Recent Change in Pregnancy and Lactation Labeling

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Recent Changes in Pregnancy and Lactation Labeling:
Retirement of Risk Categories
Leda L. Ramoz, and Nima M. Patel-Shori*
Temple University School of Pharmacy, Philadelphia, Pennsylvania

The rapid development and increased availability of novel pharmacologic therapies and pharmaceutical
products has amplified the potential for drug exposure during pregnancy. Many drugs are beneficial
for disease state management during pregnancy and provide significant fetal and maternal health benefits. However, a paucity of safety data combined with the imprecision of the current risk category system renders risk versus benefit assessment difficult. In response to decades of criticism, the U.S. Food
and Drug Administration (FDA) is implementing a new pregnancy and lactation labeling rule designed
to improve risk versus benefit assessment of drugs used in pregnant and nursing mothers. These recommendations will provide clear and detailed information for both patients and health care providers,
and they will include three main categories: risk summary, clinical considerations, and data. The new
labeling rules remove the previous letter risk categorization system (A, B, C, D, X). In this review, we
summarize the upcoming FDA labeling changes and discuss their potential consequences on clinical
practice.
KEY WORDS pregnancy, lactation, labeling, risk categories, U.S. Food and Drug Administration, FDA.
(Pharmacotherapy 2014;34(4):389–395) doi: 10.1002/phar.1385

There are an estimated 6.5 million pregnancies in the United States each year, and about 1
in every 10 women of childbearing age is pregnant each year.1 Inadequate management of
maternal disease states during pregnancy can
have detrimental effects on fetal health. Maternal
health issues during pregnancy and lactation
may require use of medication. Current evidence
suggests that 64% of women use at least one
prescription drug during pregnancy and an average of three prescription drugs during pregnancy.2 Despite uncertain safety, nearly half of
the prescription drugs used during pregnancy
are classified as risk category C, D, or X (potential fetal risk or positive evidence of fetal risk),
and 4.6% of these are from category X alone.2
This may be due in part to the high rate of unintended pregnancies (~50% of all pregnancies are
unintended)3 or the fact that ~66% of all drugs
*Address for correspondence: Nima M. Patel-Shori, Temple University School of Pharmacy, 3307 N. Broad Street,
Philadelphia, PA 19140; e-mail: [email protected].
Ó 2014 Pharmacotherapy Publications, Inc.

are categorized as category C.4 Recent changes
to pregnancy and lactation drug labeling proposed by the U.S. Food and Drug Administration (FDA) in 2008 will enable health care
practitioners to counsel women who are pregnant, breastfeeding, or of childbearing potential.
These changes will also enable practitioners and
patients to better evaluate the risks versus benefits of the use of medications in women who are
pregnant or breastfeeding.
Historical Considerations
Drug-labeling regulations were introduced
between 1962 and 1979 in response to the thalidomide disaster of the early 1960s. Thalidomide was initially prescribed as a hypnotic agent
and later used for treatment of nausea and
vomiting in pregnancy. Thalidomide caused the
tragic teratogenesis phocomelia, the congenital
absence or underdevelopment of extremities.
First submitted for approval to the FDA in 1960
by William S. Merrell Co., the thalidomide
application was expected to obtain approval in

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PHARMACOTHERAPY Volume 34, Number 4, 2014

as little as 2 months. However, thalidomide was
never approved for use in the United States primarily due to concerns of FDA pharmacologist
Dr. Frances Kelsey with regard to a lack of
safety data. Although thalidomide was never officially approved for use, it was distributed to
more than 1000 U.S. physicians for investigational use, resulting in at least 17 confirmed
cases of phocomelia in the United States. This
can be compared with the more than 8000 children born with phocomelia worldwide. Despite
unrelenting pressure from William S. Merrell
Co., Kelsey’s unwavering commitment to drug
safety helped safeguard U.S. public health and
wellness.5
The thalidomide tragedy illuminated the need
to assess all medications for teratogenic potential
prior to marketing or at least prior to use in
women who are or may become pregnant. As a
direct result, in 1962 Congress passed the
Kefauver-Harris amendments, allowing tighter
regulation of drug approval by the FDA. In
addition, the FDA developed the 1979 Labeling
for Prescription Drugs Used in Man that
included pregnancy labeling regulations and
introduction of the pregnancy letter risk categories.5 This system was developed to help guide
health care providers as they assess the risks versus benefits of medications use during pregnancy and lactation. This system consists of five
letter risk categories A, B, C, D, and X (Table
1).6 Although these regulations were pivotal in
the improvement of drug safety and efficacy,
omission of pregnancy and lactation safety data
is permitted for drugs that are not systemically
absorbed and those without adequate studies to
demonstrate risk.6, 7
Public criticism of pregnancy risk categories
has been extensive, including during the open
hearing of the Public Affairs Committee of the
Teratology Society in 1997. The committee stated a unified opinion that the pregnancy risk
categories provide a confusing and inaccurate
source of information for patient counseling,
which should be immediately revised by the
FDA.7 Common critiques included the absence
of information for accidental exposures, and the
nature, severity, timing, incidence rate, or treatability of potential fetal injury. For example,
phenytoin exposure during pregnancy is thought
to be most detrimental during the first trimester
due to potential neural tube defects. Formation
of the neural tube is only one important part of
organogenesis (the development of fetal organs),
which occurs from 6–10 weeks of pregnancy

