U.S. Department of Health and
Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
August 2002
Clinical/Medical
Guidance
for Industry
Establishing Pregnancy Exposure Registries
Additional copies are available from:
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Division of Communications Management
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Rockville, MD 20857
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or
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U.S. Department of Health and
Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
August 2002
Clinical/Medical
Guidance for Industry
Establishing Pregnancy Exposure Registries
This document is intended to provide
sponsors with guidance on how to establish pregnancy exposure
registries to monitor the outcomes of pregnancies exposed to
specific medical products.
The guidance should be used in conjunction with other
epidemiological literature on the design, conduct, and
interpretation of observational studies (e.g., International
Society for Pharmacoepidemiology 1996). Because the development
of a pregnancy exposure registry requires specialized knowledge in
a variety of areas, we encourage sponsors to obtain advice from
experts in the fields of pharmacology, embryology, teratology,
obstetrics, pediatrics, clinical genetics, and epidemiology when
designing a registry.
The ultimate goal of pregnancy exposure
registries is to provide clinically relevant human data that can
be used in a product’s labeling to provide medical care providers
with useful information for treating or counseling patients who
are pregnant or anticipating pregnancy (see Attachment A for
examples of labeling). Such data can also be used to support a
change from the originally assigned Pregnancy Category (e.g.,
acyclovir: Category C to B, budesonide inhalational powder:
Category C to B).
Randomized, controlled studies of health
effects during pregnancy require the deliberate administration of
products to pregnant women and are often not feasible (Mastroianni
et al., 1994). During clinical development of most products,
pregnant women are actively excluded from trials, and if pregnancy
does occur during the trial, the usual procedure is to discontinue
treatment and drop the patient from the study, although her
pregnancy is typically followed to term. Consequently, at the
time of a drug’s initial marketing, except for products developed
to treat conditions unique to pregnancy, there are seldom
meaningful human data on the effects of that drug during
pregnancy.
For drugs used for preventive or active
treatment in women of childbearing age, it is not uncommon for
exposure to the fetus to occur during the critical period of
organogenesis, because the woman was not aware of her pregnancy at
the time. Approximately 10 percent of women between the ages of
15 and 44 become pregnant annually. This pregnancy rate varies
considerably by age group and ranges from 1 to 18 percent per year
(Ventura et al., 2000). About half of all U.S. pregnancies are
unplanned (Colley et al., 2000).
Some women enter pregnancy with medical
conditions that require ongoing or episodic treatment (e.g.,
asthma, epilepsy, hypertension). New medical problems may develop
or old ones may be exacerbated by pregnancy (e.g., migraine
headaches, depression). Studies have shown that most pregnant
women use either prescribed or over-the-counter drugs during
pregnancy (Bonati et al., 1990, De Vigan et al., 1999, Lacroix et
al., 2000, Weiss et al., 1997).
Yet, even after years of marketing with
accumulating experience in pregnant women, data in product
labeling regarding risks of use during pregnancy rarely go beyond
the data available at the time of initial marketing.
Historically, most information about risks of
drugs in pregnancy has arisen from suspicious findings from
spontaneous adverse event reports. This passive mechanism of
surveillance has
been well described (Kennedy et al., 2000).
For identification of truly rare or unusual outcomes, this system
offers many advantages. However, some of the well-known
limitations of spontaneous reporting are particularly problematic
when trying to evaluate drug risks in pregnancy. Limitations
include the lack of denominator data, lack of controls, recall
bias associated with retrospective reporting, barriers to
reporting, and poor case documentation. These limitations can be
overcome through use of prospective pregnancy exposure registries,
which are recognized as one method for ascertaining major risks
associated with a drug exposure during pregnancy.
A pregnancy exposure registry is a
prospective observational study that actively collects information
on medical product exposure during pregnancy and associated
pregnancy outcomes.
Pregnancy exposure registries differ from
other postmarketing surveillance techniques, such as birth defect
registries and spontaneous reporting of adverse drug reactions, in
that pregnant women are enrolled before the outcome of pregnancy
is known. These other surveillance methods are retrospective with
enrollment typically based on an adverse outcome, such as an
infant born with a birth defect, and risk factors are determined
by looking backwards in time. Pregnancy exposure registries
proceed from the point of drug exposure, however, so that a single
registry can collect data on many pregnancy outcomes. This
prospective orientation is an important feature — and the major
strength — of the pregnancy exposure registry design.
Pregnancy exposure registries can:
-
! provide margins of reassurance regarding the lack
of risk when a precise measure is impossible
-
! monitor for suspected risks raised by preclinical
studies, premarketing clinical studies, or postmarketing case
reports
-
! identify factors that affect the risk of adverse
outcomes, such as dose, timing of exposure, or maternal
characteristics
-
serve as hypothesis-generating tools
A pregnancy exposure registry is not
a pregnancy prevention program.
Neither is it a mechanism to monitor and evaluate such programs.
Animal reproductive toxicology studies are an
essential tool for estimating potential risks of exposure to
medical products in pregnancy. However, the positive and negative
predictive values of such studies for humans are often uncertain
(Mitchell 2000). Animal models can be misleading when screening
for specific fetal effects by detecting associations that
ultimately turn out to be false positive (e.g., hydrocortisone and
clefts in mice) or false negative (e.g., thalidomide and no
teratogenesis in rats) (Ward 2001). The strongest concordance
between animal findings and human effects is when there are
positive findings from more than one species, although even in
this case the results cannot always be used to predict specific
human effects or incidence in humans (Rogers et al., 1996).
Regardless of findings from animal studies,
we recommend that a pregnancy exposure registry be seriously
considered when it is likely that the medical product will be used
during pregnancy as therapy for a new or chronic condition.
A medical product may also be a good
candidate for a pregnancy exposure registry when one of the
following conditions exist:
·
Inadvertent exposures to the medical product in
pregnancy are or are expected to be common such as when products
have a high likelihood of use by women of childbearing age
·
The medical product presents special
circumstances, such as the potential for infection of mother and
fetus by administration of live, attenuated vaccines
The need for a pregnancy exposure registry
increases when a medical product in one of the above categories
may have the potential to cause harm during pregnancy.
