Transcript TOXOPLASMOSIS • Primary maternal infection: 1 in 900 births (90% mothers are asymptomatic) • Re-activation with immuno-suppression • Cong Toxo in US – 1:1000

TOXOPLASMOSIS
• Primary maternal infection: 1 in 900 births
(90% mothers are asymptomatic)
• Re-activation with immuno-suppression
• Cong Toxo in US – 1:1000 – 1:10,000
• Transmission:
40%
• 1st, 2nd trimester:
17%, 25%
• 3rd trimester:
65%
• Severity greater earlier in pregnancy;
severe congenital infection rare > 20 weeks
PRENATAL SCREENING & Rx
• Most neonates with cong toxo are asymptomatic
at birth; if untreated, most develop severe
eye/ neurologic disease by adolescence.
• Most mothers asymptomatic; risk factors
present in <50%; only 8% screened in pregnancy
• Important - Rx is available for fetus/ infant
• Treatment of fetus/infant substantially
reduces disease progression
Boyer et al and the Toxoplasma Study Group; AJOG 192, 2005
NEONATAL SCREENING & MANAGEMENT
(Massachusetts 1986, New Hampshire 1988-92)
• Screening filter paper_ IgM capture immunoassay
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100 of 635,000 infants positive
Confirmed in 52 - specific IgG, IgM (1:10,000)
50 of 52 were identified only by screening
All were treated;
only 1 of 46 developed a neurologic deficit
only 1 had serious eye lesion – a macular scar
Screening identifies subclinical infections,
& early Rx reduces severe sequelae.
Guerina et a l NEJM 330:1858-6, 943
NEONATAL SCREENING PROGRAM
• Screening program for Toxo is feasible as
systems in place for specimens
• Costs: screening and follow up
~ 100,000 infants = $220,000/yr,
< $30,000/ infant identified.
• Cost-benefit ratio is favorable.
• Follow-up indicates that there has been little
progression of disease in infants treated from
birth.
TOXO – PRENATAL DIAGNOSIS
• Amniotic Fluid - PCR parasite particles
• AF and fetal blood –
specific IgM, IgA, IgG
• Blood / placental tissue
inoculation into mice
• Fetal HUS - calcifications / hydrocephalus
• Isolation of parasite
placenta, amniotic fluid, fetal blood
TOXO - ANTEPARTUM THERAPY
Consult ID.
• Documented maternal infection:
Unlike CMV, antepartum Rx with Spiramycin is
indicated - even if AF studies are negative.
• Documented fetal infection > 17 wks gest:
pyrimethamine & sulfadiazine
• Severe cong disease (25%): termination??
• HIV pos pts: evaluate and treat carefully
VARICELLA
Chickenpox in pregnancy rare = 5 in 10,000
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Maternal Inf: < 20 weeks gest:
Varicella embryopathy in 2% infants
Maternal Inf: > 20 weeks gest
Inapparent varicella, Zoster in early
childhood
Maternal Inf: 5d before to 2d after delivery
Neonatal VZV inf/ pneumonia (can be fatal)
VARICELLA IN PREGNANCY
Maternal Inf
Potential consequences
<20 wks gest
Spont abortion
Fetal Varicella Syn - 2%
any stage
Fetal death,
herpes zoster 1st yr of life
Near term
Cong disseminated varicella
Varicella pneumonia
(can be fatal)
5d<delivery
2d>delivery
VARICELLA IN PREGNANCY
State
Rx
Mat exposure
VZIG - non-immune mother
Mat infection
(Prevent FVS)
Acyclovir to Rx mother
VZIG to the risk FVS
Mat infection
5d before
or 2d>delivery
Acyclovir to mother
VZIG to neonate - ASAP
acyclovir to neonate?
Neonatal varicella
(life-threatening)
IV Acyclovir
(VZIG at birth)
FETAL VARICELLA SYNDROME - FVS
• Low birth weight
• Skin:
Cicatrical lesions
• Bone:
• CNS:
• Eye:
in dermatomal distribution
Limb hypoplasia
equinovarus, calcaneovalgus;
hypoplasia mandible, clavicle, scapula, digits.
