13 February 2010

Lower Respiratory Tract Infections



Lower Respiratory Tract Infections
By: Divya Ahuja, M.D.

Lower respiratory infections: anatomic classification
* Tracheitis; bronchitis; tracheobronchitis
* Bronchiolitis
* Bronchopneumonia
* Segmental pneumonia
* Lobar pneumonia
* Interstitial pneumonia

Case #1
* 40-year-old man
* no underlying lung disease
* 7-day history of mild shortness of breath with exertion, and a productive cough.
* Temperature = 37°C, pulse 84 beats/min, and his respiratory rate 17 breaths per minute.
* no rales are heard; scattered wheezes are heard in the lung bases.

Acute bronchitis (“chest cold”)
* Usually of viral etiology(influenza, rhinovirus, parainfluenza, RSV, human metapneumovirus)
* A common cause for overuse of antibiotics
* Bacteria implicated are
o Bordetella pertussis (whooping cough)
o Mycoplasma pneumoniae
o Chlamydia pneumoniae

Acute bronchitis
* Similar to URIs but more prolonged
* Cough persists > 5 days (upto 40 days)
* 40% will have reduction in pulmonary function
* Main differential includes
o Asthma/ bronchiolitis
o Bronchiectasis
o Chronic bronchitis (cough and sputum for 3 months during 2 years

Acute Bronchitis

* Cough in the absence of fever, tachycardia, and tachypnea suggests bronchitis, rather than pneumonia
* Antimicrobial agents are not recommended in most cases of acute bronchitis
* Antimicrobial therapy is indicated when a treatable pathogen is identified (influenza, Bordetella pertussis )

Acute exacerbations of chronic bronchitis

* Chronic bronchitis is associated with cigarette smoking and COPD
* Extent to which specific bacterial pathogens explain exacerbations is controversial.
* However, repeated bacterial infections (especially H. influenzae) contribute to deterioration of lung function.

Case # 2

* 54 year male, chronic cough x 1 year. no hemoptysis. Denies fevers, shakes, chills. No sick contacts

Bronchiectasis
* Abnormal dilatation of bronchi with chronic productive cough.
* Can be clue to cystic fibrosis in younger patients (associated with S. aureus and Pseudomonas species)
* Uncommon associations: immunodeficiency disorders, dyskinetic cilia syndrome

Case # 3
* 54 year old male
* Flu like illness 2 weeks ago
* 5 day history of chills, fever, difficulty breathing, right sided pleuritic chest pain, cough and yellow sputum

Pneumonia
* 6th leading cause of death in U.S.A.
* About 3 million cases per year; > 500,000 hospital admissions
* About 50% of cases and the majority of deaths are due to bacteria
* Precise diagnosis is usually desirable but difficult to obtain

Acute pneumonia

* History
* Symptoms-cough, sputum, fever, malaise
* Clinical setting-community acquired, nosocomial
* Defects in host defense- HIV, neutropenia
* Possible exposures

Organisms in community acquired pneumonia

Organisms:
S pneumoniae
H influenzae
o P aeruginosa
o S aureus
o Atypicals
+ Chlamydia, Legionella
+ Mycoplasma, Bordetella

Pneumonia (2)
* Streptococcus pneumoniae the most common cause of community-acquired pneumonia requiring hospitalization
* Haemophilus influenzae and Moraxella catarrhalis are increasing in frequency
* Legionella species and Chlamydia pneumoniae have emerged
* Pneumocystis carinii (HIV disease)

Pneumonia: pathogenesis
* Endogenous vs. exogenous (inhalation)
* Bronchogenous vs. lymphohematogenous
* “Pulmonary clearance”: mucociliary blanket, alveolar macrophages
* Factors that impair pulmonary clearance: viral URI; smoking; alcohol; uremia; bronchial obstruction; 100% oxygen; others

