Reviewer Guidance
Evaluating the Risks of Drug Exposure
in Human Pregnancies
This
guidance represents the Food and Drug Administration’s (FDA’s)
current thinking on this topic. It does not create or confer
any rights for or on any person and does not operate to bind FDA
or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes
and regulations. If you want to discuss an alternative
approach, contact the FDA staff responsible for implementing
this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of
this guidance.
This guidance is intended to help FDA staff
evaluate human fetal outcome data generated after medical product
exposures during pregnancy.
The goal of such evaluations is to assist in the development of
product labeling that is useful to medical care providers when
they care for patients who are pregnant or planning pregnancy.
The review of human pregnancy drug exposure data and assessment of
fetal risk (or lack of risk) requires consideration of human
embryology and teratology, pharmacology, obstetrics, and
epidemiology. Consequently, FDA staff also are encouraged to
consult with experts in these fields, as appropriate.
This guidance does not address the assessment
of experimental animal reproductive toxicology data. A separate
guidance is under development for FDA pharmacology/toxicology
reviewers that describes a process using nonclinical data to
estimate human developmental and reproductive risks from drug
exposure when human data are unavailable.
FDA’s guidance documents, including this
guidance, do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a
topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use
of the word should in Agency guidances means that something
is suggested or recommended, but not required.
The term teratogen is used to denote
the result of a hazard assessment on a particular agent (for
purposes of this guidance, a drug). The use of the term
indicates that the drug has the capacity under certain exposure
conditions to produce abnormal development in an embryo or fetus.
However, hazard assessment must be put into context. Whether a
drug causes abnormal development or not depends not only on the
physical and chemical nature of the drug but also on the dose,
duration, frequency, route of exposure, and gestational timing
involved.
Other factors that may determine whether a
particular exposure is likely to be teratogenic in a particular
instance include other concurrent exposures and the biological
susceptibility of the mother and the embryo or fetus. Throughout
this guidance, the term teratogen is used to designate
products with teratogenic potential at clinical doses used in
humans. Classifying a drug as a teratogen only indicates that
it may have the potential for producing
developmental toxicity given the appropriate conditions. For
example, a single 50-mg dose of thalidomide administered on the
26th day after conception has a significant risk of producing a
major structural malformation of the embryo. However, that same
dose of thalidomide taken in the 10th week after conception does
not produce structural malformations, and a 1-mg dose at any time
during pregnancy has no observable effect on the developing embryo
or fetus (Brent 2001).
About 4 percent (1/28) of babies are born
each year with a major birth defect or congenital malformation
(March of Dimes 2001). The March of Dimes defines a major birth
defect as an abnormality of structure, function, or metabolism
that either is fatal or that is present at birth and results in
physical or mental disability (March of Dimes 2001). For the
majority of major birth defects (about 65 percent), the etiology
is unknown (Schardein 2000). Chemically induced birth defects,
including those associated with drug exposure, probably account
for less than 1 percent of all birth defects; few drugs are proven
human teratogens at clinical doses (Koren 1998). Of the thousands
of drugs available, only about 20 drugs or groups of drugs (most
being anticonvulsants, antineoplastics, or retinoids) are
recognized as having an increased risk of developmental
abnormalities when used clinically in humans (Schardein 2000).
However, since few drugs have been systematically studied to
identify their full range of possible teratogenic risks, we cannot
assume that current knowledge is complete. The identification of
a drug’s teratogenic potential is important because drug-induced
adverse fetal effects are potentially preventable.
There appears to be a general perception that
the use of any drug at any time during pregnancy can harm the
developing embryo or fetus. In one study, pregnant women exposed
to certain nonteratogenic drugs believed that the risk for major
birth defects was 24 percent, which is similar to the known risk
from exposure to thalidomide during the gestational time of most
sensitivity (Koren 1989). Another study (done in Canada) reported
that even health professionals who were shown drug labeling with
“reassuring” text (i.e., labeling that explicitly stated that the
drug itself does not cause fetal malformations when used in
pregnancy) still rated those drugs as having some risk for causing
birth defects (Pole 2000). This exaggerated fear could lead to
termination of a wanted pregnancy or to unnecessary withholding of
needed drug therapy during pregnancy.
Although knowledge of teratogenic potential
is a critical part of a drug’s benefit/risk profile, pregnant
women are rarely included in clinical trials (Mastroanni 1994).
There may be inadvertent pregnancy exposures during clinical
trials of new products, but available data are usually
insufficient to permit an adequately powered statistical
analysis. Consequently, when a drug is first marketed there are
usually no human data on the effects of in utero drug exposure.
The only data on fetal effects initially available in the product
labeling usually comes from animal reproductive toxicology
studies.
Despite the lack of information on the safety
of drug use during pregnancy, most pregnant woman likely will be
exposed to drugs. Fetal exposure can occur before a woman knows
she is pregnant. Some women enter pregnancy with medical
conditions that require continuing drug therapy. New medical
problems may develop during, or old ones may be exacerbated by,
pregnancy.
Because little is known before marketing
about a drug’s teratogenic potential, postmarketing surveillance
of drug use in pregnancy is critical to the detection of
drug-induced fetal effects. With current postmarketing
surveillance methods, this process can take considerable time.
