The Newborn 1
Learning Objectives
❏ Calculate an Apgar score
❏ Use knowledge of birth injuries to predict symptomology
❏ Demonstrate understanding of newborn screening, fetal growth/maturity, and neonatal infections
APGAR SCORE
A newborn infant at birth is noted to have acrocyanosis, heart rate 140/min, and grimaces to stimulation. She is active and has a lusty cry. What is her Apgar score?
Table 1-1. Apgar Scoring System
Evaluation
Heart
Respiration None Irregular, shallow, gasps Crying
Color Blue Pale, blue extremities Pink
Tone None Weak, passive Active
Reflex irritability None Facial grimace Active withdrawal
Apgar scores are routinely assessed at 1 and 5 minutes, and every 5 minutes thereafter as long as resuscitation is continuing.
• The 1-minute score gives an idea of what was going on during labor and delivery.
• The 5-minute score gives an idea of response to therapy (resuscitation).
In general, the Apgar score is not predictive of outcome; however, infants with score 0−3 at ≥5 minutes compared to infants with score 7−10 have a worse neurologic outcome.
Newborn Care
• Vitamin K IM
• Prophylactic eye erythromycin
• Umbilical cord care
• Hearing test
• Newborn screening tests
BIRTH INJURIES
On physical exam, a 12-h-old newborn is noted to have nontender swelling of the head that does not cross the suture line. What is the most likely diagnosis?
Injury Specifics
Skull fractures In utero from pressure against bones or forceps; linear: most common
Brachial palsy Erb-Duchenne: C5–C6; cannot abduct shoulder; externally rotate and supinate forearm; Klumpke: C7–C8 ± T1; paralyzed hand ± Horner syndrome
Clavicular fractureEspecially with shoulder dystocia in vertex position and arm extension in breech
Facial nerve palsyEntire side of face with forehead; forceps delivery or in utero pressure over facial nerve
Caput succedaneumDiffuse edematous swelling of soft tissues of scalp; crosses suture lines
Cephalohematoma Subperiosteal hemorrhage: does not cross suture lines
Outcome
• Linear : no symptoms and no treatment needed
• Depressed: elevate to prevent cortical injury
Most with full recovery (months); depends on whether nerve was injured or lacerated; Rx: proper positioning and partial immobilization; massage and range of motion exercises; if no recovery in 3–6 mo, then neuroplasty
Palpable callus within a week; Rx: with immobilization of arm and shoulder
Improvement over weeks (as long as fibers were not torn); need eye care; neuroplasty if no improvement (torn fibers)
Disappears in first few days; may lead to molding for weeks
May have underlying linear fracture; resolve in 2 wk to 3 mo; may calcify; jaundice
Table 1-2. Common Injuries During Deliveries
PHYSICAL EXAMINATION—NORMAL AND ABNORMAL FINDINGS
A newborn infant has a blue-gray pigmented lesion on the sacral area. It is clearly demarcated and does not fade into the surrounding skin. What is the most likely diagnosis?
A newborn has a flat, salmon-colored lesion on the glabella, which becomes darker red when he cries. What is the best course of management?
Table 1-3. Physical Examination—Common Findings (see remaining chapter for other specific findings)
Finding/DiagnosisDescription/Comments
Skin
Cutis marmorataLacy, reticulated vascular pattern over most of body when baby is cooled; improves over first month; abnormal if persists
Salmon patch (nevus simplex) Pale, pink vascular macules; found in nuchal area, glabella, eyelids; usually disappears
Mongolian spotsBlue to slate-gray macules; seen on presacral, back, posterior thighs; > in nonwhite infants; arrested melanocytes; usually fade over first few years; differential: child abuse
Erythema toxicum, neonatorum Firm, yellow-white papules/pustules with erythematous base; peaks on second day of life; contain eosinophils; benign
Hemangioma Superficial: bright red, protuberant, sharply demarcated; most often appear in first 2 months; most on face, scalp, back, anterior chest; rapid expansion, then stationary, then involution (most by 5–9 years of age); deeper: bluish hue, firm, cystic, less likely to regress; Rx: (steroids, pulsed laser) only if large and interfering with function
Head
Preauricular tags/pits Look for hearing loss and genitourinary anomalies.
Coloboma of iris Cleft at “six o’clock” position; most with other eye abnormalities; CHARGE association
Aniridia Hypoplasia of iris; defect may go through to retina; association with Wilms tumor extremitieS
Polydactyly >5 number of fingers or toes. No treatment needed if good blood supply.
USMLE® is
NEWBORN SCREENING
A 1-month-old fair-haired, fair-skinned baby presents with projectile vomiting of 4 days’ duration. Physical exam reveals a baby with eczema and a musty odor. Which screening test would most likely be abnormal?
Every newborn is screened before discharge or day 4 of life. It is more reliable if done after 48 hours of oral feedings (substrates for metabolic diseases).
The total diseases screened are determined by the individual state. Some examples:
• Phenylketonuria
• Tyrosinemia
• 21-hydroxylase deficiency
• Galactosemia
• Hb SS
• Hb C
• Hypothyroidism
• Cystic fibrosis
Table 1-4. Comparison of Two Newborn Screening Diseases*
Phenylketonuria (PKU) Classic Galactosemia
Defect Phenylalanine hydroxylase; accumulation of PHE in body fluids and CNS
Presentation Mental retardation, vomiting, growth retardation, purposeless movements, athetosis, seizures
Associations Fair hair, fair skin, blue eyes, tooth abnormalities, microcephaly
Other comments Normal at birth; gradual MR over first few months
Treatment Low PHE diet for life
Gal-1-P uridylyltransferase deficiency; accumulation of gal-1-P with injury to kidney, liver, and brain
Jaundice (often direct), hepatomegaly, vomiting, hypoglycemia, cataracts, seizures, poor feeding, poor weight gain, mental retardation
Predisposition to E. coli sepsis; developmental delay, speech disorders, learning disabilities
May begin prenatally— transplacental galactose from mother
No lactose—reverses growth failure, kidney and liver abnormalities and cataracts, but not neurodevelopmental problems
Definition of abbreviations: CNS, central nervous system; G-1-P, galactose-1-phosphate; MR, mental retardation; PHE, phenylalanine.
*Items in bold have a greater likelihood of appearing on the exam.
FETAL GROWTH AND MATURITY
Table 1-5. Intrauterine Growth Restriction (IUGR)
Type Reason Main Etiologies
Symmetric Early, in utero insult that affects growth of most organs
Asymmetric (head sparing)
Relatively late onset after fetal organ development; abnormal delivery of nutritional substances and oxygen to the fetus
Genetic syndromes, chromosomal abnormalities, congenital infections, teratogens, toxins
Uteroplacental insufficiency secondary to maternal diseases (malnutrition, cardiac, renal, anemia) and/or placental dysfunction (hypertension, autoimmune disease, abruption)
Gestational Age and Size at Birth
Preterm Large for Gestational Age (LGA)—Fetal Macrosomia
• Premature—liveborn infants delivered prior to 37 weeks as measured from the first day of the last menstrual period
• Low birth weight— birthweight <2,500 grams. This may be due to prematurity, IUGR, or both
• Birth weight >4,500 grams at term
• Predisposing factors: obesity, diabetes
• Higher incidence of birth injuries and congenital anomalies
Complications
Etiology dependent; delivery of oxygen and nutrients to vital organs usually normal
Neurologic (asphyxia) if significant decreased delivery of oxygen to brain
Post-term
• Infants born after 42 weeks’ gestation from last menstrual period
• When delivery is delayed ≥3 weeks past term, significant increase in mortality.
