FDA pregnancy categories: Help or hindrance?

A pharmacist receives a phone call from a panicked patient. She has been taking paroxetine for 2 years and has just found out she is pregnant. She googled and found multiple mentions of class-action lawsuits arising from the combination. Her physician said something about a “Category D” and advised her to discontinue the medication. She stopped it suddenly and is now experiencing discontinuation symptoms. What should the pharmacist do?

In 1979, the FDA adopted the Pregnancy Category System to give guidance regarding the risks of medications in pregnancy. The categories are:

Category A: Adequate and well-controlled studies in pregnant women have failed to demonstrate risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters).

Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women or animal reproduction studies have shown an adverse effect (other than decrease in fertility), but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters).

Category C: Animal reproduction studies have shown an adverse effect on the fetus or there are no adequate and well-controlled studies in humans, and the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.

Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.

Category X: Studies in animals or humans have demonstrated fetal abnormalities or there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit.

There are many shortcomings with this current system and the ways in which it has been interpreted. Some historical points are worth noting here. At the time these categories were created, the general assumption was that pregnant women did not need to use medications.¹ The primary goal “was to inform counseling between a physician and a patient planning a pregnancy – to provide evidence-based, risk/benefit guidance prospectively, before an embryofetal exposure occurred.”² Since that time, it has been recognized that some conditions benefit from treatment during pregnancy, including asthma, hypertension, migraine, psychiatric disorders, diabetes, gestational diabetes, pregnancy-induced hypertension, preterm labor, preeclampsia, hyperemesis and morning sickness.³ One study found that 64% of women were prescribed a medication during pregnancy.⁴ Furthermore, 50% of pregnancies are unplanned,² and therefore prospective pharmacotherapeutic plans are not always discussed, and inadvertent exposure is common.

The main criticism of the category system is that it oversimplifies what is in fact a very complicated, individualized clinical decision.⁵ The risk of untreated illness and/or possible benefits of the medication are mentioned briefly as considerations, but are not elaborated on and are often overshadowed by the perception of risk of the medication. The categories also do not discuss gestational age and the effects of drug exposure at various trimesters of the pregnancy, nor do they address the differing dosages needed at various stages due to pharmacokinetic changes of pregnancy, such as decreased gastrointestinal motility, increased volume of distribution and resultant hypoalbuminemia, liver enzyme induction and increased renal clearance.³ Another major gap is the lack of information on medication use during lactation.³

Additional criticism surrounds the application of the categories. They are often seen as a grading system, where the risk increases as one progresses from A through X.²⁵ In fact, a medication that is new to the market is often rated as a category B, as there are no studies yet to show potential risk. It is often assumed that medications within the same category carry the same risk, though the specifics for each medication can vary widely in terms of types, frequency, and severity. This is especially true for category C, which contains 65-70% of all medications.²

The actual wording of each category is sometimes ignored and assumptions are made. For example, some have considered D to mean the medication is teratogenic and should not be used, but it in fact states that the potential benefits may outweigh the risks. Category X also can be misinterpreted as only teratogens, but it also includes medications where the risk outweighs possible benefits in pregnant women, such as oral contraceptives.²

Another round of criticism comes from the interpretation of animal vs. human studies. For example, category B includes two types of scenarios – one where there is failure in animal studies to show risk but without well-controlled human studies, the other where adequate and well controlled studies in humans demonstrate safety. The most important data should be from human studies, and those are immensely difficult to conduct.⁶ Most data on medications in pregnancy comes from various types of epidemiologic studies, which do not reach the gold standard of randomized, controlled trials.

Again, one of the main criticisms of the category system is that is focuses on risks of medications, but is being used for clinical management of complicated situations without due regard to the risks of untreated illness. Fortunately, the FDA is currently considering a new system of reporting pregnancy and lactation data that should address a number of concerns. In 1997 an interdisciplinary task force was put in place to develop a more clinically useful system.³ The task force identified the following problems with the current system:

• Lack of data on drug effects on humans, resulting in an emphasis on animal data

• An inability to interpret the C category clinically

• Difficulty assigning drugs to the A category

• Does not take into account timing of drug exposure during pregnancy

• No information on the medication safety in lactation ³⁶

The FDA concluded that a category system was not appropriate, and that a “narrative labelling model can best convey the potential risks of each drug or biologic based on available animal and/or human data”.² After years of further consultations and committee meetings, a new system was proposed in 2008.7–10 Under the proposed regulations, all drug monographs will be required to include pregnancy and lactation subsections. This information will be divided into three major parts: fetal risk summary, clinical considerations and data.

Each section on pregnancy and lactation in the new labelling will start with pregnancy exposure registry information, if available. It will also give a general statement regarding the background risk of adverse pregnancy outcomes such as birth defects and pregnancy loss.¹² The risk summary will incorporate human and animal data, the clinical consideration section will address risk assessment and inadvertent exposure, and the data section will summarize the evidence in the other two sections.²⁵ This information will be given for both pregnancy and lactation. While this proposal has been in place since 2008 and extensive consultations have taken place, it is unknown when the new labelling requirements will take effect.

A final criticism that still needs to be addressed is that the FDA has not always updated categories when new data emerge. For example, they moved paroxetine to Category D because of unpublished data that showed a possible increase in cardiac abnormalities. When further studies showed a lack of association, they did not move paroxetine back to Category C.¹¹ It is essential that the information in the new labelling be updated as new information becomes available through pregnancy registries and studies. New initiatives with pregnancy registries may yield some of this information.¹²

So, what is the role of the pharmacist in all of this? As can be seen from the case presented above, pharmacists will often be called upon to give information to patients and health care providers about the risks of medications in pregnancy. Unfortunately, studies have found that 90% of pharmacists directly referred patients to their physician, without giving any information and only 14% referred to the literature to dispense evidence-based information.¹³ With a proper understanding of the current FDA categories and access to the literature, pharmacists should be able to offer more.

With regards to the case, even with paroxetine in Category D, the “potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks”. Besides the risks of untreated illness, the risks of discontinuation effects need to be taken into account. A full discussion about paroxetine with the patient and physician needs to include topics such as severity of illness, symptoms, supports in place, accessibility of other treatments, and the risks and benefits of continuing or discontinuing paroxetine. Only with this in-depth discussion should a decision be made. The proposed updates to the FDA pregnancy categories could help facilitate this discussion immensely.

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