Once a medication is marketed, there are many resources that can provide observational data regard-ing drug safety in pregnancy.
POST-MARKETING SOURCES OF DATA
REGARDING REPRODUCTIVE AND DEVELOPMENTAL SAFETY OF PRENATAL DRUG EXPOSURES
Once
a medication is marketed, there are many resources that can provide
observational data regard-ing drug safety in pregnancy.
1. Clinician case
reports published
in the medical literature can
delineate a phenotype in an affected infant born to a mother with a specific
prenatal medication exposure. However, these reports must be initiated
spontaneously and therefore may involve investigator as well as publication
bias. Furthermore, without a known denominator of exposed pregnancies that do
or do not result in infants with the specific malformation, it is difficult to
determine if the reported defect(s) represent an increase over baseline. If the
phenotype is sufficiently unique, e.g. the isotretinoin embryopathy (Lammer et al., 1985), then a series of case
reports can strongly suggest a hypothesis that can be confirmed using other
methods.
2. Centralized
adverse event reporting systems (AERSs) can provide a systematic
method for the accumulation of case reports from a variety of resources. For example,
under the U.S. FDA’s AERS, manufacturers and distributors of FDA-approved
pharmaceuticals are mandated to report events such as congenital anomalies as
they are reported to them or are published in the scientific literature, in
associa-tion with prenatal exposures to their drugs. The FDA receives
additional reports through the MedWatch program, an educational and promotional
effort, which facilitates spontaneous reporting from health-care providers
(Kessler, 1993; Goldman and Kennedy, 1998). And finally, consumers may provide
informa-tion to the manufacturer or directly to the FDA.
One
advantage of such systems is that reports can be accumulated from a variety of
resources in a timely fashion. Although these systems have typi-cally not been
fruitful in terms of identifying new human teratogens, once a possible
teratogenic expo-sure has been identified through other methods, these systems
have been useful resources for exploring the specific characteristics
surrounding exposed and affected pregnancies. For example, the angiotensin II
converting enzyme (ACE) inhibitor fetopathy, which includes a unique pattern of
renal tubular dysplasia and hypocalvaria occurring in association with second
or third trimester use of one of the drugs in the ACE inhibitor group, was
first reported by a clini-cian (Pryde et
al., 1993). However, the frequency of similar or related abnormalities in
relation to gesta-tional timing of exposure and dose of the drug was
identifiable through review of a series of 110 ACE inhibitor adverse event
reports submitted to the FDA through 1999 (Tabacova et al., 2000). Similarly, case reports and cohort studies that
identified the increased risk for a variety of neonatal complications with late
pregnancy exposure to some antidepressants (Spencer, 1993; Chambers et al., 1996) have been confirmed and
classified into possible pathogenetic subtypes using adverse event reporting
data (Moses-Kolko et al., 2005; Sanz et al., 2005).
The
primary limitations of such systems are simi-lar to those of case reports
appearing in the medical literature. Reports must be initiated spontaneously,
which may involve bias in the types and number of actual events that are
reported as well as an erosion in the motivation to report these events the
longer a product is on the market. Spontaneous reporting systems rely on the
‘prepared mind’ to make a link between medication exposure and preg-nancy
outcome, a link more likely for outcomes normally rare and extremely severe and
less likely for outcomes considered common or with subtle presentation. In
addition, adverse event reports do not provide denominator information on the
number of exposed, affected or unaffected pregnancies that could be used to
develop a birth prevalence rate for purposes of comparison with baseline rates
for a spec-ified outcome in the general population.
