Transplacental Infection: Frequency, Testing, and Treatment

Summary

Background:

Infections transmitted through the placenta are caused by viruses [e.g., cytomegalovirus (CMV) and parvovirus B19 (B19V)], bacteria (e.g., Treponema pallidum spp. pallidum), and protozoa (e.g., Toxoplasma gondii). These infections may have serious consequences for the unborn child. In this article, we discuss current aspects of prevention, testing, and treatment.

Method:

This narrative review is based on pertinent publications (1946–1015) retrieved by a selective search in the PubMed/MED-LINE, Cochrane Library, ClinicalTrials.gov, and Google Scholar databases, along with the guidelines of medical societies.

Results:

The current incidence of transplacental infection in Germany is ca. 1 : 200 (CMV) to 1 : 500 000 neonates (syphilis). The diagnosis is made by the serological demonstration of antibodies. Before the 20th week of gestation, the rate of vertical transmission is lower, but the potential for permanent harm is markedly higher than in the second half of pregnancy. 5–50% of transplacental infections lead to miscarriage or premature birth. Most infected fetuses are asymptomatic at birth, but there is still a 7–14% risk of sensorineural hearing loss from CMV and a 10–30% risk of retinochoroiditis from toxoplasmosis. Up to 60% of symptomatic neonates have long-term neurocognitive sequelae. Anti-infectious treatment is therefore indicated.

Conclusion:

The most important preventive measures are hygiene education for pregnant women and prophylaxis against exposure. Anti-infectious treatment of pregnant women can reduce the risk of transmission, and the treatment of symptomatic neonates can improve the outcome.

Information on CME.

This article has been certified by the North Rhine Academy for Continuing Medical Education. The questions may be found at the end of this article. The closing date for entries is 28 May 2027. Participation is possible at cme.aerzteblatt.de

Infections during gestation pose a significant threat to both mother and child. According to the World Health Organization (WHO), 11 out of every 1,000 pregnant women worldwide have infection-related complications (1). Transplacental infections are caused by viruses including cytomegalovirus (CMV), parvovirus B19 (B19V), rubella virus, human immunodeficiency virus (HIV), and hepatitis B virus, as well as by bacteria (Treponema pallidum, Listeria) and parasites such as Toxoplasma gondii. They usually cause no maternal symptoms but are suspected to contribute to 10–30% of miscarriages and stillbirths (2). The potential role of transplacental infection in congenital malformations, which affect 3 out of 100 live births, is insufficiently characterized (3). Especially in the first trimester, transplacental infection can severely impair organogenesis. 85–95% of infected fetuses are asymptomatic at birth, but 7–30% develop sequelae such as hearing loss or retinochoroiditis during childhood (4, 5–5). In this CME article, we focus on the types of transplacental infection that were recently addressed in an updated guideline (CMV), those whose epidemiological features are changing (B19V, Treponema), and those for which the proper modes of screening and treatment are currently under debate (Toxoplasma gondii; Table 1).

Table 1. Synopsis of transplacental infections: the treatment of pregnant women and neonates.