“Typical” versus “atypical” pneumonia

* “Typical” (virulent bacteria): abrupt onset; productive cough with purulent sputum; pleuritic chest pain; impressive physical findings; leukocytosis or leukopenia
* “Atypical” (viral, Mycoplasma pneumoniae, others): gradual onset, nonproductive cough; substernal chest pain; unimpressive physical exam; white blood count normal

Typical versus atypical pneumonia

Classic pneumococcal pneumonia

* Antecedent upper respiratory infection
* Sudden onset with single violent chill, then fever
* Pleuritic chest pain
* Signs of lobar consolidation on exam
* If untreated, terminates gradually by “lysis” or suddenly by “crisis”

Atypical pneumococcal pneumonia

* Caught early: signs of consolidation may be absent
* Elderly: fever, classic history may be absent
* COPD: CXR and physical findings are distorted
* Ethanolism: blunted history; prostration, leukopenia
* Epilepsy: lack of history; fever and tachycardia may be attributed to seizures; anaerobes may co-exist
* Recurrent pneumonia: In same area, suggests obstruction or bronchiectasis

Some current problems with pneumococcal disease

* Failure of antibiotic therapy to improve survival during first 3 days
* Vaccine efficacy and distribution
* Resistance to penicillin G
* Overwhelming sepsis in asplenic persons
* Need for developing better diagnostic techniques

Group A streptococcal pneumonia

* Rare, except during influenza epidemics
* Large empyema (“pus in the chest”) is characteristic

Hemophilus influenzae pneumonia

* 2% to 18% of community-acquired pneumonias;
* Predisposition: underlying lung disease, alcoholism, recent URI, advanced age
* Often a patchy segmental pneumonia or bronchopneumonia
* Virtually-diagnostic Gram’s stain: small, pleomorphic gram-negative coccobacilli

Moraxella catarrhalis pneumonia

* AKA: Neisseria catarrhalis; Branhamella catarrhalis
* A large gram-negative diplococcus
* Causes pneumonia and bronchitis especially in persons with chronic lung disease
* Often a patchy bronchopneumonia

Mycoplasma pneumoniae pneumonia

* The classic “primary atypical pneumonia”
* Typically occurs in younger adults, often the parents of young children
* Subtle presentation
* Favors lower lobes
* Pleural effusion may occur (up to 20%)

Some nonrespiratory manifestations of Mycoplasma pneumoniae pneumonia

* Myringitis (sometimes bullous)
* Hemolytic anemia
* Arthritis, arthralgias, myalgias
* Pericarditis, myocarditis
* Hepatitis (mild)
* Erythema multiforme, other rashes
* Meningitis, meningoencephalitis, neuropathy

Chlamydia pneumoniae pneumonia

* Accounts for <5% of community-acquired pneumonias
* C. pneumoniae more commonly causes pharyngitis and hoarseness
* Bronchitis is often insidious
* Pneumonia usually mild and localized but difficult to eradicate

Legionella pneumophila pneumonia

* Up to 23% of community-acquired pneumonias but with wide geographic distribution
* L. pneumophila is not part of the normal flora; a true inhalation disorder
* CXR: patchy or nodular infiltrates that may progress rapidly; up to 50% are bilateral

Legionella pneumophila pneumonia (2)

* Relative bradycardia in 65%
* Neurologic findings in 26%
* Gram’s stain may show purulence without a predominant microorganism
* Laboratory: may have hyponatremia; elevations of AST (SGOT), alkaline phosphatase, and bilirubin; proteinuria, hematuria, and renal failure

Treatment

* S. pneumoniae resistance is increasing
* Options are cephalosporins, amox/clvulanic acid, macrolides, doxycycline, a respiratory fluoroquinolone
* All atypicals are covered by the macrolides , doxycycline and the fuoroquinolones
* Judge the severity to see if outpatient treatment will suffice

Aspiration (“mouth flora”) pneumonia

* usually presents as a subacute illness in patients with some combination of alcoholism, malnutrition, homelessness, and poor dentition
* sputum often has foul odor
* Necrotizing pneumonia; lung abscess(es) with air-fluid levels; empyema

