Congenital and Perinatal Infection

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Congenital and Perinatal Infection
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Congenital Infections Presentation

• Intrauterine growth retardation
• Microcephaly
• Hydrocephalus
• Intracranial calcifications
• Thrombocytopenia
• Blueberry muffin skin rash
• Hepatosplenomegaly, conjugated hyperbilirubinemia
• Chorioretinitis
• Cataracts

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Blueberry Muffin Skin Rash
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Etiologies of Congenital Infection

• Toxoplasmosis T
• Syphilis Other
• Rubella R
• Cytomegalovirus C
• Herpes simplex H
• HIV
• Lymphocytic choriomeningitis virus
• Parvovirus B19
• Varicella

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Diagnosis of Congenital InfectionGeneral Tests

• CBC
• Total/direct bilirubin, liver enzymes
• Total IgM
• Bone radiographs
• CSF exam
• Eye exam
• CNS imaging

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Diagnosis of Congenital InfectionSpecific Tests

• Toxoplasmosis IgM, IgG
• RPR
• Rubella IgM
• Rubella culture eye, urine, nasopharynx
• Urine culture for CMV
• Herpes simplex IgM, IgG
• CSF routine studies, quantitative VDRL, HSV PCR
• Parvovirus B19 PCR
• Lymphocytic choriomeningitis virus infant IgM
  and IgG, mother IgG

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How Toxoplasmosis is Transmitted
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Toxoplasmosis

• Toxoplasma gondii, protozoan, cats are host
• 70-90 asymptomatic
• Symptoms maculopapular rash, thrombocytopenia,
  lymphadenopathy, hepatomegaly, splenomegaly,
  jaundice, hydrocephalus, microcephaly,
  chorioretinitis, seizures, deafness
• Diagnosis IgM, IgG, intracranial calcifications
• Treatment pyrimethamine, sulfadiazine

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Toxoplasmosis Chorioretinitis
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Congenital Syphilis Symptoms

• Asymptomatic 50
• Fever, lymphadenopathy, irritability, failure to
  thrive
• Jaundice, hepatosplenomegaly
• Mucocutaneous palmar/plantar bullae,
  maculopapular rash trunk/limbs, mucosal lesions,
  condylomata lata
• Anemia (BM arrest, hemolysis), thrombocytopenia,
  low/high WBCs
• Meningitis
• Snuffles (serous rhinitis)
• Bone changes osteochondritis of humerus, tibia

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Congenital Syphilis Snuffles
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Congenital Syphilis Diagnostic Studies

• Quantitative RPR
• CSF exam cell count, protein, VDRL
• CBC, platelets, liver enzymes
• Long bone radiographs
• Demonstration of spirochetes tissue/fluid
• HIV testing

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Congenital Syphilis Bone Changes
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Congenital Syphilis Treatment and Follow-up of
the Newborn

• Choice of regimens for confirmed or probable
  congenital syphilis
• Penicillin G 100-150,000 unit/kg/day x 10-14 days
  (50,000 unit/kg/dose IV BID x 7 days, then TID
  for a total of 10 days)
• Procaine penicillin G 50,000 unit/kg/day IM once
  daily x 10 days (may not adequately treat CNS)
• ampicillin is not a suitable alternative
• RPR at 3, 6, 12 months
• Complicated cases should be referred to specialist

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Congenital Rubella Clinical Findings

• Asymptomatic 50 at birth
• Sensorineural hearing loss
• Mental retardation
• PDA, peripheral pulmonic stenosis
• Ocular cataracts, chorioretinitis, glaucoma
• Microcephaly
• Blueberry muffin rash
• Metaphyseal radiolucencies

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Congenital Rubella Vertical Transmission

• Transplacental passage of virus
• Greatest risk for congenital defects and hearing
  loss early in the pregnancy
• Non-immune pregnant women
• do not immunize during pregnancy
• no cases of malformation due to rubella vaccine
  in women immunized during pregnancy
• avoid exposure to rubella
• post-partum vaccine

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Congenital Rubella skin Lesions
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Congenital Rubella Syndrome
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Congenital Rubella Diagnosis and Treatment

• Diagnosis
• Rubella specific IgM
• culture nasopharynx, blood, urine, CSF, throat
• Treatment supportive

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Cytomegalovirus Transmission

• Vertical transmission
• transplacental and perinatal acquisition
• maternal primary and reactivated CMV
• Incidence
• 2.5
• most are asymptomatic - 95

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Cytomegalovirus Clinical Findings In
Symptomatic Infants

