Diseases of I n f a n c y & C h i l d h o o d

1. Diseases of Infancy & Childhood

2. Diseases of Infancyand Childhood • Congenital Anomalies • Birth Weight and Gestational Age • Birth Injuries • Perinatal Infections • Respiratory Distress Syndrome (RDS) • Necrotizing Enterocolitis • Intraventricular Hemorrhage • Hydrops • Inborn Metabolic/Genetic Errors • Sudden Infant Death Syndrome (SIDS) • Tumors

3. INFANT MORTALITY • USA 1970: 20 • USA 2000: 7 • USA WHITE: X • USA BLACK: 2X • SWEDEN 3 • INDIA 82

4. Major Time Spans • Neonatal period • first four weeks of life • Infancy • the first year of life • Age 1 – 4 years (preschool) • Age 5 – 14 years (school age)

5. MORTALITY by TIME SPAN • NEONATE (0-4 WEEKS): CONGENITAL, PREMATURITY • UNDER ONE YEAR: CONGENITAL, PREMATURITY/WEIGHT, SIDS • 1-4 YEARS: ACCIDENTS, CONGENITAL, TUMORS • 5-14 YEARS: ACCIDENTS, TUMORS, HOMICIDES • 15-24 YEARS: ACCIDENTS, HOMICIDE, SUICIDE (NONE ARE “NATURAL” CAUSES)

6. 1Rates are expressed per 100,000 population 2Excludes congenital heart disease

7. Congenital Anomalies • Definitions • Causes • Pathogenesis

8. Malformations primary errors of morphogenesis, usually multifactorial e.g. congenital heart defect Disruptions secondary disruptions of previously normal organ or body region e.g. amniotic bands Deformations extrinsic disturbance of development by biomechanical forces e.g. uterine constraint Sequence a pattern of cascade anomalies explained by a single localized initiating event with secondary defects in other organs e.g. Oligohydramnios (Or Potter) Sequence Syndrome a constellation of developmental abnormalities believed to be pathologically related e.g Turner syndrome

9. Malformations Polydactyly & syndactyly Cleft Lip Severe Lethal Malformation

10. Disruption by an amniotic band

11. Oligohydramnios (Or Potter) Sequence Oligohydramnios (decreased amniotic fluid) Renal agenesis Amniotic leak Fetal Compression flattened facies club foot (talipes equinovarus) Pulmonary hypoplasia fetal respiratory motions important for lung development Breech Presentation

12. The Oligohydramnios “Sequence”

13. Infant with oligohydramnios sequence

14. Organ Specific Anomalies Agenesis: complete absence of an organ Atresia: absence of an opening Hypoplasia: incomplete development or under- development of an organ with decreased numbers of cells Hyperplasia: overdevelopment of an organ associated with increased numbers of cells Hypertrophy: increase in size with no change in number of cells Dysplasia: in the context of malformations (versus neoplasia) describes an abnormal organization of cells

15. Implantation and the Survival of Early Pregnancy • Only 50-60% of all conceptions advance beyond 20 weeks • Implantation occurs at day 6-7 • 75% of loses are implantation failures and are not recognized • Pregnancy loss after implantation is 25-40% NEJM 2001; 345:1400-1408

17. #1 #2 #3

18. CAUSES OF ANOMALIES Genetic karyotypic aberrations single gene mutations Environmental infection maternal disease drugs and chemicals irradiation Multifactorial Unknown

20. Embryonic Development • Embryonic period • weeks 1- 8 of pregnancy • organogenesis occurs in this period • Fetal period • weeks 9 to 38 • marked by further growth and maturation

21. Critical Periods Of Development

22. Genetic Causes • Karyotypic abnormalities • 80-90% of fetuses with aneuploidy die in utero • trisomy 21 (Down syndrome) most common karyotypic abnormality (21,18,13) • sex chromosome abnormalities next most common (Turner and Klinefelter) • autosomal chromosomal deletion usually lethal • karyotyping frequently done with aborted fetuses with repeated abortions • Single gene mutations • covered in separate chapters

23. Maternal Viral Infection Rubella (German measles) at risk period first 16 weeks gestation defects in lens (cataracts), heart, and CNS (deafness and mental retardation) rubella immune status important part of prenatal workup Cytomegalovirus most common fetal infection highest at risk period is second trimester central nervous system infection predominates

24. Drugs and Chemicals • Drugs • 13 cis-retinoic acid (acne agent) • warfarin • angiotensin converting enzyme inhibitors (ACEI) • anticonvulsants • oral diabetic agents • thalidomide • Alcohol • Tobacco

25. Teratogen Actions • • Proper cell migration to predetermined locations that influence the development of other structures • • Cell proliferation, which determines the size and form of embryonic organs • • Cellular interactions among tissues derived from different structures (e.g., ectoderm, mesoderm), which affect the differentiation of one or both of these tissues • • Cell-matrix associations, which affect growth and differentiation • • Programmed cell death (apoptosis), which, as we have seen, allows orderly organization of tissues and organs during embryogenesis • • Hormonal influences and mechanical forces, which affect morphogenesis at many levels

26. Diabetes Mellitus • Fetal Macrosomy (>10 pounds) • maternal hyperglycemia increases insulin secretion by fetal pancreas, insulin acts with growth hormone effects • Diabetic Embryopathy • most crucial period is immediately post fertilization • malformations increased 4-10 fold with uncontrolled diabetes, involving heart and CNS • Oral agents not approved in pregnancy • Diabetics attempting to conceive should be placed on insulin