MR, seizures, cortical atrophy
chorioretinitis, nystagmus,
microphthalmia, cataract,
corneal opacities, optic atrophy,
NEAR-TERM MATERNAL VARICELLA
Within 5 d before to 2 d after delivery
Neonatal attack rate 25% - 50%
Neonatal disease severe as mat antibody
develops only > 5th day of mom’s rash
Incubation - 9 to 15 days
Severe varicella pneumonia.
Disseminated cutaneous & visceral lesions
Mortality > 30%, if untreated.
HORIZONTAL TRANSMISSION-VARICELLA
• Unusual
• Most neonates: protected by mat. antibody
• 30 wk, < 1 kg. neonates:
could be susceptible - VZIG
• Screen rapidly for VZV antibody
VZIG to susceptible neonates
• VZIG to all neonates following exposure ?
B19 INFECTION IN PREGNANCY
• Fetal inf - 30% to 50%.
• Most fetal infections are self-limited
• Fetal loss: 15% <20 wks vs. 2% >20 wks
• Parvo virus binds to an antigen of the P-system
blood group – P antigen
• Viral infection of fetal erythrocyte precursors
causes destruction & arrest of RBC production.
• Fetus can develop anemia, myocarditis,
CHF and nonimmune hydrops
PARVO VIRUS INFECTION
• 50% pregnant women immune.
• Infection in pregnancy = 2- 3%
• If a pregnant woman is exposed
IgG and IgM should be determined ASAP
• IgG antibody shortly after exposure indicates
preexisting immunity
• If susceptible, repeat serologies 4 wks.
• B19-specific IgM antibody indicates recent
infection.
• Monitor for possible fetal involvement.
Monitoring in Pregnancy
• MSAFP ?
• Wkly US
• Development of hydrops 2 to 17 wks
• Doppler - middle cerebral peak systolic velocity
is a sensitive indicator of fetal anemia and may
precede the development of hydrops.
(sensitivity =94%, specificity=93%)
• Increased blood velocity in anemic fetuses
probably reflects the increased CO that occurs
with the decline in blood viscosity.
HYDROPS - PARVOVIRUS
• Spontaneous resolution of anemia and hydrops
often occurs if > 20 wks
• Fetus can rapidly deteriorate and should be
monitored
• If fetal anemia or hydrops persists
determine fetal hemoglobin level.
• If fetal Hgb is <5 g/dL
consider intrauterine blood transfusion
CONGENITAL CMV INFECTION
• Most common congenital infection
1% newborns infected
40,000 /yr in US
• Leading infectious cause of:
Mental Retardation, Cerebral Palsy,
or, most commonly, hearing impairment
involving > 8,000 infants/ yr in the US
CONGENITAL CMV INFECTION
• Live births/yr - US
• Congenital infection1%
Symptomatic
Fatal
Sequelae
Asymptomatic
Sequelae
• Total sequelae/death
10%
10%
90%
90%
15%
4,000,000
40,000
4,000
36,000
8150
EPIDEMIOLOGY
• 40-60% mid/upper SE vs. 80% low SE infected
• US: 40-85% adults seropositive
In developing countries, almost 100%.
• After an active replication stage, CMV enters a
latent stage in leukocytes and other tissues. Like
other herpes viruses, CMV reactivates during
relative immuno-compromise, such as pregnancy
TRANSPLACENTAL TRANSMISSION
• PRIMARY MATERNAL INFECTION:
2-6% mothers/yr seroconvert in pregnancy
Transmission 40 – 50 %
Earlier mat. inf. = more severe the fetal inf.
• RECURRENT MATERNAL INFECTION:
Transmission 0.5-1.5%
most infants asymptomatic
• REINFECTION – new CMV strain
RECURRENT MATERNAL INFECTION
• Preconceptional immunity offers only partial
protection
• Of 46 mothers with preexisting immunity,
16 infants had symptomatic inf.
11 of 16 mothers - new epitopes of the virus
• Co-infection with HIV is a risk factor
TRANSMISSION
• Natal:
2%-28% of seropositive women
shed CMV during delivery.
