Intrauterine Infection

Intrauterine infection

• Abortion /stillbirth• Congenital Malformation• IUGR• Prematurity• Acute neonatal disease/delayed neonatal

disease• Asymptomatic• Persistent infection with late sequelae

• Timing (which trimester)

Signs & symptoms of IU infections• IUGR• Microcephalus/hydrocephalus• Intracranial calcifications• Chorioretinitis• Cataracts• Myocarditis• Pneumonia• HSM• Direct hyperbilirubinemia• Anemia/thrombocytopenia• Seizures/SNHL/blindness• Skin

Blueberry Muffin

• Dermal erythropoiesis• CMV• Rubella• Parvo• Congenital Leukemia• Rh hemolytic disease

Pregnant Women Screening (CDC)

• HIV• Syphilis• HBsAg• C trachomatis• N gonorrhhoeae if at risk• GBS (35-37 w)

Toxoplasmosis

Toxoplasma gondii human infection:• Undercooked meat (oocysts)• Contact with contaminated materials

(sandbox) (oocysts)• Organ/BM transplantation (tachyzoite/cyst)• IU (maternal infection during pregnancy)

Primary Acquired Toxoplasmosis

• Mononucleosis like (fever, myalgia, rash, lymphadenopathy, hepatitis, meningitis, encephalitis, pericarditis, unilateral chorioretinitis, myo/pericarditis)

Ocular Toxoplasmosis

Congenital or acquired30-40% of chorioretinitis in USA and western Europe

Toxoplasmosis in immunocompromised

• AIDS, malignancy, cytotoxic therapy, organ transplants, stem cell transplant (Tox+→Tox-)

• CNS 50%, also heart, lung, GI• Toxoplasmic encephalitis 25 to 50% untreated

HIV

Congenital Toxoplasmosis

• 1st trimester 17% severe infection• 3rd trimester 65% mild infection • Susceptibility (HLA DQ3 etc)• Wide range of presentation• 50% of infected are asymptomatic at birth almost all of them

will develop ocular involvement• 10% severe CNS & systemic• Untreated that presents later in the first 1yr 80% IQ<70• IUGR, lymphadenopathy, HSM, pneumonitis, nephrotis

syndrome, metaphyseal lucency• SIADH, hypothyroidism, hypopit

Congenital Toxoplasmosis

• Hydrocephalus• Seizures• Microcephalus, developmental delay• CSF abnormal in 30% (sometimes protein

>1gr)• Calcifications more in caudate nucleus and

basal ganglia• SNHL static or progressive?

Diagnosis of Toxoplasmosis

• Cultures (mice peritoneal fluid or tissue cultures 6-10 days for tachyzoites, if mouse survives and seroconverts at 6 weeks brain cysts)

• Serology:Sabin-Feldman dye testSpecific, sensitive, difficult

Serology cont.• IgG indirect fluorescent antibody 1-2wk after infection, peaks at 6-8 wk, persist fo life at

low titers, not standardised• IgM IFA for older children, only 25% of congenital• IGM ELISA more sensitive and specific (50-75%)• ISAGA (immunosorbent agglutination assay) combines

IGA, IGE and IGA, no FP is the best fot congenital infection

• Differential agglutination (HS/AC) (useful for pregnant women)

“recent antigen” “late antigen”

Diagnosis cont.

• Avidity (12 vs 16 wk)• Body fluid coefficient• Enzyme-linked immunofiltration assay ELIFA

85% sensitivity for congenital Toxo• PCR in amniotic fluid 17-21 gest week 95%

sensitive, PCR from WBC of neonate• Ocular = characteristic lesion with positive

serology

Newborn suspected of toxo?

• General, ophtalmologic, neurologic ex• Head CT• Toxo PCR from peripheral blood buffy coat• Toxo specific and total IGG, IGM, IGE, IGA• CSF for Toxo PCR (+general CSF )• Mice inoculation

Treatment

• Pyrimethamine & Sulfadiazine

• Folinic acid (leukovorin) !!!• During pregnancy Spiramycin

Contraindicated in first trimesterDHFR inhibitor, bone marrow↓

Rash, hematuria, crystalluriaHypersensitivity, especially with HIV

Duration of treatment

• Acquired (if at all…) 4-6 wk• Ocular untill sharp borders usually 2-4 wks +

steroids• AIDS for life or until CD4>200 for more than 6

mts and no lesions• Congenital for 1 year

Pregnant woman

• If infection during the 6 mo prior to conception treat as described for the pregnant

• Spiramycin for prevention if motherdevelops acute toxo until 24 w

• If fetus is infected P&S&FA after 1st trimester• Acute toxo after 24 w = P&S&A• Amniotic fluid PCR 17-21 wk• Prevention!!!

HSV

Specific antiviral therapyNonspecific antiviral therapyPassive immunizationActive immunization

HSV

• Primary• Non-primary first infection• Recurrent symptomatic and asymptomatic

• Only in humans• Direct mucocutaneous contact• Any anatomic site• Predisposition

Incidence of Neonatal HSV Infection and Other Congenital Infections in North America.

Corey L, Wald A. N Engl J Med 2009;361:1376-1385.

Clinical Presentation

• Herpes Gingivostomatitis• Herpes Labialis• Herpes gladiatorum/scrumpox• Whitlow• Eczema Herpeticum• Genital Herpes (15% aseptic meningitis)• Ocular Herpes

HSV Clinical Manifestations cont.

• CNS infection: HSV1 encephalitis, Mollaret meningitis (HSV2)• Immunocompromised: mucositis, esophagitis,

tracheobronchitis, pneumonitis, sepsis-like

Pathogenesis of Neonatal Herpes Simplex Virus (HSV) Infection.