Study	Design	Intervention	Results	Remarks
Treatment during pregnancy
Shahar-Nissan, 2020 (14) CMV	•RCT, double-blind, placebo-controlled	•8.0 g of valacyclovir per day for primary CMV infection in the first trimester until amniocentesis	•Transmission rate ↓ 5/45 (11%) in the intervention group vs. 14/47 (30%) in the placebo group (OR 0.29, 95% CI: [0.09; 0.9], p = 0.027), fetal CMV-related morbidities (OR 0.38, [0.09; 1.56]	•3 pregnancy terminations (1 i ntervention, 2 placebo) due to CMV abnormalities, 3 terminations due to CMV-PCR-positive amniotic fluid
Kosian, 2023 (25) B19V	•Retrospective case series	•Intrauterine transfusion for severe anemia due to B19V	•186 transfusions in 103 fetuses, overall survival 87/103 (84.5%); first transfusion at 19+3 weeks of gestation (range: 13-31 weeks)	•Risk factors for IUF: hydrops, lower mean hemoglobin, lower platelet counts
Mandelbrot, 2018 (29) toxoplasmosis	•Open-label RCT, multicenter	•Pyrimethamine + sulfa (PS) vs. spiramycin (S) in cases of confirmed toxoplasmosis in the first trimester	•Transmission rate, definite congenital toxoplasmosis (↓): 12/65 (18.5%) in the PS group vs. 18/60 (30%) in the S group (p = 0.147); Prenatal ultrasound abnormalities: 0% in the PS group vs. 8.6% in the S group (p = 0.012)	•6 children affected despite negative PCR in amniocentesis; effect of PS stronger when treatment begins < 3 weeks after seroconversion
Tong, 2023 (38) syphilis	•Meta-analysis of observational studies	•Penicillin treatment for active syphilis	•Preterm birth rate ↓: OR 0.48 [0.39; 0.58]; n = 11,043, 15 studies; stillbirth rate ↓: OR 0.21 [0.12; 0.35]; n = 14,667, 8 studies; low birth weight ↓: OR 0.5 [0.42; 0.59]; n = 9778, 7 studies); perinatal mortality and pregnancy complications ↓	•No adjustment for potential confounding factors (evidence level classified as low)
Treatment of congenitally infected neonates
Ki mberlin, 2015 (17) cCMV	•RCT, double-blind, placebo-controlled	•6 months: 16 mg/kg body weight (twice daily) of valganciclovir for symptomatic cCMV infection (placebo: 6 weeks)	No improvement in hearing after 6 months (intervention: 36/47 vs. placebo: 37/49, p = 0.41) At 24 months: Improvement in hearing with intervention 77% vs. 64%; OR 2.61; [1.05; 6.43], p = 0.04; and higher scores on the Bayley Scales of Infant and Toddler Development (Language)	•Adverse effects of valganciclovir: neutropenia (19%), elevated liver enzymes; lower risk of hearing impairment with lower viral load; monitoring of viral load is controversial
Journé, 2024 (34) toxoplasmosis	•Case series, France (1987–2021)	664 infected newborns 521 (80.7%) antenatal PS/S 632 (97.8%) postnatal PS/S*	12-year follow-up: 187/664 (29%) children had at least one ocular lesion, with peaks at 7 and 12 years	•Substantial risk of retinochoroiditis despite screening and ante-/postnatal atreatment
Walker 2019 (39) syphilis	•Cochrane	•Benzathine penicillin vs. no intervention for suspected neonatal syphilis	Congenital syphilis (↓) due to antibiotic treatment (RR 0.12, [0.001; 2.09], n = 22), serological “cure”: RR 2.13 [1.06; 4.27]	•Study terminated prematurely (four infants in the untreated group had contracted syphilis)

^*529 children received pyrimethamine-sulfadoxine

B19V, parvovirus B19; BW, body weight; cCMV, congenital CMV infection; CI, confidence interval; CMV, cytomegalovirus; IUF, intrauterine fetal death; OR, odds ratio; PCR, polymerase chain reaction; RCT, randomized controlled trial; RR, relative risk; vs., versus

Learning objectives

This article is intended to enable the reader to:

• give a realistic estimate of the prevalence of common transplacental infections in Germany,

• know the basic principles of diagnostic testing for transplacental infections, and

• evaluate preventive strategies and current treatment approaches for transplacental infections.

The pathogenesis of transplacental infection

The physiology of gestation is characterized by immune adaptations that strike a balance between defense against infection and prevention of fetal “rejection,” as the maternal immune system recognizes the fetus as “semi-foreign” tissue (6). From the 12th week of gestation (WoG) onward, an immunological state of tolerance dominates, with a shift in helper T-cell (Th) immunity toward a Th2 profile (7). This explains the increased susceptibility to infection in pregnant women compared to non-pregnant women. Pathogens can either infect the fetus directly or impair the function of the fetomaternal interface. The placenta is a very effective defensive barrier but can also be a reservoir for tissue cysts in Toxoplasma gondii infection. Treponema pallidum infects the placenta first, then the amniotic cavity (8). The P blood group antigen on trophoblasts is the primary placental target of B19V (9). CMV can be transmitted directly but can also impede cytotrophoblast differentiation and invasion, thereby causing placental fibrosis, which, in turn, impairs the fetal blood supply (10). A better understanding of the pathogenesis of transmission and manifestation of transplacental infections is needed so that targeted treatment can be optimized. Nonetheless, primary prevention through improved public education, hygiene, and exposure prophylaxis is crucial (Table 2).