~ 50% of their infants
develop CMV at 4-6 wks
• Postnatal: human milk or saliva
blood transfusions
NATAL INFECTION
• Incubation: 4 to 12 wks
• Term infants:
afebrile pneumonia-50% of exposed infants.
rarely, hepatitis or encephalitis.
mild – maternal CMV IgG antibodies,
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no sequelae or SNHL
Preterm infants <1,500 g:
more severe pneumonitis
exacerbation of BPD
postnatal steroids -progression of CMV inf
BREAST MILK TRANSMISSION
• Seropositive mothers:
shed virus 20% – 70% of the time in BM
• 60% term infants fed virus positive breast milk
develop inf but it is benign due to mat(Ig)G.
• 15%-25% preterm infants (no mat IgG) develop
symptoms: As & Bs, hepatosplenomegaly, pallor,
neutropenia, thrombocytopenia, elevated LFT.
Neurologic sequelae ??
• Co-infection with HIV - risk fctor
TRANSFUSION-ACQUIRED CMV
• Infection in LBW infants may be severe
• Characterized by a gray ashen pallor,
respiratory distress, pneumonia,
hepatosplenomegaly, hepatitis, atypical
lymphocytosis, thrombocytopenia, and
hemolytic anemia
• 10% mortality.
CLINICAL SIGNS
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Nonimmune hydrops
Prematurity, IUGR
Jaundice
Hepatosplenomegaly
Petechiae, Purpura
Blueberry muffin spots
Chorioretinitis
Microcephaly
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Lethargy
Poor feeding
Hypotonia
Seizures
Inguinal hernia
Defective enamelization
of deciduous teeth:
40% symp newborns
5% asymptomatic
CLINICAL SIGNS
• Anemia
• Pneumonia
• Thrombocytopenia
• Calcifications
• Elev. liver enzymes
• Hyperbili
(direct and indirect)
• Elevated CSF protein
(periventricular,
thalamic, cortical)
• Ventriculomegaly Cortical dysplasia
SENSORINEURAL HEARING LOSS
Most common birth defect in the US
All etiologies
4000/yr
Sympt. CMV
300- 500/yr
(30%-65% SNHL)
Asympt. CMV
(8%-15% SNHL)
1500- 2000/yr
SENSORINEURAL HEARING LOSS
• UN Hearing Screen can miss CMV - SNHL.
SNHL can develop after newborn period.
• SNHL is progressive ~ hearing deterioration
throughout childhood and into adolescence.
• Cochlear implantation - as early as 1 year of
age if bilateral profound hearing loss
DAIGNOSIS - CMV CULTURE
• Virus must be isolated in urine /saliva
<3 wks of age to prove congenital infection
• If >3 wks of age, cannot differentiate
congenital, natal, or postnatal infection unless
the infant previously has had a negative
culture.
This distinction is important because congenital
infection is associated with hearing impairment.
• Shell-vial culture-helps rapid identification.
CMV DNA PCR & CMV-IgM
CMV DNA PCR
• CSF: preferred test
positive result = poor neurologic outcome.
• Blood; positive = active infection
associated with hearing loss
• Newborn heel stick dried blood spots:
opportunity for universal screening?
CMV IgM not recommended for neonates
False-positives and false-negatives occur
Rx - GANCYCLOVIR
• RCT – 6mg/kg q12; IV x 6 wk, central line
• 1991-99, 100 infants enrolled
• <1month of age, > 32wk gest. BW >1200g
• With CNS involvement:
• microcephaly, abnormal CT scan or HUS,
abnormal CSF, chorioretinitis, hearing loss
<1month of age, > 32 wk gest, BW<1200g
Kimberlin, Lin, Sanchez et al ACOG abstract 2000
Rx GANCYCLOVIR
• RCT – 100 infants, 6mg/kg q12; IV x 6 wk
association between GCV Rx and lack of
progression of SNHL (up to 2 yrs)
• Produces significant neutropenia
(63% in Rx group vs 20% placebo)
• Oral val-ganciclovir trial ongoing.
MATERNAL DIAGNOSIS
Is it primary infection?
