Congenital Infections: Identification, Treatment and Outcomes

Herpes Simplex Virus (HSV)

-2 types of HSVàboth can cause neonatal disease -HSV type-1 -HSV Type-2 -Both members of Herpesviridae family -Double stranded DNA -Develop life long latency in sensory neural ganglia Notice the cluster of vesicular lesions noted on this neonate/infants scalp that is indicative of HSV infection. These lesions are highly infectious though not all neonates with HSV infections will develop vesicular lesions.

Toxoplasma gondii: Detection/Testing

-Antenatal -PCR from amniotic fluid or fetal blood -Culture from blood or placental tissue -Postnatal -Serum testing of cord blood or blood sample from neonate for PCR or antibody screening (Palo Alto*) -IgA, IgE testing preferred -Untreated, however may demonstrate clinical signs of infection over time PCR looking for parasitic DNA Palo Alto reference lab is the recommended source for sending specimens for testing. Palo Alto infant panel includes specific testing that can determine acute infection vs. later stage infection along with avidity testing Antibodies detected 1-2 months post infection and IgM testing is unreliable (high false-neg and false-pos) and takes a while to drop so timing of infection is difficult to detect

CMV Detection/Testing

-Antibody screening not as effective in newbornsàmaternal testing IS helpful -CMV culture is gold standard (throat or urine) but is time intensive and challenging for some labs -CMV PCR (blood or saliva) -Dried blood spot testing (low sensitivity) -Dried saliva spot testing has been validated Presence of maternal antibodies and immaturity of neonatal immune system impede testing PCR testing looking for viral DNA

Routine ACOG testing during pregnancy-Early pregnancy

-CBC -Blood Type -UA/Urine Cx -Rubella -Hepatitis B (+/- C) -STI's (RPR, GC/Chl) -HIV -TB -Varicella

Rubella diagnostic testing

-CBC, LFTs, electrolytes, HUS/RUS, ECHO, LP, CXR and long bone films, serial hearing ophthalmologic exams -Long term management requires following for endocrine complications (ie: DM, hypothyroid)

Parvovirus B19 (fifth disease)

-Characterized by distinctive facial rash (slapped cheek), with pruritic macular rash on the trunk that spreads to the extremities. May be preceded by non-specific illness (fever, malaise, myalgia, headache) -Transmitted by respiratory droplets, through blood products, or vertical (transplacental) transmission Characteristics in children with Parvovirus infectionàit is quite important to counsel pregnant mothers who present to primary care clinics with their older children to be alert to signs and symptoms of their own viral illness. vertical (transplacental) transmission ~1-3 wees following maternal infection

Prenatal suspicion

-Confirmed/suspected exposure to viral infection Maternal flu-like illness -Concern over fetal growth -Evidence of fetal anomaly -Evidence of fetal anemia -Evidence of placental pathology -Evidence of Hydrops Fetalis Concern over fetal growth is the most common reason to initiate a work-up for congenital infections. Other problems identified during routine ultrasound evaluations can include evidence of fetal anomaly, fetal anemia, or placental pathology.

Rubella clinical manifestations

-Congenital rubella syndrome severe and disabling -Features: -Adenopathy -Radiolucencies in long bones -Encephalitis, hydrocephalus, SNHL (60%) -Cardiac defects (pulmonary arterial hypertrophy, PDA, Coarctation) (58%), hypertension -Cataracts (78%), Chorioretinitis, micro-opthalmia -Growth restriction -Hepatosplenomegaly, thrombocytopenia, purpura, anemia, jaundice Radiolucencies only last a few weeks and typically do not have long term effects Treatment is aimed at supportive therapy—no definitive treatment for rubella

Syphilis

-Develops from infection by the spirochete Treponema pallidum -Unable to cultivate in vitro -Congenital syphilis occurs following infection of the placenta and can occur at any stage of the pregnancy

Zika diagnosis

-Diagnosis -Difficult as 80% are asymptomatic infections -Rates of microcephaly are not consistent in all countries and may be due, in part, to mutations with increased virulence -Trioplex Real-Time RT-PCR (rRT-PCR) assay and the Zika MAC-ELISA (authorized for emergency use by FDA) -Molecular testing (RNA nucleic acid testing) on paired urine and serum samples with corresponding IgM

