Studies of Drug Induced Birth Defects

Dr. Arvind Nag. K

Major birth defects life threatening, require major surgery, or present a significant disability, affect approximately 24% of liveborn infants. Minor Malformations are of lesser clinical importance, and vary considerably in their definition, detection, and prevalence. Teratogenesis is a unique adverse drug effect, affecting an organism (the fetus) other than the one for whom the drug was intended (the mother). Whatever benefit/risk accrues to the mother, only the fetus is at risk for birth defects.

 drugs teratogenic potential when it is first marketed is unknown development of predictive in vitro tests in limited by the ignorance of embryonic mechanisms testing in animals is only rarely predictive Premarketing clinical studies do not provide this information either Women of child bearing age!

Drugs known to be teratogenic

high risk teratogens Drugs producing major defects in a high proportion (roughly, 25%) of exposed pregnancies (e.g., thalidomide and isotretinoin). moderate risk teratogens (More common) increase the rate of specific birth defects by 5 20-fold (e.g., carbamazepine and neural tube defects).

 Such drugs may be prohibited or removed from the general market may be restricted to prescription by selected physicians education of physicians and patients combined, in some cases, with restricted access to the drug Most known teratogens, such as phenytoin and valproic acid, pose moderate risks balanced by clinical benefits. Physicians are expected to discuss the benefits and risks with their patients.

Unknown teratogens
Labels may offer a general warning against use in pregnancy, but these hardly contribute to rational drug therapy: Where the true teratogenic risk is nil, these warnings deny potentially useful therapy where the true risk is elevated, the nonspecific warnings offer little practical discouragement to use in pregnancy.

Alleged Teratogens
Bendectin (Dicyclomine Hydrochloride) overwhelming guilt among women who give birth to a malformed child and anxiety among currently-pregnant women consultations with physicians, to diagnostic procedures (e.g., amniocentesis), to elective termination of the pregnancy

The Fallacy of Class Action Teratogenesis

The Class effect may not be applicable to all teratogens

 malformations produced by a drug may vary according to the timing of exposure, the sensitivity of the end organ (i.e., embryologic tissue), and the teratogenic mechanism The need to focus on specific birth defects dramatically affects sample size requirements a cohort study of a few hundred exposed pregnancies to identify a doubling of the overall rate of birth defects For ruling out a doubling larger numbers

 to detect a doubling of risk for a relatively common specific birth defect 20 000 exposed pregnancies To rule out a doubling of risk for the same defect far larger sample size

 prescription drugs generally become OTC based on a history of wide use and safety This history rarely includes systematic information on potential human teratogenicity. These exposures should be a focus of pharmacoepidemiologic research

Recall Bias
the difference in recall accuracy could lead to false positive associations. However, the simple possibility of recall bias does not invalidate interview-based studies, and there are various approaches to minimizing this problem

Recall Bias
Restricting analysis to mothers of malformed infants (False + ve) including a wide range of malformations among controls (False ve) focused questions Complete info. Questions about use according to various indications and about drugs by specific names Increase recall

Outcome
Birth defects often classified by organ system (e.g., musculoskeletal) Whenever possible, on the basis of the embryologic origin for a given defect. For e.g., neural crest cells form various structures of Face/ears Heart & neural tube

The retinoid isotretinoin interferes with neural crest cell migration/development produces malformations of the Ear Heart & Neural tube

Confounding
Potential Confounders: maternal age race geography & socioeconomic status