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

Pregestational diabetes mellitus or gestational diabetes mellitus ^[2][3]

Diabetic embryopathy

• Onset: first trimester
• Pathophysiology: hyperglycemia → inhibition of myoinositol uptake → abnormalities in the arachidonic acid-prostaglandin pathway → birth defects and spontaneous abortion
• Effects
  • Congenital heart disease: transposition of the great vessels, ventricular septal defect, truncus arteriosus, tricuspid atresia, patent ductus arteriosus, dextrocardia
  • Neural tube defects
  • Caudal regression syndrome
    • Definition: rare structural anomaly of the caudal region
    • Clinical features
      • Mild to severe motor function impairment, paralysis; , and/or bladder incontinence
      • Anorectal malformations and sacral agenesis (aplasia or hypoplasia of the sacrum and/or lumbosacral spine)
      • Lower limb or foot deformities are common.
    • Prognosis: severe disease in the neonatal period that often results in infant death secondary to cardiac and renal complications
  • Duodenal atresia
  • Small left colon syndrome: self-limiting inability to pass meconium
  • Vertebral anomalies
  • Cleft palate
  • Flexion contracture of the limbs
  • Renal agenesis

Diabetic fetopathy

• Onset: second and third trimester
• Pathophysiology: chronic fetal hyperglycemia → fetal hyperinsulinemia, islet cell hyperplasia, ↑ insulin-like growth factor, and ↑ growth hormones → ↑ metabolic effects and oxygen demand → fetal hypoxemia
• Effects
  • Macrosomia: birth weight > 90^thpercentile or > 4000–4500 g/8 lb 13 oz–9 lb 15 oz (due to stimulated growth and adipogenesis) → increased risk of birth injuries (e.g., shoulder dystocia)
  • Polycythemia (associated with an increased risk of hyperviscosity syndrome and hyperbilirubinemia)
  • Neonatal hypoglycemia
  • Electrolyte imbalances (hypocalcemia, hypomagnesemia)
  • Respiratory distress (due to insufficient production of pulmonary surfactant)
  • Hypertrophic cardiomyopathy (polycythemia → redistribution of iron → iron deficiency in cardiac tissue and hypoxemia → impaired cardiac remodeling)
  • Polyhydramnios (fetal hyperglycemia → fetal polyuria)

Graves disease ^[4]

• Neonatal thyrotoxicosis (see “Neonatal hyperthyroidism”)
• Microcephaly
• Frontal bossing and triangular facies
• Craniosynostosis
• Developmental and behavioral problems

Hypothyroidism ^[5]

• Leads to congenital hypothyroidism with a possible congenital iodine deficiency syndrome (secondary to iodine deficiency)

Maternal obesity ^[6]

• Neural tube defects
• Cleft lip and cleft palate
• Congenital heart disease
• Limb reduction abnormalities

Phenylketonuria ^[7][8]

• IUGR
• Microcephaly
• Intellectual disability
• Congenital heart disease

Alcohol: fetal alcohol syndrome (embryo-fetal alcohol syndrome) ^[9]

• Epidemiology
  • Most common cause of teratogenic damage in children (0.2–1.5 per 1,000 live births) ^[10]
  • Most common preventable cause of intellectual disability in the US
• Pathophysiology: failed neuronal and glial cell migration
• Clinical findings
  • Dysmorphic features ^[11]
    • 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)
    • Renal anomalies (aplastic/dysplastic kidneys) leading to hypertension
    • Prenatal or postnatal growth retardation → short stature
    • 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 ; ^[12]
      • Typically occurring during the 3^rd–4^th week of pregnancy ^[13]
      • Potential genetic causes include
        • Mutations in SHH gene coding for sonic hedgehog protein
        • Trisomy 13
      • Associated clinical features
        • Craniofacial abnormalities (cyclopia and/or cleft lip/palate)
        • Endocrine disorders related to pituitary dysfunction (e.g., diabetes insipidus)
        • Seizures and epilepsy
  • 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

Cigarette smoking during pregnancy ^[14][15]

• Pathophysiology
  • 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 and 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

Opioids

• Fetal dysgenesis
• Placental abruption
• Respiratory depression
• Neonatal abstinence syndrome

Cocaine ^[16]

• Causes vasoconstriction in the placental vessels
• Intrauterine growth retardation and low birth weight
• Increased risk of preterm labor and placental abruption

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

Diethylstilbestrol ^[17]

• 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 ^[18]

• 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: e.g., radiation exposure from x-ray, CT, and/or nuclear medicine imaging ^[19]
• Pathophysiology: chromosomal damage or cell death
• Effects
  • Microcephaly
  • Intellectual disability
  • Growth restriction
  • Malignancy

Lead ^[20]

• Etiology: maternal lead poisoning (blood Pb ≥ 50 μg/dL)
• Effects
  • Spontaneous abortion
  • Stillbirth
  • Hemangiomas, lymphangiomas, hydroceles, skin tags, undescended testes
  • VACTERL ^[21]

Mercury ^[22]

• 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