Parvovirus B19: Diagnosis

-Diagnosis: -Diagnosis made when symptoms of infection seen (either in mom with exposure hx or fetus) -IgM detectable 7-10 days following infection (peak 10-14) -Parvovirus B19 DNA PCR- highly sensitive (96%) -Amniocentesis can diagnose fetal infection -Close monitoring for fetal hydrops or evidence of severe fetal anemia -May require intra-uterine fetal transfusions

CMV Epidemiology

-Double-stranded DNA -Largest member of the herpes viral family -Persists for life with periodic reactivations and viral shedding -Toddlers infected post-natally are known to shed virus for a mean of 18 months post-exposure (Plosa et. Al. 2012) -Highest incidence of in utero transmission is following primary maternal infection during pregnancy (32%) Initial maternal infection at the mucosal level with replication occurring and viral spreading to visceral organs -Transmission to fetus/neonate-horizontally, vertically or via transfusion/transplantation -Infected maternal leukocytes cross into the placenta -Incubation period unknown for horizontal transmission -Transmission can be prevented with good hand hygiene practices Congenital CMV infection occurs via the transplacental route in the fetus though post-natal infection can occur via several other pathways (breastmilk, salivary contact, blood) (placental pathology can detect CMV resulting in placentitis) Manifest 3-12 weeks following blood transfusions or 1-4 weeks following transplants (variations due to viral inoculum size and route of infection)

Rubella

-Epidemiology -U. S. immunization rates >90% -However rubella vaccine not routinely provided in all countriesà still a disease of concern world-wide -Non-immunized women 10-20% susceptible -Congenital defects directly proportional to gestational age at time of infection -First 8 weeks~75% -Weeks 9~12-50% -Weeks 13~20-20% ->20 weeks gestation~0-10% transmission -Some slight increase in transmission at term gestation Congenital defects linked to organogenesis timeframe maternal viremia results in necrotic foci within the chorionic villi and the placental capillaries resulting in necrotizing vasculitis with focal inflammatory response. Since the fetal immune system is not functional, the virus begins replicating without an inflammatory response resulting in fetal infection and organ damage. The resulting malformations are caused either due to the cytopathic effect of the rubella virus or due to reduced mitosis in the virus infected cells caused by chromosomal breakdown and the formation of a mitosis inhibiting protein. Consequently, the lack of adequate cell mass affects organogenesis and results in hypoplasia or arrested development of the affected organs Spread by droplet method (coughs and sneezes) and is highly contagious

Toxoplasma gondii: Epidemiology

-Epidemiology: -Protozoa—intracellular parasite -Contraction of disease occurs via 3 main methods: -Foodborne -Zoonotic-Primary host—feline -Congenital-mother to child -Three strain types-types I & II most commonly associated with congenital infection Foodborne: contamination of undercooked meats such as pork, lamb or venison as well as shellfish such as oysters, clams, and mussles. Cats are infected by eating infected rodents, birds or other small animals resulting in oocysts excreted in feces with subsequent ingestion. (domestic cat who doesn't go outside has an ~12% chance of infection). Ingestion can occur following changing of litter in litter boxes (change litter box daily as the parasite doesn't become infectious until 1-5 days after being shed), contaminated surfaces (cats on counter tops), unwashed hands following gardening or eating unwashed fruit/vegetables , or ingestion of contaminated drinking water Rare instances of transmission via blood transfusions, solid organ transplant, or via handling of infected blood

Enterovirus Coxsackie

-Group of viruses that includes Polio, Human enteroviruses A-D with subspecies of Coxsackie, enterovirus, and echovirus -Coxsackie well known for hand, foot, mouth disease -Transplacental transmission at any time of pregnancy with risk to fetus higher during times of organogenesis -Coxsackie B and Enterovirus 11 has been noted to be transmitted as nosocomial infection within ICU's and can cause overwhelming illness

CMV prevention

-Hang hygiene most effective for horizontal transmission -CMV negative blood donors combined with transfusion practices using irradiated and leuko-reduced transfusions** -Pasteurization (72 °C x5 secs) or freezing of human milk (to -20°C) Especially when changing diapers due to asymptomatic excretion Data available that leukocyte reduced transfusions for most high risk patients-as the virus is carried within the WBC's the risk is lowered with packed RBC transfusions

