DRUG INDUCED BIRTH DEFECTS

THE NATURE OF BIRTH DEFECTS AND THEIR RELATION TO DRUG :

Major birth defects , typically defined as those that are life threatening, require major
surgery ,or present a significant disability, affect approx.3-4% of live born infants.
Major malformations are of lesser clinical importance, and estimates of their prevalence vary
considerably.
Teratogenesis is unique kind of adverse drug effect , since it affects an organism other than
the one for whom the drug was intended
whatever caution physician might exercise in their prescribing of drugs to pregnant women ,
they have little control over what consumers purchase over the counter or obtain from their
friends , relatives and neighbors.

CLINICAL PROBLEMS TO BE ADDRESSED BY EPIDEMIOLOGY RESEARCH

Like other adverse effects Teratogenesis is a critical aspect of a drugs benefit/risk profile, and
such information obviously should be available to prescribers and consumers
Teratogenesis raises as a uniquely important clinical issue.
fetus is the innocent bystander with respect to its mother therapy.
Second ,Teratogenesis is not a concern limited to women who are pregnant when drug
treatment is initiated ; it must also be a concern among women who might become pregnant
after a drug is prescribed .

DRUGS KNOWN TO BE TERATOGENIC

There are the approaches applied to the drugs known to be teratogenic
In case of thalidomide, the drug was prohibited from the general market
For most known teratogens, such as phenytoin and valproic acid, the absolute risk to the fetus is
modestly elevated and the drug is felt to fill and important clinical need
The third approach involves a formal program of physician and patient education combined, in some
cases with restricted access to the drug
The education component is intended to assure that physicians and patients are informed about drug
teratogenicity and the importance of avoiding the pregnancy
DRUGS FOR WHICH TERATOGENIC RISK IS UNKNOWN :
the vast majority of prescription drugs and virtually all non-prescription drugs fall into this category
Regulatory agencies or manufactures in various countries may offer a general warning against
unnecessary use in pregnancy , but such cautions hardly contribute to rational drug therapy.
DRUGS FOR WHICH TERATOGENESIS IS ALLEGED AND CLINICAL CONSEQUENCES

In one notorious situation, allegations to be teratogenicity resulted in widely used drug being
withdrawn from the market
The anti nausea drug Bendectin used widely to treat nausea and vomiting of pregnancy, was alleged to
cause of variety of birth defects

Despite the evidence however the manufacturer withdrew the drug from the market as a result of
active and potential litigation
Following widely publicized allegations that spray glue adhesives were teratogenic , a US regulatory
agency withdrew the production from the market
METHODOLOGIC PROBLEMS TO ADDRESSED BY EPIDEMIOLOGY RESEARCH
Although serious birth defects occur in approximately , 3-4% of live born infants , we cant consider
birth defects as a single , homogeneous outcome. In fact , physical birth defects include a wide range
of malformations that vary in many ways, including their gestational timing, embryologic tissues of
origin, and mechanism of development
As an illustration of variations in embryologic tissue of origin , some cardiovascular malformations ,
but not others , are derived from the neural crest cells that migrate from the area surrounding the
primitive neural tube
SAMPLE SIZE CONSIDERATIONS
Epidemiology studies must consider rates of specific birth defects has a dramatic effect on sample size
requirements, both for estimating risk and for providing assurances of safety
With respect to risk in a population of women taking a given drug , cohort study with sample size of a
few hundred exposed pregnancies might be sufficient to identify a doubling of 3-4% overall rate of
birth defects
However , each of the specific defects which together for, the overall category of birth defects occur
with far less frequency , ranging from about 1 per 1000 live births for oral cleft to 1 or fewer per
10000 for hemimelia/ phocomelia.
EXPOSURE
There are 2 concerns regarding drug exposure that require special consideration in birth defect studies.
One is importance of non prescribed drugs and other is the issue of recall of drug exposure
1) Non prescribed drugs
Most epidemiology research focuses attention on prescribed drugs, in part because many studies
utilize data sources with inadequate information on non prescribed drugs and in part because of the
view that prescribed drugs pose the greater potential for risk
Although the effects of non prescribed drugs on the fetus are largely unstudied, it is note worthy that
these agents comprise a substantial proportion of drug exposure in pregnancy