Table 2. The primary prevention of transplacental infections^*.

Measure	Protects against	Recommendations
•Avoid contact with people who have an acute infection (fever, rash)	•Cytomegalovirus, parvovirus B19 infection	•In the event of a parvovirus B19 outbreak in the area, consult a doctor; targeted exposure prophylaxis is difficult, as infectivity is highest before symptoms appear
•Avoid contact with saliva and urine from infants and young children	•Cytomegalovirus	•Wash hands after contact with urine and saliva; do not kiss children on the mouth; do not share eating utensils or towels with children
•Avoid contact with cat feces; wash hands regularly	•Toxoplasmosis	•Do not clean the litter box yourself; wear gloves when gardening
•Do not consume certain foods; maintain good kitchen hygiene	•Toxoplasmosis	•Do not consume unwashed vegetables/fruit, pre-cut, packaged salads, raw sprouts, or meat and sausage products made from raw, smoked, or undercooked meat; thoroughly clean cutting boards
•Avoid unprotected sexual intercourse	•Syphilis	•Use condoms; get tested for sexually transmitted diseases after possible exposure

^*The Committee on Maternity Protection issued a background paper on primary prevention in 2022: www.ausschuss-fuer-mutterschutz.de/fileadmin/content/Dokumente/MuSchH_01-2022_Information_zur_Relevanz_von_Infektionserregern_in_Deutschland_aus_Sicht_des_Mutterschutzes.pdf

Cytomegalovirus

The incidence of congenital CMV infection (cCMV) in Germany is 2–6 per 1,000 neonates. The most common source of CMV infection in pregnant women is the urine and saliva of CMV-shedding young children (11). Its seroprevalence among pregnant women in Germany is 40–50%. Many women in healthcare professions are CMV-negative when they realize that they are pregnant. Those working in pediatric hospitals as physicians, as well as those employed in daycare centers and schools, are often forbidden to work after a risk assessment pursuant to §10 of the Maternity Protection Act because of potential contact with Risk Group 2 biological agents including CMV. Implementation of mandatory protection for CMV-negative pregnant women within the organizational structure of the hospital or other institution, while enabling continued employment, should be the goal. The S2K Guideline 187–066 on maternal protection, now under consensus review, is intended to help standardize the management of occupationally exposed pregnant women.

The prevalence of primary CMV infection among pregnant women in Germany is 0.5–1%. Less than 1% of seropositive pregnant women have a recurrent CMV infection, i.e., reinfection with a new CMV strain or reactivation of a latent infection; maternal recurrent CMV infection leads to 10–30% of cases of cCMV (11). cCMV infections due to recurrent maternal CMV infection can be severe. Vertical transmission rates are approximately 35% in the first trimester and 65% in the third trimester. Severe developmental abnormalities are mainly due to maternal primary infections in the periconceptional period up to approximately the 20th week of gestation; they affect 10–20% of infected neonates (eTable) (4, 11–12).

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

Women whose CMV status is unclear when pregnancy becomes known should be tested promptly for their current infection status (CMV-IgM and CMV-IgG) (11), even though this is not covered by health insurance under the current maternity guidelines (Mu-RL) of the German Joint Federal Committee (13). Serologic testing is always indicated in cases of relevant exposure, clinical suspicion, or abnormalities on ultrasound, with seroconversion confirming a primary infection. CMV IgG avidity testing, which measures the strength of the binding of antibodies against CMV, can help narrow down the timing of the maternal infection. High CMV IgG avidity is inconsistent with a recent primary infection, but low avidity does not prove it (Table 3).

Table 3. Transplacental infections: screening and diagnostic testing.