Table 1. Current Pregnancy Risk Categories and the Standardized Language Delineated by the FDA
Risk
category
A

B

C

D

X

FDA statement
Adequate and well-controlled (AWC) studies
in pregnant women have failed to
demonstrate a risk to the fetus in the first
trimester of pregnancy (and there is no
evidence of a risk in later trimesters)
Animal reproduction studies have failed to
demonstrate a risk to the fetus, and there are
no AWC studies in pregnant women or
animal studies that demonstrate an adverse
effect, but AWC studies in pregnant women
fail to demonstrate a risk to the fetus during
the first trimester of pregnancy (and there is
no evidence of risk in later trimesters)
Animal reproduction studies have shown an
adverse effect on the fetus, there are no AWC
studies in humans, and the benefits from the
use of the drug in pregnant women may be
acceptable despite its potential risks; or
animal studies have not been conducted and
there are no AWC studies in humans
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
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

Reprinted with permission from reference 6.

and when risk of teratogenic effects from drug
exposure is highest.8–10 Such congenital malformations produced during teratogenesis can be
compared with the use of angiotensin-converting
enzyme inhibitors or angiotensin II receptor
blockers during pregnancy, where prenatal exposure is associated with a specific fetotoxicity
(fetal renin-angiotensin system blockade syndrome).8, 11 Although teratogenesis results in
physical defects, fetotoxic substances cause
injury due to deleterious effects on fetal development and growth, potentially resulting in
death.11
In addition, these affects may be compared to
the risks of fetotoxicity throughout child development. Human clinical data suggest that the
use of selective serotonin reuptake inhibitors
(SSRIs) during pregnancy, particularly the third
trimester, may increase risk of neurobehavior
disruptions, perinatal complications, and possi-

RECENT CHANGES IN PREGNANCY AND LACTATION LABELING Ramoz and Patel-Shori
bly result in withdrawal syndrome and abnormal
neurobehavior beyond the neonatal period.8, 12–14
Fluoxetine is excreted in breast milk, and the
manufacturer does not recommend its use during breastfeeding.8, 13, 15, 16 Further investigation is required to elucidate the full effects of
SSRIs on fetal development and neurobehavior
from prenatal exposure and exposure during
breastfeeding.8, 15 The complexities of drug use
in the pregnant patient are insufficiently
addressed in such a minimalized system, resulting in an overall inability to assess risks versus
benefits of therapy accurately during pregnancy.
The pregnancy risk category system not only
provides a deficit of information, but it also generates added confusion about the relative risk of
drugs stratified within each category. Risk categories are frequently misinterpreted as a graded
system, with drugs in the same category sharing
the same risk. For example, inclusion of drugs
within the A, B, and C risk categories are based
primarily on risk of harm to the developing fetus
due to drug exposure. However, inclusion of
drugs within the D and X categories is based not
only on the risk to the developing fetus but also
any potential benefits of maternal (and subsequent fetal) health in preventing a potentially
severe or life-threatening disease state.7, 17
It is important to note that two drugs within
the same pregnancy risk category do not necessarily share the same risk. For example, both
isotretinoin and oral contraceptives are category
X drugs. Whereas the teratogenic effects of isotretinoin in humans are well known throughout
the pharmacologic community, oral contraceptives are not as well known for having a harmful
effect on fetal development, although they have
demonstrated some developmental abnormalities. Specifically, oral contraceptive exposure late
in pregnancy has been associated with masculinization of the female infant in humans (~0.3%
incidence).8, 18 Oral contraceptives are considered category X drugs because they induce
developmental defects, but the primary reason is
because there is no benefit in taking a medication designed for preventing pregnancy in a
woman who is already pregnant.8 Compared
with other risk categories, the risk C classification is increasingly confusing due to the inclusion of drugs that either “animal reproduction
studies have shown an adverse effect on the
fetus, 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” or “animal stud-