For example, with thalidomide, it took almost 4 years before the
link between thalidomide use during pregnancy and phocomelia was
recognized (Lenz 1961, McBride 1961). The recognition of the more
subtle pattern of malformations associated with warfarin use
during pregnancy took more than 20 years (Pettifor 1975). Some
drugs may induce teratogenic effects that are not clinically
evident until many years after birth, such as the reproductive
tract abnormalities associated with DES exposures in utero (Herbst
1975).
It is important that the FDA and sponsors
routinely review all available data on drug exposure during
pregnancy and work together to provide up-to-date product labeling
that reflects what is known and not known about human fetal risk
or lack of risk.
The
following is a list of factors to consider when presented with
human pregnancy data and faced with making a determination whether
and how the data should be included in the product labeling. A
discussion of each factor follows.
·
Background prevalence of adverse pregnancy outcomes
·
Combined vs. individual rates of birth defects
·
Major vs. minor birth defects
·
Timing of exposure
·
Intensity of exposure
·
Variability of response
·
Class effects
Every pregnancy has a risk of an abnormal
outcome regardless of drug exposure. Reproductive toxicologists
generally consider the four major manifestations of abnormal fetal
development to be growth alteration, functional deficit,
structural malformation, and death (Schardein 2000). The purpose
of collecting and evaluating data on drug exposure during
pregnancy is to address whether a particular drug exposure
increases the risk of abnormal fetal development above the
background rate.
Clinical classifications of pregnancy
outcomes include live births, elective terminations, and fetal
losses, i.e., spontaneous abortions (loss prior to 20 weeks
post-conception), and fetal deaths/stillbirths (loss beyond 20
weeks post-conception) (Ventura 2000). Based on national data for
1996 (the most recent year for which data are available) only 62
percent of clinically recognized pregnancies result in a live
birth; 22 percent end in elective termination and 16 percent
result in spontaneous abortions (1 of 7 known pregnancies) or
fetal death/stillbirth (1 of 200 known pregnancies) (Ventura 2000,
March of Dimes 2001). Among live births, preterm birth (before
the 35th week after conception) and low birth weight (<2500 grams)
are also considered adverse pregnancy outcomes occurring in 1 of 8
and 1 of 12 live births, respectively (March of Dimes 2001).
Although the March of Dimes reports an
overall background birth defect prevalence of 4 percent of births,
this percentage can change depending upon the definition of birth
defect (e.g., inclusion of abnormalities of cosmetic importance),
the specific population studied, and the time period beyond birth
used for detection. The term birth defects, as used by the
March of Dimes, refers to congenital anomalies identified
by codes 740-759 of the Ninth Revision of the International
Classification of Diseases (ICD-9) (Petrini 1997). The rate of
some birth defects will be influenced by whether prenatally
diagnosed defects and/or elective terminations are included, and
whether prenatal defects are confirmed postnatally. For example,
a large percentage of pregnancies with anencephaly are terminated
and will not be captured in birth statistics other than as a
termination. Prenatally diagnosed hydronephrosis and ventricular
septal defects may resolve before delivery or soon afterward and
will be overcounted if included only on the basis of prenatal
diagnosis. Unfortunately, prenatally diagnosed defects may not be
evaluated postnatally at all if the outcome is a stillbirth or
elective termination. This not only precludes confirmation of the
diagnosis, but also the ability to ascertain additional less
obvious conditions.
To assess whether the therapeutic use of a
drug results in an increase in adverse fetal effects, one commonly
compares the rate of birth defects seen in a study population to
some background rate. However, all-inclusive background rates of
all major birth defects may include infants with genetic syndromes
and chromosomal abnormalities that may not be caused by a
medication or other toxic exposure. Therefore, at best such rates
constitute very crude comparisons.
Population estimates can vary considerably
by maternal age, race, geographic region, socioeconomic status,
and time period (e.g., the availability of diagnostic tools can
change over time). In addition, maternal disease states (e.g.,
diabetes) can influence pregnancy outcomes and fetal development
with outcome rates within a particular disease population being
very different from rates for the general population. Therefore,
when evaluating whether exposure to a drug during pregnancy
increases the risk for any adverse pregnancy or fetal outcome, it
helps to know the background rate of the outcome in a population
as similar as possible to the study population.
It is easier to detect an increased risk
for an abnormal outcome that occurs at a relatively high
background rate (e.g., spontaneous abortion) than it is to detect
an increased risk for an abnormal outcome that occurs at a
relatively low background rate (e.g., oral clefts).
Consequently, the statistical power of a study to detect an
increased risk of adverse fetal effects that normally occur at a
low rate is often limited. When collecting pregnancy exposure
data on a previously unidentified teratogen that behaves like
isotretinoin in causing serious, obvious effects in about 25
percent of exposed live-born infants, it will not take many
exposed pregnancies before the problem is detected. However, a
teratogen that behaves like valproic acid, which causes neural
tube defects at a rate of 1 to 2 percent in exposed infants (a
tenfold increase over background), requires a much larger number
of exposed pregnancies to detect. One report of 12 normal infants
following gestational exposure to valproic acid (Hiilesma 1980)
was misleading because the number of exposures was not sufficient
to detect an effect size of 1 to 2 percent. It took a
retrospective case control study to demonstrate the association (Bjerkedal
1982, Robert 1982).