3. Pregnancy drug
exposure registries have been one
method of evaluating drug safety in pregnancy dating back to the Swedish
lithium registry established in 1962 (Schou et
al., 1973). Similar manufacturer-sponsored registries have been
successfully completed for fluoxetine (Goldstein, Corbin and Sundell, 1997) and
acyclovir (Andrews et al., 1992;
Preboth, 2000), whereas several others are presently ongoing. A current listing
is available on the U.S. FDA’s Office of Women’s Health website
(http://www.fda.gov/ womens/registries/registries.html). All traditional
pregnancy registries involve spontaneous reporting of exposed pregnancies. The
collection of exposure and outcome data is usually accomplished through the
healthcare provider who initiates contact with the registry; however, in some
registry designs, exposure and outcome data are collected from the pregnant
woman herself. Although pregnancy outcome reports can be collected
retrospectively, most current drug registries also identify and follow exposed
pregnancies prospectively, i.e. ascertain women during gestation, and collect
exposure and other information before the known outcome of that pregnancy. In
these cases, the registry may be considered a targeted follow-up study.
The
registry approach has many advantages includ-ing timely and centralized
ascertainment of exposed pregnancies that can parallel prescribing practices
for newly marketed medications. Particularly if the exposure is rare, this may
be the most efficient method for collecting pregnancy outcome data as quickly
as possible. Industry-sponsored registries can utilize the existing mechanism
of pregnancy expo-sures and events that are reported to the sponsor’s medical
information departments both nationally and internationally to more efficiently
identify poten-tial registry participants (Shields et al., 2004). The registry approach when used to accumulate
prospec-tive reports can provide good quality information about the temporal
association between exposure and outcome. In addition, prospective registry
designs provide a defined denominator of exposed women that facilitates
comparisons of congenital anomaly rates to those of a reference group.
These
registries generally have the ability to detect a meaningful increase in the
overall frequency of major congenital anomalies that are evident at birth
relative to the overall birth prevalence of major congenital anomalies in the
general population (Koren, Pastuszak and Ito, 1998; White and Andrews, 1999;
Shields et al., 2004). Especially for
high-risk teratogens such as
isotretinoin or thalidomide, such an approach is arguably the most efficient,
cost-effective and timely method for identifying such agents quickly. For
high-risk teratogens associated with a characteristic and frequently occurring
pattern of major congenital anomalies recognizable at birth, only a small
number of exposed pregnancies is necessary to infer potential teratogenicity
(Koren, Pastuszak and Ito, 1998).
However,
in the broader sense of pharmacovigilance for human teratogenicity, there are
several limitations of the traditional pregnancy registry approach. As these
studies depend on spontaneous reporting of exposed pregnancies, selection bias
may be involved. It is also difficult to project sample sizes. Even with
successful identification and recruitment of a high proportion of all exposed
pregnancies occurring in the population, the absolute number of exposed
pregnancies in the registry, and/or the specific timing of those exposures in
gesta-tion, is unlikely to provide sufficient power to rule out or identify any
but the most dramatic increased risks of specific congenital anomalies. This is
of particu-lar concern in that most known human teratogens are associated with
increased risks for specific patterns of birth defects and other adverse
outcomes rather than an increase in all birth defects across the spectrum.
Thus,
an important function of a typical pregnancy registry is to generate hypotheses
on the basis of ‘signal’ detection when higher than expected numbers of
specific malformations are reported, with additional studies required to
confirm or refute the signal (Cham-bers et
al., 2006).
Other
limitations of traditional pregnancy registries include the difficulty in
identifying an appropriate comparison group. Many registry designs do not
include a registry-specific comparison group. Instead, outcomes in exposed
pregnancies are frequently compared with externally derived reference rates for
the general population. Depending on the character-istics of exposed pregnant
women who are included in the registry, the use of external reference
statistics, without the ability to adjust for possible confounding, may not
represent the most appropriate comparison. Some registry designs do involve
recruitment of an internal comparison group with collection of infor-mation on
potential confounders so that comparisons can adjust for differences between
groups (Scialli, 1999). Other registry designs that involve multiple drugs used
for the same disease can address this prob-lem in part by comparing pregnancies
with the expo-sure of interest to pregnancies with exposure to other
medications used for the same disease (Scialli, 1999; Holmes, Wyszynski and
Lieberman, 2004). Another approach is that used by the antiretroviral drugs in
Pregnancy Registry. In this design, pregnancies with first-trimester exposure
to the drugs of interest are compared with pregnancies in which exposure did
not begin until the second or third trimester (Watts et al., 2004).
