Reviewer Guidance
 
Evaluating the Risks of Drug 
Exposure in Human 
Pregnancies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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) 
 
April 2005 
Clinical/Medical 
J:\!GUIDANC\6777fnlcln7.doc 
4/14/2005   
Reviewer Guidance 
Evaluating the Risks of Drug 
Exposure in Human 
Pregnancies 
 
 
Additional copies are available from: 
 
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Division of Drug Information, HFD-240 
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Food and Drug Administration 
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http://www.fda.gov/cder/guidance/index.htm 
 
or 
 
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1401 Rockville Pike, Rockville, MD  20852-1448 
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http://www.fda.gov/cber/guidelines.htm 
 
 
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) 
 
April 2005 
Clinical/Medical 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION.............................................................................................................1 
II.  BACKGROUND...............................................................................................................2 
III.  CRITICAL FACTORS IN EVALUATING THE EFFECTS OF DRUG 
EXPOSURE IN HUMAN PREGNANCIES...................................................................4 
A.  Background Prevalence of Adverse Pregnancy Outcomes........................................................4 
B.  Combined vs. Individual Rates of Birth Defects.........................................................................6 
C.  Major vs. Minor Birth Defects......................................................................................................7 
D.  Timing of Exposure........................................................................................................................8 
E.  Intensity of Exposure...................................................................................................................10 
F.  Variability of Response................................................................................................................11 
G.  Class Effects..................................................................................................................................12 
IV.  SOURCES OF HUMAN DATA ON GESTATIONAL DRUG EXPOSURES.........12 
A.  Case Reports.................................................................................................................................13 
B.  Epidemiology Studies...................................................................................................................13 
1. Prospective Studies........................................................................................................................14 
a.  Cohort studies.........................................................................................................................14 
b.  Pregnancy exposure registries................................................................................................15 
2. Retrospective Studies.....................................................................................................................16 
a.  Birth defect registries..............................................................................................................16 
b.  Case control studies................................................................................................................16 
V.  RESOURCES FOR MORE INFORMATION............................................................17 
VI.  OVERALL ASSESSMENT OF POSTMARKETING HUMAN DATA...................18 
VII.  LABELING.....................................................................................................................19 
REFERENCES............................................................................................................................20 
ATTACHMENTS 
A.  Critical Periods in Human Development...................................................................................24 
B.  Considerations when Evaluating Case Reports of the Effects of Drug Exposure During 
Pregnancy.....................................................................................................................................26 
C.  Considerations when Evaluating Epidemiology Studies on the Effects of Drug Exposure 
During Pregnancy........................................................................................................................27 
 
  Contains Nonbinding Recommendations 
 
1
Reviewer Guidance  
Evaluating the Risks of Drug Exposure  
in Human Pregnancies 
 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) 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.   
 
 
 
 
I.  INTRODUCTION 
 
This guidance is intended to help FDA staff evaluate human fetal outcome data generated after 
medical product exposures during pregnancy.2  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.3 
 
                                                 
1 This guidance has been prepared by the Pregnancy Outcomes Working Group of the FDA Pregnancy Labeling 
Taskforce in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and 
Research (CBER) at the Food and Drug Administration.   
 
2 Throughout this document, the terms medical product and drug include drug and biological products including 
vaccines.   
 
3 In November 2001, the FDA issued a draft reviewer guidance on Integration of Study Results to Assess Concerns 
about Human Reproductive and Developmental Toxicities.  When finalized, it will represent the Agencys thinking 
on this issue.  (http://www.fda.gov/cder/guidance/index.htm) 
  1 Contains Nonbinding Recommendations 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys 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. 
 
 
II.  BACKGROUND  
 
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 drugs 
teratogenic potential is important because drug-induced adverse fetal effects are potentially 
preventable. 
 
  2 Contains Nonbinding Recommendations 
 
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 drugs 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 drugs 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.   
 
 
  3 Contains Nonbinding Recommendations 
 
III.  CRITICAL FACTORS IN EVALUATING THE EFFECTS OF DRUG 
EXPOSURE IN HUMAN PREGNANCIES 
 
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 
 
A.  Background Prevalence of Adverse Pregnancy Outcomes  
 
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 
  4 Contains Nonbinding Recommendations 
 
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). 
 