When reviewing studies or case series, a
reviewer should consider whether there are enough exposures to
demonstrate an increase in risk if such a risk exists. Any
studies reporting no increase in the background rate of birth
defects in exposed pregnancies can be viewed with skepticism
unless the power of study to detect or rule out a stated level of
risk is also included (Ferencz 2000).
Human
teratogens generally increase rates of specific defects or a
spectrum of defects. For example, thalidomide causes limb, spine,
and central nervous system (CNS) defects; isotretinoin causes ear,
CNS, and cardiac defects; valproic acid causes neural tube
defects; warfarin causes cartilage defects; and angiotensin II
converting enzyme (ACE) inhibitors cause renal functional effects
(Mitchell 2000).
In addition to evaluating the overall rate of
birth defects in the study population, it is also important to
look at rates of individual birth defects. A population that
experiences a tenfold increase in a specific rare birth defect
(e.g., spina bifida from 0.04 percent to 0.4 percent) as a result
of exposure to a teratogen may still have a total birth defect
rate (i.e., all malformations) that is not measurably different
from that in a reference population.
It has been suggested that the possibility
of detecting a teratogen can be increased by grouping individual
malformations according to an understanding of their embryologic
tissue of origin (Mitchell 2000, Scheuerle 2002). Mitchell uses
the example where interference with the normal development of the
neural crest would lead to malformations of tissues derived from
neural crest cells which, in the earliest stages of embryogenesis,
migrate to form a variety of structures including those of the
face/ears, parts of the heart, and the neural tube. A case in
point is isotretinoin which interferes with neural crest cell
migration/development and leads to specific malformations of the
ear, heart, and neural tube (Mitchell 2000).
For general information on background
population rates, refer to Table 1, which lists the leading
categories of birth defects according to the March of Dimes,
whereas Table 2 lists the range of reported state-level rates for
some individual birth defects as reported to the National Birth
Defects Prevention Network.
Table 1.
Leading Categories of Birth Defects
Birth Defect |
Estimated Prevalence |
Heart and circulation
Muscles and skeleton
Genital and urinary tract
Nervous system and eye
Respiratory tract
Metabolic disorders
|
1 in 115 births
1 in 130 births
1 in 135 births
1 in 235 births
1 in 900 births
1 in 3,500 births |
Source: March of Dimes, National
Perinatal Statistics (http://www.modimes.com)
Table 2. Birth
Defect Surveillance Data from Selected States*
Birth Defect |
Range in Rates per 10,000 Live
Births |
Anencephalus
Anophthalmia/microphthalmia
Anotia/microtia
Atrial septal defect
Cleft lip with and without cleft palate
Cleft palate without cleft lip
Endocardial cushion defect
Esophageal ataresia/tracheosophageal
fistula
Gastroschisis
Hydrocephalus without spina bifida
Hypoplastic left heart syndrome
Hypospadias and epispadias
Microcephalus
Obstructive genitourinary defect
Omphalocele
Pulmonary valve atresia/stenosis
Pyloric stenosis
Rectal and large intestinal atresia/senosis
Reduction deformity: lower limbs
Reduction deformity: upper limbs
Spina bifida without anencephalus
Tetralogy of Fallot
Transposition of great vessels
Ventricular septal defect
|
0.00 – 4.92
0.39 – 3.73
0.19 – 6.43
10.51 – 70.29
4.48 – 22.98
3.52 – 9.35
1.11 – 6.84
0.83 – 5.20
0.90 – 6.59
0.59 – 19.34
0.51 – 3.94
1.59 – 46.61
0.51 – 15.65
3.43 – 35.26
0.45 – 3.48
1.17 – 20.71
0.18 – 30.70
1.02 – 9.02
0.74 – 5.35
0.75 – 5.02
1.36 – 8.08
1.49 – 8.08
1.02 – 6.68
8.41 – 79.18
|
*Rates
represent data contributed to the National Birth Defects
Prevention Network from 30 states. Rates for most of the states
were based on 5 years of data from 1995 – 1999. However, four
states provided data for only 1 to 3 years. Not all states
reported data for all defects. State birth defect surveillance
programs vary considerably in their methodologies, definitions,
and inclusion criteria. Because of these differences, the data
cannot be combined to give overall rates for the United States;
therefore data are presented as a range of rates.
Source: National Birth Defects Prevention Network, 2002, “Birth
Defects Surveillance Data from Selected States, 1995 – 1999,”
Teratology, 66:S129-S211.
Most case reports and studies of birth
defects focus on major birth defects (i.e., those
incompatible with life or requiring medical/surgical
intervention). The term minor birth defect generally
refers to minor physical anomalies with less clinical importance
that represent deviations from what is considered normal
and do not have obvious medical, surgical, or cosmetic
consequences. Minor birth defects are more common than major
ones, occurring in 14 to 40 percent of live births (Leippig
1987). Clearly, what constitutes a minor birth defect may be
subjective, hence the wide range of prevalence estimates.