Zika

-Has spread rapidly since discovery in Brazil in 2015 -Most notable adverse pregnancy outcome is severe microcephaly and other brain anomalies -Strong push toward public education regarding mosquito control and bite prevention -Specifically targets neural progenitor cells and highest risk is early in pregnancy when organogenesis is occurring

Syphilis: Early findings (within 2 years)

-Hepatosplenomegaly -Rhinitis (nasal secretions highly infective) -Lymphadenopathy -Mucous membrane lesions -Pneumonia -Osteochondritis -Pseudo paralysis -Maculo-papular rash -Edema -Hemolytic anemia (Coombs -) -Thrombocytopenia -IUGR -Jaundice

Herpes Simplex Virus (HSV): Epidemiology

-Humans are natural reservoir -Life long latency with periodic reactivation ->90% of adults have HSV-1 by 5th decade, though not all with clinical disease -Both HSV-1 and HSV-2 can cause genital infection -Rate of HSV-2 infection higher in women without immunity to HSV-1 ~2/3 infected women are asymptomatic or have subclinical features leading to delayed diagnosis Both types of HSV (1 & 2) can be responsible to neonatal disease and the most vulnerable time for initial exposure occurs during pregnancy. Though HSV infection in the neonate is relatively uncommon, evaluation of potentially exposed neonates is quite common. It is estimated that between 20-25% of the adult population have HSV-2 (typically thought of as genital) while HSV-1 (historically thought of as the virus causing fever blisters) now accounts for anywhere between 20-50% of genital lesions within the US. It is imperative for the APN to be able to identify the neonate at risk for HSV infection as well as recognize the signs and symptoms of this disease in order to initiate therapy in a timely manner.

Congenital Rubella Syndrome (CRS)

-Incidence of infection has decreased from 57,686 cases in 1969 to fewer than 10 cases annually -Why? -Belongs to the Togavirus family, single stranded RNA virus -Transplacental, vertical transmission or inhalation of aerosolized particles These photos demonstrate findings consistent with CRS (left picture is another picture of "blueberry muffin" lesions, right picture demonstrates congenital cataracts). Congenital rubella, the epidemic led to an estimated 11,250 fetal deaths, 2,100 newborn deaths, 20,000 babies born with CRS. According to the CDC, between 2005-2015 8 babies with CRS were reported in the US

Cytomegalovirus

-Incidence: -CMV: most common congenital viral infection in the U.S. with ~40,000 infants/year infected -10-15% develop s/s of CMV sequelae -Most common cause of sensorineural hearing loss (SNHL) in children (25%) https://www.cdc.gov/cmv/hearing-loss.html -World-wide rates of infection range from 40-100% depending on location -Humans are the only host and transmission occurs through close contact with body fluids (vaginal/cervical/seminal fluids, urine, saliva, breast milk, and blood products) According to data published by the WHO and CDC, CMV can infect people of all ages with over 50% of the population infected by the age of 40 (and 33% infected by age 5). CMV is a latent virus (with period of dormancy and shedding) and it can evade both the innate and adaptive human immune system. A healthy immune system can manage, but not eliminate, the virus and CMV status should be known prior to treatments that alter the immune system such as solid organ transplant or hematopoietic stem cell transplantation.

Toxoplasma gondii

-Incidence: -Seropositive women* range from 11-77% depending on country of origin -World-wide ~200,000 neonates born with congenital toxoplasmosis -US ~ 400-4,000 cases annually -Most common congenital parasitic infection in US ~85% of women susceptible in US Seropositive women of childbearing age (between the ages of 15-49y) ranges from 11-77%. More common in areas of the world with hot and humid climates increasing the survival of the oocytes

Syphilis: Late finding

-Late findings -Not infectious and represents scaring from early disease -Hutchinson teeth -Mulberry molars -Saddle nose deformity -Interstitial dermatitis -Healed chorioretinitis -Secondary glaucoma -Corneal scarring -Intellectual disability, -Hydrocephalus, -Epilepsy -Optic nerve atrophy Most neonates develop symptoms between the 3rd-14th week of life Hutchinson's teeth~defect in enamel of secondary/permanent teeth