• Characteristics
Increased birth weight
Absence of lanugo Decreased/absent vernix
Desquamating, pale, loose skin
Abundant hair, long nails
If placental insufficiency, may be meconium staining
SPECIFIC DISORDERS
Endocrine Disorders
Infants of diabetic mothers
You are called to see a 9.5-pound newborn infant who is jittery. Physical exam reveals a large plethoric infant who is tremulous. A murmur is heard. Blood sugar is low.
• Maternal hyperglycemia (types I and II DM) → fetal hyperinsulinemia
• Insulin is the major fetal growth hormone → increase in size of all organs except the brain
• Major metabolic effect is at birth with sudden placental separation → hypoglycemia
• Infants may be large for gestational age and plethoric (ruddy).
• Other metabolic findings: hypoglycemia and hypomagnesemia (felt to be a result of delayed action of parathyroid hormone)
• Common findings
– Birth trauma (macrosomia)
– Tachypnea (transient tachypnea, respiratory distress syndrome, cardiac failure, hypoglycemia)
– Cardiomegaly—asymmetric septal hypertrophy (insulin effect, reversible)
– Polycythemia (and hyperviscosity) → hyperbilirubinemia → jaundice
– Renal vein thrombosis (flank mass, hematuria, and thrombocytopenia) from polycythemia
– Increased incidence of congenital anomalies
° Cardiac especially VSD, ASD, transposition
° Small left colon syndrome (transient delay in development of left side of colon; presents with abdominal distention)
° Caudal regression syndrome: spectrum of structural neurologic defects of the caudal region of spinal cord which may result in neurologic impairment (hypo, aplasia of pelvis & LE)
• Prognosis—Infants of diabetic mothers are more predisposed to diabetes and LGA infants are at increased risk of childhood obesity.
• Treatment
– Monitor carefully and advocate good glucose control during pregnancy. Follow glucose carefully in infant after delivery.
– Early, frequent feeds: oral, NG if episodes of hypoglycemia continue
– Intravenous dextrose infusion if above does not result in euglycemia
Respiratory Disorders
Respiratory distress syndrome
Respiratory
Transient tachypnea of the newborn
Pneumonia
Diaphragmatic hernia
Choanal atresia
Respiratory Distress
Meconium aspiration syndrome
Nonrespiratory
Cardiac: cyanotic CHD
Heme: anemia, polycythemia
Other: infectious, metabolic, neurologic
1-1. Respiratory Distress
Respiratory distress syndrome (RDS)
Shortly after birth, a 33-week gestation infant develops tachypnea, nasal flaring, and grunting and requires intubation. Chest radiograph shows a hazy, ground-glass appearance of the lungs.
• Deficiency of mature surfactant (surfactant matures biochemically over gestation; therefore, the incidence of surfactant deficiency diminishes toward term.)
• Inability to maintain alveolar volume at end expiration → decreased FRC (functional residual capacity) and atelectasis
• Primary initial pulmonary hallmark is hypoxemia. Then, hypercarbia and respiratory acidosis ensue.
• Diagnosis
– Best initial diagnostic test—chest radiograph
° Findings: ground-glass appearance, atelectasis, air bronchograms
– Most accurate diagnostic test—L/S ratio (part of complete lung profile; lecithin-tosphingomyelin ratio)
° Done on amniotic fluid prior to birth
• Best initial treatment—oxygen
• Most effective treatment—intubation and exogenous surfactant administration
• Primary prevention
–Avoid prematurity (tocolytics)
– Antenatal betamethasone
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Figure
Transient tachypnea of the newborn (TTN)
• Slow absorption of fetal lung fluid → decreased pulmonary compliance and tidal volume with increased dead space
• Tachypnea after birth
• Generally minimal oxygen requirement
• Common in term infant delivered by Cesarean section or rapid second stage of labor
• Chest x-ray (best test)—air-trapping, fluid in fissures, perihilar streaking
• Rapid improvement generally within hours to a few days
Meconium aspiration
• Meconium passed as a result of hypoxia and fetal distress; may be aspirated in utero or with the first postnatal breath → airway obstruction and pneumonitis → failure and pulmonary hypertension
• Chest x-ray (best test)—patchy infiltrates, increased AP diameter, flattening of diaphragm
• Other complications air leak (pneumothorax, pneumomediastinum)
• Prevention—endotracheal intubation and airway suction of depressed infants with thick meconium
• Treatment—positive pressure ventilation and other complex NICU therapies
Diaphragmatic hernia
• Failure of the diaphragm to close → abdominal contents enter into chest, causing pulmonary hypoplasia.
• Born with respiratory distress and scaphoid abdomen
• Bowel sounds may be heard in chest
• Diagnosis prenatal ultrasound; postnatal x-ray (best test) reveals bowel in chest
• Best initial treatment immediate intubation in delivery room for known or suspected CDH, followed by surgical correction when stable (usually days)
Gastrointestinal and Hepatobiliary Disorders
See also GI chapter on this topic.
Umbilical hernia
• Failure of the umbilical ring closure, weakness of abdominal muscles
• Most are small and resolve in 1-2 years without any treatment
• Surgery if getting larger after 1-2 years, symptoms (strangulation, incarceration), and/or persistent after age 4
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Omphalocele
• Failure of intestines to return to abdominal cavity with gut through umbilicus
• Covered in a sac (protection)
• Associated with other major malformations and possible genetic disorders (trisomy)
• Large defects need a staged reduction (use of a surgical Silo), otherwise respiratory failure and ischemia
Gastroschisis
• Defect in abdominal wall lateral to umbilicus (vascular accident)
• Any part of the GI tract may protrude
• Not covered by a sac
• Major problem with the intestines: atresia, stenosis, ischemia, short gut
• Surgery based on condition of gut; if no ischemia, large lesions need a staged reduction as with omphalocele
Necrotizing enterocolitis (NEC)
• Transmural intestinal necrosis
• Greatest risk factor is prematurity; rare in term infants
• Symptoms usually related to introduction of feeds: bloody stools, apnea, lethargy, and abdominal distention once perforation has occurred
• Pneumatosis intestinalis on plain abdominal film is pathognomonic (air in bowel wall)
• Treatment: cessation of feeds, gut decompression, systemic antibiotics, and supportive care; surgical resection of necrotic bowel may be necessary
Imperforate anus
• Failure to pass stool after birth
• No anal opening visible
• Treatment is surgical correction.
• May be part of VACTERL association.
Jaundice
A 2-day-old infant is noticed to be jaundiced. He is nursing and stooling well. Indirect bilirubin is 11.2 mg/dL; direct is 0.4 mg/dL. Physical exam is unremarkable except for visible jaundice.
• Pathophysiology
– Increased production of bilirubin from breakdown of fetal red blood cells plus immaturity of hepatic conjugation of bilirubin and elimination in first week of life
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Note
Work up for pathologic hyperbilirubinemia when:
• It appears on the first day of life
• Bilirubin rises >5 mg/dL/day
• Bilirubin >13 mg/dL in term infant
• Direct bilirubin >2 mg/dL at any time
– Rapidly increasing unconjugated (indirect reacting) bilirubin can cross the bloodbrain barrier and lead to kernicterus (unconjugated bilirubin in the basal ganglia and brain stem nuclei) Hypotonia, seizures, opisthotonos, delayed motor skills, choreoathetosis, and sensorineural hearing loss are features of kernicterus.