Pneumonia: some clues
* Tularemia: rabbits and hares; ticks and fleas; inhalation (e.g., after mowing over carcasses)
* Psittacosis: birds
* Plague: ground squirrels, chipmunks, rabbits, prairie dogs, rats
* Legionnaire’s disease: contaminated aerosols (air coolers; hospital water supplies)
* Histoplasmosis: dust from soil enriched with bird or bat droppings; Mississippi and Ohio River valleys
* Coccidiodomycosis: southern California (esp.. San Joachin Valley); southwest Texas, Arizona, N Mexico
* Pneumocystis carinii: HIV risk factors
* Relative bradycardia: viral infection; Mycoplasma pneumoniae; Psittacosis; Tularemia; Legionella
* Q fever (Coxiella burnetii): goats, cattle, sheep
* Meliodosis: travel to S.E. Asia, East Indies, Australia, Guam, South or Central America
* Brucellosis: cattle; goats; pigs; abattoir works and veterinarians
* Anthrax: cattle, swine, horses; goat hair, wool, or hides

Pneumococcal pneumonia: Predisposing factors
* Sickle cell disease
* Asplenia
* IgG disorders: agammaglobulinemia, myeloma, chronic lymphocytic leukemia
* Nephrotic syndrome
* Cirrhosis
* Alcoholism

Case # 4
* RA 57 year Caucasian male
* Cough , dyspnea, diarrhea for weeks
* No response to cephalexin
* CT sinuses - normal
* Progressive malaise and presented to ER
* pO2 on 100% NRB- 90, Creatinine 1.8, WBC: 12
* CXR-read as normal, HIV positive

Pneumonia in AIDS patients
* When in doubt, respiratory isolation for Tb
* S. pneumoniae is the number 1 cause
* Investigations
o Obtain sputum for gram stain and culture
o Other serology and antigen testing as indicated (histoplasma, cryptococcus, PCP, coccidio, etc.
o AFB stain if indicated(sensitivity with 3 specimens is about 60%)

PCP: Diagnosis (Imaging)
Chest x ray: PCP pneumonia with bilateral, diffuse granular opacities.
Credit: L, Huang, MD, HIV InSite

Chest x ray: PCP pneumonia with bilateral perihilar opacities, interstitial prominence, hyperlucent cystic lesions. Credit: HIV Web Study, www.hivwebstudy. org, © 2006 University of Washington

PCP
* PCP is a SUBACUTE pneumonia, CD4 usually <200
* Dyspnea, dry cough, chest discomfort
* In 30% patients
o CD4 > 200
o CXR normal
* TMP/SMX and steroids if hypoxic

Tuberculosis in HIV patients
* Occurs at any CD4 count
* Primary TB
o Occurs especially in people with advanced HIV infection
o Comprises about 1/3 of TB cases in HIV patients
* Reactivation of latent TB
o More likely in HIV-infected patients
o 7-10% annual risk in HIV-infected patients with positive tuberculin skin test (TST)
+ In HIV uninfected, 5-10% lifetime risk
* Patients with TB have HIV viral loads and faster progression of HIV

Case # 5
* 45 year female
* Intubated in the ICU for 7 days
* Now has worsening fever, leukocytosis and increased oxygen requirement

Nosocomial pneumonia
* Role of oropharyngeal colonization, especially of gram-negative rods (Pseudomonas, acinetobacter, etc.) : by end of one week, 45% of ICU patients are colonized; pneumonia develops in 23% of colonized patients versus 3.3% of non-colonized patients
* Risk factors to colonization: more advanced illness, longer duration in the hospital, antibiotics, intubation, azotemia, underlying pulmonary disease

Case # 6
* 23 year male, acute leukemia and bone marrow transplant
* Is severely neutropenic due to chemotherapy

Cavitary pneumonia
* Tuberculosis
Actinomyces
Nocardia
Klebsiella
Staphylococcus aureus
Anaerobic organisms
* Fungal infection Histoplasmosis
Coccidiomycosis, aspergillus

