eTable. Transplacental Infections: testing, clinical consequences, and treatment.

	Cytomegalovirus	Parvovirus B19	Toxoplasmosis	Syphilis
Routes of transmission (postnatal, excluding blood transfusions and transplantation)	Transmission through close contact with body fluids containing the pathogen (e.g., saliva, urine, blood, breast milk, sexual contact)	Droplet transmission (possibly also smear transmission through contact with contaminated surfaces)	Ingestion of infectious oocysts from the environment (e.g., contaminated soil or vegetables) or consumption of undercooked meat products containing cysts	Sexual contact
Risk of vertical transmission during primary infection	Periconceptional: approx. 20% 1st trimester: 30–40% 2nd trimester: 30–50% 3rd trimester 60–70% The transmission risk (TR) for CMV recurrence is <3%.	Throughout pregnancy: 30–50% (higher in the third trimester)	1st trimester: 10–20% 2nd trimester: 30–50% 3rd trimester: 60–80% Evidence for “natural” vertical transmission, i.e., without antenatal therapy, is very limited.	50–70% in cases of secondary or early latent syphilis (duration of infection < 1 year) at the time of delivery; mother-to-child transmission is possible throughout pregnancy.
Consequences for the fetus	Currently no reliable evidence of increased risk of miscarriage Risk of fetal damage is highest during primary infection around conception/in the 1st trimester (20–30%); 5–10% increased risk of preterm birth	Fetal complication rate significantly lower than vertical transmission rate Excess risk of intrauterine fetal death in case of infection during WoG <9+0, 4.7 %; 9–20, 6.6 %; >20+6, 0%. Risk of anemia/hydrops in case of infection during pregnancy: <9+0: 0.7%; 9–20: 6.5%; >20+6: 2.3%	Infection in early pregnancy carries a 5–20% excess risk of spontaneous abortion; the highest risk of damage (especially to the CNS) occurs with fetal infection in the 1st and 2nd trimesters	Increased risk of intrauterine fetal death and preterm birth. In cases of symptomatic fetal infection, treatment may trigger preterm birth → initiation of inpatient treatment
Prenatal abnormalities	Extracerebral: echogenic bowel, growth restriction, hepatomegaly, ascites, anemia, cardiomegaly, hydrops, amniotic fluid abnormalities Cerebral: ventriculomegaly, microcephaly, calcifications, cysts, periventricular echogenicity, abnormalities of the corpus callosum, cerebellum, and cortex	Anemia, tricuspid insufficiency, cardiomegaly, hyperechoic bowel, ascites, pleural effusions, placentomegaly, hydrops CNS defects (especially cerebellar) after severe intrauterine anemia with hydrops	Extracerebral (isolated in approx. 10%): growth restriction, echogenic bowel, ascites, hepatomegaly, splenomegaly Cerebral (isolated in approx. 50% of cases): hyperechoic foci, progressive ventriculomegaly, periventricular abscesses, subependymal cysts	Usually no ultrasound abnormalities before 18 weeks of gestation; hepatomegaly (80%, resolves late), placentomegaly, hydrops fetalis, anemia, ascites, polyhydramnios
Consequences for the neonate	10–15% symptomatic at birth mild: maximum of two transient findings, e.g., thrombocytopenia, intrauterine growth restriction moderate: persistent findings or isolated CNS abnormalities (cysts) severe: neurological abnormalities (calcifications, ventriculomegaly, microcephaly, polymicrogyria), organ damage (liver failure), chorioretinitis, pancytopenia, sepsis 7–14% of asymptomatic neonates develop a hearing impairment within the first 6 years of life.	Term infants with prenatal infection are usually asymptomatic; rarely, persistent congenital anemia or myocarditis; increased risk of neurological impairment after severe intrauterine anemia with hydrops	Approx. 10% symptomatic at birth Severe forms: hydrocephalus, >3 cerebral calcifications, RC with macular involvement <5% at birth; classic triad; 10–30% of congenitally infected children develop RC(even during or after ante- and postnatal therapy). Risk factors for developing RC include symptoms or laboratory diagnosis before or at birth; incidence of RC without treatment is unclear; additional symptoms: thrombocytopenia, hepato-splenomegaly, myocarditis, and pneumonia	50% already symptomatic at birth Early stage (within 2 years): rhinitis, exanthem, respiratory distress, hepatobiliary dysfunction, anemia, thrombocytopenia; up to 60% with neurological symptoms (meningitis, cranial nerve deficits, hearing impairment, cataracts); periostitis, bone fractures, and demineralization Late manifestation: Hutchinson’s triad (barrel-shaped teeth, parenchymatous keratitis, sensorineural hearing loss), saddle nose, perforated palate
