DOI: 10.1097/JPN.

0000000000000097

EXPERT OPINION

PERINATAL

Jackie Tillett, ND, CNM, FACNM

Medication Use During Pregnancy

and Lactation
The New FDA Drug Labeling
he United States Food and Drug Administration
(FDA) has changed and updated the drug labeling for pregnancy risk. This change will become
effective on June 30, 2015, for drug applications submitted on or after this date. Applications for drugs approved from June 30, 2001, until the rule takes effect
have 3 to 4 years to modify their labeling depending
upon when the application to the FDA was approved.1
The current letter system will no longer be used.
The new labeling is based on providing information for counseling and decision making by the patient
and healthcare providers and will rely less on simple
categories that may be misleading to women, nurses,
providers, and pharmacists. This information is important for nurses, as nurses provide much of the counseling for pregnant women in clinics, obstetrical triage
settings, and labor units. Women who are pregnant
or breastfeeding often look to nurses for advice and
information.
The FDA initiated the original pregnancy risk categories for medications in response to the thalidomide
tragedy in Europe in the early 1960s. Thalidomide was
prescribed for pregnant women as a sleep aid and as a
treatment of nausea and vomiting. Thalidomide caused
phocomelia during fetal development, an unknown effect prior to the widespread use of the drug at the time.
Phocomelia is the congenital absence or underdevelopment of the extremities. There were more than 8000
children born worldwide with phocomelia caused by
the use of the drug during pregnancy.2 This tragedy
alerted healthcare providers and FDA staff to the need
for assessment of medications for fetal effects prior to
the use of a particular drug in the United States.
After much discussion and input from physicians,
pharmaceutical companies, scientists and researchers,

Disclosure: The author has disclosed that she has no significant relationships with, or financial interest in, any commercial companies pertaining
to this article.
The Journal of Perinatal & Neonatal Nursing

and FDA staff, the pregnancy labeling regulations were

instituted in 1979. The pregnancy labeling categories
were developed as a guide for healthcare providers to
assess the risks and benefits of a particular drug for a
pregnant woman.2 This system uses 5 categories with
labels A, B, C, D, and X (see Table 1).
During the time the category system was being developed, pregnant women were much less likely to
use drugs during pregnancy. Pregnant women were
younger and so thought to be healthier than the pregnant population today.3 In the United States, the average age at which women first get pregnant has risen, the
number of pregnant women who have chronic illnesses
has increased, and the use of both prescription drugs
and over-the-counter medications by pregnant women
has increased.3
As the use of prescription drugs by pregnant women
has increased, it has become evident that the current
classification system is oversimplistic and does not aid
healthcare providers with decision making about these
drugs during pregnancy. Providers, pharmacists, and
patients commonly perceive the categories to be an indication of increasing risk.3 For example, category B is
seen as a safer drug than category C. This is not necessarily true. The risk and benefit of the drug should
still be carefully assessed and considered. More than
50% of prescription drugs available in the United States
are category C, which essentially means that there is no
research available on the effects of the drug on human
fetuses.4 Categorizing drugs as category D or category
X is based not only on the risk to the developing fetus
but also on the utility of the drug to treat illness during
pregnancy. Drugs in all of the categories do not present
the same risk. Category X includes isotretinoin and oral
contraceptives. Isotretinoin has demonstrated fetal teratogenicity; oral contraceptives have not been shown to
cause fetal abnormalities early in pregnancy but simply
have no therapeutic use to the pregnant woman.
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97

EXPERT OPINION

PERINATAL

Table 1. The letter system of pregnancy risk

categories
A

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 a 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.

Abbreviation: AWC, adequate and well-controlled.

Adapted from US Food and Drug Administration.1

ery subsection and combine this information into the

Pregnancy section. The labeling will also include information about prescribing drugs for males of reproductive age. The Nursing Mothers section will be renamed
Lactation. Both sections will include data from studies.
Human studies must precede animal studies. Studies
with animals must include the species of animal and
a comparison of the animal dose and the human dose
equivalent.2
The format and overview of the information to be
included in the revised labeling are listed in Table 3.
Comparison of the 2 systems of labeling shows the utility of the new system and the lack of clarity of the
previous system. The information given in the new system is not only longer and more technical but also
more useful both for patient counseling and for the
healthcare providers understanding of the true risk
and/or benefit of a drug. The information is streamlined in such a way that allows for ease of use and
comprehension. Healthcare providers will not have to