Herpes Simplex Virus (HSV): Maternal Diagnosis

-Lesion cultures -HSV IgG and IgM with type specific differentiation Neonatal diagnosis -Viral surface cultures: -Eyes, nares, mouth, umbilicus, rectum -Lesion cultures—remains gold standard -Blood and/or CSF PCR -HSV IgM -Imaging when determining other disease sequelae When making a diagnosis, it is imperative to have testing of Mother performed to determine initial vs. recurrent HSV disease (especially important for women presenting with a lesion at the time of delivery as it helps to determine the neonatal treatment plan). Neonatal diagnosis frequently requires several samples to determine the type and severity of the infection. Blood and CSF PCR is highly valuable due to the decrease in time needed for diagnosis, though viral culture remains the definitive method for diagnosing HSV infection. CSF PCR is necessary to determine CNS involvement as this information aides in determining treatment duration HSV IgM would be the only testing in the neonate as any IgG antibodies would likely be acquired through passive immunity from the mother, thus serologic testing is frequently deferred in deference to the culture and PCR testing

Treatment for congenital CMV

Symptomatic CMV infection have been demonstrated to have improved audiologic and neurodevelopmental outcomes when treated -Oral: -Valganciclovir: 16 mg/kg/dose BID x6 months (adjusting for weight gain monthly) _Parenteral: -Ganciclovir: 6 mg/kg/dose BID -Significant neutropenia can develop with treatment and dosing needs to be adjusted (50% reduction recommended) Treatment still debated even with evidence of symptomatic infection. New treatments are being investigated (CMV IVIG, CMV vaccine) Treatment may still be recommended through the age of 2 as late-onset neuro symptoms may be diminished Treatment with Ganciclovir blocks viral DNA synthesis and terminates chain replication and has been demonstrated to result in improved audiologic and CNS outcomes Myelosupression (neutropenia, anemia, thrombocytopenia) reported as side effects Cleared renally Additional medications available for other therapies (Foscarnet (IV)—used in HIV infected infants/children or those demonstrating resistance); Cidofovir (IV) in children

Syphilis Treatment for Neonates

Treatment for neonates -(2) Benzathine Pen GàIM injection only (50,000 IU/kg) -(3) Aqueous Pen G IV every 12 hours (<1 week) or every 8 hours (>1 week) x10 days** Cannot interrupt treatment-if misses more than 1 day of treatment then the entire 10 day course needs to be repeated!! Maternal treatment also with Pen G- requires desensitization prior to treatment

Enterovirus Coxsackie: Treatment

Treatment is supportive only

Cytomegalovirus (CMV)

Ventriculomegaly along with intracranial calcifications seen in the picture

Initial exposure to pathogen

With the maternal initial exposure, she begins to produce IgM antibodies fairly quickly but IgG antibodies are slower to develop. This leads to viral exposure in the placenta, barrier likely becomes disrupted due to inflammatory process increasing the risk of viral pathogen crossing into the fetal system (without any aid from maternal IgG antibodies). This infection overwhelms the fetal system and leads to disease. Can you see how an initial exposure is different from subsequent exposures? In subsequent exposures there is a much more robust maternal immune response along with adequate IgG antibodies to assist the fetus with a potential exposure.

congenital infections (TORCH)

-More than just TORCH infections -TORCH originally described in 1971 and was designed to guide a diagnostic work-up for critically ill neonates -Panel of testing developed of most common pathogens known at that time -"TORCH" or "TORCHeS" testing panels now outdatedàapproach is now for specific testing -Testing detected antibody response -Single serum test Congenital infections was previously known by the acronym TORCH infections. The panel of testing first described in 1971 was used as a guide to drive the diagnostic work-up of critically ill neonates and consisted of a panel of pathogens that were known at the time. Over time the (O or Other) began to include more and more pathogens and the work-up broadened significantly making a "panel" challenging. The approach has changed to specific antigen/antibody testing and PCR testing

Toxoplasma gondii: congenital infections

-Most often occurs via transplacental route during primary infection -Once infected, will have life long immunity -Risk of transmission increases with date of infection -13 weeks gestation ~15% transmission -36 weeks ~ 70% transmission -However sequelae worse if exposed earlier in pregnancy ~70% of newborns are asymptomatic at birth Some evidence suggests that routine Newborn screening can be used to detect toxoplasmosis: 10,000 newborns screened (seven found to be positive on screening and required infant/maternal testingà six confirmed positive (86% reliability)

Enterovirus Coxsackie: Neonatal illness

-Neonatal illness severity depends on GA -Coxsackie B and Enterovirus 11 can cause severe systemic illness with early symptoms of poor feeding, respiratory distress, listlessness -Progress to more severe symptoms of myocarditis or fulminant hepatitisà mortality up to 70% in these cases