391

ies have not been conducted and there are no
adequate and well-controlled studies in
humans.”6, 7
Upcoming Labeling Changes
To address these concerns, the FDA has proposed a new Pregnancy and Lactation Labeling
Rule (“the Rule”).6 Goals of the Rule include
providing a format conducive to patient counseling and facilitating the transfer of clinical information without providing a scripted protocol for
the health care provider that may become dated
as new data are discovered. The new format of
the Rule is designed to help provide patient-specific therapy and improve the overall standard of
care. The Rule was first proposed in 2008 and
has undergone extensive revision by the health
care community including teratology experts.
Currently, the final version of the Rule is in the
writing and clearance process. The FDA has
announced that publication of the final version
of the Rule will be accompanied by information
for industry and health care practitioners.19
A copy of the most recent version of the Rule
can be found at the FDA Web site (www.fda.gov) and at www.regulations.gov. Once finalized, the Rule will be published in the Federal
Register in the same manner as the 1979 pregnancy and lactation labeling regulations. In the
future, updated content requirements of the new
rule will be found on each drug’s respective prescription drug label (package insert). These can
be accessed through the National Library of
Medicine on a Web site called Daily Med (http://
dailymed.nlm.nih.gov/).19 The Rule currently
states that there will be a minimum of a 120-day
lag period between publication of the final rule
and implementation of the Rule. The following
prescription drug applications submitted for
approval by the FDA on the following dates will
be required to follow the updated pregnancy
and lactation labeling rule:

• Applications



submitted on or after June 30,
2006
Applications for which approval was pending
on June 30, 2006
Applications approved between June 30,
2001, and June 30, 2006

Drug applications approved after June 30,
2001, but before publication of the Rule will
have a minimum of 3 years to submit labeling
with updated content. Drug applications
approved prior to June 29, 2001, are not subject

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PHARMACOTHERAPY Volume 34, Number 4, 2014

Table 2. Overview of New Pregnancy and Lactation Labeling
General information
Contact information if pregnancy registry available and general statement about background risk
Fetal risk summary
Based on all available data, this section characterizes the likelihood that the drug increases the risk of developmental
abnormalities in humans and other relevant risks. More than one risk conclusion may be needed. For drugs that are not
systemically absorbed, there is a standard statement that states that maternal use is not expected to result in fetal
exposure
For drugs that are systemically absorbed:

• When there are human data, include a statement about the likelihood of increased risk based on these data. This statement is followed by a description of findings
• Include a standard statement about likelihood of increased risk based on animal data
Clinical considerations
This section provides information on the following topics:

• Inadvertent exposure: known or predicted risk to the fetus from inadvertent exposure to drug early in pregnancy
• Prescribing decisions for pregnant women:
• Describe any known risk to the pregnant woman and fetus from the disease or condition that the drug is intended
to treat
• Information about dosage adjustments during pregnancy
• Maternal adverse reactions unique to pregnancy or increased in pregnancy
• Effects of dose, timing, and duration of exposure to drug during pregnancy
• Potential neonatal complications and needed interventions
Data
Human and animal data are presented separately, with human data presented first

• Describe study type, exposure information (dose, duration, timing), any identified fetal developmental abnormality, or
other adverse effects
• For human data, include positive and negative experiences, number of subjects, and duration of study
• For animal data, include species studied, and describe doses in terms of human dose equivalents (provide basis for
calculation)

Reprinted with permission
Labeling/UCM093313.pdf).19

from

FDA.gov

(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/

to the updated pregnancy and lactation labeling
rule and are not required to implement updated
content requirements. However, if any such
applications carry a pregnancy risk category designation, they will be required to remove that
designation within 3 years of the efficacy date of
the Rule.6
Format of the new label incorporates a new
streamlined design led by a brief description of
any pregnancy registry contact information
(Table 2). Although many medications have not
been studied in pregnant women, it is important
to educate both the health care provider and the
patient on registries that collect and maintain
data on the effects of medication use by pregnant and nursing women. The new label also
includes the following brief background risk
statement for all pregnancies: “All pregnancies
have a background risk of birth defect, loss, or
other adverse outcome regardless of drug exposure. The fetal statement risk summary below
describes (name of drug) potential to increase
the risk of developmental abnormalities above
the background risk.”6 Core elements of the