Complications of pneumonia
* Pleuropulmonary: lung abscess; adult respiratory distress syndrome (ARDS); pleural effusion; empyema; bronchopleural fistula; bronchiectasis; fibrosis; slow resolution
* Extrapulmonary: meningitis; brain abscess; endocarditis; pericarditis; arthritis; osteomyelitis

Lung Abscess
* Lung abscesses are usually caused by mouth flora(viridans strep, anaerobes, etc.)
* They need prolonged courses of antibiotics
* Options are the clindamycin, amox/clavulanic acid, pip/tazo, carbapenems

Pneumonia: Summary
* 6th leading cause of death and most common nosocomial infection causing death
* Precise diagnosis desirable but all-too-often not obtained
* Bronchoalveolar lavage and endobronchial sampling are now standard in nosocomial or difficult to diagnose pneumonia


Lower Respiratory Tract Infections.ppt

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Tube Thoracostomy: Complications and the Role of Prophylactic Antibiotics



Tube Thoracostomy: Complications and the Role of Prophylactic Antibiotics
By Ashley Laird

Indications for Tube Thoracostomy
* PTX (spontaneous, iatrogenic, traumatic)
* Hemothorax
* Chylothorax
* Decreased breath sounds in unstable patient after blunt or penetrating trauma
* Multiple rib fractures, sucking chest wound, subcutaneous air in intubated trauma patient
* Complicated pleural effusion, empyema, lung abscess
* Thoracotomy, decortication
* Pleural lavage for active rewarming for hypothermia

Complications
* Undrained PTX, hemothorax, or effusion despite TT clotted hemothorax, empyema, fibrothorax
* Improper placement +/- iatrogenic injuries (lung, diaphragm, subclavian, right atrium)
* Recurrent PTX after tube removal
* Intrapleural collections following tube removal
* Thoracic empyema

Factors Influencing Complications: Louisville study
* Prior studies report TT complication rates of 3-36%
* Etoch SW, Bar-Natan MF, Miller FB, Richardson JD. Tube Thoracostomy: Factors related to complications. Arch Surg. 1995; 130:521-525.
o Retrospective chart review (U of Louisville)
o 379 trauma pts, 599 tubes

Factors Influencing Complications: Louisville study
* Complications:
o Empyema
o Undrained PTX or effusion
o Improper tube placement (+/- iatrogenic injury)
o Post-tube PTX
o Other
* Measures:
o Rate of complications in association w/ TT setting, operator, patient characteristics, MOI, and severity of injury

Factors Influencing Complications: Louisville study
* Overall rate of complications: 21% per patient (16% per tube)
* 8.2% of complications required thoracotomy

Factors Influencing Complications: Setting
* 48% of tubes placed in ED, 23% in OR, 12% in ICU, 7% on floor, and 9% at OSH prior to transfer
* Significantly higher complication rate when TT performed in outside hospital prior to transfer (33%, p<.0001)
* No significant difference in complication rates between TT in ED (9%) vs. TT in other areas of study hospital (7%)

Factors influencing Complications: Operator
* 59% of tubes placed by surgeons, 26% by ED physicians, 8% by physicians prior to transfer
* Highest complication rate for tubes placed by physicians in outside hospitals, mostly nonsurgeon physicians (38%)
* Complication rates for TT’s in study hospital: 13% for ED physicians, 6% for surgeons (p<.0001)
* For TT’s in ED: 13% complication rate for ED physicians vs 5% complication rate for surgeons (p<.01)

Factors influencing Complications: Mechanism/Severity of Injury

* No difference in complication rate related to:
o Age and sex of patients
o Mechanism of injury (23% for blunt vs 18% for penetrating)
o ISS
* Significantly increased complication rate related to:
o ICU admission (29% vs 11%, p<.0001)
o Mechanical ventilation (29% vs 15%, p<.002)
o Presence of hypotension (SBP<90) on admission (31% vs 17%, p<.003)