Table 1-6. Physiologic Jaundice Versus Pathologic Jaundice
Physiologic Jaundice
Pathologic Jaundice
Appears on second to third day of life (term)May appear in first 24 hours of life
Disappears by fifth day of life (term)—7th Variable
Peaks at second to third day of life Variable
Peak bilirubin <13 mg/dL (term) Unlimited
Rate of bilirubin rise <5 mg/dL/d
Usually >5 mg/dL/d
The causes of hyperbilirubinemia with respect to bilirubin metabolism are as follows:
• RBC metabolism
–Increased number of RBCs
° Normal newborn (normal Hct 42−65)
i. Physiologic jaundice
° Polycythemia (Hct >65)
i. Increased RBC production: Chronic hypoxia, IUGR, post-mature; IODM, Beckwith-Wiedemann syndrome (insulin effect); maternal Graves’ disease (transplacental antibodies); trisomies (unknown mechanism)
ii. Extra RBCs entering the circulation: delayed cord clamping, twin-twin transfusion
iii. Treatment: partial exchange transfusion with normal saline (dilutional)
–Increased hemolysis
° Immune-mediated (labs: high unconjugated bilirubin, may be anemia, increased reticulocyte count, positive direct Coombs test)
i. Rh negative mother/Rh positive baby: classic hemolytic disease of the newborn (erythroblastosis fetalis)
ii. ABO incompatibility (almost all are type O mother and either type A or B baby): most common reason for hemolysis in the newborn
iii. Minor blood group incompatibility (Kell is very antigenic; Kell negative mother), uncommon
° Non-immune mediated: same as above but Coombs is negative; need to see blood smear
i. Smear shows characteristic-looking RBCs: membrane defect (most are either spherocytosis or elliptocytosis)
ii. Smear shows normal-looking RBCs: enzyme defect (most are G6PD deficiency then pyruvate kinase deficiency)
iii. Extravascular: excessive bruising, cephalohematoma
• Bilirubin is then bound to albumin and carried in the blood; bilirubin may be uncoupled from albumin in the blood stream to yield free bilirubin, e.g. neonatal sepsis, certain drugs (ceftriaxone), hypoxia, acidosis.
• Bilirubin is transported to the hepatocytes: within the hepatocytes is the conversion of unconjugated (laboratory indirect-acting) fat-soluble bilirubin to conjugated (glucuronide) water-soluble bilirubin (laboratory direct-acting) by the action of hepatic glucuronyl transferase (GT).
–Decreased enzymatic activity of GT
° Normal newborn first week of life
° Primary liver disease of systemic disease affecting the liver (sepsis, TORCH, metabolic diseases)
° No GT activity: Crigler-Najjar syndrome (type I)
• Transport through the intrahepatic biliary system to the porta hepatis for excretion into the duodenum; abnormalities of transport and excretion cause a conjugated (direct) hyperbilirubinemia (>2 mg/dL direct-acting bilirubin in the blood in the newborn)
– Biliary atresia (progressive obliterative cholangiopathy): obstruction at birth due to fibrosis and atresia of the extrahepatic ducts (and so no gall bladder); then variable severity and speed of inflammation and fibrosis of the intrahepatic system which ultimately leads to cirrhosis
° Most present in first 2 weeks of life with jaundice (conjugated hyperbilirubinemia), poor feeding, vomiting, lethargy, hepatosplenomegaly, persistent acholic stools and dark urine
° Best initial test: U/S (triangular fibrotic cord at porta hepatis; no evidence of normal ductal anatomy; no gallbladder
° Most accurate test (next step): percutaneous liver biopsy (is pathognomonic for this process)
° Best initial treatment (palliative): hepatic portojejunostomy (Kasai procedure)
° Best long-term management: liver transplant
–Liver disease (primary or secondary to systemic disease): cholestasis (sepsis, perinatal infections, metabolic disease, neonatal hepatitis, severe hypothyroidism and others
• Intestinal transport and excretion: most bilirubin is eliminated in the stool with final products synthesized with help of colonic bacteria; some bilirubin is eliminated in the urine, some is reprocessed in the liver due to enterohepatic circulation (along with bile acids); intestinal beta-glucuronidase hydrolyzes glucuronide-bilirubin bonds to yield some unconjugated bilirubin, which is absorbed into the portal circulation and transported back to the liver to be acted upon by hepatic glucuronyl transferase
– Increased enterohepatic circulation
° Intestinal obstruction
° Decreased colonic bacteria (first week of life, prolonged antibiotics, severe diarrhea)
Breast feeding jaundice vs. breast milk jaundice (see text box)
Physiologic
Indirect
Coombs (+)
• Rh/ABO incompatibility
• Minor blood groups
High Hgb
• Polycythemia
– Twin-twin transfusion
– Maternal-fetal transfusion
– Delayed cord
– I UGR
– Infant of diabetic mother
(−)
Pathologic
Direct
• Sepsis
• TORC H infections
• Hypothyroidism
• Galactosemia
• Cystic fibrosis
• Choledochal cyst
• Biliary atresia
• Dubin-Johnson
• Rotor syndrome
Normal/low Hgb
• Spherocytosis
• Elliptocytosis
• G6PD deficiency
• Pyruvate kinase
• Hemorrhage
• Cephalohematoma bruising
• Bowel obstruction
• Breast feeding
• Crigler-Najjar
• Gilbert syndrome
Breast-Feeding Jaundice versus Breast-Milk Jaundice
Breast-feeding jaundice means a baby is not nursing well and so not getting many calories. This is common in first-time breast-feeding mothers. The infant may become dehydrated; however, it is lack of calories that causes the jaundice. Treatment is to obtain a lactation consultation and rehydrate the baby. The jaundice occurs in the first days of life.
Breast-milk jaundice occurs due to a glucuronidase present in some breast milk. Infants become jaundiced in week 2 of life. Treatment is phototherapy if needed. Although the bilirubin may rise again, it will not rise to the previous level. The baby may then be safely breast fed. The jaundice will be gone by 2–3 months.