Information regarding potential harm can be based on one or more
of the following:
·
animal reproductive toxicology studies
·
structure‑activity relationships
·
pharmacological class
·
human case reports
Pregnancy exposure registries are unlikely to
be warranted in the following situations: (1) there is no
systemic exposure to the medical product, or (2) the product is
not, or rarely, used by women of childbearing age.
A pregnancy exposure registry can be
initiated by a sponsor at any time. The decision to establish a
pregnancy exposure registry should include consideration of both
the need for pregnancy risk information and the feasibility of
successfully completing the registry. When the purpose of the
pregnancy exposure registry is to assess margins of safety, to
monitor for potential harm, or to detect safety signals, it is
appropriate to initiate the registry as soon as possible, such as
at the time of initial marketing, when a new indication is
approved, or when patterns of use reveal that the product is used
by women of reproductive age. In some cases, FDA may ask a
sponsor to conduct an exposure registry under an IND before
approval or, more typically, as part of a phase-4 commitment. A
pregnancy exposure registry could also be started when there is a
need to evaluate suspected risks raised by spontaneous adverse
events reports or published case reports.
A pregnancy exposure registry’s design
should reflect its underlying objectives. These objectives can
range from open-ended safety surveillance to testing a single
specific hypothesis. The principles of epidemiologic research and
those of observational research, in particular, apply to the
design and conduct of a pregnancy exposure registry. Some of
these principles are discussed in the 1996 International Society
for Pharmacoepidemiology’s Guidelines for Good Epidemiology
Practices for Drug, Device, and Vaccine Research in the United
States.
Thoughtfully developed, formal, written
protocols ensure consistency of data collection and analysis.
Pregnancy exposure registries should be based on well-documented
and consistently applied procedures, from recruitment of an
adequate number of participants to interpretation of registry
results, to avoid introducing factors that might bias the data.
Because some fetal effects are relatively rare, even small or
minor flaws in registry design and execution can have a large
effect on the final results.
Consideration should be given to addressing
the following critical elements in any pregnancy exposure registry
protocol:
·
objective(s) of the pregnancy exposure registry
itself
·
anticipated frequency of drug exposure during
pregnancy
·
comparison groups
·
sample size to rule out a difference between the
exposed and comparison groups at a predetermined level or to
detect a predetermined level of risk; and how long it may take
to enroll that number of women
·
how to determine eligibility for enrollment
·
source of information on drug exposure during
pregnancy (e.g., health care provider, pregnant woman)
·
congenital anomalies and other fetal effects of
interest, including inclusion and exclusion criteria, and the
time period for identification
·
information to be collected related to an
individual pregnancy outcome and the source of that information
(e.g., mother, prenatal health care provider, infant’s health
care provider)
·
disposition of data from protocol ineligible
pregnant women
·
methods to be used to assess risk including an
analytical and statistical plan
·
importance of an independent data monitoring
committee
·
importance of obtaining institutional review board
(IRB) review and informed consent
·
criteria for termination of the registry
To facilitate the eventual inclusion of
data from the registry into the product labeling, we recommend
that the appropriate premarketing and postmarketing review
divisions at FDA be consulted to review the draft protocol.
The background section of a protocol should
describe why the registry is being conducted. Findings from the
following should be summarized, along with conclusions regarding
potential risks to human pregnancy:
·
animal reproductive toxicity studies
·
other relevant pharmacological and toxicological
studies such as those that address structure activity
relationships
·
any available human data, such as spontaneous
reports
·
earlier human studies
The background section should also summarize
the potential benefits of the product, especially if there are
benefits unique or particularly relevant to pregnant women. We
recommend that the characteristics of the patient population
expected to use the product be described in terms of the number
and proportion of all women with the labeled indication by age
group and that an annual estimate of potential product exposure in
pregnant women be calculated. Any assumptions made when
calculating these values should be clearly stated and the
best-case and worst-case scenarios discussed.
In addition, the medical condition for which
the product has a labeled indication and its impact on the
pregnant woman and the fetus, should be described, including the
effects of nontreatment. The expected characteristics of exposure
during pregnancy (dose, timing, duration), and the likelihood that
the treatment would be discontinued at recognition of pregnancy
should be discussed.
1. Patient
recruitment
To enroll
an adequate number of eligible pregnant women, we recommend an
active recruitment plan. A variety of strategies should be used
to ensure as broad coverage as possible. Some strategies that
have been used with moderate success by current registries include
announcement of the registry and contact information in the
medical product labeling; similar notices in the product circular,
promotional materials, and product Internet pages; as well as
announcements in lay and professional magazines, journals and
newsletters; personal mailings to specialists; and exhibits at
professional meetings. We encourage sponsors to work together
and with FDA, the Centers for Disease Control and Prevention (CDC),
the Organization of Teratogen Information Services (OTIS), and
other relevant organizations such as patient advocacy groups
(e.g., American Diabetes Association) and medical societies (e.g.,
American Rheumatology Society), to endorse or assist in the
conduct of pregnancy exposure registries, thereby facilitating
patient recruitment.
Recruitment materials should not actively promote an individual
product’s use in the special population of pregnant women, unless
the package insert contains supporting information. Recruitment
materials should not imply that product safety and efficacy
information in pregnant women exists beyond the information
contained in the currently approved labeling.
As with
all other product-specific promotional materials, those related to
pregnancy exposure registries are subject to 21 CFR 314.81(b)(3)
or 601.12(f)(4) and, under those regulations, must be submitted to
FDA at the time of first use. In general, any registry-related
promotional materials and recruitment materials can be discussed
with and reviewed by FDA prior to use, but such a review is not
required. However, if the product is approved under an
accelerated approval mechanism (21 CFR 314 subpart H or § 601
subpart E), submission prior to the time of first use is required
(§§ 314.550 and 601.45).
2. Sources of baseline and follow-up information
We recommend examining all alternatives for
obtaining information to determine the appropriate methodology
based on, for example, the patient population involved, the
suspected risk of the medication in pregnancy, and the number of
enrollees needed.
a. Health care professionals as information sources
Most pregnancy exposure registries rely
upon voluntary reports from health care professionals (e.g.,
Reiff-Eldridge et al., 2000). The advantages of using information
obtained from health care professionals are convenience and less
monetary expense because the medical sophistication of the source
makes this method of obtaining information very efficient.
However, there are several drawbacks to this approach.
·
Health care providers may not be highly motivated
to complete a questionnaire, so a substantial loss to followup
may occur.