Factors Influencing Complications: University Hospital study
* Deneuville M. Morbidity of percutaneous tube thoracostomy in trauma patients. Eur J CT Surg. 2002; 22:673-678.
o Prospective observational study (University Hospital, Guadeloupe)
o 128 trauma pts, 134 tubes
o ‘Non-thoracic’ operators vs. thoracic surgeons

Factors Influencing Complications: University Hospital study
* Overall complication rate 25% (29% per tube)
o 5 (12.8%) improper placement, no iatrogenic injury
o 4 (10.3%) improper placement w/ iatrogenic injury (lung x 2, diaphragm, subclavian artery)
o 4 (10.3%) undrained hemothorax/PTX
o 12 (30.8%) post-removal PTX
o 7 (18%) post-removal fluid collection
o 3 (2.3%) empyema
o 4 (10.3%) combined
* 18 (46.2%) of complications required surgery (thoracotomy or VATS)

Factors Influencing Complications: University Hospital study
* No difference in complication rate related to:
o Blunt trauma vs. penetrating wounds
o Indication for TT: hemothorax vs PTX
o Presence of pulmonary contusion, abdominal injury, or need for immediate abdominal surgery
* Significantly increased risk of complication related to:
o Polytrauma (RR 2.7, p<0.05)
o Need for assisted ventilation (RR 2.7, p<.003)
o TT by non-thoracic surgeons (RR 8.7, p<.0001 for blunt trauma and RR 12.5%, p<.0001 for penetrating trauma)

Thoracic Empyema
* Causes of post-traumatic empyema:
o Iatrogenic infection during TT
o Direct infection from penetrating injury
o Secondary infection from associated intra-abdominal injuries w/ diaphragmatic disruption or hematogenous or lymphatic spread to pleural space
o Secondary infection of undrained hemothoraces
o Parapneumonic empyema resulting from posttraumatic pneumonia, contusion, or ARDS

Thoracic Empyema
* Empyema occurred in 1.8% (Louisville study) and 2.3% (University Hospital study) of patients undergoing TT
* No difference in rate of empyema related to setting or operator
* No difference in rate of empyema related to administration of antibiotics within 24 hours of initial TT in Louisville study (2% vs 2%)


‘Prophylactic’ Antibiotics in TT: EAST Guidelines
* Does ‘prophylactic’ antibiotic use in injured patients requiring TT reduce the incidence of empyema and/or pneumonia?
* Paucity of literature, especially well-designed multi-institutional double-blinded trials that control for setting, operator, mechanism of injury, timing of antibiotic administration, choice and dose of antibiotic, and duration of prophylaxis

‘Prophylactic’ Antibiotics in TT: EAST Guidelines
* Luchette FA, Barrie PS, Oswanski MF, Spain DA, Mullins CD, Palumbo F, Pasquale MD. Practice Management Guidelines for Prophylactic Antibiotic Use in Tube Thoracostomy for Traumatic Hemopneumothorax: the EAST Practice Management Guidelines Work Group. J Trauma. 2000; 48(4):753-7.
o MEDLINE search (1977-1997) for references using query words: antibiotic prophylaxis, chest tubes, human, drainage, tube thoracostomy, infection, empyema, and bacterial infection-prevention and control.
o 11 articles reviewed: 9 prospective series, 2 meta-analyses

Prophylactic’ Antibiotics in TT: EAST Guidelines
* Articles classified by Agency for Health Care Policy and Research (AHCPR) methodology
o Class I: prospective, randomized, double-blinded, controlled trials
o Class II: prospective, randomized, non-blinded trial
o Class III: retrospective series of patients or meta-analysis
* Four class I articles, five class II, and two class III meta-analyses

Prophylactic’ Antibiotics in TT: Conclusions and Recommendations
* Incidence of empyema in placebo groups ranged from 0-18%, compared to 0-2.6% in antibiotic groups
* Two class I studies saw a reduced incidence of empyema w/ antibiotic Rx (Cant, 1993; Grover, 1977)
* Two class II studies saw no benefit w/ antibiotics (Mandal, 1985; Demetriades, 1991)
* Other studies didn’t control for MOI
* Insufficient evidence to support prophylactic antibiotics as a standard of care for reducing incidence of empyema or PNA in patients requiring TT