Finally,
as registries typically rely on a wide vari-ety of individual healthcare
providers and/or moth-ers themselves to report pregnancy outcome, there is a
potential for the misclassification of outcomes such as major congenital
anomalies with respect to accurate and complete diagnosis and/or suspected
etiology (Honein et al., 1999).
Furthermore, subtle or less easily recognizable teratogenic effects, such as
the fetal alcohol syndrome or the minor struc-tural abnormalities that comprise
the anticonvulsant embryopathy, are unlikely to be identified by the
obstetrician or general pediatrician who is report-ing outcomes to a registry.
In addition, especially when the healthcare provider is the primary source of
registry information, there is concern that a substantial proportion of
pregnancy exposure reports will be lost to follow-up, thereby potentially
biasing conclusions that can be drawn from registry data.
In
recent years, with the increasing number of preg-nancy registries established
by industry sponsors as part of post-marketing commitments or initiated by
other groups interested in generating pregnancy safety data, the U.S. FDA has
produced a guidance docu-ment (U.S. FDA Office of Women’s Health, 2002) that
establishes principles for the design and conduct of pregnancy registries. The
guidance document is intended to improve and standardize the overall qual-ity
and ultimate value of the data collected through pregnancy registry methods. In
addition, a second recently approved Center for Drug Evaluation and Research
(CDER) guidance document sets standards for reviewers who are evaluating human
data on the effects of in utero drug
exposure on the developing fetus (U.S. FDA Office of Women’s Health, 1999).
Taken together, these guidelines provide a framework for the collection and
interpretation of pregnancy exposure and outcome data that can contribute to
consistency and improved quality in the collection and evaluation of safety
data generated through pregnancy registries.
4. Birth defects monitoring
or surveillance systems are designed to provide population- or hospital-based
identification of congenital anomalies to measure trends and to respond to
unusual clusters of events. At this level of information gathering, if an
upward trend in the birth prevalence of a certain defect or a time-related
cluster of an unusual pattern of defects coincides with the widespread use of a
new medication, then surveillance programs can function as an early warning
system (Khoury et al., 1993). Because
an unusual pattern of congenital anomalies may occur with extreme rarity within
any one surveil-lance system, these efforts are enhanced by collabora-tions
such as the International Clearinghouse of Birth Defects Monitoring Systems
(ICBDMS), which has been in existence since 1974 (Erickson, 1991; Khoury et al., 1994).
5. Birth defects
case–control studies can be classified into
one of the two general approaches. The first group might be termed classical
hypothesis-testing case– control designs, whereas the second involves ongoing
case–control surveillance for drug-induced congenital malformations.
Using
the first design, cases and controls are iden-tified with the specific intent
to measure the asso-ciation between a risk factor and a specified birth defect
or group of defects. This approach requires that a priori decisions be made regarding the research questions,
selection of the appropriate control group and adequate power and sample size.
For exam-ple, based on concerns raised in the literature, this design was
successfully used to document an asso-ciation between congenital facial nerve
paralysis, or Möbius’s syndrome, and first-trimester use of miso-prostol
(Pastuszak et al., 1998).
The
second approach, case–control surveillance, is not based on a pre-defined set
of hypotheses but is instead focused on gathering a broad range of exposure and
potential confounder information for malformed cases and controls over an
indeterminate period to create a large repository of data suitable for testing
multiple future hypotheses. This approach has been incorporated into some birth
defects monitor-ing programs in the United States and is the general design of
the U.S. National Birth Defects Prevention Study (Carmichael et al., 2006). These methods are also
used on an ongoing basis in programs such as the Slone Epidemiology Center’s
hospital-based surveillance study based at Boston Univer-sity (Mitchell et al., 1981; Hernandez-Diaz et al., 2000), the Latin American
Collaborative Study of Congenital Malformations (ECLAMC) that involves over 70
hospitals in several South American coun-tries (Castilla and Peters, 1992) and
the population-based Hungarian Congenital Malformation Registry (Czeizel et al., 2000). These programs usually
involve ascertainment of malformed cases as well as system-atic sample
selection of non-malformed infants who can be used as controls. Exposure and
other risk-factor information is generally gathered by postnatal mater-nal
interview either in person or by telephone and, in some cases, is supplemented by
review of medi-cal records or pregnancy log books. In addition, some designs
have incorporated DNA sampling and bank-ing from case and control children and
their parents so that future hypotheses regarding genetic susceptibility or
gene–environment interaction can be tested.