new labeling rule include three main subsections
(in the following order): risk summary, clinical
considerations, and data for both pregnancy and
lactation sections.6 The updated Rule proposes
to combine the previous sections of “pregnancy”
and “labor and delivery” into a single “pregnancy” category; the “breastfeeding” section will
be converted into a “lactation” section.19
Pregnancy: Risk Summary, Clinical
Considerations, and Data
The risk summary section first describes the
probability of developmental abnormalities or
adverse outcomes in humans and may contain
more than one summary depending on other relevant risks. After the risk statement, a brief
characterization of risk is described following a
format depending on the origin of the data. If
the risk is based on human data, there will be a
brief description of data supporting the risk
statement. If the potential risk is inferred from
only animal data (Table 3), a standardized statement will describe the risk using the following

RECENT CHANGES IN PREGNANCY AND LACTATION LABELING Ramoz and Patel-Shori

393

Table 3. Updated Pregnancy Labeling for a Fabricated Drug (Alphathon) for Which Only Animal Data Are Available for
Developmental Toxicity Findings
General information
All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The
fetal risk summary below describes Alphathon’s potential to increase the risk of developmental abnormalities above the
background risk
Fetal risk summary
Based on animal data, the likelihood that Alphathon increases the risk of developmental abnormalities is predicted to be
high (see Data section)
Clinical considerations
Asthma complicates ~1% of all pregnancies, resulting in higher perinatal mortality, low–birth weight infants, preterm
births, and pregnancy-induced hypertension compared to outcomes for nonasthmatic women. Because of the risks of even
mild maternal hypoxia to the developing fetus, asthma should be clinically well controlled during pregnancy. There are
no human studies evaluating Alphathon use in pregnant women. The time of gestation at which risk may be greatest is
unknown; therefore, risks of inadvertent exposure in early gestation cannot be evaluated. Animal data suggest that
Alphathon exposure may result in early fetal loss and anomalies of major organ systems. There are no data regarding
dosage adjustment needs in pregnancy. Given the lack of human data and the risks suggested by animal data, prescribers
should consider alternative treatments for asthma for pregnant women when possible (especially during the first
trimester) and for women planning pregnancy
Data
Human data:

• There are no data on human pregnancies exposed to Alphathon
Animal data:

• Reproductive studies performed during early pregnancy in rats at oral doses 0.75–1.0 times the recommended human



dose (adjusted for body surface area) showed implantation loss, fetal resorptions, and major congenital anomalies of
the cardiac, skeletal, and renal systems without signs of maternal toxicity
Reproductive studies performed in early pregnancy in rabbits at doses ~0.33–1.0 times the recommended human dose
(adjusted for body surface area) showed increased postimplantation loss. Studies at three times the human dose
showed significant fetal loss without signs of maternal toxicity
The effects of Alphathon on fetal growth, labor, or postnatal complications were not evaluated in the animal studies

Reprinted with permission
Labeling/UCM093313.pdf).19

from

FDA.gov

(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/

Table 4. Updated Lactation Labeling for a Fabricated Drug (Gammatol) for Which Human Data are Available
Risk summary
Gammatol is secreted in human milk. At a maternal dose of 400 mg daily, the average milk concentration, collected over
24 hrs after dosing, was 10 mcg/ml, which is lower than maternal serum drug concentrations at steady state. Based on an
average milk consumption of 150 ml/kg/day, a 2-mo-old infant would consume ~6 mg/day of Gammatol through breast
milk, which is ~1.3% of the maternal dose. No studies have been performed to assess infant absorption and exposure to
Gammatol from breast milk. No studies have been performed to assess the impact of Gammatol on milk production or its
effects on the breastfed child
Clinical considerations
Because Gammatol is taken once daily, mothers can reduce infant exposure by taking their Gammatol dose immediately
after breastfeeding at the time of day when feedings are less frequent
Data
A lactation study was performed in 30 women who were 2 mo postpartum and exclusively breastfeeding their infants. All
women enrolled in the study were taking a single dose of Gammatol 400 mg daily. Breast milk samples were collected
from each breast at the beginning and end of each feeding for 24 hrs after a Gammatol dose. An average maximum milk
concentration of 20 mcg/mL occurred 3 hrs after dosing, and drug concentrations in milk rapidly declined over the next
12 hrs. The average milk concentration was 10 mcg/ml. No drug was detectable in milk samples obtained 36 hrs or later
after dosing. No data are available to assess the impact of Gammatol on milk production or its effects on the breastfed
child
Reprinted with permission
Labeling/UCM093316.pdf).19

from

FDA.gov

(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/

specific language delineating a scale: none, low,
moderate, high, or unknown. The Rule will
apply to all drugs, including those with no sys-

temic absorption and with limited data demonstrating risk. If a drug is not systematically
absorbed, it must contain the following state-