Prophylactic Antibiotics in TT: Conclusions and Recommendations
* Extreme variability in choice of antibiotic, dosing, and duration of therapy among studies
* One class I study reported no empyema in patients receiving cefazolin for 24hrs compared to 5% incidence in placebo group (Cant et al, 1993)
* Administration of antibiotics for >24hrs did not significantly reduce risk of empyema compared with shorter duration (Demetriades, 1991)

Prophylactic’ Antibiotics in TT: Conclusions and Recommendations

* Incidence of pneumonia in placebo groups ranged from 2.5-35.1%, compared to 0-12% in antibiotic groups
* In most reports, significant reduction in pneumonitis seen in patients receiving prolonged antibiotics (but also see increased cost and length of hospital stay)
* Presumptive, rather than prophylactic therapy, in setting of acute trauma

‘Prophylactic’ Antibiotics in TT: Conclusions and Recommendations

* Recommendations (for isolated chest trauma)
o Level I: insufficient data to support level I recommendation as standard of care
o Level II: insufficient data to suggest prophylactic antibiotics reduce incidence of empyema
o Level III: sufficient class I and II data to recommended prophylactic antibiotic use in patients receiving TT after chest trauma. A first generation cephalosporin should be used for no longer than 24hrs. There may be a reduction in incidence of PNA, but not empyema.


Recommendations
* Additional training of all trauma physicians
* Early thoracotomy or VATS in settings of persistent fluid collection or multiple chest tube placements as means to prevent against development of empyema
* First generation cephalosporin for no more than 24 hours
* Further research!

Tube Thoracostomy: Complications and the Role of Prophylactic Antibiotics.ppt

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11 February 2010

Tools of Prenatal Diagnosis



Tools of Prenatal Diagnosis
By:Julie Moldenhauer, MD
Reproductive Genetics
Maternal Fetal Medicine
Obstetrics and Gynecology

Objectives:
* Discuss various prenatal screening and testing tools
* Discuss the timing of the various tools in gestation
* Discuss benefits and risks of various options
* Review the difference between screening and testing
Baseline Risk for Birth Defects in the General Population is 3-5%
What Can We Diagnose in the Prenatal Setting?
* Structural Abnormalities
o Congenital heart disease
o Spina bifida
o Gastroschisis
* Chromosomal Abnormalities
o Trisomy 21
o Triploidy
* Infections
o Parvovirus
o Cytomegalovirus
o Toxoplasmosis
* Growth Abnormalities
* Hematologic Abnormalities
o Anemia
o Thrombocytopenia
* Functional Defects
o Arthrogryposis
o Renal dysfunction
* Syndromes
o Skeletal Dysplasia
o Diabetic embryopathy

Prenatal Diagnosis Tools

* History
o Personal History
o Family History
* Population Screening
* Serum Screening
* Ultrasound
* Fetal MRI
* Invasive Diagnosis
o Chorionic villus sampling
o Amniocentesis

History is a Screening Tool!
o Maternal Age
+ > 35 years at delivery
o Obstetric History
+ Prior baby born with Down syndrome
+ Prior stillbirth
o Medical History
+ Is mom diabetic? How well controlled is her sugar?
+ Does she have PKU?
+ Is she hypertensive?
o Medication Exposures
+ What medications?
+ When was the exposure?
o Environmental Exposures
+ Does she work in a preschool and was exposed to parvovirus?
+ Is she exposed to high doses of radiation?
o Family History
+ Brother with hemophilia
+ Uncle with cystic fibrosis
+ Ethnic background
+ Consanguinity

As maternal age increases, the risk for aneuploidy increases. This is due to maternal meiotic nondisjunction.
Maternal age > 35 at the time of delivery is considered “Advanced Maternal Age” or AMA
The risk for recurrence of chromosome abnormalities is dependent upon the genetic mechanism involved.
Trisomy: 1% or maternal age-related risk
Translocation:
Maternal carrier: 10-15%
Paternal carrier: 2%