• Treatment of hyperbilirubinemia
– Phototherapy
° Complications: loose stools, erythematous macular rash, overheating leading to dehydration, and bronze baby syndrome (occurs with direct hyperbilirubinemia; dark, grayish-brown discoloration of the skin [photo-induced change in porphyrins, which are present in cholestatic jaundice])
– Double volume exchange transfusion—if bilirubin continues to rise despite intensive phototherapy and/or kernicterus is a concern
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Coombs
Figure 1-2. Jaundice Workup
Table 1-7. Hyperbilirubinemia and Jaundice
Reason for
Etiology
Excessive bruising/ cephalohematoma
RBCs → Hgb → Bilirubin Indirect
Immune hemolysis
• Rh
• ABO
• Minor blood groups Anti-Rh, anti-A, anti-B, anti-minor blood group Abs Indirect
Polycythemia High Hct, Hgb → high bilirubin
Non-immune hemolysis Abnormal RBC → splenic removal Indirect
Displacement of bound bilirubin from albumin Free bilirubin in circulation
Familial nonhemolytic hyperbilirubinemia (Crigler-Najjar syndrome) Absence of glucuronyl transferase (type I) vs. small amount of inducible GT (type II)
Extrahepatic obstruction— biliary atresia
Cholestasis (TORCH, sepsis, metabolic, endocrine)
Bowel obstruction
Breast feeding jaundice
cannot leave the biliary system
function → decrease bilirubin excretion
enterohepatic recirculation
enterohepatic recirculation
Breast milk jaundice Increased enterohepatic recirculation
• Normal to slightly low Hgb/Hct
• Normal to slight increase in reticulocytes Phototherapy
• Low Hgb/Hct (anemia)
• Increased reticulocytes
• Rh negative mother and Rh positive baby
• Type O mother and type A or B baby
• Direct Coombs positive
• Decreased RBCs
Phototherapy + possible exchange transfusion
(Hct >65)/ normal Increased RBCsPhototherapy + partial exchange transfusion
(anemia)/ increased
• If no membrane defect →, G6PD, PK activity
• Characteristic RBCs if membrane defect
• Decreased RBCs
Phototherapy + transfusion
Phototherapy + exchange transfusion
liver biopsy Portojejunostomy, then later liver transplant
and P, other select labs suggestive of underlying etiology
obstruction + phototherapy
Phototherapy + hydration + teach breast feeding
Phototherapy + continued breast feeding
Note
Toxoplasmosis
Other (syphilis, varicella, HIV, and parvovirus B19)
Rubella
Cytomegalovirus (CMV)
Herpes
INFECTIONS
Neonatal Sepsis
A 3-week-old infant presents with irritability, poor feeding, temperature of 38.9°C (102°F), and grunting. Physical examination reveals a bulging fontanel, delayed capillary refill, and grunting.
• Signs and symptoms are very nonspecific.
• Risk factors
– Prematurity
– Chorioamnionitis
– Intrapartum fever
– Prolonged rupture of membranes
• Most common organisms: group B Streptococcus, E. coli, and Listeria monocytogenes.
• Diagnosis—sepsis workup: CBC, differential and platelets, blood culture, urine analysis and culture, chest radiograph (Lumbar puncture not routinely performed unless there is a likelihood of meningitis, e.g., irritability, lethargy, hypothermia, etc.)
• Treatment
– If no evidence of meningitis: ampicillin and aminoglycoside until 48–72-hour cultures are negative
– If meningitis or diagnosis is possible: ampicillin and third-generation cephalosporin (not ceftriaxone)
Transplacental Intrauterine Infections (TORCH)
TORCH infections are typically acquired in first or second trimester. Most infants have IUGR.
Toxoplasmosis
Toxoplasmosis is a maternal infection worldwide, due primarily to ingestion of undercooked or raw meat containing tissue cysts. Ingestion of water or food with oocytes that have been excreted by infected cats (fecal contamination) is the most common form of transmission in the United States. Advise pregnant women not to change/clean cat litter while pregnant.
• Findings
– Jaundice, hepatosplenomegaly
– Thrombocytopenia, anemia
– Microcephaly
– Chorioretinitis
– Hydrocephalus
– Intracranial calcifications
– Seizures
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
• Outcomes
– Psychomotor retardation
– Seizure disorder
– Visual impairments
• Treatment—maternal treatment during pregnancy reduces the likelihood of transmission significantly (spiramycin)
– Infants are treated with pyrimethamine, sulfadiazine, and leucovorin.
phil.cdc.gov
Congenital rubella
• Classic findings when maternal infection occurs in first 8 weeks’ gestation.
• Findings
– Blueberry muffin spots (extramedullary hematopoiesis), thrombocytopenia
– Cardiac—PDA, peripheral pulmonary artery stenosis
– Eye—cataracts
– Congenital hearing loss
– Thrombocytopenia
– Hepatosplenomegaly
• Outcomes
– Hearing loss
– Persistent growth retardation
– Microcephaly
– Mental and motor retardation
Cytomegalovirus (CMV)
• Primary infection (higher risk of severe disease) or reactivation of CMV
• Findings
– Hepatosplenomegaly, jaundice
– Periventricular calcifications
– Intrauterine growth retardation
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Figure 1-3. Congenital Cataract Secondary to Maternal Rubella Infection
– Chorioretinitis
– Microcephaly
– Thrombocytopenia, hemolytic anemia
• Outcomes
– Sensorineural hearing loss
– Neuromuscular abnormalities
– Mental retardation
Herpes simplex
• Keratoconjunctivitis, skin (5–14 days), CNS (3–4 weeks), disseminated (5–7 days)
• Best diagnosis: PCR, any body fluid
• Best treatment: IV acyclovir ASAP
• Outcomes
– Microcephaly, spasticity
– Deafness
– Blindness
– Seizure disorder
– Psychomotor retardation
– Death
• Prevention is elective Cesarean section when active disease or visible lesions are identified; however, this is not 100% effective.
• Treatment—acyclovir
Congenital syphilis
• Transplacental transmission usually during second half of gestation
• At-risk infants must undergo serologic testing at the time of delivery.
• Findings
– Early (birth–2 yrs): snuffles, maculopapular rash (including palms of soles, desquamates), jaundice, periostitis, osteochondritis, chorioretinitis, congenital nephrosis
– Late (>2 years of age): Hutchinson teeth, Clutton joints, saber shins, saddle nose, osteochondritis, rhagades (thickening and fissures of corners of mouth)
• Diagnosis—Treponema in scrapings (most accurate test) from any lesion or fluid, serologic tests
– Infant with positive VDRL plus pathognomonic signs; if not, perform serial determinations—increasing titer in infection
– Most helpful specific test is IgM-FTA-ABS (immunoglobin fluorescent treponemal antibody absorption) but it is not always positive immediately.
• Treatment—penicillin
Varicella
• Neonatal
– Seen when delivery occurs <1 week before/after maternal infection
– Treat with VZIG (varicella zoster immune globulin), if mother develops varicella 5 days before to 2 days after delivery.
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
• Congenital
– Associated with limb malformations and deformations, cutaneous scars, microcephaly, chorioretinitis, cataracts, and cortical atrophy
– Associated with infection during 1st or 2nd trimester
Many of the findings of the TORCH infections are very similar, so note the most likely presentations:
• Toxoplasmosis: hydrocephalus with generalized calcifications and chorioretinitis
• Rubella: the classic findings of cataracts, deafness, and heart defects
• CMV: microcephaly with periventricular calcifications; petechiae with thrombocytopenia
• Herpes: skin vesicles, keratoconjunctivitis, acute meningoencephalitis
• Syphilis: osteochondritis and periostitis; skin rash involving palms and soles and is desquamating; snuffles (mucopurulent rhinitis)
SUBSTANCE ABUSE AND NEONATAL WITHDRAWAL
A 2-day-old infant is noticed to have coarse jitters and is very irritable with a highpitched cry. A low-grade fever is reported, as well as diarrhea. Maternal history is positive for heroin use.
Table 1-8. Neonatal Features of Maternal Major Illicit Drug Use
Opiates
High incidence low birth weight, most with intrauterine growth restriction
Increased rate of stillborns
No increase in congenital abnormalities
Early withdrawal symptoms, within 48 hours
Tremors and hyperirritability
Diarrhea, apnea, poor feeding, high-pitched cry, weak suck, weight loss, tachypnea, hyperacusis, seizures, others
Increased risk of sudden infant death syndrome
Cocaine
No classic withdrawal symptoms
Preterm labor, abruption, asphyxia
Intrauterine growth restriction
Impaired auditory processing, developmental delay, learning disabilities
High degree of polysubstance abuse
Central nervous system ischemic and hemorrhagic lesions
Vasoconstriction → other malformations
• Diagnostic tests: a good history and the clinical presentation usually are sufficient to make the diagnosis. Meconium toxicology can detect opioid and cocaine exposure after the first trimester. Urine drug screening provides maternal drug use data for only a few days prior to delivery. Cord blood sample has become the best test for diagnosis.
