Background: Major congenital malformations (MCMs) are a significant cause of infant morbidity and mortality
and constitute an important societal and economic burden.
Methods: We conducted a literature review to synthesize current evidence on MCMs. Specific objectives were to: 1)
summarize internationally reported prevalence of MCMs based on registries and surveillance systems; 2) describe the
epidemiology of different MCM types including critical periods and causative factors; 3) to identify the role played by
principal known teratogens on the increase in the risk of MCMs; and 4) determine challenges associated with the
epidemiologic assessment of potential risk factors for MCMs as well as potential preventive measures.
Results: It is estimated that 7.9 million infants worldwide are born every year with a MCM, yet there is considerable
variation in reported rates across countries. This may be attributable to varying definitions arising from heterogeneity
among different classes with respect to critical periods for embryogenesis and organogenesis. There is also substantial
etiologic heterogeneity among MCMs classes that potentially contribute to challenges in epidemiologic studies.
Modifiable factors such as pharmacologic exposures have received considerable attention and a number of drugs have
been shown to be teratogenic including folic acid antagonists, angiotensin converting enzyme inhibitors, antidepressants,
anticonvulsants, coumarin derivatives and retinoids including isotretinoin.
Conclusion: The majority of MCMs are due to unexplained causes. Other contributing factors include genetics,
environmental factors, multifactorial inheritance, maternal-related conditions, and maternal drug or chemical exposure.
However, there remains a need to better understand the epidemiology of MCMs when studying drug effect during