Minor birth defects may have predictive value
in identifying more serious associated problems. Estimates of the
predictive value of three or more minor birth defects for an
associated major defect range from 19.6 to 90 percent (compared to
1.3 to 2.4 percent of those with no minor birth defects) (Leippig
1987). Identification of a higher-than-expected frequency of
infants with three or more minor defects, and especially a
specific pattern of these defects, may be a more sensitive screen
for possible human teratogens than evaluation of the increased
risk of any major birth defect (Chambers 2001). Assessing minor
birth defects in children who have a major birth defect is also
important because a complete description of all abnormalities can
help identify a pattern characteristic of the exposure and improve
the ability to attribute causality. A pattern of minor defects
may represent the mild end of a spectrum of effects with a major
defect, occurring less frequently, at the other end of the
spectrum. For example, the spectrum of effects resulting from in
utero exposure to carbamazepine ranges from 11 percent of
exposed infants with minor craniofacial defects and nail
hypoplasia to 1 percent of exposed infants with a neural tube
defect (Jones 1989, Hernandez-Diaz 2001).
When interpreting data on drug exposure
during pregnancy, it is important to consider the timing and
duration of exposure and their relationship to windows of
developmental sensitivity. Agents that produce adverse effects on
the fetus typically do so during discrete sensitive periods of
fetal development that vary depending on the particular
teratogenic process and target organ. Each part, tissue, and
organ of an embryo has a critical period during which its
development may be disrupted (see Attachment A). For example, the
most critical period for brain development is from 3 to 16 weeks
post-conception, but its development may be disrupted after this
because the brain is differentiating and growing rapidly (Moore
1998).
When evaluating pregnancy outcome data, it is
important to identify the frame of reference for the reported
gestational age. Determining the gestational week of exposure
based on the date of last menstrual period versus the date of
conception can produce a 2-week time difference that can be
critical when evaluating an association between a birth defect and
drug exposure. In this guidance, when gestational age is
mentioned, it refers to time since conception.
During the first 2 weeks after conception the
developing embryo is not susceptible to teratogenesis (Moore
1998). Drug exposures during this time period are not known to
cause congenital anomalies in human embryos; however, such
exposures may interfere with cleavage of the zygote or
implantation of the blastocyst and/or cause early death and
spontaneous abortion of the embryo (Moore 1998).
In humans, the embryo is most easily
disrupted during organogenesis (3 to 8 weeks post-conception) when
the tissue and organs are forming. During this time, teratogenic
agents may induce gross structural abnormalities readily seen at
birth. However, although more common with teratogenic exposures
during the main embryonic period, the production of important
anatomic defects is not limited to organogenesis, as evidenced by
the microcephaly seen with maternal alcohol abuse during the fetal
period (Moore 1998).
Later in gestation, the fetus rapidly grows
and matures, undergoing active cell growth, differentiation, and
migration, particularly in the CNS. Exposures during this period
may cause physiologic defects such as minor anomalies of the
external ear, growth retardation or functional disorders such as
mental retardation. However, important abnormalities can also be
produced by late pregnancy exposures such as the fetal alcohol
syndrome seen with alcohol abuse, the renal function effects seen
with the use of ACE inhibitors, and the cartilage defects seen
with the use of warfarin.
Knowledge of the sensitive period for human
target organ development facilitates optimal data interpretation.
For example, if drug exposure occurred after the critical period
of development for an organ, the exposure is an unlikely cause of
the organ malformation (e.g., an infant born with transposition of
the great vessels that are formed during the first trimester, who
was exposed to the drug only in the third trimester).
Evaluating the timing of exposure is also
important when assessing the power of a study. For example,
consider a drug that causes a tenfold increase in neural tube
closure defects, from 0.1 percent to 1 percent. Formation of the
neural tube begins about day 18 after conception and, with normal
development, the neural tube closes by the end of the fourth week
of gestation (Moore 1998). A hypothetical study identifies
100,000 women exposed during the first trimester of pregnancy, but
only 1,000 of the women were exposed during the sensitive period.
The 1,000 pregnancies with exposure during the sensitive period
produce 10 cases of neural tube defects based on a 1 percent rate
while 99 cases are seen in the other 99,000 pregnancies based on
the background rate of 0.1 percent. The total of 109 affected
children from 100,000 exposed pregnancies produces a 0.11 percent
rate, which probably would not be appreciated as different from
the background rate of 0.1 percent and would not identify the real
increase due to the exposure to the drug.
Table 3 lists the sensitive periods for
exposure to some known teratogens. However, as a practical
matter, the sensitive period for exposure to a drug, if there is
one, is usually unknown. In situations where no clear toxicity
has been identified, it is common to globally assess risk from
first trimester exposures because that is the time of
organogenesis. There are two potential sources of error in using
this global approach. First, as seen in the previous example,
sensitive time periods for a particular problem may make up a
small portion of the first trimester. Therefore, if numbers
allow, it is recommended that exposures during the first trimester
be analyzed by gestational week post-conception of fetal
development. Second, drug-induced fetal toxicities may not be
limited to the first trimester or may produce abnormalities during
more than one exposure window. If studies exclude second and
third trimester exposures, they will not be able to identify
potentially important adverse effects that occur later in
pregnancy, such as those seen with the ACE inhibitors.
Table 3.