• IgG seroconversion – ELISA
• New CMV specific IgM – immunoblot
• IgG avidity index: Anti CMV IgG has low avidity
for first 14 wks after conversion
• IgG avidity index & IgM–immunoblot combination
may help identify primary inf.
Guerra et al: AM. J Ob Gyn 2000
CMV - PRENATAL US
• Oligohydramnios
• Polyhydramnios
• IUGR
• Fetal ascites, hyper-echogenic bowel
• Microcephaly, ventriculomegaly
• Intracranial calcifications
• Hepatosplenomegaly
CMV - PRENATAL DIAGNOSIS
Fetus infected? Symptomatic?
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Viral culture amniotic Fluid
Viral culture fetal blood
DNA-PCR & quantitative PCR
CMV-IgM in cordocentesis – not v. sensitive
Ultrasound
Hematologic tests
Guerra et al: AM. J Ob Gyn 2000
CHILD CARE CENTERS
• Plastic surfaces and toys harbor CMV for hours
• Viruria: ~ 70% infected >18 mth old children.
• 30% seroconversion among mothers whose
children shed CMV vs 0% if children don’t shed
• Child to mother transmission confirmed.
• Young children in child care centers are
important source of primary CMV infection for
pregnant women.
PREVENTION
• Meticulous hand hygiene after exposure to
urine or saliva from infants and toddlers and
immunocompromised patients
• Standard precautions only.
• Pregnant women are not excluded from caring
for infants who are infected with CMV.
• Routine screening is not recommended for
women of childbearing age as no interventions
are available.
PREVENTION
• Transfusion-acquired infection:
CMV antibody-negative blood products,
leukofiltration of blood to remove WBC,
frozen deglycerolized RBCs as they lack viable
leukocytes.
• Breast Milk acquired CMV:
Freezing human milk –20°C for 3-7d.
Pasteurization (62.5°C) not routinely available.
• CMV vaccine - investigational.
GENITAL HSV– ALARMING PREVALENCE
• 30% women of childbearing age have
antibodies to HSV-2
• Seroconversion during pregnancy: 2% - 3%
• Genital HSV-1 infections increasing !!
• Overall, 500,000 new cases/ yr. added
to the pool of > 45 million cases in the US.*
NEONATAL HSV INFECTION
Tragedy for the neonate/family
• 1:3200 LB = 1,500 cases/yr in the US
• Intrapartum transmission > 90%
• HSV-2 = 75%; HSV-1 = 25% cases
• The severity of neonatal HSV disease, has
increased over the past 5 years
HSV –INTRAPARTUM TRANSMISSION
• If vaginal delivery and
1st episode primary g-HSV 57%
1st episode non-primary g-HSV 25%
reactivated g-HSV at delivery:
2%
• Most mothers - no history or symptoms
Brown ZA, JAMA 2003;289:203–209.
IMPORTANCE OF MATERNAL IMMUNITY
• HSV inf occurred in 4 of 9 infants born to
women who acquired genital HSV near the onset
of labor, 5 had lesions at the time of labor,
none had antibodies to HSV type
• HSV inf occurred in 0 of 94 infants born to
women who acquired genital HSV earlier during
pregnancy, all had seroconverted before the
onset of labor
• (4 of 9) vs. (0 of 94) P<0.001
NEJM, 97
RISK FACTORS-NEONATAL INFECTION
40,000 cultured in labor – 202 positive (0.5%)
neonatal infection = 10/202 = 5%
Odds Ratio
• Culture positive
346
• CS (1% vs 8%)
0.14
• First episode infection
33
• Fetal monitoring
7
• HSV-1 vs HSV-2
17
Brown et al (2003 - JAMA)
Neonatal HSV -Incidence & Outcome
hi-dose acyclovir
Disease
(onset)
Incidence, Mortality, Morbidity
%
%
%
SEM
45
0
5
CNS
35
5
65
Disseminated
20
30
40
(2-3 wks)
(< 1 wk)
HSV- EARLY DETECTION/ RX
• Time from onset to Rx = 6 days
has not changed in 20 years; because,
>75% mothers are asymptomatic;
> 50% infants have no skin lesions