• Microcephaly, intracranial calcifications
• Thrombocytopenia, petechiae, purpura
• Conjugated hyperbilirubinemia, elevated liver
  enzymes, liver failure
• Interstitial pneumonitis
• Hearing loss
• Mental retardation
• Neurologic impairment, cerebral palsy
• Chorioretinitis
• Intestinal pseudo-obstruction like illness

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CMV Calcifications
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CMV Hydrocephalus, Calcifications
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Cytomegalovirus Diagnosis

• CMV titers
• IgM, IgG
• Acute and convalescent
• Urine culture for CMV
• Excretion may be intermittent
• CNS imaging
• Eye exam

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Cytomegalovirus Treatment

• Supportive
• Platelet transfusion
• Anti-viral treatment
• Ganciclovir may reduce sequelae, but of limited
  efficacy
• CMV hyperimmune globulin
• Infectious disease consultation

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Lymphocytic choriomeningitis virus

• Arenavirus, shed by rodents
• Symptoms in adults influenza like illness -
  fever, malaise, myalgia, retro-orbital headache,
  photophobia
• Congenital infection hydrocephalus,
  chorioretinitis, intracranial calcifications,
  microcephaly, mental retardation, neurologic
  sequelae, visual loss
• Diagnosis culture, acute and convalescent
  titers
• Treatment supportive

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Lymphocytic Choriomeningitis Virus -
Hydrocephalus
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Parvovirus B19

• Associated with multiple disorders
• Erythema infectiosum (fifth disease)
• Aplastic crisis (hemolytic disorders, sickle
  cell)
• Chronic anemia in immunosuppressed
• Acute arthritis
• Fetal hydrops and death due to anemia
• (?)Efficacy of intrauterine transfusion
• Spontaneous recovery of fetal hydrops can occur

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Varicella

• Maternal varicella before 20 weeks congenital
  anomalies reported to be 1-2
• Cicatricial skin lesions
• Limb hypoplasia
• CNS, ocular, neurologic
• Maternal varicella in last 5 days of pregnancy to
  2 days post partum
• VZIG 125 units IM indicated in exposed infants
• Skin lesions, pneumonitis, dissemination reported
• Add acyclovir if signs or symptoms develop

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Congenital varicella
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Varicella perinatally acquired
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Perinatally Acquired Infection Basic Principles

• Maternal colonization or infection
• Amniotic fluid
• Blood
• Genital tract secretions
• Breast milk
• Direct skin contact, environment
• Timing and duration of exposure
• Interventions, prophylaxis

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Herpes Simplex Epidemiology

• Vertical transmission most common
• perinatal exposure with ROM and delivery
• 50 risk if infant exposed to primary maternal
  HSV
• lt1-5 risk if infant exposed to recurrent
  maternal HSV
• increased risk in premature infants (reduced IgG)
• C-section reduces risk if ROM lt 4-6 hour
• Horizontal transmission reported
• nursery outbreaks
• Time of onset 2 days - several weeks

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Herpes Simplex Clinical Presentation

• Fever
• skin vesicles
• encephalitis
• seizures
• respiratory distress, pneumonia
• hepatitis
• septic shock like syndrome

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Herpes Simplex Skin Lesions
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Herpes Simplex Skin Lesions
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Herpes Simplex Skin Lesions
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Herpes Simplex Conjunctivitis
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Herpes Simplex Oral Lesions
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Herpes Simplex Encephalitis
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Neonatal Herpes Simplex Treatment

• Acyclovir 60 mg/kg/day divided q 8 hr x 14 days
  (21 days for systemic or CNS)
• Ocular HSV add ophthalmic trifluridine,
  iododeoxyuridine, or vidarabine
• Supportive control seizures, respiratory and
  cardiovascular support
• Reduce cutaneous or ocular spread
• High mortality rate for CNS or systemic HSV, even
  with treatment

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Management of HSV Exposure

• Recurrent maternal HSV
• risk is very low observation only
• Primary maternal disease
• risk is high
• viral throat culture at 24-48 hr of age
• empiric therapy is controversial
• Premature infant - risk may be greater

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HIV

• Transmission is vertical
• In utero, intrapartum (most common), and
  postnatal (breastfeeding)
• Risk factors

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Zidovudine (AZT) for reduction of perinatal HIV
transmission

• pregnancy begin 200 mg PO 3x/day at 14-34 wk,
  continue throughout pregnancy
• intrapartum 2 mg/kg x 1 h, then 1 mg/kg/h IV
  until delivery
• newborn 2 mg/kg 4x/day PO begining at 8-12 h of
  age until 6 weeks of age
• referral to pediatric HIV center