Down syndrome phenotype caused by trisomy 21
Down syndrome phenotype caused by 14;21 translocation

Maternal Diabetes: Reproductive Risks
* Fetal and Neonatal
o Congenital anomalies: 6-12%
o Intrauterine fetal demise
o Macrosomia – Shoulder dystocia
o Growth restriction
o Hyperbilirubinemia
o Hypoglycemia
o RDS
o Polycythemia
o Organomegaly
o Long term – obesity and carbohydrate intolerance
* Obstetric
o Spontaneous preterm labor
o Polyhydramnios
o Preeclampsia (15-20%)
o Intrauterine growth restriction
o Shoulder dystocia
o Cesarean delivery

Caudal Regression Syndrome
Teratogen Exposure
Fetal growth
Organogenesis complete
Eyes, heart, lower limbs
Axial skeleton, limb buds, musculature
CNS
None, “ALL or NONE”
* Examples:
* Accutane
* ACE inhibitors
* Lithium
* Antiepileptic drugs (AEDs)
* Anticoagulants: warfarin
* Antidepressants
* Methotrexate
* Thalidomide

Teratogen Exposure
* Fetal effects are timing and dose dependent

* Each medication is assigned a pregnancy category based on available data; A-D, X
* www.Reprotox.org
* www.otispregnancy.org

Ultrasound images of fetal hydrops – abnormal collection of fluid in multiple body compartments.
Mom works at a daycare where there was a Parvovirus B19 or Fifth Disease outbreak 4 weeks ago. Parvovirus causes fetal aplastic anemia that can be life-threatening.

Suspicion of diagnosis by altered maternal serum titers of Parvo IgG and IgM and confirmed by amniotic fluid PCR for Parvo.
Confirmed Parvo infection in a fetus with hydrops can be treated with intrauterine blood transfusions.

Fetal Ultrasound Showing Cardiac Rhabdomyoma
Fetal MRI Showing Tubers
Prenatal Findings Consistent with Tuberous Sclerosis Confirmed as Neonate
Screening for Genetic Disease
Ethnic Group Disease
African American Sickle Cell Disease: 1/12
Mediterranean Beta-Thalassemia: 1/30
Southeast Asian Alpha-Thalassemia: 1/20
Caucasian Cystic Fibrosis: 1/25

ASHKENAZI JEWISH ANCESTRY
GENETIC CARRIER TESTING
Gaucher’s disease
Bloom syndrome
Mucolipidosis IV
Niemann-Pick disease type A
Fanconi Anemia Group C
Familial Dysautonomia
Cystic Fibrosis
Canavan disease
Tay-Sachs disease
Detection rate
Carrier Frequency
Disease Incidence
Testing and screening options should be made available to all pregnant women
Prenatal Screening & Testing
When Screening
(risk estimate)
Definitive
(Invasive)
First Trimester
FIRST screen*
Ultrasound
CVS

Second Trimester
Maternal Serum Screen*
Ultrasound
Amnio
Cordo
*First and Second Trimester Integrated and Sequential Screening

Test Performance
* Detection rate – the percentage of affected that are test “positive”
o (the higher, the better)
* False positive rate – the percentage of unaffected that are test “positive”
o (the lower, the better)

Goals in Prenatal Screening:
* High sensitivity - low false positive rate
* Wide availability
* Reproducibility and accuracy
o Human error, testing conditions

First Trimester Screening
o 11-13 6/7 weeks (CRL 39-79 mm)
o Maternal serum sample for PAPP-A and Free b-HCG
o Ultrasound for Nuchal translucency
o Detection Rates:
+ 80% for Trisomy 21
+ 90% for Trisomy 18
+ Does not screen for NTDs