• Need high index of suspicion
• Vesicular skin lesions: begin Rx (pending Cx)
• Check liver transaminases in sick infants
  in disseminated HSV
HSV-CULTURES
• Culture at 24 - 48 hrs – results in 2-7d
skin, conjunctiva, mouth/nasopharynx, rectal,
urine, blood, CSF
• Hi-risk /symptomatic: Rx pending cultures
• Positive cultures from any site obtained > 48hrs
= viral replication rather than colonization
• CSF cultures usually negative in encephalitis
PCR DNA-CSF test of choice
test before & after RX
HSV: DIAGNOSTIC TESTS
• Tzanck prep – low sensitivity,
not recommended as diagnostic test
• DFA stain scrapings– same day, sensitive
• ELISA – detection of HSV in skin lesions
• Eye consult
• EEG, MRI (temporal lobe involved)
• Histopathology
HSV:TREATMENT
• IV acyclovir: 60 mg/kg/d IV– in 3 divided doses
“Hi dose” – has greatly improved survival &
morbidity
• 21d for CNS &/or disseminated;
14 d for SEM
• Ocular disease – topical Rx in addition to IV Rx
(trifluridine or iododeoxyuridine or vidarabine)
ORAL ACYCLOVIR SUPPRESSIVE RX
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Acyclovir 300mg/m2 /dose PO TID
16 Infants with confirmed HSV-2 SEM
Rx initiated < 1 month; Rx for 6 months
13/16 (80%) had no recurrences
Historical controls – 54% no recurrences
SE-neutropenia; resistant HSV mutant
Kimberlin et al-CASG-J Ped Inf Dis 1996
NEONATAL HSV– PO ACYCLOVIR
• Oral acyclovir suppressive Rx
after second recurrence – not after initial
• Monitor for neutropenia
• Consider CSF PCR – symptomatic recurrences
• Enroll in study protocols
CASG Consensus
HSV Encephalitis
• CSF PCR may be negative in early encephalitis
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(only70% sensitivity)
Repeated LP is indicated
CSF may be normal/mildly abnormal
Insufficient evidence
- oral ACV to "suppress” CNS-HSV
Use oral ACV as part of a clinical trial.
Need to evaluate the efficacy of chronic ACV
and its prodrugs (higher levels in brain)
Commentary by Frenkel, MD
MATERNAL TREATMENT
• First episode HSV in pregnancy,
400mg Acyclovir PO TID 7-14d
Safe to use in pregnancy
• Suppressive Rx ~36wks
(primary or recurrent maternal inf)
•  lesions at delivery
•  CS,  viral shedding
•  neonatal HSV
Scott et al Infect Dis Ob Gyn 2000
HSV-PREVENTION
• Careful history /exam
No scalp electrodes if HSV suspected
• ROM + active lesions at term = stat CS,
some experts even if > 6hrs ROM
• ROM + genital lesions + lungs immature:
? IV acyclovir to mom
EXPECTANT MANAGEMENT-P PROM
• PPROM <32 wks + active lesions
delay of delivery is appropriate
betamethasone
acyclovir
broad-spectrum antibiotics
• Mean interval from recognition to delivery
13 days; r =1-35d
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Scott et al Infect Dis Ob Gyn 2000 (ACOG)
HSV-PREVENTION
• Identify susceptible women at 24-28 wks using
new gG-based type specific serology testing
• Seronegative mothers:
partner serology unknown/discordant
educate (condoms, abstinence 3rd trimester)
consider suppressive Rx for discordant partner
• Seropositive mothers–
Counsel – recurrent lesions use suppressive Rx
HSV TYPE-SPECIFIC SEROLOGY
• Subclinical genital herpes in the mother in late
pregnancy is responsible for most neonatal
herpes cases.
• HSV type-specific serology (recently available
in US) should be used for prenatal testing.
• Counseling: safe sexual practices, abstinence
should be provided to patient/partner,
depending on results of the serologic testing.