Corey L, Wald A. N Engl J Med 2009;361:1376-1385.

Perinatal inf

• Fewer than 30% of mothers have history of herpes

• Primary (>30% risk) vs recurrent (<2%)• Scalp electrodes• Intrauterine: skin vesicles, microcephaly,

keratononjuctivitis• During delivery: SEM, encephalitis,

disseminated

SEM

• 5-11 days few small vesicles• If untreated may progress

Encephalitis

• 8-17 days irritability, lethargy, poor feeding, poor tone, seizures

• Usually no fever• Vesicles 60%• If untreated 50% will die

Disseminated

• 5-11 days• Sepsis• Vesicles 75%• If untreated 90% will die

Dx

• DNA PCR• HSV IGM unreliable• HSV IGG only for retrospect• Cultures

Tx

• Acyclovir• Valacyclovir• Famciclovir (prodrug of penciclovir)• Foscarnet, cidofovir• Perinatal infection – high dose (60mg/kg/day)

Common Misperceptions about Neonatal Herpes.

Corey L, Wald A. N Engl J Med 2009;361:1376-1385.

Outcome of Neonatal Herpes.

Corey L, Wald A. N Engl J Med 2009;361:1376-1385.

Cytomegalovirus

• The most common cause of congenital infection

• Important opportunistic pathogen• β-herpes group• Large (200-300nm)

Pathogenesis

• Attachment gB, gH proteins (interact with cell surface heparan sulfate)

• Cytoplasmic inclusion typical (accumulation of nucleocapsids and tegument in the Golgi ap.)

Pathogenesis

• Mucosal (UR or genital)• Viremia• Leukocytes and endothelial cells infection• CMV-encoded cell traffic machinery• Different tissues tropism (PM healthy people

CMV was found in salivary, lung, kidney, liver, pancreas, gut, etc)

• Viral shedding 4-6 weeks after acquisition (saliva, urine, genital)

Pathogenesis cont

• Interfere with immune response• Maintenance of viral genome in CD34+ cells,

also kidney and salivary• Severity of disease parallels the immunity

impairment• Antibodies modify cannot prevent infection• Critical role of T-cell mediated (most severe

infection after BMT recipients, AIDS (<100cd4) and solid organ after ATG treatment)

Pathogenesis

• Majority of congenital infections are benign• Congenital symptomatic at birth CMV=Microcephaly, IC calcifications, CSF protein↑↑,

seizures, cochlear, vestibular defects (Mondini dysplasia), retinitis, hepatitis

• 40% of maternal primary are transmittes• First trimester = 26% symptomatic (32%),

third=6%(15%)

Epidemiology

• At areas with high seropositivity >50% positive at 1 yr, >90% of first time mothers

• US overall prevalence is 59%• Child care centers• Second peak adolescents (sexual transmission)• Vertical (10% of seropositive mothers shed

CMV at genital tract, 50% of neonates will be infected)

Epidemiology

• Congenital CMV 0.2-2.2% live births• Nosocomial: breast milk, blood products

(leukocytes!), organ T, BMT, BW<1250g• Child care workers at risk, medical workers are

considered not at risk

Clinical

• Heterophil-negative mononucleosis (mean duration of fever 14 days)

• Peak ALT usually <300 IU/L• The expected course is recovery without

sequellae in healthy host

Clinical – unusual complications

• DVT, uveitis, persistant trmbocytopenia, hemolytic anemia, myocarditis, GI ulcerations, transverse myelitis, Guillain-Barre, encephalitis

Clinical manifestations – congenital CMV

• >90% appear healthy at birth• 7-10% petechiae, microcephaly,

thrombocytopenia, conjugated hyperbilirubinemia, optic atrophy, seizures, poor sucking reflex etc etc

• 5% of asymptomatic at birth will have CNS seq• 7-10% will have progressive SNHL

CMV in premature

• 20y ago transfusion related syndrome in VLBW• Rare today because of leukocytes filtration• 59% of premature <1500 gr newborns of CMV

positive mothers who were fed mother’s milk were infected, half of them symptomatic (?)

• Compared with term less maternal IGG• Symptoms = sepsis like• No consensus, controversial studies

Transplant patients

• Solid organ: Most common RN DP (majority will develop disease w/o

treatment)Can occur at RP also if profound immunosuppressed (5-25%)4-12 weeks after transplantationFever, malaise arthralgia, hepatitis, pancytopemia,

deterioration of graft functionPneumonitis is more common in lung or heart lung

transplantsAntithmocyte globulin or anti Tlymph ab at risk

Hematopoietic Stem Cell Transplantation

• Similar as SOT• Pneumonia and GI disease!!!• Prior to routine antiviral therapy 40% interstitial

pneumonia (half of them CMV with 50% mortality)

• At risk DP RN, GVH, lymphopenia• Due to ativiral therapy only 5% HSCT will

develop CMV during first 120 d but late onset disease has become a problem

CMV in AIDS

• Extremely low CD4 (<50)• Usually retinitis, esophagitis or colitis• Controversial in neurological AIDS syndromes• Adults>children

Lab

• In the healthy IGG, IGM (unreliable during pregnancy), IGG avidity

Lab - congenital

• Detection of CMV in body fluids within first 3 weeks

• Culture, shell vial, PCR• Quantification in blood – to assess risk of

sequella

Lab Dx Immunocompromised

• Quantification of CMV DNA in blood (different techniques: whole blood, leukocytes, plasma)

• pp65 antigenemia (immunofluorescence staining)

• Lack of standartization

Rx

• Acquired healthy – not indicated• Congenital symptomatic ganciclovir 12

mg/kg/day in two doses daily for 6 weeks “deserve consideration”

• Congenital asymptomatic “no evidence to support” but…