Diseases of the Infancy

• Congenital Anomalies


  Anatomic defects that are present at birth, but some may not become clinically apparent until years later (e.g. Cardiac and Renal defects)
• Congenital


  Born with, but does not imply or exclude a genetic basis
• Morphogenesis


  Can be impaired by different errors
• Types of Congenital Anomalies

  • Malformations
  • Disruptions
  • Deformations
  • Sequence
• Malformations


  Primary errors of morphogenesis, in which there is an intrinsically abnormal developmental process
• Disruptions


  Result from secondary destruction of an organ or body region that was previously normal in development
• Deformations


  Represent an extrinsic disturbance of development, due to localized or generalized compression of the growing fetus by abnormal biomechanical forces
• Sequence


  A cascade of anomalies triggered by one initiating aberration
• Malformation Syndrome


  A constellation of congenital anomalies which is believed to be pathologically related, caused by a single etiologic agent
• Congenital Anomaly Types


  • Agenesis
  • Aplasia
  • Atresia
  • Hypoplasia
  • Hyperplasia
  • Dysplasia
• Causes of Congenital Anomalies

  • Genetic
  • Environmental
  • Multifactorial
• Genetic Causes


  Chromosomal syndromes, single gene mutations
• Environmental Influences


  Viral infections, drugs, irradiation during pregnancy
• Environmental Causes


  • Rubella
  • Thalidomide
  • Alcohol
  • Diabetes mellitus
• Multifactorial Inheritance


  Interaction of environmental influences with two or more genes of small effect
• Multifactorial Malformations


  • Cleft lip and palate
  • Neural Tube Defects
• Pathogenesis of Congenital Anomalies

  • Timing of prenatal teratogenic insult
  • Interplay between environmental teratogens and intrinsic genetic defects
• Embryonic Period


  First 9 weeks of pregnancy, high susceptibility to teratogens
• Fetal Period


  9 weeks to birth, reduced susceptibility to teratogens but susceptible to growth retardation or injury to already formed organs
• Environmental Teratogens and Genetic Defects

  • Cyclopamine (inhibits Hedgehog signaling)
  • Valproic Acid (disrupts HOX proteins)
  • Retinoic Acid (deregulates TGFβ signaling)
• Major Risk Factors for Prematurity

  • Preterm premature rupture of membrane (PPROM)
  • Intrauterine Infection
  • Structural Abnormalities
  • Multiple Gestations
• PPROM


  Spontaneous rupture of membranes before 37 weeks of gestation
• PROM


  Spontaneous rupture of membranes after 37 weeks of gestation
• Intrauterine Infection


  • Major cause of preterm labor, involves inflammation of placental membranes and umbilical cord
  • Common microorganisms include Mycoplasma, Ureaplasma, Gardnerella, Trichomonas, Gonorrhea, Chlamydia, Malaria, HIV
  • Deregulates prostaglandin expression, inducing uterine contractions
• Structural Abnormalities


  • Uterine distortion, compromised cervical support, placental issues
• Hazards of prematurity include Neonatal Respiratory Distress Syndrome, Necrotizing Enterocolitis, Sepsis, Intraventricular and Germinal Matrix Hemorrhage
• Intrauterine infection


  Inflammation of the placental membranes (chorioamnionitis) and inflammation of the umbilical cord (funisitis)
• Most common microorganisms leading to preterm labor

  • Mycoplasma hominis
  • Ureaplasma urealyticum
  • Gardnerella vaginalis
  • Trichomonas
  • Gonorrhea
  • Chlamydia
  • Malaria
  • HIV
• Endogenous TLRs


  Key players in the process of preterm labor
• Signals produced by TLR engagement

  1. Deregulate prostaglandin expression

  2. Induce uterine smooth muscle contractions
• Structural Abnormalities


  • Uterine distortion (Uterine fibrinoids)
  • Compromised structural support of the cervix (Cervical incompetence)
  • Placenta previa
  • Abruption placentae
• Multiple Gestations can lead to preterm labor
• Hazards of prematurity


  • Neonatal Respiratory Distress Syndrome (Hyaline Membrane Disease)
  • Necrotizing Enterocolitis
  • Sepsis
  • Intraventricular and germinal matrix hemorrhage
• Fetal Growth Restriction (FGR)


  Small-for-gestational-age (SGA) infants (<2500g at term) suffer from FGR which may result from fetal, maternal, or placental abnormalities, although in many cases the specific cause is unknown
• Fetal Abnormalities that can cause FGR

  • Chromosomal disorders
  • Congenital anomalies
  • Congenital infections
• TORCH group of infections


  • Toxoplasmosis
  • Rubella
  • Cytomegalovirus
  • Herpesvirus
• Symmetric growth restriction (Proportionate FGR)


  All organ systems are similarly affected
• Placental Abnormalities that can cause FGR

  • Umbilical-Placental Vascular anomalies (e.g. Single umbilical artery, abnormal cord insertion, placental hemangioma)
  • Placental Abruption
  • Placenta Previa
  • Placental Thrombosis and Infarction
  • Placental Infection
  • Multiple Gestations
• Asymmetrical or disproportionate growth retardation

  Placental causes of FGR tend to result in this, with relative sparing of the brain
• Physiologically, this general type of FGR

  Is viewed as a down-regulation of growth in the latter half of gestation because of limited availability of O2 or nutrition