  5 Contains Nonbinding Recommendations 
 
B.  Combined vs. Individual Rates of Birth Defects 
 
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  1 in 115 births 
Muscles and skeleton  1 in 130 births 
Genital and urinary tract  1 in 135 births 
Nervous system and eye  1 in 235 births 
Respiratory tract  1 in 900 births 
Metabolic disorders  1 in 3,500 births 
 
Source:  March of Dimes, National Perinatal Statistics 
(http://www.modimes.com) 
  6 Contains Nonbinding Recommendations 
 
Table 2.  Birth Defect Surveillance Data from Selected States* 
Birth Defect  Range in Rates per 
10,000 Live Births 
Anencephalus  0.00  4.92 
Anophthalmia/microphthalmia   0.39  3.73 
Anotia/microtia  0.19  6.43 
Atrial septal defect  10.51  70.29 
Cleft lip with and without cleft palate  4.48  22.98 
Cleft palate without cleft lip  3.52  9.35 
Endocardial cushion defect  1.11  6.84 
Esophageal ataresia/tracheosophageal fistula  0.83  5.20 
Gastroschisis  0.90  6.59 
Hydrocephalus without spina bifida  0.59  19.34 
Hypoplastic left heart syndrome  0.51  3.94 
Hypospadias and epispadias  1.59  46.61 
Microcephalus  0.51  15.65 
Obstructive genitourinary defect  3.43  35.26 
Omphalocele  0.45  3.48 
Pulmonary valve atresia/stenosis  1.17  20.71 
Pyloric stenosis   0.18  30.70 
Rectal and large intestinal atresia/senosis  1.02  9.02 
Reduction deformity:  lower limbs  0.74  5.35 
Reduction deformity:  upper limbs  0.75  5.02 
Spina bifida without anencephalus  1.36  8.08 
Tetralogy of Fallot    1.49  8.08 
Transposition of great vessels  1.02  6.68 
Ventricular septal defect      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. 
 
C.  Major vs. Minor Birth Defects 
 
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 
  7 Contains Nonbinding Recommendations 
 
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).   
 
D.  Timing of Exposure 
 
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).   
 
  8 Contains Nonbinding Recommendations 
 
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 
  9 Contains Nonbinding Recommendations 
 
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). 
 
E.  Intensity of Exposure  
 
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.   
 
  10 Contains Nonbinding Recommendations 
 
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). 
 
F.  Variability of Response 
 
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 drugs 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 drugs metabolites reach fetal tissue and thereby lead to 
variable rates and types of toxicity manifested. 
 
  11 Contains Nonbinding Recommendations 
 
G.  Class Effects 
 
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. 
 
 
IV.  SOURCES OF HUMAN DATA ON GESTATIONAL DRUG EXPOSURES 
 
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.4  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. 
 
                                                 
4 21 CFR 310.305, 314.80, 314.98, 600.80, and 600.81 require sponsors to report adverse drug experiences from all 
sources (e.g., spontaneous reports, literature, studies).  All congenital anomalies are considered serious ( 314.80(a) 
and  600.80(a)) and must be reported to the Agency within 15 days if unexpected ( 314.80(c)(1)(i) and  
 600.80(c)(1)(i)). 
 
The ICH guidance for industry E2C Clinical Safety Data Management:  Periodic Safety Update Reports for 
Marketed Drugs provides recommendations on what to include in a periodic report.  It specifically lists positive or 
negative experiences during pregnancy or lactation as one safety issue to be explicitly addressed in the Overall 
Safety Evaluation section of the Periodic Safety Update Report (PSUR).  On March 14, 2003, the FDA published a 
proposed rule that would incorporate these requirements into the FDAs postmarketing safety reporting regulations 
(68 FR 12406). 
 
21 CFR 314.81(b)(2)(vii), 314.98(c), and 601.70 require a sponsor to submit in an annual report the status of certain 
types of postmarketing studies, including clinical safety studies, whether the FDA required the study or the applicant 
committed to it in writing.  This requirement would include any epidemiologic study directed to the safety of drug 
use during pregnancy (e.g., pregnancy exposure registries) to which the applicant committed in writing.   
  12 Contains Nonbinding Recommendations 
 
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).   
 
A.  Case Reports 
 
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.   
 
B.  Epidemiology Studies 
 
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 
  13 Contains Nonbinding Recommendations 
 
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 studys 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.   
 
1.  Prospective Studies  
 
a.  Cohort 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 Childrens Study, currently under development 
by NIH,5 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 
                                                 
5 http://nationalchildrensstudy.gov. 
  14 Contains Nonbinding Recommendations 
 
cohort, makes the detection of even a substantial drug-induced increase in the rate of any 
individual defect very difficult if not impossible. 
 
b.  Pregnancy exposure registries 
 
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 infants 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 
  15 Contains Nonbinding Recommendations 
 
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.6  The Pharmacists 
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. 
 
2.  Retrospective Studies 
 
a.  Birth defect registries 
 
Birth defect registries such as the Centers for Disease Control and Preventions (CDCs) 
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).   
 
b.  Case control studies 
 
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 
                                                 
6 See guidance for industry Establishing Pregnancy Exposure Registries.  
(http://www.fda.gov/cder/guidance/index.htm) 
  16 Contains Nonbinding Recommendations 
 
Epidemiology Centers Birth Defects Study (Mitchell 1981) or the CDCs 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. 
 
 
V.  RESOURCES FOR MORE INFORMATION 
 
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)  
  Shephards 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) 
 
  17 Contains Nonbinding Recommendations 
 
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 FDAs 
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.   
 