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HIV perinatal prophylaxis

• Reduction of vertical transmission with AZT as
  compared to placebo in women with mildly
  symptomatic disease
• Connor EM et al. NEMJ 19943311173
• placebo 25.5
• prenatal, intrapartum, postnatal 8.3

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HIV Benefit persists even with abbreviated
prophylaxis

• DNA PCR on HIV exposed infants with incomplete
  prophylaxis.
• Wade NA et al. NEJM 19983391409
• prenatal 6.1
• intrapartum 10.0
• lt 48 h postnatal 9.3
• gt 48 h postnatal 18.4

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HIV mode of delivery

• Metanalysis of 15 NA/European studies
• 8533 mother-child pairs
• adjusted for antiretroviral Rx, maternal stage of
  disease and birth weight
• elective C-section prior to labor or ROM
• International Perinatal HIV Group
• NEJM 1999340977

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HIV mode of delivery

• other mode (vag, non-elective C/S) 16.7
• elective C-section
  8.4
• other mode, complete retroviral Rx 7.3
• elective C/S, complete retroviral Rx 2.0
• International Perinatal HIV Group
• NEJM 1999340977

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Hepatitis B

• Vertical transmission
• Blood exposure during labor and delivery
• In utero transmission lt 2 of cases
• Maternal HBsAg HBeAg 70-80
• Maternal HBsAg HBeAg- 5-20
• Chronic carrier, hepatitis, cirrhosis,
  hepatocellular carcinoma

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Infant born to HBsAg mother management

• Avoid skin to skin until infant bathed
• Hepatitis B vaccine within 12 hr
• HBIG given at separate site
• Complete standard HBV schedule
• Preterm lt 2 kg 1st dose not counted, total 4
  doses
• HBsAg and anti-HBsAg at 9-15 months of age
• Breast feeding not precluded controversial

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Infant born to HBsAg unknown mother management

• Avoid skin to skin until infant bathed
• HBV within 12 hours
• If mother HBsAg , HBIG within 7 days
• Premature infant lt 2 kg give both HBV and HBIG
  within 12 hours, if unable to determine maternal
  status by 12 hours.
• Complete standard HBV schedule
• Preterm lt 2 kg 1st dose not counted, total 4
  doses

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Hepatitis C

• Prevalence in adults in U.S. - 1.8
• Vertical transmission - 5 of infants born to
  mothers with hepatitis C
• No specific preventive measures
• Breast feeding is allowed
• Transmission not proven
• Cracked or bleeding nipples may be risk
• Test infant at 18 months anti-HCV
• Earlier testing with HCV RNA PCR

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Enterovirus

• Commonly occurs in summer and fall seasons
• History of maternal illness late in pregnancy
• Perinatal vertical transmission from mother to
  infant
• Outbreaks reported in NICUs
• Presents in the first 2 weeks
• Neonatal symptoms fever, lethargy, poor feeding,
  respiratory distress
• Clinical syndromes aseptic meningitis, sepsis,
  cardiomyopathy, hepatitis, pneumonia, pulmonary
  hypertension

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Etiology of Early Onset Sepsis

• Group B Strep (GBS) 67
• Non-GBS organisms
• E Coli 25
• Others 8
• Enterococcus, staph aureus, strep pneumonia,
  candida.

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Epidemiology of Group B Strep

• Maternal Colonization 15-40
• 50-75 of newborns born to colonized mothers
  become colonized during birth
• Attack Rate ( infected nb/ colonized
  mothers) 1-2
• Neonatal Early Onset Disease
• 1-4 per 1000

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Risk Factors for Neonatal Infection in Colonized
Mothers

• Prolonged rupture of membranes gt 18 hr
• Premature birth esp lt 34 weeks
• Intrapartum fever
• African-American Race
• Maternal age lt 20 yr
• Previous birth of GBS infected infant
• Heavy maternal colonization, e.g. bacteruria
• Low levels of anti-GBS capsular antibody

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Maternal GBS Disease

• UTI
• amnionitis
• endometritis
• wound infection

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Neonatal GBS Disease

• Early Onset Disease
• symptomatic infection occurring during 1st week
• results from vertical transmission during labor
  or delivery
• constitutes 80 of neonatal GBS infection
• pneumonia and overwhelming sepsis more common

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Prevention of early onset group B strep

• GBS is sensitive to Ampicillin and Penicillin
• Failure of prenatal administration of Amp/PCN to
  eradicate colonization
• Failure of immediate postnatal treatment with
  Penicillin
• Lack of treatment efficacy in several studies
• increased morbidity from Penicillin resistant
  organisms in one study