·
A health care provider may have a real or
perceived medical, legal, or ethical conflict of interest if (s)he
prescribed the product, or (s)he may be reluctant to seek out
and disclose information on pregnancy outcome without maternal
consent, even when no specific patient identifiers are part of
the collection.
·
Exposures occurring during pregnancy are usually
reported by the prenatal health care provider or by a specialist
treating a specific condition in the mother (e.g., neurologist
treating migraine); these providers often know little about the
infant after delivery.
A variation of this method relies on the
health care provider to obtain informed consent from the pregnant
woman to acquire medical records from both the prenatal and
pediatric providers.
Another model relies on spontaneous reports
from both health professionals and patients (e.g., Goldstein et
al., 1997, Shields et al., 2001).
b. Pregnant women as information sources
Some pregnancy exposure registries recruit
and enroll women directly (e.g., The North American Pregnancy and
Epilepsy Registry, 1998, Chambers et al., 2001). Typically,
informed consent is obtained from the woman on enrollment.
Recruitment of a motivated patient population can minimize loss to
followup and provide more extensive information. Obtaining
informed consent may confirm patient motivation and facilitate
cross-validation of information reported by the woman by allowing
for examination of medical records and interviews with the
appropriate health care providers. However, a potential
methodological problem with this approach is that the
nonparticipation of patients who do not give consent can introduce
selection bias. Also, obtaining information directly from
pregnant women costs more as a result of the need for more
intensive followups and medical validation of self-reports.
3. Selection of a comparison group
With a pregnancy exposure registry, a
comparison group should be used to assess risk or provide a
measure of assurance of safety. Comparison groups can be either
internal to the study (e.g., defined and followed along with the
exposed group of interest) or external to the study (e.g.,
information collected outside of the study by other investigators
that is deemed relevant to the issue under investigation).
Registries may include both internal and external comparison
groups, as varying findings between them can be instructive. The
strategy for selection of an appropriate comparison group(s)
should be made when designing the pregnancy exposure registry and
included in the protocol.
Options for comparison groups include:
Internal:
·
unexposed, concurrently enrolled pregnant women
matched or stratified in relation to the exposed group to control
for important covariates
·
women within a multidrug registry (see section VI(B)(12)
— multidrug pregnancy exposure registries) with a common
indication or underlying risk factors who are not taking the
medical product of interest
External:
·
surveillance systems (e.g., from the National Birth
Defects Prevention Network, the Metropolitan Atlanta Congenital
Defects Program)
·
background rates of grouped or individual outcomes
(e.g., from the National Center for Health Statistics (NCHS), the
International Clearinghouse for Birth Defects Monitoring Systems)
·
other pregnancy exposure registries
Enrollment of a concurrent comparison group
of unexposed pregnant women, while most desirable
methodologically, may not be possible, and may exceed the scope of
most registries. A background rate or the prevalence of
congenital anomalies in a population based surveillance system or
other pregnancy exposure registry may often be the only available
comparator.
If background rates or information from a
surveillance system are chosen as a comparison group, it is
important to be aware of the limitations of whatever existing
system is used (e.g., the National Birth Defects Prevention
Network does not collect information on all congenital anomalies,
NCHS may have accurate data on spontaneous abortions, but only on
those requiring hospital care) so that appropriate analyses can be
designed.
Additional considerations when choosing a
comparison group from an existing system are the ascertainment
methods used by the system, how outcomes are defined and
identified, and the characteristics of the underlying population
from which the cases are taken. The potential impact of any
differences on the interpretation of data from the pregnancy
exposure registry should be acknowledged and discussed in the
protocol.
As there is usually no one ideal comparison
group, we encourage the use of more than one comparison group to
improve the validity of the registry.
4. Privacy and human subject protection issues
The importance of informed consent and use of
an institutional review board (IRB) in the design of each
pregnancy exposure registry should be considered, even for those
registry designs thought to fall in the category of surveillance
as opposed to a targeted study.
The protocol must comply with ethical principles and regulatory
requirements involving human subjects research as specified in the
federal regulations for the protection of human subjects (45 CFR
part 46, 50, and 56). All pregnancy exposure registries should
consult an IRB to ensure that the collection of data and all other
procedures associated with the registry will withstand scientific
and ethical scrutiny.
If informed consent is to be obtained from
the patient, the text of the informed consent form should be
included in the registry protocol. Pregnancy exposure registries
are not designed to provide direct benefit and should not
represent any risk to either the pregnant woman or the fetus;
therefore, the decision to participate in the registry rests
solely with the pregnant woman (see subpart B of 45 CFR part 46).
If the registry seeks to obtain information on the child after
birth either through physical examination (minimal risk) or
medical record review (no risk), either parent may consent for the
child (see subpart D of 45 CFR part 46).
5. Eligibility requirements
Women should be enrolled in a pregnancy
exposure registry prospectively (i.e., after exposure to a product
but before the conduct of any prenatal tests that could provide
knowledge of the outcome of pregnancy). If the condition of the
fetus has already been assessed through prenatal testing (e.g.,
targeted ultrasound, amniocentesis), such reports are usually
considered retrospective. It is also desirable that women be
enrolled who had drug exposure at the point in gestation with the
highest risk of causing fetal effects. For congenital anomalies,
this is most often the first trimester, but there are clearly
drugs for which the suspected critical exposure period is in the
later trimesters or for which the product is likely to be
specifically initiated later in pregnancy.
Commonly, with active recruitment of patients
into a pregnancy exposure registry, both prospective and
retrospective reports will be received in spite of the desire for
enrollment prior to knowledge of the outcome. It should also be
anticipated that cases will be received where exposure is outside
the time period of interest. The protocol should clearly
delineate the disposition of all cases.
Because it may be difficult to obtain
enrollment before prenatal testing on a consistent basis, to
achieve an adequate sample size, some pregnancy exposure
registries have included pregnancies with normal prenatal tests.
However, inclusion of pregnancies with some a priori knowledge of
normal outcome as prospective cases and exclusion of those with
prenatal tests indicating a defect may potentially bias the
results toward a lower overall defect risk (Honein et al., 1999).
If it is necessary to include pregnancies
with some prenatal testing to achieve adequate numbers, then data
analysis should address whether enrollment after prenatal testing
biased the results.