It therefore important that research include consideration of non prescribed can include only OTC
drugs, but also prescription drug products that were obtained from friends, neighbors and relatives,
depending on specific drugs
More than 20 % of exposure to prescription drugs can come from such non prescribed sources
2) Recall bias
Because of the sample size demands described above , many researchers have turned to the case
control approach for the study of birth defects .
More than other drug induced adverse Out comes , the birth of malformed child carries an emotional
burden and guilt that many affect recall of exposures in pregnancy.
By definition , recall bias cant exist if reporting of drug exposure is complete among cases and
controls.
The closer one comes to that ideal , the less the likelihood of recall bias .
It thus becomes critical how one elicits exposure information.
Studies that use open ended questions about drug exposure invite differential recall between mothers
of malformed and normal infants.
Recall bias is also substantially increased when women are ashamed about use according to various
indications and it is further increased when drugs are asked by specific names.
In short , by improving ascertainment of drug exposure among birth case and controls , a carefully
designs questionnaire can substantially reduce the opportunity for recall bias.
OUTCOME
Given the etiologic heterogeneity of malformations, some have attempted to classify birth defects
according to specific categories.
Classified defects by organ system , such as musculoskeletal or cardiovascular
However , classification in this way has little embryologic or teratologic basis , and a more
appropriate approach is to create categories that reflects the embryologic tissue of origin.
Although our ignorance about the origins of most birth defects may limit our ability to create
categories which share a common etiology
It is preferable, whenever possible , to classify birth defects according to an understanding of their
embryologic origins
CONFOUNDING:
Among those variables that require routine considerations are maternal age , race , geography , and
socioeconomic status
An understanding of epidemiology of given defect or exposure often identifies other variables that
may act as confounders in specific analysis

For eg, ethnic background is strongly related to the risk of neural tube effects, maternal age is strong
risk factor for gastroschisis, and alcohol consumption has been associated with defects from neural
crest
Since medication use may be associated with various other health behaviors , one may need to
consider health behaviors , and even nutrition , in studies of certain exposures and outcomes.
BIOLOGIC PLAUSIBILITY
Our ignorance about the biologic mechanisms by which most human birth defects occur complicates
our ability to determine when a finding may be biologically plausible
There are few associations for which in vitro and animal experiments support their biologic
plausibility.
These include the increased risk of defects derived from neural crest cells among infants exposed to
retinoid , the decreased risk of neural tube defects among infants exposed to folic acids
And the increased risk of defects resulting from vascular disruption among infants exposed to cocaine.
However , biologic mechanisms remain unknown for most well accepted drug effect associations
CURRENTLY AVAILABLE SOLUTIONS
Cohort and casecontrol designs are the favored approaches used to generate and test hypotheses
regarding drugs and birth defects.
Cohorts
Three types of cohorts relevant to the pharmacoepidemiologic study of birth defects include studies
designed to follow large populations exposed to various agents, use of data sets created for other
purposes, and follow-up studies of selected exposures.
This approach involves following a population of pregnant women with collection of data on
exposures, outcomes and co-varieties.
CaseControl Studies
The rarity of birth defects overall, and particularly specific defects, argues for the use of the case
control design when exposure prevalence is sufficiently high.
Such studies may be conducted on an ad hoc basis or within the context of casecontrol surveillance
Case Reports
Review of well-documented case reports can provide useful insight into the spectrum, severity, and
natural history of an adverse drug effect, as well as its reversibility, predictability, and preventability.
Understanding these factors should be a critical component of any decision to design or implement
programs like Phase IV and ad hoc Postmarketing Epidemiologic Studies
Pharmacoepidemiologic studies are sometimes relied upon to characterize further the nature and
magnitude of safety signals arising during pre-approval clinical trials or from postmarketing
spontaneous case reports.

A comprehensive understanding of factors contributing to drug safety risk

High quality case reports may suggest junctures along the causal path where intervention might be
useful and effective.
Careful review of drug usage data may also contribute by documenting patterns of use that are
intrinsically unsafe or that are off-label.