The
primary advantage of any case–control approach in studies of rare events such
as congenital anomalies is the enhanced power to detect or rule out a
mean-ingful association for a given sample size. In contrast to pregnancy
registries or other prospective designs, this method is often the only
appropriate approach for detecting moderate or low-level teratogenic expo-sures
associated with specific major malformations. Furthermore, to the extent that
case–control surveil-lance studies collect comprehensive information on
potential confounders, including vitamin use, tobacco and alcohol, this
approach can provide reassurances that moderate effect sizes are not
attributable to these other factors. Other advantages of case–control surveillance
include, to a varying degree, relatively complete ascer-tainment of the
congenital anomalies of interest within a defined population, concurrent
selection of controls from the same population and the ability to validate the
classification of diagnoses.
In
addition, this approach provides flexibility in the ultimate use of the data,
i.e. based on specific research questions, subsets of cases and controls can be
selected from the entire data set to test or confirm specific hypotheses. For
example, this method was useful in confirming the protective effect of
antena-tal folic acid supplementation in reducing the inci-dence of neural tube
defects (Werler, Shapiro and Mitchell, 1993) and in refuting a previous finding
of an association between maternal loratadine use and the genito-urinary tract
anomaly, hypospadias (CDC, 2004). Furthermore, case–control surveillance data
are amenable to hypothesis generation. For example, these data were used to
first raise the question of an association between pseudoephedrine and
gastroschi-sis (Werler, Mitchell and Shapiro, 1992).
The
limitations of case–control studies of any type generally relate to the use of
retrospective data collection and the selection of controls. For example,
maternal interviews may be conducted in some cases many months after completion
of the pregnancy, which raises the possibility, although controversial, of
limited recall of early pregnancy medication use (Tomeo et al., 1999). In addition, the potential for serious differential
recall bias among mothers of malformed infants relative to mothers of
non-malformed controls has been cited by some (Khoury, James and Erickson,
1994), whereas the potential bias associated with the use of malformed controls
has been suggested by others (Prieto and Martinez-Frias, 2000). With respect to
the use of appropriate controls, case–control surveillance studies have the
advantage of flexibility in the selection of one or multiple control groups,
malformed or not, from the larger data set as judged necessary for any specific
analysis.
Because
case–control surveillance programs are ongoing, they have the potential to
recognize an asso-ciation with a newly marketed medication; however, they may
have limited sensitivity in this regard. These studies may miss an association
if the medication of interest is related to a relatively unusual or uncommon
congenital anomaly and/or that specific defect is not included in the range of
selected anomalies for which maternal interviews are conducted. In addition, if
new medications are infrequently used among pregnant women, then weak or
moderate associations may be difficult to detect. However, for medications that
are more commonly used – e.g. by 1% or more of preg-nant women – given the
rarity of congenital anoma-lies in general, these approaches provide a
relatively powerful method of hypothesis testing and hypothesis generating and
can be effectively used alone and in conjunction with other methods.
6. Large cohort
studies can
involve open cohorts that are
population-based and ongoing or can be hospital-or health insurer-based and/or
of limited duration. For example, the Swedish Registry of Congenital
Malfor-mations in combination with the Swedish Medi-cal Birth Registry
encompasses nearly all births in Sweden and utilizes exposure interviews
conducted by midwives during the first trimester of pregnancy as well as data
recorded prospectively in medical records (Ericson, Kallen and Wiholm, 1999).