PAPP-A
b-HCG
T21
T18

Increased NT vs Cystic Hygroma
* Increased NT > 95th%
o With or without septations
* Structural defects
o Heart defects most common
* Syndromic associations
* Chromosomal defects
o Exponential increase with increased NT
o 50% Down syndrome
o 25% Trisomy 13 or 18
o 10% Turner Syndrome
o 5% Triploidy
o 10% other

NT > 3 mm is ABNORMAL
Second Trimester Serum Screening: Chromosome Abnormalities

* Maternal Serum Screening
o 15-20 weeks
o Triple screen: 60% for T21
o Quad screen: 70% for T21
o Gestational Age Dependent**
* Targeted Ultrasound
o 50% aneuploid fetuses will have ultrasound markers
AGE +AFP +hCG +uE3 +InhA
DR at 5% FPR
2nd trimester
single double triple quadruple
Serum Screening Test Performance at a fixed 5% False Positive Rate (Dating by Ultrasound)

Prediction
SURUSS
FASTER
Second Trimester Serum Screening: Neural Tube Defects
* Neural Tube Defects
o Spina Bifida
o Anencephaly
* AFP increased in “open” defects
* Sensitivity
o 90% anencephaly
o 80-85% open spina bifida
* False positive – 3-4%
Interpreting a Quadruple Screen

Bottom Line: AFP is increased with NTDs and decreased with chromosome abnormalities

Elevated MSAFP
* Incorrect Dates – most common reason
* Multiples
* Congenital Nephrosis
* Ventral Wall Defects
* IUFD
* Adverse Pregnancy Outcomes
o Stillbirth
o Placental abruption
o Preterm labor
o Oligohydramnios
o IUGR

Ultrasound detection of aneuploidy
Nuchal Fold
CPC
Duodenal atresia
Pyelectasis
Clinodactyly
Second trimester sonographic markers of Down syndrome
AV Canal
Trisomy 18
Edward Syndrome
* Close to 90% detected by prenatal scan
* US:
o Growth restriction
o Clenched fists
o >90% with cardiac defects
o Multiple malformations
* Grim prognosis
o 50% Stillbirth
o 50% die within the first week
o 5-10% survive the first year

Trisomy 13
Patau Syndrome
Fetal Anatomy by Ultrasound
Ventral Wall Defect
Gastroschisis
NTDs
Lemon Sign
Banana Sign
Meningomyelocele Sac
Meningomyelocele Sac on Newborn
PGD: Preimplantation Genetic Diagosis
Pearls for Invasive Testing
* Risk for Sensitization
o Mom Rh negative – Rhogam
o Other antibodies may increase risk
* Risk for Infection transmission
o Hepatitis B
o Hepatitis C
o HIV
o Need to know familial mutations prior to performing invasive testing

Chorionic Villus Sampling
* Performed 10-14 weeks
* Does not test for ONTD
* Technique – “Placental biopsy”
o Transabdominal
o Transcervical
* Risk for limb reduction defects if performed < 9 weeks
* Loss rate 1/100-1/200
* Risk for mosaicism (~1%)

Transcervical
CVS
Transabdominal
Performed at 10-14 weeks
Amniocentesis
* > 15 weeks
* Loss rate 1/200 (probably closer to 1/300-1/500)
* Tests for ONTD
* Technique
o Fine gauge needle
o Ultrasound guidance
o Aspiration of 20-30 cc of fluid

PERFORMED ROUTINELY 15-20 WEEKS
Ultrasound Guided Procedure
AMNIOCENTESIS
Cordocentesis
* Percutaneous Umbilical Blood Sampling
* Loss rate 1/100-1/200
* Typically done after 18 weeks
* Ability for:
o Rapid karyotype
o Blood/platelet counts
o Direct fetal injections/transfusions

Fetal Blood Sampling
“PUBS”
Conclusions

* Many options for screening and testing.
* Prenatal screening should provide the most effective test to the greatest number of women.
* The best method of screening is yet to be determined.
* Patient preference should be considered.
* Testing and screening should be available to all women.

Tools of Prenatal Diagnosis.ppt

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