6. Data collection
We recommend collection of the following
baseline information on the patient once eligibility has been
determined:
·
patient identifier, and, if collecting data
directly from the pregnant woman, contact information, including
an alternative contact(s) if possible
·
health care provider name(s) and contact
information
·
date of the last menstrual period and estimated
delivery date
·
exposure to medical product of interest, including
dosage, route, and dates of administration
·
medical indication for taking the product
·
exposure information on all other medical products
used, including prescription products, over-the-counter (OTC)
products, dietary supplements, vaccines, and insertable or
implantable medical devices
·
other medical conditions
Attachment B provides a list of additional
possible maternal and neonatal data elements to consider. What is
collected and the source(s) of information depend on a variety of
factors and should be modified appropriately for the specific
condition or exposure of interest. We recommend that data
collection be as complete as possible, without sacrificing the
quality of information for quantity of data.
If using an internal comparison group, for
consistency, all information should be collected in an identical
manner from both exposed and comparison group women. The registry
protocol should include a detailed description of how information
will be obtained. This description will help minimize variation.
When information is obtained directly from the pregnant woman,
we recommend a medical record abstraction or an interview with a
patient’s health care provider to confirm information obtained
from the woman.
7. Patient follow-up
The objective(s) of the registry should
determine the type, extent, and length of patient followup. The
feasibility of obtaining reliable infant outcome information is a
critical consideration in pregnancy exposure registry design.
While prenatal health care providers are a good source of
information on outcomes, such as spontaneous abortions, elective
terminations, live births, and pregnancy complications, they are
not a good resource for information on infant conditions not
readily diagnosed at or soon after birth. The infant’s health
care provider is the best resource for full information on the
health status of the infant.
Followup information can be obtained by:
·
mailed questionnaires
·
telephone interviews
·
reviews of medical record abstractions
·
reviews of birth records
·
combinations of the above
The protocol should include a plan and
rationale for followup contacts during and/or after pregnancy.
The followup contact should obtain details on the pregnancy
course, outcome, status of the infant, and any evidence of
abnormalities.
We recommend the protocol also include:
·
the number, frequency, and timing of followup
contacts
·
who will be contacted (mother, prenatal health
care provider, infant’s health care provider, other)
·
how contact will be made (mail, telephone, other)
·
how and what data will be collected at each
contact
For consistency, pregnancies enrolled in the
registry should be followed in the same manner. Losing track of a
particular subgroup of women, if the reason they are lost is in
some way related to their pregnancy outcome, can bias the registry
results. Additionally, losing a large proportion of registry
participants wastes resources and can invalidate an otherwise
well-designed pregnancy exposure registry.
8. Pregnancy outcomes
Pregnancy outcomes include spontaneous
abortions (loss before 20 weeks), elective terminations, fetal
deaths/stillbirths (loss after 20 weeks) and live births. Within
each of these categories the fetus or infant can be evaluated as
to the presence or absence of anomalies or other fetal effects.
We recommend that:
·
The protocol specify a priori which
pregnancy outcomes will be included and what fetal effects will
be assessed as well as the inclusion and exclusion criteria
(Holmes 1999) and measures of severity, if applicable, for
congenital anomalies or other abnormalities of interest.
·
The time period for ascertainment be designated
·
A classification scheme such as the CDC birth
defects code list
be used and specified in the protocol. The types of congenital
anomalies or other fetal effects and the level of detail may
vary, depending on the characteristics of the registry design.
It has been suggested that grouping defects that share
embryology and pathogenesis increases the likelihood that a
teratogenic effect will be seen (Scheuerle et al., 2002).
·
The data collected and the timeframe for followup
of live births be consistent with the research question(s) of
interest. For example, in studies where the effects on the
fetus or infant require some time to manifest an extended
followup is appropriate. congenital anomalies and other complex
abnormalities be reviewed and classified by a specialist in the
field. For example, not all limb defects are the same; certain
combinations of defects may constitute a syndrome or have a
common etiology recognizable only by a specialist.
Misclassification or inappropriate grouping of outcomes may lead
to erroneous conclusions.
·
If using an internal comparison group, the method
of assessment and type of personnel responsible for assessment
of infants be identical for both the exposed and comparison
groups. Blinding of assessors to exposure would also decrease
the probability of bias.
9. Sample sizes for registries
Determination of an adequate sample size
depends on the objective and design of the registry.
Consideration should be given to the anticipated frequency of
product exposure in pregnant women that will influence the ability
for timely enrollment of pregnant women and the baseline incidence
of pregnancy outcomes and congenital anomalies or other
abnormalities of interest.
We recommend that sample sizes be
sufficient to show either “no” difference based on an acceptable
limit for the confidence interval of the difference between the
exposed and comparison group, or alternatively, to detect a
clinically significant difference (e.g., an x-fold increase in the
outcome of concern).
In the protocol and when reporting results
from pregnancy exposure registries, the statistical power of the
registry to rule out or detect a difference based on the
anticipated or existing sample size should be specified.
To calculate sample sizes for a pregnancy
exposure registry, five variables need to be specified (Strom
2000):
·
a or
Type I error (the probability of concluding there is a
difference when one does not exist) and whether one-tailed or
two-tailed. Conventionally, a
is usually set at 0.05 although this need not be the case. The
smaller the a, the
larger the required sample size.
·
b or
Type II error (the probability of missing a real
difference). b is
usually set at 0.1 or 0.2 although this need not be the case.
The smaller the b, the
larger the required sample size.
·
minimum relative risk to be detected. The
smaller the relative risk to be detected or ruled out, the
larger the required sample size.
·
background incidence of abnormality of
interest in unexposed group. The rarer the outcome of interest,
the larger the required sample size.
·
ratio of unexposed to exposed subjects. If
using an internal comparison group, increasing the number of
unexposed pregnancies per exposed pregnancy (up to a maximum of
4) can reduce the number of exposed pregnancies required and
increase the statistical power.
Several different formulas can be used to
calculate the required sample size based on these variables (e.g.,
Gail 1974, Strom 2000). We recommend consulting a statistician to
determine which method should be used based on the specific
requirements of the registry.