27. Birth Weight and Gestational Age • Appropriate for gestational age (AGA) • between 10 and 90th percentile for gestational age • Small for gestational age (SGA) , <10% • Large for gestational age (LGA) , >90% • Preterm • born before 37 weeks (<2500 grams) • Post-Term • delivered after 42 weeks

28. Prematurity • Defined as gestational age < 37 weeks • Second most common cause of neonatal mortality (after congenital anomalies) • Risk factors for prematurity • Preterm Premature Rupture Of fetal Membranes (PROM) • Intrauterine infection • Uterine, cervical, and placental abnormalities • Multiple gestation

29. Fetal Growth Restriction • At least 1/3 of infants born at term are < 2.5kg • Undergrown rather than immature • Commonly underlies SGA (small for gestational age) • Prenatal diagnosis: ultrasound measurements • Classification • Fetal • Placental • Maternal

30. Fetal FGR • Chromosomal abnormalities • 17% of FGR overall • up to 66% of fetuses with ultrasound malformations • Fetal Infection • Infection: TORCH (Toxoplasmosis, Other, Rubella, Cytomegalovirus, Herpes) • Characterized by symmetric growth restriction – head and trunk proportionally involved

31. Placental FGR • Vascular • umbilical cord anomalies (single artery, constrictions, etc) • thrombosis and infarction • multiple gestation • Confined placental mosaicism • mutation in trophoblast • trisomy is common • Placental FGR tends to cause asymmetric growth with relative sparing of the head

32. Maternal FGR • Most common cause of FGR by far • Vascular diseases • preeclampsia (toxemia of pregnancy) • hypertension • Toxins • ethanol • narcotics and cocaine • heavy smoking

33. Organ Immaturity • Lungs • alveoli differentiate in 7th month • surfactant deficiency • Kidneys • glomerular differentiation is incomplete • Brain • impaired homeostasis of temperature • vasomotor control unstable • Liver • inability to conjugate and excrete bilirubin

34. APGAR (Appearance, Pulse, Grimace, Activity, Respiration)

35. Apgar Score and 28 Day Mortality • Score may be evaluated at 1 and 5 minutes • 5 minute scores • 0-1, 50% mortality • 4, 20% mortality • ≥ 7, nearly 0% mortality

36. Perinatal Infection Transcervical (ascending) inhalation of infected amniotic fluid pneumonia, sepsis, meningitis commonly occurs with PROM passage through infected birth canal herpes virus– caesarian section for active herpes Transplacental (hematogenous) mostly viral and parasitic HIV—at delivery with maternal to fetal transfusion TORCH-Toxo, Other, Rubella, Cmv, Herpes parvovirus B19 (Fifth), erythema infectiosum bacterial Listeria monocytogenes

37. Fetal Lung Maturation

38. Neonatal Respiratory Distress Syndrome (RDS) 60,000 cases / year in USA with 5000 deaths Incidence is inversely proportional to gestational age The cause is lung immaturity with decreased alveolar surfactant surfactant decreases surface tension first breath is the hardest since lungs must be expanded without surfactant, lungs collapse with each breath

39. RDS Risk Factors • 1) Prematurity • by far the greatest risk factor • affected infants are nearly always premature • 2) Maternal diabetes mellitus • insulin suppresses surfactant secretion • 3) Cesarean delivery • normal delivery process stimulates surfactant secretion

40. RDS Pathology • Gross • solid and airless (no crepitance) • sink in water • appearance is similar to liver tissue* • Microscopic • atelectasis and dilation of alveoli • hyaline membranes composed of fibrin and cell debris line alveoli (HMD former name) • minimal inflammation

43. V/Q Mismatch

44. RDS Prevention and Treatment • Delay labor until fetal lung is mature • amniotic fluid phospholipid levels are useful in assessing fetal lung maturity • Induce fetal lung maturation with antenatal corticosteriods • Postnatal surfactant replacement therapy with oxygen and ventilator support

45. Treatment Complications • Oxygen toxicity • oxygen derived free radicals damage tissue • Retrolentalfibroplasia • hypoxia causes ↑ Vascular Endothelial Growth Factor (VEGF) and angiogenesis • Oxygen Rx suppresses VEGF and causes endothelial apoptosis • Bronchopulmonary “dysplasia” • oxygen suppresses lung septation at the saccular stage • mechanical ventilation • epithelial hyperplasia, squamousmetaplasia, and peribronchial and interstitial fibrosis were seen with old regimens of ventilator usage and no surfactant use, but are now uncommon • lung septation is still impaired

46. Necrotizing Enterocolitis • Incidence is directly proportional to prematurity, like RDS • approaches 10% with severe prematurity • 2000 cases yearly in USA • Pathogenesis • not fully understood • intestinal ischemia • inflammatory mediators • breakdown of mucosal barrier

47. Necrotizing Enterocolitis

48. Hydrops Fetalis • Chromosomal abnormalities • Turner syndrome with cystic hygromas • other • Cardiovascular with heart failure • anemia with high output failure • immune hemolytic anemia • hereditary hemolytic anemia (α-thalassemia) • parvovirus B19 infection • twin to twin in utero transfusion • congenital heart defects

49. Hydrops Fetalis

50. Immune Hydrops • Fetus inherits red cell antigens from the father that are foreign to the mother • Mother forms IgG antibodies which cross the placenta and destroy fetal RBCs • Fetus develops severe anemia with CHF and compensatory ↑ hematopoiesis (frequently extramedullary) • Most cases involve Rh D antigen • mother is RhNeg and fetus is Rh Pos • ABO and other antigens involved less often