Parvovirus B19

see picture

Cytomegalovirus (CMV)

An extra-medullary erythropoiesis with the typical "blueberry muffin appearance" common in viral infections (not necessarily specific to CMV) in the bottom 2 pictures

Enterovirus Coxsackie: Diagnosis

Diagnosis -Viral culture from stool, rectal swab, nasopharyngeal aspirates, and/or CSF -Diagnosis may be delayed with viral culture up to 2-6 days -PCR testing of CSF and/or nasopharyngeal aspirates faster but may have some misidentification

Syphilis Diagnosis

Diagnosis: -Treponemalà looking for antibodies to treponema spirochete -Florescent treponemal antibody absorption (FTA-ABS) -Treponemal particle agglutination (TP-PA)àless sensitive in primary infection than FTA -Non-Treponemalà looking for antibodies -Venereal Disease Research Laboratory (VDRL) -Rapid Plasma Reagin (RPR) -Antibodies pass across the placenta making fetal/neonatal diagnosis challenging -If titers 4x higher in neonate than mother more indicative of infection Any positive non-treponemal test needs to be followed up with a treponemal test antibodies against substances released by cells when they are damaged by T. pallidum (cardiolipin and lecithin)

Syphilis: Epidemiology

§Epidemiology ~1 million pregnancies affected by syphilis worldwide with 40% resulting in fetal or perinatal death -Risk Factors -Teenage pregnancy -Poor prenatal care -High Treponemal titers or late treatment -Illegal drug use, sexual promiscuity/prostitution, history of other STI's, contact with anyone with a STI, low SES, limited education -Maternal Signs/symptoms: -Fever, weight loss, anorexia, fatigue, arthralgias

Microorganisms can overwhelm this protective placental function leading to fetal infection and preterm labor. Organisms reaching the fetus across the placenta include (most common):

§Treponema pallidum, HIV, Parvovirus B19, Rubella, Toxoplasma gondii, and CMV Infections that lead to an overwhelmed response has been demonstrated to correlate to preterm labor and delivery (chorioamnionitis, effect of cytokine release)

Syphilis: Epidemiology

In 2018 there was an increase in primary and secondary syphilis from 2017àwith Baltimore City demonstrating >45.29/100,000 and PG County documenting the second highest rate in the state at 16.8 cases Increase most notable in males (89% of P&S cases) Increased for all racesàHowever, the incidence in the black/AA population is 3x that of all other racial groups Maryland ranked 7th highest in congenital syphilis rates based on 2017 data

Fetal Protections-Maternal immunity

Innate: 1st exposure -Toll-like receptors (TLRs): essential for recognition of micro-organisms and induction of inflammatory signals -Humans possess 10 different TLRs—all are present within the placenta (trophoblast) Adaptive: repeated exposure, memory response -Passive immunity passed from mother to fetus/neonate Maternal immune system a balancing act during pregnancy (protect Mother, not reject fetus)àinfectious non-self (bacteria/viruses) and the non-infectious self (mother, placenta, fetus) TLRs—present on surface of phagocytes and other cells, expression patterns vary according to stage of pregnancy Inflammatory signals: type 1 interferons, inflammatory cytokines and chemokines Different TLRs respond to different organisms and alteration of TLR function has been demonstrated in PTL, preE and IUGR (increased risk for transmission of infection)

Parvovirus B19: pathophysiology

Pathophysiology: -Parvo shows high affinity for erythroid progenitor, endothelial, and myocardial cells leading to direct cell injury as well as apoptosis -Clinical manifestations: -Most common symptomsà placentomegaly, severe fetal anemia and myocarditis -May result in fetal death, non-immune hydrops fetalis, thrombocytopenia, prematurity -Effects most severe when infection occurs prior to the end of the first trimester A fetus/neonate born following intrauterine exposures to parvovirus are severely anemic leading to complications associated with myocardial dysfunctionàascites, anasarca, pericardial and pleural effusions