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PHARMACOTHERAPY Volume 34, Number 4, 2014

ments within the risk summary: “(Name of
drug) is not absorbed systemically from (part of
body) and cannot be detected in the blood.
Maternal use is not expected to result in fetal
exposure to the drug.”6, 7
The second section of the labeling formation,
clinical considerations, will include relevant
information for prescribing decisions and patient
care along with information about unintended
exposures. This section also addresses the risks
of untreated conditions, dosage adjustment
information during pregnancy, unique or
increased adverse reactions present during pregnancy, and potential fetal complications and
possible interventions. Information detailing use
during labor and delivery will be contained
under the clinical considerations subsection.
The final segment of the new pregnancy label,
the data section, will include a detailed discussion on the clinical trial or study. Drug information such as dosage, duration, timing, type of
fetal abnormality, or other adverse outcomes
observed will be declared in this section. Human
data will be discussed before animal data, and
animal data must include species information
and compare to human dose equivalent (must
provide a basis for comparison such as body surface area).6, 19
Lactation: Risk Summary, Clinical
Considerations, and Data
The previous “Nursing Mothers” section will
be relabeled “Lactation.” The core of the
updated lactation label will follow the same
format as the updated pregnancy label with
sections including a risk summary, clinical considerations, and data segment (Table 4). Any
adverse effects on the breastfed infant and milk
production must be described. A drug undetectable in breast milk that is also not shown to
affect quantity and quality of breast milk or does
not adversely affect the breastfed child will contain the following label: “The use of (name of
drug) is compatible with breastfeeding.”6
Drugs present in breast milk must include a
description of the concentration and sensitivity
of assay used to measure the quantity of drug
found in breast milk and the estimated daily
infant dose during breastfeeding. Clinical considerations include adverse effects to the infant,
monitoring recommendations, and associated
interventions as well as a description of any
feeding techniques or dosage adjustments to
minimize infant drug exposure.6, 7, 19

Elimination of the Letter Risk Categories
The Rule also proposes the retirement of the
highly criticized letter risk categories (A, B, C, D,
X). This should help eliminate some of the confusion regarding drug use and fetal health risk. The
Rule delineates removal of all pregnancy risk categories from any drug application within 3 years
of its effective date. Undoubtedly, there will be
new drug applications approved within this 3year time frame that will adhere to the updated
pregnancy and lactation labeling requirements.6
This creates an interim where there will exist not
only a new, but also a dual, pregnancy risk stratification system. This raises additional potentially
serious concerns for health care practitioners
attempting to optimize the clinical care of pregnant and lactating patients. Prudent health care
practitioners should keep a close watch on the
upcoming debut of these changes.
In a categorical fashion similar to the risk categories, the Rule proposes the use of standardized language (“none, low, moderate, high, or
unknown” [Table 3]) to describe the risk for
drugs in which only animal studies are available.6 Although the Rule provides an added benefit of including much more information than
what was provided for the risk categories, it is
important to note that most of the prescription
medications only provide animal data to support
safety and efficacy use. This underscores the
importance of enrolling patients who are taking
medications during pregnancy in pregnancy registries. It is also important to emphasize the
importance of making educated health care decisions using a patient-specific versus a standardized one-size-fits-all approach.
Conclusion
The rapid evolution of modern pharmacy
practice necessitates constant revision of policy
and procedure to maintain the safety and welfare
of patients. Implementation of the new Pregnancy and Lactation Labeling Rule will improve
the ability of health care practitioners and
patients to better understand the risks associated
with medications (or lack thereof) during pregnancy and lactation. The new labeling design
should provide additional information necessary
for providing the best standard of care for both
the mother and child during pregnancy and
breastfeeding that was not present in the original
pregnancy labeling rule. This streamlined format
will enable practitioners to identify critical infor-

RECENT CHANGES IN PREGNANCY AND LACTATION LABELING Ramoz and Patel-Shori
mation quickly during a busy workday and navigate the complexity of medication use and therapies within this specific subgroup of patients to
provide optimal recommendations. Overall, the
Rule will improve the standard level of care and
risk management of pregnancy and of childbearing or breastfeeding patients.

9.
10.
11.

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