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Prevention of early onset group B strep

• Only success at maternal treatment is intrapartum
  antibiotic prophylaxis
• Boyer and Gottof, 1986
• Reduces maternal colonization
• Reduces neonatal colonization
• Reduces attack rate of GBS by 80-95
• Allen et al, meta-analysis, 1993 30 fold
  decrease in neonatal infection

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Strategies to Reduce GBS Disease

• AAP, 1992
• 26-28 week cultures of all pregnant women
• intrapartum prophylaxis for
• positive cultures
• ROM gt 12 hr
• onset of labor or ROM lt 37 wks
• intrapartum fever
• previous birth of an infant with GBS disease
• Will treat approx 3.4 of all mothers, to prevent
  50 of Early Onset GBS disease

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Strategies to Reduce GBS Disease

• ACOG
• Prophylaxis for
• preterm labor lt 37 wks
• PROM lt 37 wks
• ROM gt 18 hr
• previous child with GBS disease
• maternal fever during labor
• Note cultures not included in decision
• Will treat approximately 18.3 of mothers and
  prevent 68.8 of early onset GBS disease

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Risks of Maternal Treatment - Why not treat all
mothers?

• Fatal anaphylaxis to Ampicillin 1 per 100,000
• Pseudomembraneous enterocolitis (Clostridium
  dificile)
• incidence of other less severe maternal reactions
• risk of antibiotic resistance among GBS or other
  organisms

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Failures of GBS Prophylaxis

• Late administration of intrapartum antibiotic
  prophylaxis (lt 4 hr before birth)
• Inadequate dosing
• Failure to recognize mothers at risk

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Prophylaxis Failures

• Importance of hospital guidelines
• Surveillance study, 1997
• 165 hospitals surveyed
• 96 (58) had established departmental guidelines
  for maternal prophylaxis
• Lower early onset GBS incidence in hospitals with
  guidelines
• .58/1000 vs 1.29/1000 (p.006)

Factor SE, et al, OB GYN 200095377-82)
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Failures of Intrapartum Prophylaxis

• CDC study 1998-1999 629,912 births
• 312 infants with GBS early onset sepsis (0.5/1000
  births)
• 62 had no maternal risk factors
• 52 of women were screened for GBS
• Relative Risk of neonatal GBS in screened vs risk
  based approach was 0.48 (0.38-0.61)

Schrag SJ, et al, NEJM 2002347233-9.
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Failure of Intrapartum Prophylaxis

• Reasons for failure of risk-based approach
• Incidence of GBS colonization in mothers who have
  no risk factors on presentation
• Failure of identification of risk factors when
  present

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CDC Guidelines Updated 2002

• All pregnant women should be cultured at 35-37
  weeks gestation
• Penicillin prophylaxis preferred, due to narrow
  spectrum
• Prophylaxis recommended for
• Positive cervical culture for GBS
• GBS bacteruria during gestation
• Previous infant born with invasive GBS disease
• Risk factors in absence of culture results
• Gestation lt 37 wks
• Fever
• ROM gt 18 hr
• Prophylaxis not needed for Cesarean sections for
  culture positive mothers with intact membranes

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Change in Epidemiology of Early Onset Sepsis

• Does widespread use of Intrapartum Antibiotic
  Prophylaxis lead to emergence of resistant
  organisms?

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Stoll B, et al, Changes in Pathogens Causing
Early Onset Sepsis in Very Low Birthweight
Infants, NEJM 2002347240-7

• 5447 VLBW infants born 1998-2000
• Compared to 7606 VLBW infants born 1991-93

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Explanations for Ampicillin Resistance

• Selection of resistant organisms from maternal GU
  tract
• Especially in preterm infants
• Change in NICU resistance patterns
• Change in resistance patterns of ambulatory
  patients
• Change in general resistance patterns

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Hyde T, et al, Trends in Incidence and
Antimicrobial Resistance of Early-onset Sepsis
Population Based Surveillance in San Francisco
and Atlanta, Ped 2002110690-5.