HSV Maternal risk factors

-Low SES, female gender, minority ethnic group, longer duration of sexual activity, number of sexual partners, h/o other STI's -Highest risk of transmission is with primary infection -Diagnosis of primary vs. non-primary infections can be challenging in women with no known prior history -57% risk for first episode primary (never HSV-1 or 2) -25% risk for first episode non-primary infection -2% risk for recurrent genital herpes Anywhere between 20-33% of women are seronegative to either type of HSV prior to pregnancy thus at risk for contracting the infection during pregnancy and of the women who do contract the infection 60-80% of women have NO clinical features of an HSV lesion. In non-primary infections, If a mother is exposed to the virus that is not their primary HSV virus (previously had HSV-1 and then exposed to HSV-2 while pregnant) the risk for infection to the fetus/neonate is 25%. The risk for infection with the disease the mother has exposure to (either/both HSV-1 and 2) decreases to 2% due to the fact that the mother has already developed an immune response to the virus and that antibody response can be protective to the fetus/neonate. Acquisition occurs one of 3 ways •Intrauterine (5%) •Intrapartum (85%) •Post-partum (10%)

Toxoplasma gondii treatment

-Maternal -Treatment within 8 weeks of seroconversion demonstrated to decrease maternalàchild transmission -Treatment with Spiramycin, cotrimoxazole, and folinic acid. RCT's still needed -Neonatal -Combination of pyrimethamine-sulfadiazine and folinic acid for 1 year** -If develop bone marrow suppression then 21 day cycles can be used with breaks of 30 days. -Prednisone considered for neuro/retinal symptoms -Long term developmental and visual follow-up needed -Prevention: -Maternal education on proper hygiene and food preparation Education of toxo and hygiene practices decreases risk of contraction and should be first line of education. For those of you providing any prenatal counseling, discussion of proper cleaning practices, avoidance of raw or undercooked foods in addition to hand hygiene practices will be essential. Pyrimethamine (pai·ruh·meh·thuh·meen) is listed as a pregnancy category C and is especially avoided during the period of organogenesis (but in countries of the world where malaria is a significant concern, the WHO does recognize that the risk of malaria outweighs the risk of using Pyrimethamine. Spiramycin is most effective if initiated within 8 weeks of seroconversion **See the recommendation in the RedBook, or on the CDC website for dosing recommendations as the dosing and intervals change several times during the course of therapy. During 30 day breaks only use spiramycin for treatment

CMV-Maternal risk factors increase the incidence and severity

-Maternal age (young) -Non-white status -Single marital status -CMV immune status -No immunity-40% transmission with increase in fetal disease severity -Seropositive- 1-2% transmission -Neonatal risk factors- prematurity Transmission via blood transfusion significantly reduced due to use of leuko-reduced/CMV negative blood products. BM transmission in term neonates without sequelae, however in preterm neonates patients may have sepsis-like illness (pneumonitis, enteritis, thrombocytopenia and hepatitis)

Important questions to include in the HPI when determining the presence and potential source of congenital infection:

-Maternal health status? Age? Marital status? -High risk behaviors? Drug history? -Any recent travel outside the US? Country of origin? -Immunization history? Ever had chicken pox? Other common childhood infections (Fifth disease; Hand/foot/ mouth)? -Are there animal exposures? Any other children in the home? Ages of those children? Daycare? -Any recent illnesses in the home? Any symptomatic illnesses during pregnancy? -Occupational exposures? Young and unmarried women are at an increased risk for primary HSV exposure as well as other STI's (especially in the Baltimore/MD area as syphilis is a common pathogen in our area). High risk behaviors such as sex workers, human trafficking, IV drug use Those with young children or working with young children are at an increased risk for Fifth's diseaseàParvovirus B19; Hand, foot, mouthàCoxsackie Animal exposuresàdomesticated animals (especially cats), farm animal exposures, un-pasteurized milk

Enterovirus Coxsackie: Maternal presentation

-Maternal presentation may be asymptomatic or with febrile illness and may include -Vomiting, diarrhea, rash, petechiae, purpura, rashà hand, foot, mouth most typical presentation with small painful maculopapular or vesicular lesions

Toxoplasma gondii: Maternal risk factors increasing incidence and severity

-Maternal risk factors increasing incidence and severity -Cat owners (litter box) -Tropical climate ( survival of oocysts) -Consumption of raw, rare, undercooked meat -Signs of maternal disease -Fatigue, fever, headache, malaise, myalgia, lymphadenopathy Cat owners at lowest riskà strictly indoor cats fed diet of dried, cooked or canned food with low risk of ingesting oocysts Other rare maternal symptoms: hepatitis, pneumonia, myocarditis, encephalitis and deafness