Examples of Critical Timing of Exposure for Some Known Teratogens
Teratogen |
Critical Timing of Exposure |
Thalidomide |
Exposure between days 24 to 36
post-conception can produce limb and other defects (Moore
1998). |
Diethylstilbestrol (DES) |
Exposure before the 9th week
post-conception leads to a precancerous vaginal adenosis in
73 percent of female offspring, but in only 7 percent of
female offspring exposed after the 17th week
post-conception. Clear-cell carcinoma has not been reported
in female offspring who were exposed in utero after the 18th
week post-conception (Herbst 1975). |
ACE inhibitors |
Exposure in the 2nd and 3rd trimester
of pregnancy is associated with fetal hypotension, renal
tubular dysplasia, anuria-oligohydramnios, growth
restriction, hypocalvaria, and death (Sedman 1995). |
Warfarin |
Exposure in the latter half of the 1st
trimester (6 to 12 weeks post-conception) produces the
greatest susceptibility to skeletal features of fetal
warfarin syndrome (Scialli 1995). |
Dosing, including frequency and duration of
exposure, is also an important consideration. Typically, a drug
must cross the placenta and reach the fetus in sufficient
concentration to cause an effect. Most nonprotein agents do cross
the placenta, the exceptions being highly charged agents or
certain very large molecules like heparin and insulin. Maternal
changes during pregnancy in absorption, volume of distribution,
metabolism, plasma protein binding, and excretion also will affect
the extent to which the fetus is exposed. These parameters are
dynamic over the course of pregnancy. For example, some products
may be more readily transported across the placenta during late
gestation than during early gestation because of an increased
unbound fraction in maternal circulation, increased utero-placental
blood flow, increased placental surface area, or changes in fetal
circulation. Agents that undergo relatively little metabolism in
the fetus, but are excreted into the amniotic fluid by the
well-developed fetal kidney in the third trimester, may have
greater exposure as the fetus continually swallows amniotic
fluid.
All teratogens have a threshold below which
adverse effects do not occur. Conversely, almost all exposures
can be toxic to the fetus if the dose is high enough, even if only
indirectly through maternal toxicity (e.g., low birth weight or
mortality because the mother is too sick from the medication to
eat).
Products that interfere with fetal
development may produce manifestations along a continuum of
response that may be closely connected with a dose-response
relationship. A dose-response curve is usually seen in animal
studies, but is rarely seen in humans because of the relatively
narrow range of standardized clinical doses. An exception is the
dose-response effect in humans that can be seen with alcohol.
Alcohol at low doses throughout pregnancy is associated with
slightly decreased birth weight. At high doses, it has effects on
fetal neurologic development, and at progressively higher doses,
it is associated with microcephaly and other visible anatomic
effects (Ernhart 1987).
People differ in their responses to specific
medications, which may at least partially be due to genotypically
determined differences in metabolism or receptors. Just as
therapeutic or adverse effects related to a given drug do not
occur in all exposed individuals, exposures during a sensitive
time period known to increase the incidence of adverse pregnancy
outcomes may do so only in a fraction of those infants exposed.
For example, more than half of infants with similar in utero
exposure to phenytoin are unaffected, about one-third show some
congenital anomalies, and only 5 to 10 percent develop fetal
hydantoin syndrome (Moore 1998).
Although the effects of known teratogens are
generally predictable from a population perspective, the nature
and extent of effects are not necessarily possible to predict in
individual patients under similar conditions. The teratogenicity
of an exposure can be influenced by both the maternal and fetal
genotypes, which may result in differences in cell sensitivity,
placental transport, metabolism, receptor binding, and
distribution (Polifka 1999). Even at the same dose in the same
gestational window, there can be a range of possible outcomes.
Because of this variability, assessment of a drug’s potential
teratogenesis ought to consider the full range of birth defects.
It is important to remember that the
concept of variability extends not only to toxic responses, but
also to baseline attributes of populations. Birth weight, for
example, varies by race and sex. Normative growth curves
developed in Caucasian populations that are used to evaluate
African-American or Asian-American babies may result in
over-diagnosis of growth impairment. Genetic differences in
metabolism of a drug by the mother, the placenta, and the fetus
may contribute to variation in how much of a drug’s metabolites
reach fetal tissue and thereby lead to variable rates and types of
toxicity manifested.
Understanding
the structure/activity relationships and pharmacological mode of
action of a class of therapeutic agents in some circumstances can
provide a prediction of the possible safety and efficacy of a new
agent. However, such knowledge is generally not predictive of
human teratogenesis (Mitchell 2000). For example, thalidomide and
glutethimide are closely related by chemical structure, but there
is no evidence that glutethimide is teratogenic (Heinonen 1977).
While the introduction of a new product from
a class of drugs with known human teratogenicity will solicit
heightened scrutiny, it cannot be assumed that the product will
also be teratogenic. Similar findings in the animal studies for
the new product compared to the class would be cause for more
concern, whereas clean animal data would lessen the concern.
Information on human gestational drug
exposures will emerge during the postmarketing phase for virtually
all drug products. Human pregnancy outcome data will be sent to
the Agency either directly by voluntary reporters or via the
sponsors as required by federal regulations.
The data will come from a variety of sources. For the most part,
data will not be derived from controlled clinical trials, but from
observational studies.
No single methodology can delineate the
complete spectrum of adverse outcomes associated with prenatal
exposure to a drug. Therefore, it is important to consider
information from all available postmarketing surveillance sources
to optimize detection and characterization of the reproductive
effects of prenatal drug exposure.
Brief descriptions of the most common types
of data and study designs follow. More in-depth information on
the strengths and weaknesses of each can be found in
pharmacoepidemiology texts elsewhere (Hartzema 1998, Strom 2000).