HSV-Prevention
• Identify susceptible women at 24-28 wks
using new gG-based type specific serology
• Seronegative woman:
partner unknown or discordant -educate
(condoms, abstinence in 3rd trimester)
consider suppressive Rx discordant partner
• Seropositive –
Counsel – recurrent lesions use suppressive Rx
PEDIATRIC HIV
• US:
80% drop
1990
1000-2000 new HIV /yr
2004
280 – 370 new HIV/ yr
• GLOBAL burden remains tremendous:
2002
3.2 million living with AIDS
800,000 new HIV/ yr
Dramatic Progress
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1981
1984
1985
1987
1994
1995
2002
2004
1st AIDS cases reported
Virus identified
ELISA; Blood testing
W.Blot approved; AZT approved
ACTG –076 report (26% - 8%)
viral load assay; HAART
rapid testing – blood - approved
rapid testing – saliva - approved
TRANSMISSION
• During Pregnancy
• Intrapartum
• Breast feeding
30% (PCR+ <48hrs)
70%
excess risk to uninfected = 12 –14%
INTRAPARTUM RISK FACTORS
• Risk Increased, if:
• ROM >4hrs, even on ZDV (if viral load detectable)
• Prolonged labor
• Preterm delivery
• Invasive procedures
• Chorioamnionitis
• Advanced maternal disease, low CD4
• Risk Reduced,if:
• HAART Rx
• Maternal HIV-RNA <500-1000 copies/ml
• Elective CS before labor/ROM
(unless viral load low)
MATERNAL VIRAL LOAD
“critical predictor of transmission”
RNA copies/mL.
<500
500 -1000
>100,000 copies
(if untreated)
Risk
0%
0-2%
40%
63%
Rx decreases transmission at all viral loads
WITS study NEJM ,99
HIV – LAB DIAGNOSIS
HIV Infected infants:
• Positive tests
- 2 separate specimens,
excluding cord blood
HIV Not-infected infants:
• Negative tests - 2 separate specimens,
>1 month of age
and 1 performed > 4 mths
HIV DNA-PCR
the preferred screening test
• Test at < 48 hrs; 2 wks, 1-2 mths, 2-4 mths
• Infection = positive test on 2 separate samples
• Infected infants:
30 % positive by < 48 hrs
93% positive by 2 weeks
Almost all positive by 1 month
HIV RNA-PCR
• NOT for routine screening –
too many false positives
• Quantitative test
• Useful for viral load monitoring
in infected infants
Preventing Transmission
• Routine counseling & testing early in pregnancy
• ZDV (PACTG 076) - 1st trimester
• HAART if HIV- RNA is >1,000 copies/mL
Plasma HIV-1 RNA levels should be monitored
• CS if HIV-1 RNA levels >1,000 copies/mL
• CS if RNA levels <1,000 copies/mL ?
Mother’s informed decision should be honored.
MIRIAD STUDY
Mother Infant Rapid Intervention at Delivery
• 16 hospitals – Nov, 2001 - Nov, 2003.
24-hour counseling, Rapid HIV-1 antibody test
&, if indicated, Rx
• Rapid HIV-1 antibody test (OraQuick)
Simple, finger-stick blood
Results 20 min.
Sensitivity
100%;
Specificity
99.9%
JAMA. 2004;292:219-223. (includes Stroger Hospital)
PERINATAL TRANSMISSION
REDUCTION
• Intrapartum
• IV ZDV and Nevarapine
• Infant :
• ZDV – ASAP < 6 hrs of birth for 6 wk
• Add Nevarapine (?early, 2 doses)
MIRIAD BENEFITS
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1999
2000
2001**
2002
2003
Pos Mothers Pos Infants
37
3
41
1
25
0
45
0
36
0
PERINATAL HIV PREVENTION ACT-2004
Every health care provider in charge of caring
for a newborn infant shall, within 24-48 hrs of
the newborn's birth, provide counseling and
perform HIV testing when the HIV status of
the mother is unknown, if the parent or
guardian does not refuse testing.
The provider shall document in the woman's
medical record that counseling and the offer
of testing were given, and that no written
refusal was given.
UNIDENTIFIED MOTHERS
• 1/3rd of infants born to unidentifed HIV
infected mothers will be prevented from
acquiring HIV disease, even if ART is given
ONLY to the newborn after birth.
• Prophylactic Rx should be initiated within the
first 24 to 48hrs.