Rubella Detection

-Maternal symptoms lasting 1-5 days: -Low-grade fever, headache, malaise, mild coryza, conjunctivitis -Arthritis, arthralgia occurs in up to 70% of women -Diagnosis occurs through serum + for rubella specific IgM or 4 fold increase in IgG titers (occurs ~10 days following contact) -Cord blood for Rubella specific IgM -Amniotic fluid for PCR -Neonatal -Cord blood or serum sample for Rubella specific IgM -Viral culture or PCR from either oropharynx, eye, throat, CSF, stool and urine Maternal immunization status should be determined early in pregnancy care Coryza—symptoms consistent with head cold

Herpes Simplex Virus (HSV): Clinical manifestations

-Maternal: -Lesions~ present as painful erythematous papules initially that rapidly progress to vesicles (often in clusters) -Frequently rupture, highly contagious fluid -May develop pustules with inflammatory response -Develop into ulcers with erythematous base and crust over -Most often lesions noted on vulva, labia, vaginal introitus or cervix -Neonatal: -Intrauterine exposure (rare): -Cutaneousà active lesions, scaring, cutis aplasia, hyper/hypo pigmentation -Neuro~ microcephaly, intracranial calcifications, hydranencephaly -Ocularà chorioretinitis, microphthalmia, optic atrophy -Peri-partum and post-partum exposure: -SEM diseaseà45% of infections, doesn't include CNS or other organ systems -CNS diseaseà30% of infections, may have lesions but no other organ system involvement -Disseminated diseaseà25% involving multiple organ systems including CNS (2/3rd) and lesions Intrapartum disease occurs with exposure to infectious lesions around the time of delivery Postpartum disease occurs as a result of contact with infectious lesion commonly oro-labial or other cutaneous source

Additional testing for the at risk fetus

-Organism specific IgM and IgG (with avidity*) testing -PCR testing from amniotic fluid -Serial ultrasound* (with doppler blood flow evaluation of the middle cerebral artery) When completing a work-up for congenital infections, antibody testing (IgM and IgG) should include avidity testing. Avidity testing (looking at multiple antigen binding sites working simultaneously thus increasing the strength): After an initial/primary infection, the IgG antibody produced has low avidity (not as many antigen binding sites) because it is not mature. After about 4 months, the antibodies mature and develop more antigen binding sites increasing the avidity. Therefore, if a woman has low-avidity IgG and positive IgM, she is likely to have a recent primary infection. (CMV/Toxo). Remember that IgM antibodies are the first antibodies made following exposure to a pathogen. IgG antibodies are the most prevalent and are the only antibodies with the ability (small size) to cross into the fetal circulation. Serial doppler ultrasound readings evaluate the placenta as well as the fetus (placentamegaly—evidence of inflammation and congestion within the placenta or fetal hydrops—effusions in the abdominal, pleural, or peritoneal cavities in addition to anasarca); Increased MCA flow indicative of fetal anemia

Additional Pathogens

-Parvovirus B19 -Listeria -Tuberculosis -Varicella -Enterovirus -Coxsackie -Zika Listed above are pathogens that are included on an expanded panel.

Syphilis Pathogenesis

-Pathogenesisà congestion of placenta decreases blood flow to fetus leading to growth restriction, miscarriage, stillbirth -Stages of infection: -Primary stage: lasting 3-6 weeks with painless, resolving papule -Secondary stage: occurs 6-8 weeks later with diffuse inflammation and disseminated rash (palms and soles of feet) -Latent stage: asymptomatic and if untreated will lead to final stage -Tertiary (final) stage: develop granulomas affecting bones and joints as well as CV and Neuro systems -Infection of fetus occurs with active, untreated, or inadequately treated infection Unlike many other congenital infections, disease is completely treatable and prevention of infection in fetus is possible Diagnosis and treatment of Mom via prenatal care is vital as well as ensuring treatment of partner(s)

CMV clinical manifestations

-Prenatal: -Oligo/Poly hydramnios -Periventricular calcifications -Hyperechoic bowel -Neonatal: -CNS: Microcephaly; Periventricular calcifications; hypotonia, ventriculomegaly, seizures, SNHL, cerebellar hypoplasia, polymicrogyria, developmental delay, chorioretinitis -Skin: Jaundice, petechiae, purpura -GI: Direct hyperbilirubinemia, elevated LFT's, hepatomegaly -Hematologic: Thrombocytopenia, anemia, splenomegaly -Intra-uterine growth restriction

