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Intrauterine Infection

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

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Intrauterine Infection

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  1. Intrauterine Infection

  2. Intrauterine infection • Abortion /stillbirth • Congenital Malformation • IUGR • Prematurity • Acute neonatal disease/delayed neonatal disease • Asymptomatic • Persistent infection with late sequelae

  3. Timing (which trimester)

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

  5. Blueberry Muffin • Dermal erythropoiesis • CMV • Rubella • Parvo • Congenital Leukemia • Rh hemolytic disease

  6. Pregnant Women Screening (CDC) • HIV • Syphilis • HBsAg • C trachomatis • N gonorrhhoeae if at risk • GBS (35-37 w)

  7. Toxoplasmosis Toxoplasmagondiihuman infection: • Undercooked meat (oocysts) • Contact with contaminated materials (sandbox) (oocysts) • Organ/BM transplantation (tachyzoite/cyst) • IU (maternal infection during pregnancy)

  8. Primary Acquired Toxoplasmosis • Mononucleosis like (fever, myalgia, rash, lymphadenopathy, hepatitis, meningitis, encephalitis, pericarditis, unilateral chorioretinitis, myo/pericarditis)

  9. Ocular Toxoplasmosis Congenital or acquired 30-40% of chorioretinitis in USA and western Europe

  10. 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

  11. 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, metaphyseallucency • SIADH, hypothyroidism, hypopit

  12. 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?

  13. 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

  14. Serology cont. • IgG indirect fluorescent antibody 1-2wk after infection, peaks at 6-8 wk, persist fo life at low titers, not standardised • IgMIFA 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”

  15. 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

  16. 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

  17. Treatment • Pyrimethamine & Sulfadiazine • Folinic acid (leukovorin) !!! • During pregnancy Spiramycin Rash, hematuria, crystalluria Hypersensitivity, especially with HIV Contraindicated in first trimester DHFR inhibitor, bone marrow↓

  18. 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

  19. 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!!!

  20. HSV Specific antiviral therapy Nonspecific antiviral therapy Passive immunization Active immunization

  21. HSV • Primary • Non-primary first infection • Recurrent symptomatic and asymptomatic

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

  23. Incidence of Neonatal HSV Infection and Other Congenital Infections in North America. Corey L, Wald A. N Engl J Med 2009;361:1376-1385.

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

  25. HSV Clinical Manifestations cont. • CNS infection: HSV1 encephalitis, Mollaret meningitis (HSV2) • Immunocompromised: mucositis, esophagitis, tracheobronchitis, pneumonitis, sepsis-like

  26. Pathogenesis of Neonatal Herpes Simplex Virus (HSV) Infection. Corey L, Wald A. N Engl J Med 2009;361:1376-1385.

  27. Perinatalinf • 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

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

  29. Encephalitis • 8-17 days irritability, lethargy, poor feeding, poor tone, seizures • Usually no fever • Vesicles 60% • If untreated 50% will die

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

  31. Dx • DNA PCR • HSV IGM unreliable • HSV IGG only for retrospect • Cultures

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

  33. Common Misperceptions about Neonatal Herpes. Corey L, Wald A. N Engl J Med 2009;361:1376-1385.

  34. Outcome of Neonatal Herpes. Corey L, Wald A. N Engl J Med 2009;361:1376-1385.

  35. Cytomegalovirus • The most common cause of congenital infection • Important opportunistic pathogen • β-herpes group • Large (200-300nm)

  36. Pathogenesis • Attachment gB, gH proteins (interact with cell surface heparan sulfate) • Cytoplasmic inclusion typical (accumulation of nucleocapsids and tegument in the Golgi ap.)

  37. 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)

  38. 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)

  39. 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%)

  40. 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)

  41. 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

  42. 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

  43. Clinical – unusual complications • DVT, uveitis, persistanttrmbocytopenia, hemolytic anemia, myocarditis, GI ulcerations, transverse myelitis, Guillain-Barre, encephalitis

  44. 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

  45. 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

  46. 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

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