When estimating the number of exposed
pregnancies to be enrolled prospectively, it is important to be
aware that approximately 62 percent of clinically recognized
pregnancies will result in a live birth, 22 percent will end in
elective termination, and 16 percent will result in fetal loss
(i.e., spontaneous abortions and fetal death/stillbirth) (Ventura
et al., 2000). These population estimates vary considerably by
maternal age and health. In addition, the rates are based on the
general population and may not apply to specific disease groups
(e.g., epilepsy, diabetes). If the fetal effect of concern occurs
only in live born infants, it is important to estimate the number
of expected live births within pregnancies enrolled prospectively
early in gestation, considering the expected incidence of elective
terminations and spontaneous abortions, fetal deaths, and
stillbirths.
Overall, major congenital anomalies (i.e.,
those incompatible with life or requiring medical/surgical
intervention) occur in approximately 4 percent of live born
infants with individual major anomalies occurring much less
frequently (March of Dimes 2001). Minor anomalies may be 10 to 20
times more common than major ones (Leippig et al., 1987) and 20
percent of infants with one or more minor congenital anomalies
also have a major birth defect (Leippig et al., 1987).
The March of Dimes (2001) reports the
following rates for various pregnancy outcomes and fetal
abnormalities:
·
Spontaneous abortions/miscarriage (loss prior to
20 weeks): 1/7 known pregnancies
·
Low birth weight (<2500 grams): 1/12 live births
·
Fetal death/stillbirth (loss after 20 weeks):
1/200 known pregnancies
·
Any major birth defect: 1/25 live births
·
Heart and circulation defects: 1/115 live births
·
Genital and urinary tract defects: 1/135 live
births
·
Nervous system and eye defects: 1/235 live births
·
Club foot: 1/735 live births
·
Cleft lip with or without cleft palate: 1/930
live births
10. Data presentation and analysis
Descriptive statistics are the primary approach for summarizing data
from a pregnancy exposure registry. However, given the
heterogeneous nature of data obtained in pregnancy exposure
registries, there is no one format for data presentation that is
applicable for all studies. The choice of a final format depends
on outcomes identified in the registry protocol, unanticipated
findings, and expert advice. We encourage sponsors to develop
forms of data presentation and analysis that fully capture
outcomes of concern within their particular registry.
We recommend that:
·
Data collected prospectively be analyzed
separately from any collected retrospectively. All reports
within each category should be stratified by pregnancy outcome
(spontaneous abortion, elective termination, fetal
death/stillbirth, live birth) and timing of exposure. Further
stratification will depend on the amount of data available.
Retrospective reports will not provide an accurate risk
calculation, but can provide important qualitative data. For
instance, infants born with a specific constellation of
anomalies can be evaluated as a case series.
·
When risk estimates are calculated, only outcomes
from prospectively collected data be included. There are no
published epidemiologic standards for calculating risk estimates
or pregnancy outcomes using prospective data from a pregnancy
exposure registry. However, although unvalidated, one
publication offers some ideas on methods that could potentially
be used (Goldstein et al., 2001).
·
The 95 percent confidence intervals around the
estimated rates of any fetal abnormalities as well as the 95
percent confidence intervals for estimates of the differences
between exposed and comparison groups be presented.
If sample size allows, other analytic
approaches can be considered. These analyses include life table
analyses and multivariate analyses that adjust for covariates.
For multidrug registries, a within-registry comparator or nested
case-control analysis may be possible.
11. Use of an independent data monitoring committee
To ensure scientific integrity and
appropriate patient protection, we encourage each registry to have
an independent data monitoring committee similar to those used for
clinical studies.
Members of the committee could include experts in obstetrics,
embryology, teratology, pharmacology, epidemiology, pediatrics,
clinical genetics, and any relevant therapeutic areas. The
committee could advise and participate in establishing and
operating the registry. The committee could also assist in the
review of data, classification of any birth defects and the
dissemination of information to ensure that results are
interpreted and reported accurately. We recommend that the role
and duties of the committee be specified in the protocol.
12. Multidrug pregnancy exposure registries
A multidrug pregnancy exposure registry
actively collects information on exposure to various drug
therapies in specific diseases, such as human immunodeficiency
virus (HIV) (White et al., 1997), epilepsy (The North American
Pregnancy and Epilepsy Registry 1998), or asthma (Lipkowitz 1999;
Scialli 1999). In some cases, a general multidrug registry, such
as that conducted by a teratogen information service, collects
information on drugs for unrelated indications. Multidrug
registries have advantages over single drug registries with
respect to efficiency and economy. They also have the advantage
of having comparison groups of pregnant women unexposed to the
medical product of interest readily available.
To help avoid redundancy and to prevent
overburdening patients, physicians, and scientific experts with
multiple requests to participate in individual studies, we
encourage companies to work together to develop multidrug
registries. It has been suggested that rather than conduct a
separate pregnancy exposure registry for new drugs, a centralized
pregnancy exposure registry should be established for drugs of
unknown human teratogenicity that are likely to be used by women
of reproductive age (Honein et al., 1999).
The main utility of a pregnancy exposure
registry is to provide margins of reassurance about absence of
risk or to signal suspicions of risk. They are the most feasible
study design at the time of first marketing. However, other
studies may be called for to confirm or clarify any signals
obtained from a registry.
Case control studies are appropriate to
evaluate rare adverse birth outcomes and identify whether the drug
in question is an associated risk factor. Case control studies
can also evaluate outcomes that would require long-term followup
in a registry model. They can be efficiently designed and
implemented, and even nested within an existing pregnancy exposure
registry when there are questions about other risk factors or
contributing exposure details.
Studies using automated databases (e.g.,
HMOs, Medicaid) linking maternal exposure to infant outcome can
also provide drug exposure information during pregnancy (e.g.,
Drinkard et al., 2000, Cooper et al., 2002). This design allows
for evaluation of both pregnancy and fetal outcomes. However, it
may be very difficult to find enough pregnancy exposures in any
automated system unless the product is widely used, particularly
early in product marketing.
Other systems and methodologies used for
pharmacoepidemiology studies have been described elsewhere (Strom
2000; Hartzema et al., 1999).
The following information, based on current
regulations and guidance, describes how to report pregnancy
exposure registry information to the Agency.
The Agency considers pregnancy exposure
registry reports (both prospective and retrospective) as derived
from active solicitation of patient information.
