• Clinical science

Teratogenic birth defects

Summary

Teratogenic birth defects play an important role in neonatology and are common causes of intellectual disability. Teratogens are environmental factors that result in permanent structural or functional malformations or death of the embryo or fetus. Many congenital malformations are of unknown origin, but known teratogens include drugs, maternal illnesses and infections, metal toxicity, and physical agents (e.g., radiation). The fetus is most susceptible in the 3rd–8th weeks of pregnancy during organogenesis in the embryonic period; after 8 weeks, growth and function are affected. The earlier the exposure to the teratogenic agent in utero, the more severe the defects are in the embryo/fetus. However, the individual response to teratogens is highly varied and depends on genetic susceptibility and severity of the exposure.

See pharmacotherapy during pregnancy for more information on teratogenic drugs during pregnancy.

See congenital TORCH infections for more information on teratogenic infectious agents.

Overview

  • Definition of a teratogen: an environmental factor that causes a permanent structural or functional abnormality, growth restriction, or death of the embryo or fetus
  • Effects depend on multiple factors:
    • The pharmacological properties, dose, and regimen of drug exposure determine the risk of developing teratogenic birth defects.
    • Stage of pregnancy in which exposure occurs:
Stage in pregnancy Significance
Preimplantation phase
Embryonic phase
  • First trimester
  • Corresponds to the period of organogenesis
  • Most significant period for teratogenic birth defects
Phase of fetal growth and maturation
  • Second and third trimesters
  • Period of fetal growth and maturation
  • Can lead to deficits in organ function, intellect, behavior, or minor structural malformations

References:[1][2][3][4][5]

Maternal illnesses

Pregestational diabetes mellitus or gestational diabetes mellitus

Diabetic embryopathy

Diabetic fetopathy

Graves disease

Hypothyroidism

Obesity

Phenylketonuria

References:[6][7][8][9][10][11][12][13][14][15][16][17]

Substance misuse

Alcohol: Fetal alcohol syndrome (embryo-fetal alcohol syndrome)

  • Epidemiology
    • Most common cause of teratogenic damage in children (1:500–1000)
    • Most common cause of intellectual disability in the US!
  • Pathophysiology: failed cellular migration
  • Clinical findings
    • Dysmorphic features
    • Features of specific systemic defects
    • Hyperactivity, intellectual disability (e.g., learning disabilities, memory and reasoning deficits, and impaired language development) → problems in social interactions and school performance
  • Differential diagnosis: Williams syndrome (or Williams-Beuren syndrome)

Cigarette smoking

Opioids

Cocaine

References:[18][19][20][21][22][23][24][25][26]

Medications

The following drugs are no longer approved for clinical use. See pharmacotherapy during pregnancy for a comprehensive list of teratogenic drugs.

Diethylstilbestrol

Previously used as a synthetic estrogen primarily to prevent miscarriages in expectant mothers

  • Effects
    • Vaginal clear cell adenocarcinoma
    • Congenital müllerian anomalies

Thalidomide

Previously used as a sedative and to treat nausea or vomiting in pregnant women; now administered in limited indications, e.g., multiple myeloma

  • Effects: thalidomide embryopathy
    • Anotia (absence of the external ear)
    • Symmetrical amelia (complete absence of limbs)
    • Phocomelia (attachment of hand or foot to the shoulder or hip due to absence of proximal portion of limb)
    • Micromelia (“flipper limbs”)

References:[27][28][29]

Physical agents

Radiation

  • Etiology: e.g., radiation exposure from x-ray, CT and nuclear medicine imaging
  • Pathophysiology: chromosomal damage or cell death
  • Effects
    • Microcephaly
    • Intellectual disability
    • Growth restriction
    • Malignancy

References:[30][31]

Metal toxicity

Lead

Mercury

  • Etiology: methylmercury (e.g., in contaminated shellfish)
  • Effects

References:[32][33][34][35]