate of occurrence is within the baseline incidence for the studied species.7 Hydralazine is also Category C based on observed adverse events in animal reproductive studies; however, IV hydralazine is recommended for the management of acute severe hypertension in pregnancy due to the risk of inadequate treatment and the lack of a superior alternative.8

Comments from the public hearings also included criticism regarding the lack of differentiation between data from animal and human studies in the current pregnancy subsections of prescribing information.4 Amoxicillin, the recommended treatment for chlamydia in pregnant women, is a Category B drug because no congenital disorders were found during animal studies; however, no adequate and well-controlled human studies have been performed.9,10 Torsemide, which is also designated as a Category B drug, has been shown to cause adverse effects during animal reproductive studies but not in human studies performed during the first trimester of pregnancy. Data in the following trimesters do not exist.11

New FDA Proposal

Pregnancy: Based on feedback from public meetings, focus groups, and advisory committees, the FDA developed the proposed rule to address the current limitations through a detailed outline for new pregnancy and lactation labeling.2 Following approval, the new regulations will require elimination of the pregnancy letter categories and formation of a pregnancy subsection and a lactation subsection within the prescribing information. These regulations will apply to drugs approved after June 30, 2001, and allow 3 years to update to the new labeling format. Drugs approved before June 29, 2001, will not be required to follow the new regulations; however, if they contain a pregnancy risk category within the prescribing information, it must be removed within 3 years.12

Information will be presented in each subsection under the standardized headings “Fetal Risk Summary,” “Clinical Considerations,” and “Data.” Preceding these three headings, the drug’s pregnancy exposure registry and its contact information will be listed, if available.13 Pregnancy registries are studies that monitor the effects of both drugs and vaccines administered to women during pregnancy. The registries do not make medication interventions; rather they record data about pregnant women already on medications prescribed by their providers to detect any effects from the drug.14 The introduction will also include a concise statement on the background risk in all pregnancies (TABLE 2).12,13


According to the proposed rule, the pregnancy labeling subsection will contain a statement on elevated risk for developmental abnormalities due to the drug and identify whether the source of that data comes from animal or human studies under “Fetal Risk Summary.” Unlike current regulations, the new pregnancy subsection will be required for all prescription drugs including those that are not systemically absorbed and those with limited evidence of risk.12 When only animal data are present, “Fetal Risk Summary” will consist of a risk conclusion. In the event that human data are available, the risk conclusion will also include an evaluation of the data such as changes in the risk with varying dosages, treatment duration, and gestational age.

The next section, “Clinical Considerations,” is aimed at providing information to aid healthcare providers during unexpected drug exposure, in prescribing decisions, and in use during labor and delivery. Finally, the “Data” section will include a comprehensive summary of the available data upon which the information in the “Fetal Risk Summary” and “Clinical Considerations” sections are based. Human data such as drug dosage, type of developmental abnormality, and other adverse events will be described first followed by animal data, including the animal species, available correlation of the drug’s effect in animals to that in humans, and the human dosage equivalent of the animal dosage (TABLE 2).12,13

Lactation: The lactation subsection is formatted similarly to the pregnancy subsection. For applicable medications, a sentence stating that the drug can be taken while breastfeeding will appear under “Risk Summary.” Drug effects on milk production, if any and/or how much of the drug enters maternal milk, and any adverse effects that have occurred to the infant are also included in this area. The “Clinical Considerations” section will include methods to decrease drug exposure to the infant such as taking the dose at a particular time or using a “pump and dump” strategy to dispose of potentially affected milk. Adverse effects and how to monitor for them along with required dosage adjustments during lactation are also present in this section. The “Data” section will consist of the findings that support the statements in the “Risk Summary” and “Clinical Considerations” sections (TABLE 3).12,13



The final format of the proposed rule is in the process of being written and cleared by the FDA. Along with its publication, the FDA will provide guidance for industry and providers. Once the final version of the proposed rule is decided, it will replace the 1979 pregnancy and lactation regulations in the Federal Register and be implemented within 120 days. Prescribing information will be required to contain the new format for pregnancy and lactation labeling within 3 years. Implementation of the proposed rule will provide detailed and current information in a useful format to better facilitate patient advisement when it comes to medication use during pregnancy. Most importantly, it will equip healthcare providers with the clinical data they need to make informed pharmacotherapy decisions for their pregnant patients.12


1. FDA, U.S. Department of Health and Human Services (HHS). Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. 21 CFR Part 201. May 29, 2008. Fed Regist. 2008;73(104):30831-30868. www.gpo.gov/fdsys/pkg/FR-2008-05-29/pdf/E8-11806.pdf. Accessed May 8, 2014. 
2. FDA Consumer Health Information. Pregnant women to benefit from better information. May 28, 2008. www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM143746.pdf. Accessed May 8, 2014. 
3. CDC. Treating for two: data and statistics. February 19, 2014. www.cdc.gov/pregnancy/meds/treatingfortwo/data.html. Accessed July 30, 2014. 
4. Feibus KB. FDA’s proposed rule for pregnancy and lactation labeling: improving maternal child health through well-informed medicine use. J Med Toxicol. 2008;4(4):284-288. 
5. Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Front Pharmacol. 2014;5(65). http://journal.frontiersin.org/Journal/10.3389/fphar.2014.00065/full. Accessed May 24, 2014. 
6. Coumadin (warfarin) package insert. Princeton, NJ: Bristol-Myers Squibb; October 2011. http://packageinserts.bms.com/pi/pi_coumadin.pdf. Accessed May 8, 2014. 
7. Tamiflu (oseltamivir) package insert. South San Francisco, CA: Genentech, Inc; January 2013. www.gene.com/download/pdf/tamiflu_prescribing.pdf. Accessed May 8, 2014. 
8. Hydralazine. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. Updated May 5, 2014. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7034#f_pregnancy-and-lactation. Accessed May 8, 2014. 
9. Amoxicillin. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc. Updated May 5, 2014. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6346#f_pregnancy-and-lactation. Accessed May 8, 2014. 
10. Amoxicillin package insert. Eatontown, NJ: West-ward Pharmaceutical Corp; December 2006. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=de8990a6-f3b6-478f-acbe-eda961b6da4b. Accessed May 8, 2014. 
11. Torsemide package insert. Weston, FL: Apotex Corp; November 2012. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=99708985-2bc2-b753-5d67-288f0d609e90. Accessed May 8, 2014. 
12. Ramoz LL, Patel-Shori NM. Recent changes in pregnancy and lactation labeling: retirement of risk categories. Pharmacotherapy. 2014;34(4):389-395. 
13. Kweder SL. Drugs and biologics in pregnancy and breastfeeding: FDA in the 21st century. Birth Defects Res A Clin Mol Teratol. 2008;82(9):605-609. 
14. Labeling. Questions and answers on the pregnancy and lactation labeling rule. FDA. May 2008. www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093311.htm. Accessed May 8, 2014.

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