• Treatment: narcotics, sedatives, and hypnotics, as well as swaddling and reducing noxious stimulation
• Complications: infants of addicted mothers are at higher risk for low birth weight, IUGR, congenital anomalies (alcohol, cocaine), and sudden infant death syndrome, as well as of mother’s complications, such as sexually transmitted diseases, toxemia, breech, abruption, and intraventricular hemorrhage (cocaine).
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Genetics/Dysmorphology
2
Learning Objectives
❏ Demonstrate understanding of chromosome abnormalities
❏ Solve problems concerning early overgrowth with associated defects, defects with facial features as the major defect, osteochondrodysplasias, and disorders of connective tissue
❏ Explain information related to unusual brain and/or neuromuscular findings with associated defects
ABNORMALITIES OF CHROMOSOMES
Trisomy 21 (Down Syndrome)
Down syndrome is the most common pattern of human malformation.
• Genetics
– 94% full trisomy 21(nondisjunction); risk of recurrence 1–2% and then increases with advancing maternal age
– 4–6% with translocation; most are new mutations but must obtain parental karyotypes for possible balanced translocation carrier
• Findings
– Upward slanting palpebral fissures; speckling of iris (Brushfield spots); inner epicanthal folds
– Small stature, mouth open with tongue protrusion; mild microcephaly, short neck, flat occiput, short metacarpals and phalanges; single palmar crease
– Hypotonia
– Hearing loss (sensorineural, conductive, and mixed)
– Primary gonadal deficiency
– Cardiac anomaly—ECD > VSD > PDA, ASD; also MVP
– GI anomalies: duodenal atresia, Hirschsprung
– Atlanto-axial instability
– Hypothyroidism
– Acute lymphocytic leukemia (but acute myeloblastic leukemia if in first 3 years of life)
– Mental retardation, variable
Cardiac Abbreviations
ASD: atrial septal defect
ECD: endocardial cushion defect
MVP: mitral valve prolapse
PDA: patent ductus arteriosus
VSD: ventricular septal defect
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
• Natural history
– Major cause for early mortality is congenital heart disease
– Muscle tone improves with age
– Rate of development slows with age
– Early onset of Alzheimer disease
Trisomy 18 (Edwards Syndrome)
Edwards syndrome is the second most common pattern of human malformation.
• Genetics—older maternal age; nondisjunction
• Findings
– Growth deficiency
– Mental retardation
– Low-set, malformed ears; microcephaly, micrognathia; prominent occiput
– Clenched hand—index over third; fifth over fourth
– Short sternum
– VSD, ASD, PDA, cyanotic lesions,
– Rocker-bottom feet, hammer toe
– Omphalocele
• Natural history
– Many spontaneous abortions
– Feeble from birth
– Most do not survive first year
Trisomy 13 (Patau Syndrome)
Patau syndrome is a defect of midface, eye, and forebrain development → single defect in first 3 weeks’ development of prechordal mesoderm. It involves older maternal age.
• Findings
– Holoprosencephaly and other CNS defects
– Severe mental retardation
– Microcephaly; microphthalmia
– Severe cleft lip, palate, or both
– Scalp defects in parietal-occipital area (cutis aplasia)
– Postaxial polydactyly
– VSD, PDA, ASD, cyanotic lesions
– Single umbilical artery
Aniridia–Wilms Tumor Association (WAGR Syndrome)
• Genetics
– 1/70 w ith aniridia also has Wilms
– WAGR syndrome: deletion of 11p13; Wilms + Aniridia + GU anomalies + MR
– Highest risk of Wilms’ (compared to independent aniridia or GU defect)
USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
Klinefelter Syndrome (XXY)
• Genetics; most common findings manifested at puberty
• Findings
– Decreased IQ (average IQ 85 90)
– Behavioral/psychiatric problems
– Long limbs (decreased upper:lower segment ratio)
– Slim (weight/height ratio low)
– Hypogonadism and hypogenitalism (testosterone replacement at age 11 12 years) = hypergonadotropic hypogonadism (increased FSH and LH, and decreased testosterone)
– Infertility in almost all
– Gynecomastia
Turner Syndrome (XO)
• Genetics
– Generally sporadic; no older maternal age seen
– Paternal chromosome more likely to be missing
– Many mosaic patterns (including Y-chromatin)
• Findings
– Small-stature female
– Absence of one SHOX gene (short stature homeobox; embryonic regulation of skeletal system, especially arms and legs)
– Abnormal GH–IGF receptor axis
– Gonadal dysgenesis–streak ovaries in XO
– Average IQ 90
– Congenital lymphedema, residual puffiness over dorsum of fingers and toes
– Broad chest, wide-spaced nipples
– Low posterior hairline; webbed posterior neck
– Cubitus valgus (elbow) and other joint problems
– Horseshoe kidney and other renal defects
– Cardiac:
° Bicuspid aortic valve (number 1 cardiac anomaly)
° Coarctation
° Aortic stenosis, mitral valve prolapse
° Hypertension common, even without cardiac or renal disease
– Primary hypothyroidism, mostly autoimmune, and other autoimmune diseases (celiac disease)
• Natural history
– Decreased height velocity with delayed bone age
– Estrogen treatment indicated
– May increase height by 3 4 cm with growth hormone (GH)
Note
Gonadal dysgenesis is not evident in childhood, so chromosomes are warranted in any short-stature female whose phenotype is compatible with Turner syndrome.
Also consider in any adolescent with absent breast development by age 13, pubertal arrest, or primary/secondary amenorrhea with increased FSH.
Fragile X Syndrome
• Genetics
– Fragile site on long arm of X in affected males and some carrier females— Molecular diagnosis—variable number of repeat CGG (preferred diagnosis = DNA-based molecular analysis)
– With the genetic mutation, can get trinucleotide expansion during meiosis to a premutation state (50-200 repeat CGG); this is passed on to progeny and may then further expand to the full mutation (>200 CGG)
– X-linked dominant—males (most common cause of inherited mental retardation); due to lyonization (random inactivation of one X), there are generally fewer abnormalities seen in girls but they may present with decreased IQ
• Findings
– Mild to profound mental retardation; learning problems
– Large ears, dysmorphic facial features, large jaw, long face
– Large testes—mostly in puberty (macroorchidism)(fertile)
• Natural history—normal lifespan
EARLY OVERGROWTH WITH ASSOCIATED DEFECTS
Beckwith-Wiedemann Syndrome
• Genetics
– Usually sporadic
– IGF-2 disrupted at 11p15.5 (imprinted segment)
• Findings – Macrosomia
– Macroglossia—may need partial glossectomy
– Pancreatic beta cell hyperplasia—excess islets → hypoglycemia; hypoglycemia may be refractory; glucose control most important initial management
– Umbilical abnormalities, diastasis recti, omphalocele
– Hemihypertrophy → increased risk of abdominal tumors (Wilms)
• Management obtain ultrasounds and serum AFP every 6 months through 6 years of age to look for Wilms tumor and hepatoblastoma
UNUSUAL BRAIN AND/OR NEUROMUSCULAR FINDINGS WITH ASSOCIATED DEFECTS
Prader-Willi Syndrome
• Genetics
– Most with deletion at 15q11-q13–imprinted segment
– Paternal chromosome responsible USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.