 
VI.  OVERALL ASSESSMENT OF POSTMARKETING HUMAN DATA 
 
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 
  18 Contains Nonbinding Recommendations 
 
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.   
 
 
VII.  LABELING 
 
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.7  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. 
 
                                                 
7 See ICH guidance for industry E2C Clinical Safety Data Management:  Periodic Safety Update Reports for 
Marketed Drugs.  (http://www.fda.gov/cder/guidance/index.htm) 
  19 Contains Nonbinding Recommendations 
 
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Werler, MM, BR Pober, K Nelson, et al., 1989, Reporting Accuracy among Mothers of 
Malformed and Nonmalformed Infants, Am J Epidemiol, 129:415-21.   
 
Yoon, PW, SA Rasmussen, MC Lynberg, et al., 2001, The National Birth Defects Prevention 
Study, Public Health Reports, 116 (Supp. 1):32-40.
  23 Contains Nonbinding Recommendations 
 
ATTACHMENT A 
 
Critical Periods in Human Development 
 
Attachment A, which appears on the following page, was taken from The Developing Human:  
Clinically Oriented Embryology (Moore, KL and TVN Persaud, 1998, sixth edition, 
Philadelphia:  W.B. Saunders Company, p. 548) and reproduced with permission.  For an 
accurate interpretation of the diagram, it should be printed in color. 
  24 Contains Nonbinding Recommendations 
 
 
  25 Contains Nonbinding Recommendations 
 
ATTACHMENT B 
 
Considerations when Evaluating Case Reports of the Effects of Drug Exposure 
During Pregnancy 
 
  Is there information on drug dose? 
  Is there information on dates of drug therapy? 
  Is the date of conception or the LMP given? 
  Does the drug cross the placenta? 
  Was the drug given at the appropriate time during gestation to cause the reported fetal 
effect or problem? 
  Were any other medications given to the mother?  If so, are they associated with any birth 
defects? 
  What maternal attributes are included (e.g., age, race, other)?  Could they be associated 
with the reported fetal effect? 
  What is known about the mothers medical history? 
  What is known about maternal and paternal family histories of birth defects? 
  If the drug was given for treatment of a maternal disease, what is known about fetal 
effects associated with that maternal disease? 
  Does the reported fetal effect have any familial or genetic associations? 
  Did a physician evaluate and confirm the infants condition?  What is the level of 
expertise of the person who made the diagnosis? 
  What types of developmental problems were seen in the animal studies?  Is the reported 
human effect similar in presentation or mechanistically? 
  Are there any other similar human reports in AERS or in the literature? 
  What do the REPRORISK system and other reference texts say about the drug? 
  Are similar fetal effects seen with pharmacologically similar drugs? 
 
NOTE:  If important data are missing from the case report, the initial reporter should be 
contacted. 
 
 
  26 Contains Nonbinding Recommendations 
 
ATTACHMENT C 
 
Considerations when Evaluating Epidemiology Studies on the Effects of Drug 
Exposure During Pregnancy 
 
Exposure information 
  Are dose, duration, and timing of exposure included? 
  How are exposures reported and/or confirmed (e.g., patient report, health care 
professional report, medical/pharmacy records)? 
  With case control studies, what is the length of time between birth and obtaining 
information on exposures during pregnancy?  
 
Loss to follow-up 
  What is the proportion lost to follow-up? 
 
Outcome ascertainment 
  What outcomes were evaluated (e.g., spontaneous abortion, still birth, congenital 
anomalies, neurodevelopmental toxicities)? 
  When is outcome ascertained? 
  Who is the source of outcome information (e.g., mother, maternal health care provider, 
infant health care provider)? 
  Are reported adverse outcomes confirmed with medical records? 
  Are normal live births confirmed with medical records? 
  What is the length of follow-up on the infant (e.g., only at birth, up to 1 year of age)? 
 
Additional factors and influences on pregnancy outcome (potential confounders) 
  What additional information is collected (e.g., indication, concomitant medications, 
medical and family history, previous pregnancies and outcomes, socio-demographics, 
smoking, alcohol consumption)? 
 
Comparison group 
  What type of comparison group was used? 
  Did the study have an internal comparison group? 
  With case control studies, what is the impact of the comparison group on recall bias? 
 
Representativeness 
  How representative of the U.S. general population is the population covered by the 
study? 
 
Analysis and Interpretation 
  How was the risk of each outcome calculated?  Were all exposures in the denominator 
eligible to be in the numerator? 
  27 Contains Nonbinding Recommendations 
 
  How does the loss to follow-up influence the study results? 
  How are the data grouped for analysis based on timing of exposure (e.g., by trimester, by 
weeks of gestation)? 
  How does the study address concerns raised by animal studies?  Are there other relevant 
outcomes that the study was not able to address? 
 
Power 
  What level of risk is the study powered to evaluate? 
  Are confidence intervals provided? 
  28