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 acquired 30-40% 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 1 st trimester 17% severe infection 3 rd 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 test Specific, 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 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 trimester DHFR inhibitor, bone marrow↓ Rash, hematuria, crystalluria Hypersensitivity, 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 1 st trimester Acute toxo after 24 w = P&S&A Amniotic fluid PCR wk Prevention!!!

HSV Specific antiviral therapy Nonspecific antiviral therapy Passive immunization Active 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:

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:

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:

Outcome of Neonatal Herpes. Corey L, Wald A. N Engl J Med 2009;361:

Cytomegalovirus The most common cause of congenital infection Important opportunistic pathogen β-herpes group Large ( nm)

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 % 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 transplantation Fever, malaise arthralgia, hepatitis, pancytopemia, deterioration of graft function Pneumonitis is more common in lung or heart lung transplants Antithmocyte 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…