The Collaborative Perinatal Project conducted in the 1960s was a study
involving over 50 000 mother–child pairs identified at multiple sites
throughout the United States (Chung and Myrianthopoulos, 1975). Simi-lar large
longitudinal cohort studies, each to some extent addressing risk factors for
congenital anoma-lies, have recently been initiated in other countries such as
Denmark (Olsen et al., 2001) and are
in the process of being organized in the United States under the auspices of
the National Children’s Study (http://www.nationalchildrensstudy.gov/).
These
studies have the advantage of large and repre-sentative sample sizes,
prospective ascertainment of exposure information as well as data regarding a
vari-ety of potential confounders and ability to collect outcome information
over a long term of follow-up. In addition, women with and without the
expo-sure of interest are concurrently enrolled as members of the cohort,
facilitating the identification of one or more appropriate reference groups.
Like ongoing case–control designs, studies of this type can address multiple
hypotheses that need not be formulated a
priori (Irl and Hasford, 2000).
However,
even in large cohort studies, issues of sample size can be a limitation. For
example, the Collaborative Perinatal Project had inadequate power to detect
weak to moderate associations with any but the most common major congenital
malforma-tions and the most commonly used drugs due to the relatively small
numbers of women exposed to most specific medications of interest. By contrast,
the Swedish Registry with approximately 120 000 annual births, accumulated over
more than a 25-year span, has enhanced power to identify these asso-ciations,
assuming the frequency of exposure in pregnant women is sufficient to test such
hypothe-ses. For example, using the Swedish data, Kallen, Rydhstroem and Aberg
(1999) were able to iden-tify over 2000 first trimester–inhaled corticosteroid
(budesonide)-exposed pregnancies and rule out with acceptable confidence an
increased risk in overall rate of major congenital anomalies. However, the
numbers of exposed and affected infants were too small even in this relatively
large cohort to address the hypothesis of an increased risk for oral clefts,
which is the specific type of major congenital malformation that has
previ-ously been associated with maternal systemic corti-costeroid use and is
therefore of theoretical concern.
7. Small cohort
studies focused
on specific medications have been
conducted by Teratology Information Services (TIS) both in North America and in
Europe. These studies draw on a base of callers who contact a TIS-seeking
counseling regarding the safety of a medication used in pregnancy. Follow-up of
pregnancy outcome is obtained for selected exposures. These studies have
strengths similar to the registries described above with respect to the
potential for rapid identification of exposed women, particu-larly for a new
drug, as well as prospective collection of exposure and other risk factor
information. Tera-tology Information Services studies usually employ a
concurrently enrolled unexposed control group, often both a disease-matched and
a non-diseased group, which may provide the most appropriate reference groups
in this context.
Similar
to traditional pregnancy registries, the primary limitation of TIS studies
relates to sample size. Individual TIS sites either independently or in
collaboration have published studies typically involv-ing between 100 and 200
exposed subjects (Pastuszak et al.,
1993; McElhatton et al., 1999). Also,
similar to pregnancy registry
designs, TIS studies rely on spon-taneous callers for the recruitment of
subjects that may result in selection bias.
In
an effort to increase sample size and to shorten the time needed to identify a
given number of exposed pregnancies, collaborative projects among networks of
TIS sites in North America are conducted through the Organization of Teratology
Information Special-ists (OTIS) (Scialli, 1999) and in Europe through the
European Network of Teratology Information Services (ENTIS) (Vial et al., 1992; Schaefer et al., 1996). These formal
collaborations can add to the vari-ability and possibly the representativeness
of subjects in the sample and increase the obtainable sample size by drawing on
a larger population of potentially exposed women. However, even these studies,
similar to other cohort studies with moderate sample sizes, usually are only
sufficiently powered to detect or rule out very large increased risks of
specific major congenital anomalies associated with exposures.
The
primary strength of TIS studies is the abil-ity to evaluate a spectrum of
pregnancy outcomes following a given exposure, including major congen-ital
anomalies, spontaneous abortion and stillbirth, preterm delivery, pre- and
postnatal growth deficiency and, in some cases, longer term child development.