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Grant, Alexander, 298
Graves, Admiral, 107, 127, 200, 273.
Greek Colonies, 42-3, 45 n., 205.
Green Bay, Fort, 17, 25.
Green Mountain Boys, 101, 191
Greene, Nathaniel, 128, 198, 199.
Greenville Treaty. See Treaty.
Grenada, 1, 88.
Grenville, George, 53, 54 and n.
Grenville, Lord, 240 n., 246-55, 265, 285
Guildford Court House, 198.
Habeas Corpus, 74, 88 and n., 95, 193, 195, 241, 242-3, 244
Haldimand County, 234.
Haldimand, Sir Frederick, 63, 88 n., 143, 147, 150, 185, 188-95, 189 n., 190 n., 220, 224, 225, 233, 236, 239, 241, 246.
Half Moon, 174.
Halifax, 114, 188, 213, 221.
Hamilton, Alexander, 227, 282, 285
Hamilton, Lieutenant-Governor, 187, 236 n.
Hampshire Grants, 167.
Hastings, Warren, 160.
Havana, 1, 68
Hawke, Admiral, 127.
Herkimer, General Nicholas, 154-7.
Hessians.
See German Regiments.
Hey, Chief Justice, 103 and n., 104, 105 n., 106, 141
Highlanders, 20, 22, 28, 229, 230.
Hillsborough, Lord, 92, 135.
Hobkirk’s Hill, 199.
Hood, Sir Samuel, 127, 200
Hoosick river, 168, 170.
Hope, Colonel, 236 n.
Hope, Mount, 173.
Howe, Admiral, 127, 129, 130, 132, 133, 139, 196
Howe, General, 107, 125, 126, 129 and n., 130-4, 138, 139, 145, 146, 167, 168, 172, 175, 195, 213, 221, 222
Huberton, 164.
Hudson Bay, 257.
Hudson Bay Company’s Territories, 6, 7, 70, 80, 82, 210, 292.
Hudson river, 131, 132, 134, 146, 165-7, 170, 173-83, 196, 200, 203.
Hudson Straits, 3, 80.
Hunter, General, 292, 298.
Huron, Lake, 2, 5, 9, 13, 232 n., 233, 275.
Illinois, 4, 27, 84, 187.
Illinois Indians. See Indians.
Independence, Mount, 162, 163-5, 175.
Independence, War of, 90-207 et passim. Causes, 30-63, &c.
Effects, 204-7.
Indians, 5-29, 53, 57-9, 96-7, 97 n., 119-21, 124, 147-59, 153 n., 168, 185-7, 281-6.
Delawares, 23-6
Illinois, 9, 27.
Iroquois.
See Six Nations.
Mississaugas, 233.
Mohawks, 148-50, 148-9 n., 152, 232-5, 235 n.
Ojibwas, 16.
Oneidas, 58, 147.
Ottawas, 12, 16.
Pontiac’s War, 10-29, 99
Senecas, 10, 22, 24, 148, 152.
Shawanoes, 24, 27.
Six Nations, 10, 22, 58 and n., 59, 83, 147-59, 150 n., 187, 2325.
Tuscaroras, 147-8.
War with United States, 281-6.
Wyandots, 25.
Indian Territory, 5-7, 58-9, 83, 233-4.
Inglis, Bishop, 267
Isle aux Noix, 106, 123, 124, 185.
Isle Royale. See Cape Breton.
James river, 199 Jay, John, 227, 282, 284-5.
Jay’s Treaty. See Treaty.
Jefferson, Thomas, 282, 284, 289.
Jews, exclusion from Quebec Assembly, 305-6.
Johnson, Colonel Guy, 98 n., 149-51
Johnson, Sir John, 149, 152, 155, and n., 156, 242.
Johnson, Sir William, 24, 27, 28, 57, 58 and n., 59, 71, 97 and n., 102, 147, 149, 151.
Johnson’s Royal Greens, 152
Judges, exclusion from Quebec Assembly, 305-6.
Justice, Administration of, 73, 77, 79, 92, 248, 265, 272.
Kalm, Peter, 30, 31 and n.
Kaskaskia, 187.
Kaskaskia river, 9, 187.
Kempt, Sir James, 309
Kennebec river, 109.
King’s Mountain, 198.
Kingston, 9, 225, 232, 233, 242, 272.
Kirkland, Samuel, 148
Labrador, 2, 3, 80, 81, 80-1 n.
Lachine, 120
Lafayette, 184, 187, 199, 200, 250.
La Mothe Cadillac, 9.
Land Tenure, 59, 95, 243, 247, 267, 290, 291, 293.
Language Question, 248, 297
La Prairie, 123.
La Salle, 8, 9.
La Tranche river. See Thames.
Le Bœuf, Fort, 9, 11-12, 17, 20.
Le Canadien, 297, 305, 307, 311
Lecky, Professor, 38, 48, 128.
Lee, General Charles, 132, 196
Legislative Council. See Council.
Levis, 114.
Levis, Point, 110, 113.
Lexington, 90, 101, 125.
Ligonier, Fort, 17, 18, 19, 20, 21
Lincoln, Benjamin, 173 and n., 175, 197.
Liverpool, Lord, 310, 313, 315.
Liverpool Regiment, the 8th Regiment, 152, 153.
Livius, Peter, 140-4, 143 n., 194 and n., 195 and n., 237, 248, 255, 280.
Loftus, Major, 28.
Logs Town, 83.
London, Ontario, 275.
Long Sault Rapids, 2.
Loudoun, General, 126.
Loughborough, Lord, 215.
Louis XIV, 64, 230, 247.
Louisbourg, 41, 49, 50, 51, 52 n., 61, 117, 289.
Louisiana, 1, 10, 37, 50, 230, 282, 283, 302.
Loyalhannon, 19.
Loyalists, 36, 61, 106, 130, 135, 152, 169, 170, 171, 185, 191, 196, 197, 198, 208-35, 218 n., 236, 238 and n., 239, 242, 290, 292.
Loyalist Corps, 220-1, 273.
Lumber Trade, 308.
Luttrell, Captain, 237
Lymburner, Adam, 243, 247, 262.
Macartney, Lord, 304
Macdonells, the, 229, 230 and n.
Maclane, 289.
Maclean, Colonel, 108, 111, 188.
Madelaine Island, 3
Madison, President, 319.
Mahan, Captain, 130.
Maine, 84, 209.
Maitland, Sir Peregrine, 278
Marion, General, 227.
Masères, 79.
Massachusetts, 37, 52 n., 81, 85, 86, 188, 209, 221.
Maumee river, 9, 13, 16, 284, 286
McCrae, Jane, 168.
Megantic, Lake, 109.
Melville, Lord. See Dundas.
Miami, 9, 13, 16, 25, 281, 284, 286.
Michigan, Lake, 5, 9, 16
Michigan Peninsula, 286.
Michillimackinac, Fort, 9, 13, 16, 25, 239.
Militia, Canadian, 114, 294-5, 303.
Miller, Fort, 175
Milnes, Robert Shore, 292-6, 298, 316.
Mississaugas. See Indians.
Mississippi, 1, 4, 5, 9, 27, 28, 32, 51, 80, 83, 84, 187, 302
Mohawk river, 24, 145-58, 168, 169, 174.
Mohawks. See Indians.
Molson, John, 308.
Monckton, General, 12
Monmouth, Battle of, 196.