Herpes Simplex Virus: Presentation

-Presentation -Depends on type of exposure -SEM and Disseminated present earlier, 9-12 days after birth; CNS disease presents 16-19 days following birth -S/Sx frequently non-specific -Lethargy or irritability, poor oral feeding, temperature instability** -May have cutaneous lesion but absence doesn't rule it out -If Encephalitis presentà bulging AF/PF, seizures -Respiratory failure, pneumonia, hepatic failure, DIC -In premature neonate cutaneous presentation atypical ***Notice that this doesn't strictly say fever*** Not all neonates present with lesions though ~70% will and ~50% will present with s/sx's of CNS involvement

Herpes Simplex Virus: Preventation

-Prevention -Routine screening doesn't predict shedding at time of delivery -ACOG recommends C/S delivery for active lesions at time of delivery or in Mom's reporting prodromal symptoms and preferably prior to ROM—reduces risk but doesn't prevent -Antiviral suppression with oral Acyclovir or valacyclovir beginning at 36 weeks Antiviral suppression decreases presence of lesions at time of delivery and therefore reduces risk of needing C/S delivery

Herpes Simplex Virus: Treatment

-Prior to initiation of Acyclovir~disseminated disease carried an 85% mortality within the first year with only 50% of those survivors with normal neurodevelopment (improving to now down to 29% and 83% respectively following therapy) -CNS disease had improved survival(50%) but with only 33% having normal neurodevelopment. (mortality improved to 4%) -Neurodevelopment not necessarily improved with traditional dosing but with the addition of suppressive therapy x6 months improvement was achieved -Acyclovir 60 mg/kg/day divided every 8 hours (x21 days for CNS and disseminated; x14 days for SEM) -CNS disease~at end of therapy a repeat LP should be performed to document clearance Dosing with Acyclovir for the 21 day course is only with IV administration of the drug. Oral suppression therapy is initiated following the initial IV course of therapy and has been shown to improve neurologic outcomes

Routine ACOG testing during pregnancy-Third trimester testing

-Repeat CBC -Rh antibody testing -Repeat RPR, HIV, or STI's (esp for high risk) -GBS Routine ACOG testing aimed at identifying risks early in pregnancy and repeat testing aimed to identify late exposures

Zika Virus

-Single stranded RNA flavivirus that is mosquito born, also sexually transmitted -Maternal s/sx- fever rash, arthralgias, conjunctivitis -Congenital Zika syndrome -Constellation of findings including -Microcephaly (collapsed skull appearance), calcifications, arthrogryposis, redundant scalp skin, eye abnormalities, ventriculomegaly, gray/white matter loss, corpus callosum agenesis or dysgenesis Can be transmitted via bodily fluid exposure Microcephaly risk between 1-13% following first trimester infection Calcifications—heavier/more coarse occurring at the gray-white matter junctions

Toxoplasma gondii: Clinical manifestation in neonates

-Symptoms may be mild, moderate or severe (10%) -Term infants present with milder features (hepatosplenomegaly, lymphadenopathy) -Premature birth (25-50%) -CNS disorders (meningoencephalitis, intracranial calcifications, hydrocephalus, ventriculomegaly, microcephaly, seizures, chorioretinitis, deafness -Systemic symptoms: maculopapular rash, thrombocytopenia, jaundice Up to 10% of cases will present with severe clinical features and up to 80% will develop learning disabilities or visual impairment later in life. Up to 90% of asymptomatic newborns develop chorioretinitis and this may persist up to and including their 30's (~20% HAVING LESIONS AT BIRTH) There is a higher incidence of CNS disorders in preterm neonates consistent with more severe features Can be fatal to fetus

Traditional Pathogens

-Toxoplasma gondii -Other (Syphilis, HIV, Hepatitis) -Rubella -Cytomegalovirus -Herpes Simplex Virus Listed above are the traditional pathogens (though HIV was added to the panel in the mid to late 80's). Routine prenatal testing covers many of the traditional pathogens that were known to cause significant fetal and neonatal sequelae

Parvovirus B19: Treatment

-Treatment- No treatment for maternal or fetal infection, supportive therapy for neonate