Case reports describe one or a series of
clinical observations on drug exposure during pregnancy and
subsequent infant effects. Case reports are the most common
source of reported congenital anomalies, but can also be the most
difficult to interpret. It is true that most pregnancy exposures
that produce an increase in developmental risk in humans were
first suggested by case reports (Schardein 2000). However, case
reports cannot distinguish coincidence from causation and cannot
be used to assess teratogenic risk. A series of case reports
associating an unusual outcome with a drug exposure might well
raise suspicions, as in the case of thalidomide, but follow-up
evaluations are always necessary to assess risk. Unlike the case
of thalidomide, most case reports that call attention to a
putative association are not confirmed by follow-up evaluation.
Case reports were the source for allegations regarding
teratogenicity with Bendectin, but those allegations were later
disproved through epidemiologic studies (Goldberg 1986).
Conversely, case reporting of a small number of normal outcomes
can delay the identification of an association, as was the case
with valproic acid and spina bifida, where a published report of
12 normal pregnancies was too small to detect the now known 1
percent rate of affected children (Scialli 1992).
It is critical to be cautious and objective
when evaluating isolated case reports because adverse outcomes
tend to be disproportionately reported. The birth of an infant
with a birth defect can be devastating. In an effort to
understand what went wrong, health care providers and their
patients may consider drug and other exposures during pregnancy.
In contrast when a normal infant is born, there is no incentive to
recall, much less report to the FDA or in the literature, any drug
exposures during pregnancy.
Although an individual case report, by
itself, can never prove causality, a series of similar reports of
a distinct abnormality or group of abnormalities can establish a
strong association or signal the need for further research. Most
signals based on case reports will need to be further investigated
using other pharmacoepidemiologic studies. Attachment B is a
checklist that may be useful when evaluating case reports.
Formal epidemiology studies provide the best
means of evaluating whether a gestational exposure adversely
affects the developing infant. Epidemiology studies can identify
associations between a given drug exposure and abnormalities in
the newborn, and they can quantify the strength of such
associations. Also, although it is impossible to demonstrate
absolute safety, epidemiology studies can provide some measure of
reassurance if risks are not found to be elevated, and the level
of reassurance, like evidence of risk, can be quantified. The
degree of reassurance is a function of the sample size (power) of
the study. A study may report a lack of association between a
drug and birth defects simply because the study was insufficiently
powered due to a small sample size to detect anything other than a
very large difference. Thus, results from any
pharmacoepidemiology study of birth defects must take into account
what level of risk the study was capable of detecting.
In addition to a study’s power, possible
confounding by maternal indication is an important consideration.
For example, birth defects are known to occur with increased
frequency in infants born to women with certain medical conditions
(e.g., diabetes), independent of the product used to treat the
disease. With other diseases, it may not be known whether it is
the disease, the drug, or an interaction between the severity of
disease and the drug exposure that causes an observed increased
risk of birth defects. For example, after years of speculation,
it was only recently that a study suggested that the increased
risk for embryopathy seen in the offspring of women with epilepsy
is associated with gestational exposure to anticonvulsants rather
than with epilepsy itself (Holmes 2001).
Other maternal attributes such as age, race,
weight, parity, geographic location, and socioeconomic status can
cause confounding as well. For example, children born to young
mothers have a higher risk of gastroschisis (Nichols 1997), and
Hispanics have a higher risk of spina bifida (Lary 1996).
Attachment C contains a checklist that may
be useful when evaluating epidemiology studies.
Cohort studies enroll a group of pregnant
women before pregnancy outcome is known and collect information
periodically throughout pregnancy on personal demographics, a
variety of exposures, including drugs, and potential confounders.
Their offspring are examined at birth and followed for a set
amount of time. An example is the U.S. Collaborative Perinatal
Project (CPP) that enrolled about 52,000 pregnant women between
1959 and 1965, collected detailed information on their
pregnancies, and followed the children until age seven (Heinonen
1977). Another pregnancy cohort study, The National Children’s
Study, currently under development by NIH,
plans to study 100,000 children by enrolling pregnant women and
following their offspring through 21 years of age. The study will
periodically query the pregnant women and then the children about
certain exposures, including therapeutic drug use.
The strength of the cohort design is the
prospective, systematic collection of data, including exposures,
confounders, and outcome information. If the population is large,
it allows the study of multiple exposures and multiple outcomes.
However, one major weakness of these studies is that generally
small numbers of specific birth defects will be seen even in a
large study population. This, coupled with the small number of
women exposed to specific drugs within the cohort, makes the
detection of even a substantial drug-induced increase in the rate
of any individual defect very difficult if not impossible.
Pregnancy exposure registries, a type of
cohort study, prospectively enroll pregnant women exposed to one
or more specific drugs of interest (unexposed pregnant women are
sometimes included as well) and evaluate the associated pregnancy
outcomes. Structured interviews or questionnaires that gather
data on drug exposures and other confounders are administered
periodically through pregnancy and often up until the infant is 1
year old. Some registries also include an evaluation of all live
born infants by a dysmorphologist (Chambers 2001). Adverse
pregnancy outcome rates in the exposed cohort are compared to
rates in a non-exposed group drawn either from the study itself or
from population data.
