Intrauterine infections: “TORCH” מציגה: אריאלה קלוטשטיין אופק הנחיה: פרופ' יחיאל שלזינגר

What does she have?? Hypothetical case S.A. female neonate Has: Jaundice HSM Ptechiae PDA Lymphadenopathy Hearing loss

Congenital infections: 3 Routs of infection: Trans placental: TORCH Ascending/intrapartum: HSV, CMV, HBV, HIV Breast milk: HBV, CMV, HIV

Transplacental infection May occur at any time during gestation Signs and symptoms may be present at birth or be delayed for months of even years. importance of stage of embryonic life in the manifestations of the infection: 1st trimester: may alter embryogenesis and result in malformations (rubella) 3rd trimester: often results in active infection at the time of delivery (toxoplasmosis, syphilis)

Protection Maternal antibody is effective for protection of the fetus, in some of the cases (rubella) transplacental transmission of infection to a fetus is variable because the placenta may function as an effective barrier

Clinical signs and symptoms Maternal- most are asymptomatic Infant- range from early spontaneous abortion, congenital malformation, intrauterine growth restriction, premature birth, stillbirth, acute or delayed disease in the neonatal period, or asymptomatic persistent infection with sequelae later in life. In some cases, no apparent effects are seen in the newborn infant.

What is TORCH? T- Toxoplasmosis O- others R- Rubella C- cytomegalovirus (CMV) H- Herpes

Toxoplasmosis Caused by the obligate intra-cellular parasite Toxoplasma Gondii Route of infection: Fecal-oral: Cat feces uncooked meet, contaminated water and soil, unpasteurized goat milk. Usually, the infection causes a mild flu-like illness, or no illness at all. BUT, in immunocompremised or pregnant women it can be fatal, and cause symtoms such as: encephalitis, myocarditis and pneumonitis.

Toxoplasmosis- continue… Fetal transmission: in a primary infection, or chronic disease in immunocopremised mother. The risk of fetal transmission increases with gestational age The earlier in pregnancy the transmission occurs- the damage is worse.

Toxoplasmosis- continue… Signs and symptoms: 1st trimester: death, opthlmologic and CNS sequalea 2nd trimester: “classic triad”: hydrocephalus, intracranial calcifications, chorioretinitis. Jaundice, HSM, anemia, lymphadenopathy, microcephaly, developemental delay, visual and hearing problems, and seizures. 3rd trimester: usually asymptomatic at birth. תמונה תחתונה- צהבת, הפטוספלנומגליה, פורפורה טרומבוציטופנית תמונה אמצעית- קלציפיקציות תמונה עליונה- כוריורטיניטיס- Severe, active retinochoroiditis.

Toxoplasmosis- continue… Treatment: Pyrimethamine- antimalarian medication Sulfazidime Leucovorin- folinic acid

Others… We’ll just come back to it later…

Rubella- “The German Measles” Member of the Togaviridae family. Route of infection: Respiratory secretions (both direct contact and droplets) Transplacentally.

Rubella- continue… Complications: Clinical manifestations: “blueberry muffin” rash Lymphadenopathy HSM Thrmbocytopenia Interstitial pneumonitis Radiolucent bone disease IUGR Hyperbilirubinenemia Complications: Eye problems: micropthalmus, pigmentary retinopathy, cataracts, glaucoma Cardiac: peripheral pulmonic stenosis, PDA Endocrine: Diabetes mellitus Neurologic: developmental delay, encephalitis, sensorineural hearing loss

Rubella- continue… Diagnosis: Treatment: Positive infant rubella IgM titer- recent infection Culture: blood, urine, CSF, oral & nasal secretions persistently elevated or rising IgG titers over time. Treatment: Supportive care only.

Cytomegalovirus Member of the Herpesvirus family Most common congenital infection in the US (0.5-1% of live births in industrialized nations, approximately 40000 annualy in the US) Route of infection: Transplacentally During delivery Postnatally (breastmilk (causes no clinical sequelae), or direct contact with other body fluids) Maternal infection before pregnancy significantly reduces the risk of congenital CMV.