• CDC Emerging Infection Program Network, 1998-2000
• All hospitals with a delivery service in 3 county
  area of San Francisco (39,768)
• All 10 birthing hospitals in the 8 county Atlanta
  area (42, 960)

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Hyde et alEarly Onset Sepsis(positive blood
culture in 1st 7 days of life)

• N 408
• 166/408 (40.7) were GBS
• 70/409 (17.2) were E. Coli
• No change in E. Coli or GBS rates over the 3 yr
  period
• 78 of ampicillin resistant organisms were in
  prematures

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Changing Epidemiology of Early Onset Sepsis

• Term deliveries
• 3.9 million per year
• Incidence of early onset sepsis 1/1000 live
  births
• 3,900 term infants per year
• Antibiotic resistance does not appear to be a
  problem in term infants

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Changing Epidemiology of Early Onset Sepsis

• VLBW Infants
• 48,000 births/yr lt 1500 gm
• Incidence of Early Onset Sepsis 15/1000 (Stoll
  data)
• 720 preterm infants/yr
• Antibiotic resistance is a problem in VLBW
  infants
• Due to GBS prophylaxis vs background changes in
  microbial resistance patterns?
• Strategies to prevent GBS must address the
  majority of susceptible infants (5 out of every 6
  susceptible infants is term)
• Strategies must reflect the potential for
  resistance in preterm infants

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Management of Newborn Whose Mother Received
Prophylaxis

• Diagnostic evaluation and empiric antibiotics
  if
• signs and symptoms of sepsis
• lt 35 weeks gestation
• Limited Evaluation and 48 hr observation if
• Duration of prophylaxis lt 4 hr before delivery
• Asymptomatic infant
• No evaluation, but 48 hr observation if gt 4 hr
  antibiotics prophylaxis

Diagnostic Eval CBC, Diff, Bld Cult, plus CXR,
LP etc, as indicated Limited Eval CBC, diff and
Bld Cult.
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Is an LP necessary in evaluation for sepsis in
the newborn?

• Pro
• Risk of meningitis in absence of positive blood
  cultures or CNS symptoms
• Wiswell et al
• 5 yr review of U.S. Army Hospitals 169,849
  births
• Incidence of meningitis 0.25/1000 live births
• 8/43 (19) were term infants with no CNS symptoms
  and negative blood cultures

Wiswell TE et al, Ped 199595803-6
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Is an LP necessary in evaluation for sepsis in
the newborn?

• Con
• Metanalysis of 6 papers excluding Wiswell et al
• 4913 LPs successfully performed
• 19 cases of culture positive meningitis (259 LPs
  per case of meningitis)
• 16/19 cases had positive blood cultures
• Thus, 1638 successful LPs are needed to diagnose
  one case of meningitis in the absence of a
  positive blood culture
• Better blood culture technique lessens the need
  for LPs

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Blood Culture Technique

• Appropriate prep
• 30 seconds vs 10 seconds x 2
• Appropriate volume
• At least 1 ml
• Obtain from peripheral stick and central line if
  line is in more than 12 hr

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Duration of Antibiotics

• Are negative blood cultures conclusive when the
  mother has received IAP?
• Ancillary tests
• CBC
• Neutropenia
• IT ratio
• CRP

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C-Reactive Protein in Suspected Sepsis

• CRP performed on 2 successive days in early onset
  sepsis
• Sensitivity 88.9
• Specificity 73.8
• Positive predictive ability 6.0
• Negative predictive ability 99.7
• Conclusions
• In episodes where CRP was positive, only 6
  turned out to have sepsis
• In episodes where CRP was negative, 99.7 did not
  have sepsis

Benitz et al, Ped, 1998
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Decision to stop antibiotics

• Negative blood cultures at 48-72 hr
• Symptoms of mild severity (tachypnea, brief O2
  dependency, poor feeding)
• D/C antibiotics and observe 24-48 hr
• If moderate-severe symptoms decision to D/C or
  continue antibiotics depends on other factors
• Presence of chorioamniotis?
• Elevated CRP?
• Neutropenia or elevated IT ratio?

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Nosocomial infection in the NICUCommon organisms

• Coagulase negative staphylococcus
• Coagulase positive staphylococcus
• Gram negatives E coli, Klebsiella, Enterobacter,
  Serratia, Pseudomonas
• Candida albicans, parapsilosis

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Risk factors for nosocomial infection

• Central lines
• Duration of insertion
• Type of catheter Broviac, silastic
• Ventilation, endotracheal intubation
• Exposure to antibiotics
• Surgical procedures intestinal
• Use of intravenous lipids

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Strategies to reduce nosocomial infection

• Remove central lines ASAP
• Limit entries into central lines
• Medications via PIV
• Limit number of ports into central line
• Use ports rather than stopcocks
• Good handwashing
• Respiratory care, suctioning techniques
• Limit use of IV lipids

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Empiric treatment of suspected nosocomial sepsis

• Ampicillin and gentamicin
• Ampicillin and cefotaxime
• Vancomycin and gentamicin
• Vancomycin and cefotaxime