In this context, although underpowered to evaluate rare outcomes, these studies
can be useful for gener-ating hypotheses that can be tested using other
meth-ods. Furthermore, in some OTIS and individual TIS designs, exposed and
comparison children are system-atically evaluated for a pattern of both major
and more subtle minor congenital anomalies. This additional level of scrutiny
can increase the sensitivity of this approach for the identification of a
unique pattern of effects on fetal development, e.g. a pattern analogous to the
anticonvulsant embryopathy, that might not be detectable through any of the
other study methods available (Jones et
al., 1989; Chambers et al., 2001;
Lyons Jones, Johnson and Chambers, 2002).
8. Database linkage
studies,
as technological advances permit, can
offer many of the advantages of large cohort studies at potentially far less
cost. Early efforts along these lines utilized the Michigan Medicaid database,
a government health insurance program within which maternal prescription
records could be linked to pediatric billing records to identify children born
with and without congenital anoma-lies (Rosa, 1999). Similar approaches have
been used successfully elsewhere in North America and Europe. For example,
investigators in Denmark have linked prescription database records to hospital
discharge and medical birth register records for children with and without
congenital anomalies to investigate the safety of a widely used antibiotic
(Larsen et al., 2000).
In
countries where there is universal and stan-dardized healthcare delivery and
record keeping, or in countries where healthcare maintenance organi-zations or
other large membership-based providers serve a significant proportion of the
population, linked prescription and birth records provide an attractive
alternative method for testing hypotheses regard-ing drug safety in pregnancy.
For example, hospital discharge data across the Canadian population have been
used to evaluate adverse outcomes of pregnan-cies complicated by asthma (Wen,
Demissie and Liu, 2001). This approach has also been used successfully to
evaluate pregnancy exposure to clarithromycin using longitudinal claims data
for members from 12 geographically diverse United Health Group-affiliated
insurance plans (Drinkard, Shatin and Clouse, 2000). Similarly, information
from the Group Health Cooperative of Puget Sound in the United States has been
used to examine the association between topical tretinoin (Retin-A) and major
birth defects (Jick, Terris and Jick, 1993). The General Practice Research
Database in the United Kingdom is another potentially fruitful resource (Jick
and Terris, 1997; Jick, 1999). Recent efforts to develop algo-rithms for
accurately identifying pregnancies, expo-sure windows, gestational timing and
pregnancy outcomes utilizing this database hold promise for increased
utilization off these existing resources to address hypotheses related to
pregnancy exposures (Hardy et al.,
2004).
The
primary advantages of large-linked databases are the availability of large
numbers of subjects, the ability to establish temporal relationships between
exposure and outcome by constructing an histori-cal cohort and relative ease of
access to previously collected medical, administrative or claims data. This
approach also avoids some of the biases involved in studies that rely entirely
on maternal report to classify exposure, especially if that information is
collected retrospectively.
These
strengths must be weighed against the limita-tions inherent in a study design
that does not involve subject contact. For example, these studies usually
cannot insure that the medication prescribed was actu-ally taken by the mother,
taken in the dose prescribed or taken during the period critical for the
develop-ment of any specific birth defect. To remedy this limitation, some
database analytic designs involve the validation of a subset of records through
other methods such as chart review or maternal interviews. There are also
issues related to the misclassification of outcome depending on the quality of
records used to determine or exclude the diagnosis of a congenital anomaly.
Again, this limitation is not insurmount-able if it is possible to incorporate
some level of validation.
In
addition, similar to large cohort studies, even databases containing hundreds
of thousands of patient records may have limited power to test drug-specific
hypotheses due to relatively small numbers of pregnant women exposed to any
particular drug. Furthermore, for low to moderate risk teratogens, large-linked
databases often do not have immedi-ate access to information on potentially
important confounders such as maternal exposure to tobacco, alcohol, vitamins
and over-the-counter medications. However, databases can be a relatively
efficient method for surfacing and testing hypotheses related to prescription
medications, and therefore, these studies hold significant promise for the
future.
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