Accordingly, a sponsor holding marketing authorization for an
approved drug or licensed biological product must submit to the
Agency, within 15 calendar days, reports of adverse events from
the registry that are both serious and unexpected by
regulatory definition and where a reasonable possibility exists
that the drug or biological product caused the adverse event (see
21 CFR 310.305(c)(1), 314.80(c)(2)(iii) and (e), and 600.80(c)(1),
(c)(2)(iii) and (e)). Current reporting requirements in the
regulations consider any congenital anomaly within the definition
of a serious adverse event (21 CFR 314.80(a) and 600.80(a)).
Pregnancy exposure registries that are run
independently of any sponsors holding marketing authorizations are
not subject to postmarketing regulatory reporting requirements.
However, investigators running such registries may forward reports
of any serious adverse events including congenital anomalies to
the sponsor of the medical product or report directly to the FDA
MedWatch office (1-800-FDA-1088 or
http://www.fda.gov/medwatch
).
The sponsor of any pregnancy exposure
registry required by FDA or conducted as part of a written
postmarketing study commitment shall, as required under 21 CFR
314.81(b)(2)(vii), 314.98(c), 601.70, and 601.28, submit to the
Agency an annual status report. Sponsors of pregnancy exposure
registries not subject to 21 CFR 314.81(b)(2)(vii), 314.98(c), and
601.70 are invited to include a status report in the annual report
or in the periodic safety report (21 CFR 314.80(c)(2), 314.98 and
600.80(c)(2)) as recommended by the International Conference on
Harmonisation (ICH) for studies that address safety issues.
We recommend that the status report describe
the study design and summarize the status of the planned,
initiated, in progress, or completed pregnancy exposure registry
conducted by or otherwise obtained by the sponsor during the
reporting period (see information to include below). Any
publications based on data from the pregnancy exposure registry
should be included. The status report should also provide a
descriptive summary of progress to date, interpretation of
findings and appropriate analyses with comments on the clinical
significance of the findings. Copies of full reports may be
appended, if appropriate.
Where relevant to the registry, we recommend
the status report include the following, presented separately for
prospective and retrospective reports:
1. Basic Information:
·
number of pregnant women enrolled to date
·
number of pregnancies with outcome known
(stratified by live birth, spontaneous abortions, elective
terminations, fetal deaths/stillbirths)
·
number of pregnancies with outcome pending
·
number of pregnancies lost to followup
2. For pregnancies with known outcome, line
listings and summaries of:
·
demographics, obstetrical, and medical history of
mothers
·
weeks of gestational age at exposure
·
dose and duration of exposure
·
weeks of gestational age at completion or
termination of pregnancy
·
for live births and deaths/stillbirths, whether
multiple birth, small for gestational age, preterm delivery, and
congenital anomalies or other fetal abnormalities
·
for spontaneous abortions and elective
terminations, abnormalities in products of conception
We recommend that a pregnancy exposure
registry be continued until one or more of the following occurs:
·
Sufficient information has accumulated to meet the
scientific objectives of the registry (i.e., numeric targets or
effect size)
·
The feasibility of collecting sufficient
information diminishes to unacceptable levels because of low
exposure rates, poor enrollment, or loss to followup
·
Other methods of gathering appropriate information
become achievable or are deemed preferable
The criteria for termination of the study
should be predetermined and specified in the protocol.
Bonati, M., R. Bortulu, F. Marchetti, M. Romero, G. Tognoni, 1990,
"Drug Use In Pregnancy: An Overview of Epidemiological (Drug
Utilization) Studies," Eur J Clin Pharmacolo, 38:325-8.
Chambers, C.D., S.R. Braddock, G.G. Briggs, A. Einarson, et. al.,
2001, “Postmarketing Surveillance for Human Teratogenicity: A
Model Approach,” Teratology, 64(5):252-61.
Colley, G.B., M.D. Brantley, and M.K. Larson, 1997, Family
Planning Practices and Pregnancy Intention, Atlanta, GA:
Division of Reproductive Health, National Center for Chronic
Disease Prevention and Health Promotion, Centers for Disease
Control and Prevention, 2000.
Cooper, W.O., M.R. Griffin, and W.A. Ray, 2002, “Prenatal Exposure
to Erythromycin and Pyloric Stenosis,” Obstetrics and
Gynecology, 100:101-6.
De
Vigan, C., H.E.K. De Walle, S. Cordier, J. Goujard, et. al., 1999,
“ Therapeutic Drug Use During Pregnancy: A Comparison in Four
European Countries,” J Clin Epidemiol; 52(10):977-82.
Drinkard, C.R., D. Shatin, and J. Clouse, 2000, “Postmarketing
Surveillance of Medications and Pregnancy Outcomes:
Clarithromycin and Birth Malformations,” Pharmacoepidemiology
and Drug Safety, 9:549-56.
Gail, M., 1974, “Computations for Designing Comparative Poison
Trials,” Biometrics, 30:231-7.
Goldstein, D.J., K.L. Sundell, D.J. DeBrota, and W.W. Offen, 2001,
“Determination of Pregnancy Outcome Risk Rates after Exposure to
an Intervention,” Clinical Pharmacology and Therapeutics,
69:7-13.
Goldstein, D.J., L.A. Corbin, and K.L. Sundell, 1997, “Effects of
First-Trimester Fluoxetine Exposure on the Newborn,” Obstet
Gynecol, 89:713-8.
Hartzema, A.G., M. Porta, and H.H. Tilson (eds), 1998,
Pharmacoepidemiology: An Introduction, 3rd edition,
Cincinnati, OH: Harvey Whitney Books.
Holmes, L.B., 1999, “Editorial: Need for Inclusion and Exclusion
Criteria for the Structural Abnormalities Recorded in Children
Born from Exposed Pregnancies,” Teratology, 59:1-2.
Honein, M.A., L.J. Paulozzi, J.D. Cragan, and A. Correa, 1999,
“Evaluation of Selected Characteristics of Pregnancy Drug
Registries,” Teratology, 60:356-64.