CMV- continue… Clinical manifestations: 30% mortality rate Symptoms include: IUGR Microcephaly Periventricular calcifications HSM Petechiae Hearing loss Jaundice Thrombocytopenia retinitis Hypotonoia Lethargy In preterm infants may present as sepsis Clinical manifestations: Most babies are asymptomatic at birth (90%) Infants to mothers with primary infection- 5-20%: overtly symptomatic. 30% mortality rate 80% of survivors: severe neurologic morbidity Classic linear periventricular calcifications and cortical atrophy

CMV- continue… Treatment: no approved agent Complications: CNS sequelae: retinitis, sensorineural deafness, developmental delay) Will appear in 20% of asymptomatic neonates Will appear in 50% (or more!) of symptomatic neonates Diagnosis: demonstration of the virus in body fluids (e.g. urine or pharyngeal secretions). Serology for CMV IgG antibody determination are not useful in this case. Laboratory abnormalities include: abnormal blood counts (especially thrombocytopenia), hemolytic anemia, elevated transaminases, and elevated direct and indirect serum bilirubin. Treatment: no approved agent Ganciclovir- improves hearing loss and neurodevelopmental outcomes  In a phase II randomized, controlled multicenter clinical trial evaluating the use of ganciclovir for the treatment of infants with symptomatic congenital CMV infection and evidence of CNS involvement, 47 infants received ganciclovir (8 to 12 mg/kg daily in 2 divided doses for up to 6 weeks) [49]. Ganciclovir was discontinued in eight patients because of side effects but was well tolerated in the other newborns. Decreased excretion of virus was noted during ganciclovir administration, although viruria returned promptly after cessation of therapy. Sixteen percent of the infants had stabilization or improvement in hearing at six months of follow-up. Similar results were observed in a smaller trial [50]. A phase III randomized clinical trial of ganciclovir (6 mg/kg per dose IV every 12 hours) for six weeks in neonates with virologically confirmed congenital CMV disease and neurologic involvement suggested that treatment with ganciclovir prevents hearing deterioration at six months and possibly beyond [51]. The conclusions are limited because only 42 of the 100 enrolled subjects were evaluated for the primary outcome (hearing assessment at six months) [52]. In addition, neutropenia (absolute neutrophil count ≤1250/microL) was more common among ganciclovir recipients than controls (63 versus 21 percent). It remains unknown whether this early and intensive administration of ganciclovir will hasten resolution of disease, beneficially influence growth and development, decrease auditory and visual impairment, or improve intellectual outcome in these infants. Ganciclovir should not be used routinely for fear of unforeseen long-term effects, such as testicular atrophy and bone marrow suppression. However, it may be reasonable to consider in selected cases. However, anecdotal evidence does suggest that critically ill newborns, especially those who are premature and have CMV pneumonia, may benefit acutely from ganciclovir treatment. Compassionate use also may be appropriate for patients with life- or sight-threatening congenital CMV. Thus, we recommend its use only after careful consideration in selected cases. The treatment of newborns with asymptomatic congenital infection is not indicated. Even though these infants are at some risk for hearing loss, the side effects of therapy with currently available antiviral agents and the lack of established benefit argue against routine administration. The use of CMV hyperimmune globulin has not been evaluated extensively for the treatment of congenital CMV disease. However, anecdotal reports suggests some benefit [53,54]. Both CMV immune globulin and alpha interferon are being studied for the treatment of congenital CMV. The development of CMV vaccines also is underwa

Herpes simplex virus Double-stranded DNA virus of the herpesviridae family Route of infection: Primarily: during birth or virus ascending after the rupture of membranes. Transplacentally- rare Postnatally Greatest risk: primery maternal infection during third trimester.