This design is the most efficient way to
collect information on exposures with newly marketed drugs and
potentially allows for evaluation of a range of adverse outcomes
including patterns or a spectrum of malformations and functional
deficits. However, this type of study is likely to undercount
spontaneous abortions that occur because a pregnancy registry
would never be able to detect drug-induced fetal losses that occur
before pregnancy is known.
The length of time an infant is monitored and
the source of information about the infant can influence the
number of defects detected. One study reported that registries
that limited infant data collection to information from the
maternal health care provider on the infant’s status at birth were
less likely to ascertain either multiple defects per case or
internal and serious defects, particularly genitourinary defects (Honein
1999).
The choice of an appropriate comparison group
is a challenging aspect of pregnancy exposure registries.
Comparison to the general population background rate of birth
defects, although useful as a first screen, does not take into
account the influence of relevant maternal attributes that may be
related to the occurrence of birth defects, such as disease state,
age, weight, use of alcohol or tobacco, or socioeconomic status.
The ideal comparison group would be provided through concurrent
enrollment of a group of pregnant women similar in all regards
(including the disease leading to drug exposure) except for the
specific drug exposure, but this is very difficult to implement.
Registries are often limited by self-referral
bias (where women who enroll in the registry may be more or less
likely to have malformed infants). Losses to follow-up can also
limit the interpretability of registry data. Losses may be
related to whether the infant is normal or not, particularly if
the mother is not the primary provider of information to the
study.
Pregnancy exposure registries tend to be too
small or limited to resolve concerns about a drug increasing the
risk of specific birth defects; however, they can potentially
detect teratogens that, like thalidomide or isotretinoin, are so
powerful that they produce defects in a relatively high proportion
of exposed pregnancies. Thus, a cohort of only a few dozen or 100
women exposed to such a drug would be sufficiently large to
identify major teratogens. This ability is demonstrated with
isotretinoin where 36 women with first trimester exposures were
identified prospectively and followed through their pregnancies.
Of the 28 live-born infants, five (18 percent) were malformed (Lammer
1985). Furthermore, because pregnancy registries may have the
capacity to conduct specific examinations of infants born to
exposed and unexposed mothers, including up until the time the
child is 1 year old, they can identify outcomes other than major
structural malformations, such as a developmental delay.
Postmarketing pregnancy exposure registries
are being increasingly used proactively to monitor for major fetal
effects. Sponsors may develop pregnancy exposure registries,
either on their own initiative or when requested by the FDA as a
postmarketing commitment. In 2002, the Agency published industry
guidance on establishing pregnancy exposure registries to
encourage the a priori development of epidemiologically
sound, written, study protocols.
The Pharmacist’s Guide to Pregnancy Registry Studies
provides a basic checklist for evaluating pregnancy exposure
registries (Weiss 1999). A list of current pregnancy exposure
registries enrolling women is available at http://www.fda.gov/womens/registries/default.htm
Birth defect registries such as the Centers
for Disease Control and Prevention’s (CDC’s) Metropolitan Atlanta
Congenital Defects Program (Edmonds 1981) and the International
Clearinghouse for Birth Defect Monitoring Systems (International
Centre for Birth Defects 2000) monitor temporal and geographic
frequencies of birth defects. The concept of these
registries is that the introduction of a new major teratogen would
lead to an unusual frequency or clustering of particular defects.
Although no drug teratogen has ever been detected using a birth
defect registry (Khoury 1987), the registries have been used to
identify cases for use in case control studies (Robert 1982) and
to provide population-based birth defect rates for use as a
comparator in pregnancy exposure registries (Honein 1999).
Case control studies enroll infants with
specific birth defects and collect data on gestational exposures,
including drugs. The frequency of drug exposure in the cases is
compared with the frequency of exposure to the same drug in a
group of controls without the birth defects of interest.
Information on drug exposure is usually obtained retrospectively
by interviews, questionnaires, or review of medical records. Case
control studies can be conducted on an ad hoc basis or as part of
an ongoing case control surveillance study such as the Slone
Epidemiology Center’s Birth Defects Study (Mitchell 1981) or the
CDC’s National Birth Defects Prevention Study (Yoon 2001).
Although pregnancy exposure registries are
limited to screening for major teratogens on the level of
thalidomide or isotretinoin, case control studies have the
statistical power to identify teratogens with more modest risks on
the level of valproic acid. The main strength of case control
studies is their ability to evaluate the risk of rare events, and
in the setting of birth defects, this strength means that such
studies are highly efficient in identifying the risk of specific
birth defects.
Recall bias is always of concern with case
control studies. There are limitations to the specificity with
which mothers can recall their drug exposures during pregnancy,
particularly if a drug is used only occasionally for an indication
that may not be easily recalled (e.g., analgesic for a headache).
A mother of an infant born with a major birth defect may be more
likely to carefully recall all gestational events and exposures
than the mother of a normal infant (Werler 1989), and this
phenomenon, though poorly documented, must be taken into account
in the design and analysis of case control studies. One approach
that can minimize the risk of recall bias is the use of infants
with a wide range of other defects, as controls may help correct
for this bias (Lieff 1999, Mitchell 2000). Another approach is
the use of medical or pharmacy records to confirm drug exposures.
This would at least confirm that a drug was prescribed or a
prescription filled; whether the drug was actually ingested would
still be unknown.