International Society for
Pharmacoepidemeology, 1997, "Data Privacy, Medical Record
Confidentiality, and Research in the Interest of Public Health,”
http://www.pharmacoepi.org/resources/privacy.htm
International Society for
Pharmacoepidemiology, 1996, "Guidelines for Good Epidemiology
Practices for Drug, Device, and Vaccine Research in the United
States," Pharmacoepidemiology and Drug Safety, 5:333-8. http://www.pharmacoepi.org/resources/goodprac.htm
Kennedy, D., S. Goldman, and
R. Lillie, 2000, "Spontaneous Reporting in the United States," in
Strom, B., ed., Pharmacoepidemiology, 3rd
edition, England: John Wiley & Sons, Ltd., pp.151-74.
Lacroix, I., C. Damase-Michel, M. Lapeyre-Mestre, and J.L. Montastruc, 2000,
“Prescription of Drugs During Pregnancy in
France,” Lancet,
356;1735-6.
Leippig, K.A., M.M. Werler,
C.I. Can, C.A. Cook, and L.B. Holmes,
1987, “Predictive Value of Minor Anomalies. I. Association with
Major Malformations.” J Pediatr, 110:530-7.
Lipkowitz, M.A., 1999, "The
American College of Allergy, Asthma, and Immunology Registry for Allergic, Asthmatic
Pregnant Patients (RAAPP)," J Allergy Clin Immunol,
103:S364-72.
March of Dimes Birth Defect
Foundation, 2001, Facts Sheets: Birth Defects, Miscarriage, and
Stillbirth; Leading Categories of Birth Defects; and Perinatal
Profiles: Statistics for
Monitoring State Maternal and
Infant Health,
http://www.modimes.org
Mastroianni, A.C., R. Faden,
and D. Federman, (eds), 1994, “Risks to Reproduction and
Offspring,” in Women and Health Research: Ethical and Legal
Issues of Including Women in Clinical Trials, Washington,
D.C.: Natl Acad Sci Press, pp. 175-202.
Mitchell, A.A., 2000, “Special
Considerations in Studies of Drug-Induced Birth Defects,” in Strom
B.L., ed., Pharmacoepidemiology, 3rd edition,
England: John Wiley & Sons, Ltd., pp. 749-63.
Reiff-Eldridge, R., C.R.
Heffner, S.A. Ephross, P.S. Tennis, A.D. White, and E.B. Andrews,
2000, “Monitoring Pregnancy Outcomes after Prenatal Drug Exposure
Through Prospective Pregnancy Exposure Registries: A
Pharmaceutical Company Commitment,” Am J Obstet Gynecol.
182:159-63.
Rogers, J.M., R.J. Kavlock,
1996, “Developmental Toxicity,” in Klaassen CD, ed.,
Toxicology: The Basic Science of Poisons, 5th
edition, pp. 301-332.
Scheuerle, A. and H. Tilson,
2002, “Birth Defect Classification by Organ System: A Novel
Approach to Heighten Teratogenic Signaling in a Pregnancy
Registry,” Pharmacoepidemiology and Drug Safety, 11:1-11.
Scialli, A.R., 1999, “The Organization of Teratology Information
Services (OTIS) Registry Study,” J Allergy Clin Immunol.
103:S373-6.
Shields, K.E., K. Gahil, J. Seward, R.G. Sharrar, J.F. Cordero,
and E. Slater, 2001, “Varicella Vaccine Exposure During Pregnancy:
Data from the First 5 Years of the Pregnancy Registry,” Obstet
Gynecol. 98:14-9.
Strom, B.L., (ed.), 2000, Pharmacoepidemiology, 3rd
edition, England: John Wiley & Sons, Ltd.
The North American Pregnancy and Epilepsy Registry, 1998, "A
North American Registry for Epilepsy and Pregnancy, A Unique
Public/Private Partnership of Health Surveillance," Epilepsia,
39(7):793-8.
Ventura, S.J., W.D. Mosher, S.C. Curtin, J.C. Abma, and S. Henshaw,
2000, “Trends in Pregnancies and Pregnancy Rates by Outcome,
United States, 1976-96,” National Center for Health Statistics,
Vital Health Stat, 21(56).
Ward, R.M., 2001, “Difficulties in the Study of Adverse Fetal and
Neonatal Effects of Drug Therapy During Pregnancy,” Seminars in
Perinatology: proceedings from the NIH workshop to label drugs
during pregnancy, 25(3):191-5.
Weiss, S., A. Vega, C. McCloskey, B. McFarland, and C. Corelle,
October 7, 1997, “Prescription Drug Use in Pregnancy Among Women
in KPNW, 1993-1994,” Report to the Office of Women’s Health,
FDA.
White, A., R. Eldridge, and E. Andrews, 1997, “Birth Outcomes
Following Zidovudine Exposure in Pregnant Women: The
Antiretroviral Pregnancy Exposure Registry,” Acta Paediatr
Suppl, 421:86-8.
Examples of the Use of
Observational Data in Labeling
Zovirax (acyclovir)
“There are no adequate and
well-controlled studies in pregnant women. A prospective
epidemiological registry of acyclovir use during pregnancy has
collected data since June 1984. As of December 1997, outcomes of
live births have been documented in 552 women exposed to systemic
acyclovir during the first trimester of pregnancy. The occurrence
rate of birth defects approximates that of the general
population. However, the small size of the registry is
insufficient to evaluate the risk for specific defects or to
permit definitive conclusions regarding the safety of acyclovir in
pregnant women and their developing fetuses. Acyclovir should be
used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.”
Meruvax II (rubella virus vaccine live)
“In counseling women who are
inadvertently vaccinated when pregnant or who become pregnant
within 3 months of vaccination, the physician should be aware of
the following: In a 10 year survey involving over 700 pregnant
women who received rubella vaccine within 3 months before or after
conception (of whom 189 received the Wistar RA 27/3 strain) none
of the newborns had abnormalities compatible with congenital
rubella syndrome.”
Sandimmune (cyclosporine)
“The following data represent the
reported outcomes of 116 pregnancies in women receiving Sandimmune
(cyclosporine) during pregnancy, 90% of whom were transplant
patients, and most of whom received Sandimmune (cyclosporine)
throughout the entire gestational period. Since most of the
patients were not prospectively identified, the results are likely
to be biased toward negative outcomes. The only consistent
patterns of abnormality were premature birth (gestational period
of 28 to 36 weeks) and low birth weight for gestational age. It
is not possible to separate the effects of Sandimmune (cyclosporine)
on these pregnancies from the effects of the other
immunosupppressants, the underlying maternal disorders, or other
aspects of the transplantation milieu. Sixteen fetal losses
occurred. Most of the pregnancies (85 of 100) were complicated by
disorders; including pre-eclampsia, eclampsia, premature labor,
abruptio placentae, oligohydramnios, Rh incompatibility and
fetoplacental dysfunction. Preterm delivery occurred in 47%.