Monongahela river, 14.
Montcalm, 31 and n., 41, 42 n., 102, 147, 153.
Montgomery, Robert, 60, 106-13, 110 n., 114, 116-18, 118 n., 185
Montreal, 11, 12, 17, 63, 65, 67, 70, 73, 80, 91, 97, 102, 105, 10610, 119, 120, 122, 157, 189, 238, 239, 245, 247, 270, 276, 308.
Moreau, 300.
Morgan, Daniel, 113, 175, 198.
Morris, Captain, 25.
Morse, Colonel Robert, 223-4.
Mulgrave, Lord, 216.
Murray, General James, 4, 61 and n., 63-8, 67 n., 72, 73, 74, 75, 77, 78, 93, 100, 109, 114, 193, 296 n.
Muskingum river, 26.
Napoleon, 302, 308, 311, 317.
Native Question, 56-9.
Navigation Laws, 41, 47.
Navy Hall, 272.
Newark, 272, 275 and n.
New Brunswick, 80, 84, 209, 223, 224, 237, 238 n., 263, 264, 292
New England, 24, 39, 40, 41, 43, 49, 50, 52 and n., 53, 56, 62, 81, 104, 166-7, 169, 174, 196, 197, 221, 223
Newfoundland, 1, 3, 50, 69, 80, 81, 114.
New Hampshire, 101.
New Jersey, 59, 132, 186 n., 198, 200, 212, 213.
New Orleans, 1, 28, 282, 302
Newport, 133, 200.
New York, 13, 24, 40, 50, 59, 63, 69, 90, 101, 129, 130, 132, 133, 174, 175, 181, 185, 186 n., 189, 191, 195, 196, 197, 199, 200, 221, 222, 223, 224, 229, 236.
New Zealand, 45, 57.
Niagara, Fort, 9, 11, 15, 16, 22, 23, 24, 25, 185, 239, 275 and n.
Niagara river, 9, 15, 24, 82, 225, 233, 272.
Nipissim or Nipissing, Lake, 2.
Non-intercourse Acts, 308.
Nootka Sound Convention, 261.
Norfolk, 221.
North, Lord, 83, 136, 139, 192, 193, 201, 215, 216, 217, 219, 226, 227.
North-west Company, 292.
Nova Scotia, 3, 80, 209, 219, 220 n., 223, 224, 236, 236-7 n., 238 n., 267, 292, 315.
Ogdensburg, 119, 239.
Ohio, 9, 13, 18, 20, 23, 24, 28, 41, 51, 58, 59, 80, 83, 84, 239, 281, 282, 283, 284, 286.
Ojibwas. See Indians.
Oneida, 234
Oneida County, 59.
Oneida, Lake, 147.
Oneidas.
See Indians.
Onondaga, 234, and see Oswego.
Ontario, 3, 5, 6, 11, 223, 224, 229, 238, and see Upper Canada.
Ontario, Lake, 5, 9, 11, 45, 80, 83, 146, 147, 185, 225, 233, 272.
Oriskany, 148, 155-7, 157 n.
Osgoode, Chief Justice, 280, 291, 296.
Oswald, Richard, 201, 202, 217, 227
Oswegatchie.
See Ogdensburg.
Oswego, 24, 28, 146, 147, 153, 157, 158, 189, 239.
Ottawa river, 2, 3.
Ottawas.
See Indians.
Ouatanon, Fort, 9, 16, 28.
Ours or Ouse, River. See Grand river.
Palliser, Sir Hugh, 80.
Panet, M., 305, 306.
Parents Creek, 17, 18.
Peace of Paris. See Treaty.
Peel, Sir Robert, 310.
Penns, the, 83, 220.
Pennsylvania, 18, 19, 20, 26, 27, 53, 56, 57, 59, 83, 84, 85, 172, 186 and n., 218, 220, 222.
Penobscot river, 188
Pepperell, Sir W., 62.
Pepperell, Sir W., 212.
Percival, 310, 313.
Philadelphia, 13, 20, 26, 95, 129-34, 146, 175, 195, 196, 200, 213, 222.
Phillips, General, 199.
Piquet, Abbé, 119.
Pitt, the elder, 32, 37, 51, 81, 89, 126, 128, 136 n., 183.
Pitt, the younger, 201, 220, 237, 244, 245, 248, 252, 261, 262, 267, 268, 273, 287.
Pittsburg, 9, 12, 17-22, 23, 26, 51, 59, 83.
Plattsburg, 123, 124.
Plymouth Settlement, 43.
Point au Fer, 162, 239.
Pointe aux Trembles, 110.
Point Levis. See Levis, Point.
Pontiac, 10, 12, 14, 18, 23, 25, 27, 28, 99, 150, 151.
Pontiac’s War. See Indians.
Portland, Duke of, 219, 231, 240 n., 278, 285, 286, 292.
Port Royal, 41, 50.
Powys, 242, 243.
Prescott, Robert, 286-92, 296, 303, 305.
Prés de Ville, 112.
Presque Isle, 9, 11, 16, 17, 20, 25, 83, 239
Preston, Major, 107 and n., 108.
Prevost, Sir George, 196, 289 n. 309, 314, 319.
Prideaux, 147.
Prince Edward Island, 3, 80, 236-7 n., 292
Proclamation of 1763, 1-8, 58, 66, 70, 79, 82, 83, 140.
Protestant Clergy, 265-7.
Protestants, 68, 74-8, 89, 95 n., 100, 229, &c.
Quebec, Province of, 1-4, 70, 79-82, 82 n., 84, 86, 88 n., 225, 236, 238, 241, 242, 245, 246-64, 270, &c.
Quebec, Town of, 3, 41, 52 n., 60, 63, 65, 67, 69, 90, 91, 92, 95, 97, 105, 106-19, 124, 131, 185, 236, 237, 238, 247, 267, 270, 287, 289, 308, &c.
Quebec Act of 1774, 8, 37, 60, 68-89, 87 n., 93, 95, 96, 98, 100, 103-6, 140, 141, 195, 240, 242, 243-4.
Quebec Revenue Act, 87 n., 269 n.
Quiberon Bay, 127, 230.
Quinté, Bay of, 225, 233, 235 n.
Raestown. See Bedford.
Rahl, General, 133, 134.
Randolph, 282, 284.
Rawdon, Lord, 199.
Religion, 72, 74, 76-9, 86, 95 n., 248, 265-9, 294, 296-7, 310-11.
See also Protestants and Roman Catholics.
Rhode Island, 133, 167, 196, 197, 198, 200.
Richelieu river, 71, 108, 114, 122, 123, 185, 224, 239.
Riedesel, Baron, 122, 162, 164, 167, 169, 176, 177
Robertson, Colonel, 19.
Rockingham, Lord, 160, 201.
Rodney, Admiral, 127, 200, 201.
Rogers, Major Robert, 11-13, 11 n., 12 n., 13 n., 17, 18, 102
Roman Catholics, 61, 72 and n., 74, 76-9, 85-9, 95 n., 265, 266, 294, 296, 311, 312, 314, 318
Rosieres, Cape, 2.
Ross, Major, 188.
Roubaud, 31 n.
Rouillé, Fort.
See Toronto.
Royal American Regiment, 13, 20, 52 n.
Royal Highland Emigrants, 111.
Russell, Peter, 286-7.
Ryland, 309-14, 310 n.
Sabine, 227.
Sackville, Lord George. See Germain.
Saguenay river, 2 and n.
St. Charles river, 110, 112.
