Teratogenesis

Teratogenesis plays an important role in neonatology and is a common cause 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 3^rd–8^th 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.

• 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

• The physical effects of teratogens are widely varied (see individual conditions for specific manifestations).
  • VACTERL association ^[1]
    • Vertebral, anal, cardiac, tracheoesophageal fistula, renal, and limb abnormalities
    • Due to a defect during the development of embryonic mesoderm
  • Limb deformities
    • Syndactyly: fusion of two or more fingers or toes (most common congenital malformation of the limbs)
    • Polymelia/polydactyly: supernumerary limbs, fingers, or toes
    • Oligodactyly, adactyly: absence of one or more of the fingers or toes
    • Ectromelia: collective term for hypoplasia and/or aplasia of one or more long bones, resulting in limb deformity
    • Peromelia/perodactyly: amputation-like stump of a limb, finger, or toe

Diabetes mellitus (pregestational diabetes mellitus or gestational diabetes mellitus) ^[2]

• Diabetic embryopathy
• Diabetic fetopathy
• For more information, see “Fetal and neonatal complications of diabetes mellitus in pregnancy” in "Diabetes mellitus in pregnancy."

Obesity ^[3]

• Preterm birth
• Stillbirth
• Neural tube defects
• Congenital heart disease
• Cleft lip, cleft palate
• Limb reduction abnormalities
• Macrosomia

Graves disease ^[4]

• Neonatal hyperthyroidism
• Preterm birth
• Stillbirth
• Intrauterine growth restriction
• Low birth weight
• Developmental and behavioral problems

Hypothyroidism

• Congenital hypothyroidism
• Congenital iodine deficiency syndrome

Phenylketonuria (maternal PKU) ^[5][6]

• Phenylalanine embryopathy
  • Definition: the developmental malformations in a newborn resulting from PKU during pregnancy
  • Clinical findings
    • Intrauterine growth restriction
    • Microcephaly
    • Congenital heart disease
    • Intellectual disability
    • Developmental problems

For information on screening and management of substance use during pregnancy, see “Prenatal psychosocial screening.”

Alcohol: fetal alcohol syndrome (embryo-fetal alcohol syndrome) ^[7]

Epidemiology

• Most common cause of teratogenic damage in children (0.2–1.5 per 1,000 live births) ^[8]
• Most common preventable cause of intellectual disability in the US

Mechanism of teratogenesis

• Failed neuronal and glial cell migration

Clinical findings

• Dysmorphic features ; ^[9]
  • Thin upper lip
  • Smooth hypoplastic philtrum
  • Down-slanting, short palpebral fissures
  • Hypertelorism
  • Microcephaly
  • Epicanthal folds
  • Receding chin
• Features of specific systemic defects
  • Heart defects (mainly ventricular septal defect)
  • Heart-lung fistulas
  • Skeletal anomalies (limb dislocations, joint contractures, pectus excavatum/pectus carinatum)
  • Holoprosencephaly: a developmental field defect in which the forebrain fails to divide into two hemispheres, resulting in fusion of ventricles (leading to the formation of monoventricle) and other bilateral cerebral structures, e.g., basal ganglia ; ^[10]
    • Most commonly occurs during the 3^rd–4^th week of pregnancy ^[11]
    • Potential genetic causes include:
      • Mutations in SHH gene coding for sonic hedgehog protein
      • Trisomy 13
    • Associated clinical features
      • Craniofacial abnormalities (cyclopia, cleft lip/palate, hypotelorism, and/or proboscis)
      • Endocrine disorders related to pituitary dysfunction (e.g., diabetes insipidus)
      • Seizures and epilepsy
  • Renal anomalies (aplastic/dysplastic kidneys) leading to hypertension
  • Prenatal or postnatal growth retardation → short stature
• Other
  • Hyperactivity
  • Intellectual disability (e.g., impaired language development, learning disabilities, memory deficits), and subsequent problems in social interactions and school performance
• Differential diagnoses
  • Down syndrome
  • Fragile-X syndrome
  • Williams syndrome

Risk of tobacco product use during pregnancy ^[12][13]

• Mechanism of teratogenesis
  • Nicotine: ↑ catecholamine release → vasoconstriction of uteroplacental blood vessels → compromised blood flow and oxygen delivery to the fetus
  • Carbon monoxide: ↑ COHb causes tissue hypoxia
• Effects
  • Intrauterine growth restriction
  • Low birth weight
  • Increased risk of preterm labor and miscarriage (e.g., due to placental abnormalities such as placental abruption)
  • Attention deficit hyperactivity disorder (ADHD) and conduct disorder
  • Sudden infant death syndrome (SIDS)
  • Cleft lip and palate
• See “Tobacco product use in pregnancy and postpartum” for information on screening and management.

Opioids

• Mechanism of teratogenesis ^[14]
  • Not entirely understood.
  • Altered levels of neurotransmitters (norepinephrine, dopamine, and serotonin) are believed to play a role.
• Effects
  • Respiratory depression
  • Neonatal abstinence syndrome
  • Intrauterine growth restriction
  • Low birth weight
  • Fetal dysgenesis
  • Placental abruption

Cocaine ^[15]

• Mechanism of teratogenesis: cocaine → vasoconstriction of the uteroplacental placental vessels→ compromised blood flow and oxygen delivery to the fetus
• Effects
  • Intrauterine growth retardation
  • Low birth weight
  • Preterm labor
  • Placental abruption

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

Diethylstilbestrol ^[16]

• Previous use: a synthetic estrogen that is primarily used to prevent miscarriages in expectant mothers
• Effects
  • Vaginal clear cell adenocarcinoma
  • Congenital anomalies of the Müllerian duct

Thalidomide ^[17]

• Previous use: a sedative that is used to treat nausea or vomiting in pregnant women (now administered in limited indications, e.g., multiple myeloma)
• Effects: thalidomide embryopathy
  • Symmetrical amelia (complete absence of limbs)
  • Micromelia (“flipper limbs”)
  • Anotia (absence of the external ear)
  • Phocomelia: a teratogenic limb defect that is characterized by the absence of the proximal portion of a limb (hand or foot are directly attached to the shoulder or hip)

ThaLIMBdomide causes LIMB defects.

Radiation exposure during pregnancy

• Etiology: radiation exposure from x-ray, CT, and/or nuclear medicine imaging ^[18]
• Pathophysiology: chromosomal damage or cell death
• Effects
  • Microcephaly
  • Intellectual disability
  • Intrauterine growth restriction
  • Malignancy

Lead ^[19]

• Etiology: maternal lead poisoning (blood Pb ≥ 50 μg/dL)
• Effects
  • Spontaneous abortion
  • Stillbirth
  • Hemangiomas, lymphangiomas, hydroceles, skin tags, undescended testes
  • VACTERL ^[20]

Mercury ^[21]

• Etiology: methylmercury (can be found in contaminated seafood, esp. tilefish, swordfish, shark, and king mackerel)
• Effects
  • Cerebellar atrophy
  • Atrophy of the visual brain cortex
  • Polyneuritis