Seven malformations were reported in 5 viable infants and in 2
cases of fetal loss. Twenty-eight percent of the infants were
small for gestational age. Neonatal complications occurred in
27%. In a report of 23 children followed up to 4 years, postnatal
development was said to be normal. More information on
cyclosporine use in pregnancy is available from Novartis
Pharmaceuticals Corporation.”
Septra (trimethoprim and sulfamethoxazole)
“While there are no large,
well-controlled studies on the use of trimethoprim and
sulfamethoxazole in pregnant women, Brumfitt and Pursell
in a retrospective study, reported the outcome of 186 pregnancies
during which the mother received either placebo or trimethoprim
and sulfamethoxazole. The incidence of congenital abnormalities
was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of
120) in those receiving trimethoprim and sulfamethoxazole. There
were no abnormalities in the 10 children whose mothers received
the drug during the first trimester. In a separate survey,
Brumfitt and Pursell also found no congenital abnormalities in 35
children whose mothers had received oral trimethoprim and
sulfamethoxazole at the time of conception or shortly thereafter.”
Pulmicort Turbohaler (budesonide)
“As with other glucocorticoids,
budesonide produced fetal loss, decreased pup weight, and skeletal
abnormalities at subcutaneous doses of 25 mcg/kg/day in rabbits
(approximately 1/3 the maximum recommended daily inhalation dose
in adults on a mcg/m 2 basis) and 500 mcg/kg/day in rats
(approximately 3 times the maximum recommended daily inhalation
dose in adults on a mcg/m 2 basis). No teratogenic or embryocidal
effects were observed in rats when budesonide was administered by
inhalation at doses up to 250 mcg/kg/day (approximately 2 times
the maximum recommended daily inhalation dose in adults on a mcg/m
2 basis). Experience with oral corticosteroids since their
introduction in pharmacologic as opposed to physiologic doses
suggests that rodents are more prone to teratogenic effects from
corticosteroids than humans. Studies of pregnant women, however,
have not shown that PULMICORT TURBUHALER increases the risk of
abnormalities when administered during pregnancy. The results from
a large population-based prospective cohort epidemiological study
reviewing data from three Swedish registries covering
approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish
Medical Birth Registry; Registry of Congenital Malformations;
Child Cardiology Registry) indicate no increased risk for
congenital malformations from the use of inhaled budesonide during
early pregnancy. Congenital malformations were studied in 2,014
infants born to mothers reporting the use of inhaled budesonide
for asthma in early pregnancy (usually 10-12 weeks after the last
menstrual period), the period when most major organ malformations
occur. The rate of recorded congenital malformations was similar
compared to the general population rate (3.8 % vs 3.5%,
respectively). In addition, after exposure to inhaled budesonide,
the number of infants born with orofacial clefts was similar to
the expected number in the normal population (4 children vs 3.3,
respectively). These same data were utilized in a second study
bringing the total to 2,534 infants whose mothers were exposed to
inhaled budesonide. In this study, the rate of congenital
malformations among infants whose mothers were exposed to inhaled
budesonide during early pregnancy was not different from the rate
for all newborn babies during the same period (3.6%). Despite the
animal findings, it would appear that the possibility of fetal
harm is remote if the drug is used during pregnancy. Nevertheless,
because the studies in humans cannot rule out the possibility of
harm, PULMICORT TURBUHALER should be used during pregnancy only if
clearly needed.”
Data Elements to
Consider When Designing a Pregnancy Exposure Registry
A. General
Patient
identifier
Name of reporter
at initial contact with the registry
Date of initial
contact with the registry
Dates of any
followup contacts
Telephone number
of reporter
Additional contact
names and phone numbers (if reporter is the patient)
B. Maternal
Information
Source of
information (e.g., obstetrician, pregnant woman, other)
Birth date
Race
Occupation
Maternal medical history (e.g., hypertension,
diabetes, seizure disorder, thyroid disorder, allergic
disorders, heart
disease, connective disease, autoimmune disease, hepatitis, known
risk factors for adverse pregnancy outcomes including
environmental or occupational exposures, other)
Obstetrical History:
Number of
pregnancies and outcome of each (live birth, spontaneous abortion,
elective
termination, ectopic
pregnancy, molar pregnancy)
Previous maternal
pregnancy complications
Previous
fetal/neonatal abnormalities and type
Current Pregnancy:
Date of last
menstrual period
Complications during
pregnancy (including any adverse drug reactions) and dates
Number of fetuses
Labor/delivery
complications
Disease course(s)
during pregnancy and any complications
Medical product
exposures (prescription drugs, OTC products & dietary
supplements):
Name
Dosage & route
Date of first use &
duration
Indication
Recreational drug
use (e.g., tobacco, alcohol, illicit drugs) and amount
Family History (specify type,
maternal/paternal, etc.):
Spontaneous
Abortions
Anomalies/Malformations
Multiple
fetuses/births
C. Neonatal
Information
Initial:
Source of information (e.g., obstetrician,
pediatrician, mother)
Date of receipt of information
Date of birth or termination
Gestational age at birth or termination
Gestational outcome (live born, fetal
death/stillborn, spontaneous abortion, elective termination)
Sex
Pregnancy weight gain of mother
Obstetric complications ( e.g., pre-eclampsia,
premature labor, premature delivery)
Pregnancy order (singleton, twin, triplet)
Results of neonatal physical examination
including
Anomalies diagnosed
at birth or termination
Anomalies diagnosed
after birth
Weight at birth
indicating whether small, appropriate, or large for gestational
age
Length at birth
Condition at birth
(including when available Apgar scores at 1 and 5 minutes,
umbilical cord vessels and gases, need for resuscitation,
admission to intensive care nursery)
Neonatal illnesses, hospitalizations, drug
therapies
Follow-up:
Source of information (e.g., pediatrician,
mother)
Date of receipt of information
Anomalies diagnosed since initial report
Developmental assessment
Infant illnesses, hospitalizations, drug
therapies
Date created: April 19. 2006