St. Clair, General, 163, 281, 283.
St. Clair, Lake, 9, 14, 275.
St. Domingo, 273, 302.
St. Francis, Lake, 119, 225, 239.
St. Francis river, 185.
St. Jean or St. John’s Island.
See Prince Edward Island.
St. John, Lake, 2.
St. John river, 2 and n., 3, 80, 223.
St. John’s, Fort, 102, 105, 106-8, 107 n., 122, 123, 124, 239.
St. Joseph, Fort, 16
St. Lawrence, River and Gulf, 2, 5, 9, 11, 71, 80, 83, 84, 109, 119, 120, 122, 174, 185, 225, 239, 264, 270, 308
St. Leger, Colonel, 138, 145, 146-58, 157 n., 168, 169, 172, 174, 187, 236 n.
St. Louis, Lake, 120, 239.
St. Luc de la Corne, 189.
St. Roch, 110, 112.
Saints, Battle of the, 201.
Sancoick Mill, 170, 174.
Sandusky, Fort, 9, 16, 25, 27.
Sandy Hook, 196.
Saratoga, 116, 131, 160, 168, 170, 180-4, 201, 304.
Sault au Matelot, 112.
Sault St. Marie, 25.
Saunders, Admiral, 127, 273.
Savannah, 196, 201, 222.
Savile, Sir George, 87.
Schenectady, 149.
Schuyler, Fort.
See Stanwix, Fort.
Schuyler, General Philip, 106, 107, 153, 174-5.
Secretary of State for American Department, 135, 240 n.
Senecas. See Indians.
Seven Years’ War, 9, 41, 69, 99, 127, 207
Shawanoes. See Indians.
Shelburne, Lord, 74, 91, 94, 201, 214, 216, 217, 219, 220.
Shelburne, Township, 223-4.
Sherbrooke, Sir John, 188.
Sheridan, 216, 243, 244.
Simcoe, John Graves, 232 n., 234, 271-6, 273-4 n., 275 n., 284, 286-7.
Simcoe, Lake, 232 and n., 273, 274.
Six Nations. See Indians.
Skenesborough, 163, 164, 165, 166, 167, 173.
Smith, Adam, 43, 44, 45, 47, 48, 51 n., 53, 107 n.
Smith, Chief Justice, William, 255-61, 276, 280.
Sorel, 108, 114, 185, 224.
Spain, 1, 2, 282, 283, 302.
Spanish America, 38, 39, 48.
Springfield, 185.
Stamp Act, 41, 54 and n., 55.
Stanwix, Fort, 59, 147, 152-8, 157 n., 169, 172, 174, 175.
Stanwix, Fort, Agreement. See Treaty.
Stanwix, General, 18, 153.
Stark, John, 171.
Staten Island, 132.
Stillwater, 168, 170 n., 174
Stopford, Major, 107, 108 n.
Stormont, Lord, 215.
Stuart, Colonel, 199.
Stuart, James, 316
Suffolk, 95.
Sugar Hill, 163, 173.
Sullivan, General John, 187, 196.
Sulpician Seminary, 312, 314
Sumter, General, 197.
Superior, Lake, 5.
Susquehanna, 59, 151, 185.
Sydney, Lord, 240 and n., 243, 245, 246
Talon, 64, 71.
Tarleton, 197, 198
Taxation, 41, 42, 267-9, 267-8 and n., 269 n.
Tea duty, 267-8.
Tecumseh, 150.
Telegraphs, 203-4
Thames, 274, 275 and n.
Thayandenegea, 148.
See also under Brant.
Thompson, General, 122.
Thorpe, Judge, 296, 316.
Three Rivers, 63, 70, 73, 109, 110, 114, 119, 122, 189, 238, 305
Ticonderoga, 51, 90, 101, 123, 124, 125, 138, 140, 161-6, 167, 169, 172, 173, 174, 185, 281.
Titles of honour, 251, 252
Toronto, 11, 232, 274 and n., 275.
Toussaint L’Ouverture, 302.
Townshend, Thomas. See Sydney.
Trade, Lords of, 3-6, 135, 195, &c.
Treaty,
Aix la Chapelle, 49.
Amiens, 301.
Ashburton, 84.
Fort Stanwix, 59, 151.
Greenville, 286
Jay’s, 1794, 218, 285, 286.
Paris, 1763, 1, 5, 10, 27, 30, 33, 66 n., 72 and n.
Paris, 1778, 184 n.
Secret, 1762, 1.
Utrecht, 49, 50, 69.
Versailles, 1783, 33, 201-2, 208-18, 239.
Trenton, 133, 134, 135, 138, 198, 213.
Trevelyan, Sir George, 46.
Tryon County, 117, 151, 154, 187.
Tuscarawa, 26.
Tuscaroras. See Indians.
Tyendenaga, 233.
Unadilla river, 59.
Uniacke, 315.
United Empire Loyalists.
See Loyalists.
United States, 32, 33, 56, 59, 61, 84, 184, 188, 193, 204-18, 225, 226, 239, 263, 264, 265, 281-6, 300, 302, 318, &c.
Upper Canada. See Canada, Upper.
Utrecht. See Treaty.
Valcour Island, 123.
Vancouver, 261.
Vancouver Island, 261.
Vaudreuil, 120.
Venango, Fort, 9, 17, 20.
Vermont, 101, 185, 186 n, 191, 192, 239, 289.
Vincennes, Fort, 9, 28, 187.
Virginia and Virginians, 18, 20, 26, 27, 53, 59, 84, 85, 196, 198, 199, 200, 215, 220, 221.
Wabash river, 9, 16, 28, 187.
Walker, Admiral, 49.
Walker, Magistrate, 67, 97.
Walpole, Horace, 22 and n., 107 n., 115 and n., 116 and n., 124, 136, 137, 160 and n., 161, 165, 171-2 n., 180 n., 204 n.
Walsingham, 215.
Warner, Seth, 101.
Warren, Admiral, 50, 62.
Washington, George, 32, 62, 109, 127, 128, 132, 133, 134, 138, 139, 172, 184, 187, 196, 199, 200, 208, 212, 221, 282-5.
Wayne, Anthony, 283, 284, 286.
Wayne, Fort. See Miami.
Webb, General Daniel, 126, 153
Wedderburn, Solicitor-General, 88 n.
Western Territories, 80, 82, 84, 85, 86.
West Florida. See Florida.
West Indies, 1, 127, 199, 200, 223, 289.
Wilberforce, 216.
Willcocks, 316.
Willett, Colonel, 153-7, 155 n., 157 n.
William Henry, Fort. See George, Fort.
Williams, Fort, 153.
Wills Creek, 19.
Wilmington, 198.
Wilmot, John Eardley, 219, 220 n.
Windham, Township, 232.
Windham, William, 231.
Wolfe, 17, 24, 32, 52 and n., 68, 110, 114, 116, 125, 130, 183, 289.
Wood Creek, 58, 147, 153, 154, 164 n.
Wood Creek (Lake Champlain), 164 and n., 166.
Wyandots. See Indians. Wyatt, 316.
Wyoming, 185, 186 and n. 212.
Yonge, Sir George, 274
Yonge Street, 232 n., 274.
York.
See Toronto.
York, Duke of, 274-5.
York river, 199.
Yorktown, 126, 183, 199, 200, 201, 217
MAP OF EASTERN CANADA AND PART OF THE UNITED STATES
B. V. Barbishire, Oxford, 1908.