Table 2. A timeline of FDA rules for the

labeling of drugs for use during pregnancy and
lactation
1960s
1960

1962
1979

Other concerns about the Pregnancy Category system include the absence of information for accidental
exposure, lack of information about the timing of fetal exposures, and confusion about the use of animal
studies when human studies are not available.2
The Teratology Society held an open meeting of its
Public Affairs Committee in 1997 to generate public
comment. The committee published an opinion that
the categories are confusing and difficult for providers
to use and should be immediately revised by the FDA.5
The FDA published a draft concept paper in 1999. The
timeline leading to the current changes is delineated in
Table 2.
The new labeling will include a summary of the risks
of using a drug during pregnancy and lactation, a discussion of the data supporting this information, and relevant data to aid healthcare providers in decision making and counseling of pregnant and lactating women.1
The new labeling will eliminate the Labor and Deliv98

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1997

1999

2008
2014

2015

Thalidomide was used in Europe, causing

thousands of cases of phocomelia
William S. Merrell Company submits a
request for approval of thalidomide for use
in the United States to the FDA; it is not
approved
Congress passes the Kefauver-Harris
amendments, allowing tighter regulation
of drug approval in the United States
The FDA develops Labeling for Prescription
Drugs Used in Man that included
pregnancy labeling regulation and
introduces the pregnancy letter risk
categories
The Public Affairs Committee of the
Teratology Society has an open hearing
and called for changes in the pregnancy
risk categories
FDA concept paper published, proposing the
development of a new format for
pregnancy information on drug labeling;
focus groups on content begun
The first version of the Pregnancy and
Lactation Labeling Rule is proposed by the
FDA
The FDA publishes the final rule, setting
forth new categories for content and
format of the labeling of prescription drugs
with respect to use by pregnant and
lactating women
The new labeling will take effect

Abbreviation: FDA, Food and Drug Administration.

April/June 2015

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EXPERT OPINION

PERINATAL

Table 3. New FDA labeling guidelines for prescription drug use by pregnant women
Pregnancy subsection
Risk summary
Clinical considerations

Dosing and potential risks to the developing fetus including animal data
Information on inadvertent exposure
Prescribing decisions, including known risk to mother and fetus from the
disease being treated; information about dosing adjustments in pregnancy;
maternal adverse reactions unique to pregnancy; effect of dose, timing and
duration of exposure to drug during pregnancy; potential neonatal
complications and interventions
Information on pregnancy registry if one is available
Human data with study type, exposure information, identified fetal
developmental abnormalities, or other adverse effects
Positive and negative experiences, number of subjects, duration of study
Animal data with study type, exposure information, identified fetal
developmental abnormalities or other adverse effects
Species studied, doses in terms of human dose equivalents

Data

Lactation subsection
Risk summary, clinical considerations and data are the same as Pregnancy.
Adverse effects on the infant and milk production must be described.
Drugs present in human milk
Description of concentration
Description of assay used to measure the drug
Estimated daily infant dose during breastfeeding
Adverse effect to the infant and associated interventions
Feeding techniques or dosage adjustments to minimize infant drug exposure
Abbreviation: FDA, Food and Drug Administration.
Adapted from US Food and Drug Administration.1

search various references and handbooks for data. The

former system of letter demarcations was short but
conveyed both false risk and false reassurance about
drug categories and about individual drugs used during
pregnancy.
Clinicians have been waiting years for the new system; it is a genuinely useful step in providing care to
pregnant and breastfeeding women.

Jackie Tillett, ND, CNM, FACNM

Clinical Professor
Department of Obstetrics and Gynecology
University of Wisconsin School of Medicine and Public Health
Madison, Wisconsin

The Journal of Perinatal & Neonatal Nursing

References
1. US Food and Drug Administration. Content and format of labeling for human prescription drug and biological products;
requirements for pregnancy and lactation labeling. Fed Regist.
2014;79(233):7206472103.
2. Ramoz LL, Pate-Shori NM. Recent changes in pregnancy and
lactation labeling: retirement of risk categories. Pharmacotherapy. 2014;34(4):389395.
3. Frederiksen MC. The new FDA pregnancy labeling requirements for drugs. J Midwifery Womens Health. 2011;56(3):303
307.
4. Mazer-Amirshahi M, Samiee-Zafarghandy S, Gray G, van den
Anker JN. Trends in pregnancy labeling and data quality for US-approved pharmaceuticals. Am J Obstet Gynecol.
2014;211:690.e1690.e11.
5. Public Affairs Committee of the Teratology Society. Teratology
public affairs committee position paper: pregnancy labeling
for prescription drugs: ten year later. Birth Defects Res A Clin
Mol Teratol. 2007;79:627630.

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