Screening according to the Mu-RL*	No screening recommended	No screening recommended	No screening recommended	Serological screening in early pregnancy (syphilis or lues screening test)
Diagnosis in pregnant women	Basic test: CMV IgG/IgM Confirmatory/advanced testing depending on findings and clinical questions: additional serological tests (eg., 1 gG avidity, immunoblot), possibly via PCR on multiple specimens, follow-up monitoring	Basic test: B19V IgG/IgM; Confirmatory/advanced testing depending on findings and clinical questions; detection of B19V via quantitative PCR; additional serological tests (e g., IgG avidity), follow-up monitoring	Basic test: Toxoplasma IgG/IgM Confirmatory/advanced testing depending on findings and clinical questions; additional serological tests or follow-up monitoring	If the LSR is positive, confirmation is performed with a second test to detect Treponema-specific antibodies; to assess activity → detection of Treponema-specific IgM antibodies and non-specific cardiolipin antibodies
Diagnosis in the fetus	Detection of CMV in amniotic fluid by quantitative PCR	If necessary, detection of B19V in fetal blood by PCR (as part of intrauterine transfusion); detection also possible in amniotic fluid and chorionic villi	If necessary, detection of Toxoplasma in amniotic fluid by PCR
Diagnosis in the neonate	Gold standard: detection of CMV in urine by quantitative PCR (as soon as possible after birth, no later than the 3rd week of life). A positive pathogen detection in saliva/ora 1 secretions must be confirmed by urine testing; a negative pathogen detection in saliva/oral secretions rules out cCMV with >96% probabilit<.	B19V PCR only in symptomatic neonates	Determination of Toxoplasma IgM and IgA antibodies Determination of the “mother-child profile” (comparative IgG immunoblot) as indicated, pathogen detection (PCR) in multiple specimens as indicated, cerebrospinal fluid testing, IgG follow-up testing in the infant until maternal antibodies are no longer detectable	Detection of Treponema pallidum in amniotic fluid and fetal blood via PCR Detection of Treponema-specific IgM antibodies and cardiolipin antibodies in fetal blood
Treatment during pregnancy	Valaciclovir to prevent mother-to-child transmission in primary infection around the time of conception/in the 1st trimester (therapeutic trial) until amniocentesis	In cases of severe fetal anemia or hydrops fetalis → intrauterine transfusion	Before 16 weeks of gestation, spiramycin From 16 week of gestation, PSP for at least 4 weeks	Mesurement of cardiolipin Ab in serum; Determination of Treponema-specific IgM Ab PCR in multiple specimens as needed; CSF analysis as needed; serological follow-up in the infant until maternal Ab are no longer detectable
Treatment of the perinatally infected neonate	Symptomatic cCMV: valganciclovir for 6 months In cases with an abnormal hearing test results but no other symptoms: consider 6 weeks of therapy In severely III neonates, initial therapy with intravenous ganciclovir may be necessary	In cases of persistent hyporegenerative anemia, possibly attempt treatment with immunoglobulins	For symptomatic neonates, treatment with PSF for 12 months is recommended in cases of elevated cerebrospinal fluid protein (≥ 1,000 mg/dL) or active retinochorioiditis (RC) that threatens vision; additionally, steroids for infected, asymptomatic neonates; currently no standard protocol (no treatment versus 3 months of treatment)	Penicillin G intravenously for 10–14 days

^*The Mu-RL (13) stipulates the following serological tests as standard services covered by statutory health insurance in Germany: syphilis (screening with TPHAor TPPA), HIV antibody test, rubella antibody test, hepatitis B (HBsAg detection). Serological testing for toxoplasmosis is not routinely foreseen in the maternity guidelines; it is performed only in case of suspicion or offered as an individual health service. Screening tests for CMV, B19V, and other transplacental infections are not part of the standard maternity guidelines but are performed when clinically indicated or in case of suspicion.

^*Ab, antibody (-ies); B19V, parvovirus B19; cCMV, congenital cytomegalovirus infection; CMV, cytomegalovirus; CNS, central nervous system; CSF, cerebrospinal fluid; IUFT, intrauterine fetal death (miscarriage/stillbirth); LSR, syphilis serology test; Mu_RL, G-BA maternity guidelines; PCR, nucleic acid amplification via polymerase chain reaction; PSF, pyrimethamine and sulfadiazine with folinic acid; RC, retinochorioiditis; TR, vertical transmission risk; WoG, week of gestation