HSV- continue… Clinical manifestations: Complications: SEM disease: skin, eyes, mucosal involvement CNS disease- temperature instability, respiratory distress, poor feeding, and lethargy (nonspecific) Disseminated disease with multiple organ involvement Usually presents in the first 6 weeks. Most are asymptomatic at birth although many are born prematurely Complications: Untreated- high morbidity and mortality Treated: SEM- best prognosis. 50% will suffer from recurrent skin outbreks. CNS- good survival, significant neurologic sequelae

HSV- continue… Diagnosis: Treatment: IV acyclovir Serum HSV IgM HSV PCR of CSF- test of choice, may be false negative in the first 5 days HSV culture of a lesion/mucosal surface- best for SEM Treatment: IV acyclovir improves mortality in all infants Improves neurologic development in those with SEM and disseminated disease.

And…. Back to Others! HIV HBV Parvovirus B19 Syphilis HCV VZV TB

HIV Member of the retroviridae family. Route of infection to the fetus: Transplacentally During labor and delivery- the highest risk (exposure to maternal blood) Through breastfeeding Clinical manifestations: Asymptomatic at birth T-cell count declines and opportunistic infections take hold: Pneumocystis jiroveci, VZV, CMV, HSV….

HIV- continue… Diagnosis: The American Academy of Pediatrics and the CDC: HIV screening for all pregnant women in the US. According to viral load: HIV drug prophylaxis C-section before rupture of membranes (viral load greater than 1000 copies/mL at full term delivery) avoidance of breastfeeding Early detection in the infant

HIV- continue… Diagnosis: Treatment: In the infant: HIV-1 DNA/RNA pcr at: 14-21 days after birth 1-2 months 4-6 months Considered uninfected if: 2 negative tests- one after 1 month, and another at 4 months + 2 negative antibody tests from different specimens obtained at 6 months + Treatment: Infants suspected: zidovudine until 6 weeks of age Infants confirmed: further antiretroviral treatment

HBV DNA virus of the hepadnavirus family Route of infection: transplacentally- rare During delivery with exposure to maternal blood- most cases. Clinical manifestations: Most asymptomatic at birth Rarely- signs of hepatitis: jaundice, thrombocytopenia, elevated transaminase conc. , rash. The risk of morbidity and of progressing to a chronic infection and disease are inversely proportional to gestational age at the initial infection

HBV- continue… So… why are we worried? Diagnosis: Because- 25% of children chronically infected with HBV will develop hepatocellular carcinoma or cirrhosis! Diagnosis: In the US- women are screened for HBsAg If positive- the infant should receive HBV vaccine and Hepatitis B immune globulin within 12 hrs of birth. They should complete the regular program of vaccinations to HBV+two more+ HBsAg and anti-HBs testing at 9 months of age

HBV- continue… If the mother’s HBV status is unclear: Treatment: Immediate test for HBsAg: If negative- no further treatment If positive- the infant should receive HBV immunoglobin within 7 days of birth. Treatment: There is no treatment for acute HBV For chronic HBV- Lamivudine- approved for 2 years of age and older.

Parvovirus B19 Single-stranded DNA virus Hydrops fetalis:  a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments. Very high mortality rates Parvovirus B19 Single-stranded DNA virus Usually causes “fifth disease” (“slapped cheek”), and other symptoms. Route of infection: Respiratory tract secretions Contaminated blood Transplacentally Clinical manifestations: Hydrops fetalis (due to severe fetal anemia) Pleural end pericardial effusions IUGR death

Parvovirus B19- continue… Diagnosis: IgM titer from the infant serum PCR of amniotic fluid Treatment: Supportive care

Rubella!! What does she have?? Hypothetical case S.A. female neonate Has: Jaundice HSM Ptechiae PDA Lymphadenopathy Hearing loss Rubella!!

Summary Timely diagnosis of congenital infections is crucial to the initiation of appropiate therapy High index of suspicion and awareness is required: Laboratory results obtained from the mother during pregnancy Clinical manifestations including: Hydrops fetalis Microcephaly Seizures Cataract Hearing loss Congenital heart disease HSM Jaundice Rash thrombocytopenia

The END…