FDA staff have access to several external
resources that can assist in assessing reproductive toxicities
from drug exposures. The online Micromedex Integrated Index,
which can be accessed via the FDA Medical Libraries’ WebLEARN
intranet page, contains the REPRORISK system. This system
contains electronic versions of four comprehensive, periodically
updated, teratogen information databases, which are scientifically
reviewed resources that critically evaluate the literature
regarding human and animal pregnancy drug exposures. The four
databases are:
·
REPROTEXT Reproductive Hazard Reference
·
REPROTOX (www.reprotox.org)
·
Shephard’s Catalog of Teratogenic Agents (Shephard
2001)
·
TERIS Teratogen Information System
(Friedman 2000)
Other reference texts
to consult include:
·
Chemically Induced Birth Defects (Schardein 2000)
·
Drugs in Pregnancy and Lactation. A Reference Guide
to Fetal and Neonatal Risk (Briggs 1998)
·
The Women, Their Offspring, and the Malformations (Heinonen
1977)
Within the FDA, it is important for clinical
reviewers to consult each other as well as pharmtox reviewers,
drug safety evaluators, epidemiologists, and statisticians. In
particular, the FDA’s Pregnancy Labeling Team (PLT) is available
as a consultative resource. The PLT ensures that the FDA
maintains access to experts in teratology, birth defects
epidemiology, or obstetric clinical pharmacology who are approved
Special Government Employees (SGEs) and available for consultation
by request.
No set formula exists that can prove that an
association between a gestational drug exposure and adverse
pregnancy outcome is, in fact, a cause-effect relationship. There
are no known medications for which it can be said that all exposed
pregnancies would be adversely affected and only a few medications
for which it is known that a large proportion of pregnancies would
be affected. If a relationship between medication use and adverse
outcome exists, it is more typical for the relationship to
represent a relatively small increase over the background risk.
Therefore, it is probably not useful to approach the review of
data with the question: Is this medication teratogenic? What is
useful is to consider the following:
·
Does there appear to be an increased risk in exposed
infants compared to the background rate seen in unexposed
pregnancies?
·
If so, what is the apparent likelihood of increased
risk of adverse outcome associated with the medication?
Evidence from all sources, including human
data from case reports, epidemiology studies, and animal data,
should be considered collectively to determine the strength of the
relationship. To test the possibility that an association is
causal, there are six commonly used assessments that may be
helpful to apply to any accumulated data. These criteria for
evaluating the causal nature of an association were introduced by
Sir Austin Bradford Hill (Hill 1965) and subsequently modified for
use in teratology as summarized by Scialli (Scialli 1992).
·
Strength of the Association — What is the
statistical likelihood that the association did not occur by
chance alone? Is the same level of association seen in several
studies?
·
Consistency of the Association — Is the same
association seen in several reports or studies? In different
populations?
·
Specificity of the Association — How often
does the drug exposure occur without causing the effect, and how
often does the effect occur separately from drug exposure?
·
Appropriate Timing — Does the association
make chronological sense? Was the drug taken at the critical time
in development to affect the target organ?
·
Dose-Response Relationship — Does the
likelihood and magnitude of response increase with dose of the
drug? Although a dose-response relationship is not often seen in
human reports or studies because the same dose or a narrow range
of doses is typically used, in animal studies the production of
toxicity is expected to be dose dependent.
·
Biological Plausibility — Does the
association make biological sense? Does the drug cross the
placenta? Assessment of biologic plausibility requires
consideration of the dose of a potentially toxic agent, its
pharmacology, maternal and fetal metabolism, mechanism and targets
of toxicity, variability of response, and windows of likely
effect. For example, a product that is known to alter cardiac
tissue development, but not known to affect vasculature, skeletal
muscle, or bone development, is unlikely to have been responsible
for limb reduction defects in the case of a mother exposed only in
the third trimester. The type of defect seen and the timing of
exposure make this implausible.
As part of the Periodic Safety Update Report
(PSUR) sponsors are asked to specifically report on “positive or
negative experiences during pregnancy or lactation,” evaluate new
human data as they become available, in the context of what is
already known about the reproductive effects of the drug, and, if
clinically relevant, communicate conclusions regarding risk or
lack of risk associated with gestational exposure in the product
labeling.
The lack of human data must also be noted in the labeling (21 CFR
201.57(f)(6)(i)(b) and (c)).
If there is an increased risk associated
with the use of the drug during pregnancy, the labeling should
describe, to the extent possible, the specific abnormality, the
incidence, seriousness, reversibility, and correctability of the
abnormality and the effect of dose, duration of exposure, or
gestational timing of exposure on the likelihood of risk.
The labeling must also include a
description of all adequate and well-controlled studies that have
failed to demonstrate a risk from gestational exposure to the drug
(§ 201.57(f)(6)(i)(a) and (b)). Whenever possible,
for all critically assessed, valid studies, the labeling should
include confidence limits and power calculations to establish the
statistical power of the study to identify or rule out a specified
level of risk. The labeling should include and be routinely
updated with data from ongoing studies, such as pregnancy exposure
registries.
The labeling generally should not include
isolated case reports unless there has been a conscious,
scientific judgment made by the sponsor and FDA reviewer that the
quality of the reports and other factors (e.g., consistency with
animal findings; information on dose, duration, and timing of
gestational exposure; or biologic plausibility) support inclusion.
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NOTE: If important data are missing from the
case report, the initial reporter should be contacted.