The cause of birth defects is known in less than a quarter of cases

Etiology and clinical presentation of birth defects: population based study

Understanding the etiology of birth defects should be both a public health and research priority. Our findings underscore the large gaps in current knowledge of the causes of birth defects. These gaps in turn represent opportunities for both basic and translational researchers. Such research can be particularly powerful and efficient if done in collaboration with population based birth defect surveillance programs enhanced with clinical expertise and meaningful case classification. Advances in the knowledge of the causal pathway leading to birth defects can be the basis for better primary prevention interventions, resulting in longer and better lives. For clinicians and parents, it is important to understand what can be done today to prevent birth defects, in particular the role of preconception care focusing on optimal women’s health (including screening/treating chronic illnesses, attaining folic acid sufficiency, etc). In addition, investigation of potential causes of a birth defect at the time of diagnosis (such as whether a genetic condition is present) can help to better plan management and appropriately counsel families, including the relief of anxiety related to unfounded information and guilt.

Approximately 3-10% have been attributed to exogenous and environmental agents. Those environmental agents known to cause birth defects include lead; polychlorinated biphenyls; ethanol; organic mercury; and drugs such as thalidomide, diethylstilbestrol, valproic acid, and 13-cis-retinoic acid.

What is already known on this topic

  • Birth defects are common, costly, and critical
  • Two hospital based studies have tried to directly assess the proportion of birth defects with or without a known etiology

What this May 2017 study adds

  • In this population based birth defect case cohort, the cause was established in only one in every five infants
  • The inability to understand etiology in four of five cases highlights the urgent need for better basic and translational research as a basis for primary prevention and care
  • In addition, many birth defects are associated with fetal loss: estimates of the global burden of birth defects that consider only liveborn infants with isolated conditions will underestimate this burden by at least 25%, and even more for selected conditions


Etiology and clinical presentation of birth defects: population based study, BMJ 2017;357:j2249, 30 May 2017.

To assess causation and clinical presentation of major birth defects.

Population based case cohort.

Cases of birth defects in children born 2005-09 to resident women, ascertained through Utah’s population based surveillance system. All records underwent clinical re-review.

5504 cases among 270 878 births (prevalence 2.03%), excluding mild isolated conditions (such as muscular ventricular septal defects, distal hypospadias).

Main outcome measures
The primary outcomes were the proportion of birth defects with a known etiology (chromosomal, genetic, human teratogen, twinning) or unknown etiology, by morphology (isolated, multiple, minors only), and by pathogenesis (sequence, developmental field defect, or known pattern of birth defects).


Known and unknown etiology of birth defects – image credit BMJ Fig 1.

Definite cause was assigned in 20.2% (n=1114) of cases: chromosomal or genetic conditions accounted for 94.4% (n=1052), teratogens for 4.1% (n=46, mostly poorly controlled pregestational diabetes), and twinning for 1.4% (n=16, conjoined or acardiac). The 79.8% (n=4390) remaining were classified as unknown etiology; of these 88.2% (n=3874) were isolated birth defects. Family history (similarly affected first degree relative) was documented in 4.8% (n=266). In this cohort, 92.1% (5067/5504) were live born infants (isolated and non-isolated birth defects): 75.3% (4147/5504) were classified as having an isolated birth defect (unknown or known etiology).


Cause could not be identified in almost 80% of children with major birth defects.
Shouldn’t we be doing better?

These findings underscore the gaps in our knowledge regarding the causes of birth defects. For the causes that are known, such as smoking or diabetes, assigning causation in individual cases remains challenging. Nevertheless, the ongoing impact of these exposures on fetal development highlights the urgency and benefits of population based preventive interventions. For the causes that are still unknown, better strategies are needed. These can include greater integration of the key elements of etiology, morphology, and pathogenesis into epidemiologic studies; greater collaboration between researchers (such as developmental biologists), clinicians (such as medical geneticists), and epidemiologists; and better ways to objectively measure fetal exposures (beyond maternal self reports) and closer (prenatally) to the critical period of organogenesis.

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