	Cytomegalovirus	Parvovirus B19	Toxoplasmosis	Syphilis
•Screening as recommended by the Mu-RL*	•Screening not recommended	•Screening not recommended	•Screening not recommended	Serological screening in early pregnancy (syphilis screening test)
•Tests for pregnant women	•Basic testing: CMV IgG/IgM •Confirmatory/advanced testing depending on findings and clinical questions: additional serological tests (e.g., IgG avidity, immunoblot), possibly via PCR in multiple specimens, follow-up monitoring	•Basic testing: 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 testing: Toxoplasma IgG/IgM •Confirmatory/advanced testing depending on findings and clinical questions; additional serological tests or follow-up monitoring	A positive screening test is confirmed with a second test to detect Treponema-specific antibodies; to assess virulence → detection of Treponema-specific IgM antibodies and non-specific cardiolipin antibodies
•Tests for the fetus	•Detection of CMV in amniotic fluid via quantitative PCR	•If necessary, detection of B19V in fetal blood via PCR (as part of intrauterine transfusion). Detection is also possible in amniotic fluid and chorionic villi	•If necessary, detection of Toxoplasma in amniotic fluid via PCR	Detection of Treponema pallidum in amniotic fluid and fetal blood via PCR. Detection of Treponema-specific IgM antibodies and cardiolipin antibodies in fetal blood
•Tests for the neonate	•Gold standard: Detection of CMV in urine via quantitative PCR (as early as possible after birth, no later than the 3rd week of life). A positive pathogen detection in saliva/oral secretions must be confirmed by urine testing; a negative pathogen detection in saliva/oral secretions rules out a cCMV infection in > 96% of cases.	•Only in symptomatic neonates: B19V PCR	•Determination of Toxoplasma IgM and IgA antibodies •Determination of the “motherchild profile” (comparative IgG immunoblot) as indicated, pathogen detection (PCR) in various materials as indicated, CSF testing, IgG follow-up testing in the infant until maternal antibodies are no longer detectable	Quantitative determination of cardiolipin antibodies in serum Determination of Treponema-specific IgM antibodies PCR in various materials as indicated, CSF as indicated, serological follow-up in the infant until maternal antibodies are no longer detectable

^*The Mu_RL (13) stipulates the following serological tests as standard services covered by statutory health insurance in Germany: syphilis (screening with TPHA or 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; B19V, parvovirus B19; cCMV, congenital cytomegalovirus infection; CMV, cytomegalovirus; CSF, cerebrospinal fluid; Ig, immunoglobulin; LSR, syphilis serology test; Mu_RL, G-BA Maternity Guidelines; PCR, nucleic acid amplification via polymerase chain reaction; TPHA, Treponema pallidum hemagglutination assay; TPPA, Treponema pallidum particle agglutination assay

Treatment of pregnant women with valacyclovir (8 mg/day) on detection of a primary CMV infection can markedly lower the transmission rate (14–15) and tends to improve neonatal outcomes (14) (Table 1). Hyperimmunoglobulin administration is not recommended (4). In cases of primary infection, amniocentesis should be offered from the 18th week of gestation onward for testing of the amniotic fluid for CMV transmission with the polymerase chain reaction (PCR) (4, 11). If the PCR finding is positive, the initiated valaciclovir therapy can be continued (4, 15) or switched to valganciclovir in the presence of marked findings on ultrasound, such as brain calcifications; in a pilot study, this was not found to cause any relevant degree of neonatal neutropenia (Table 4) (16).

Table 4. Transplacental infections: treatment.

	Cytomegalovirus	Parvovirus B19	Toxoplasmosis	Syphilis
•Treatment during pregnancy	Valaciclovi r to prevent mother-to-child transmission in cases of primary infection around the time of conception or during the first trimester (experimental treatment) until amniocentesis	•In cases of severe fetal anemia or hydrops fetalis → intrauterine transfusion	•Before the 16th week of gestation, spiramycin; from the 16th week of gestation, PSF for at least 4 weeks	•Benzathine benzylpenicillin IM (regimen depends on the stage of infection); in the presence of HIV, neurosyphilis or abnormal findings on ultrasound → refer to a pediatric infectious disease center
•Treatment of neonates with congenital infection	Symptomatic cCMV: valganciclovir for 6 months If hearing test is abnormal but no other symptoms are present: consider 6 weeks of therapy In severely ill newborns, initial treatment with intravenous ganciclovir may be necessary	•In cases of persistent hyporegenerative anemia, treatment with immunoglobulins may be tried	•For symptomatic neonates, PSF for 12 months is recommended; in cases of high cerebrospinal fluid protein levels (≥ 1,000 mg/dL) or active retinochoroiditis threatening vision, steroids are indicated as well; for infected, asymptomatic neonates, there is no standard approach (no treatment vs. 3 months of treatment)	•Penicillin G intravenously for 10–14 days

cCMV, congenital CMV infection; HIV, human immunodeficiency virus; IM, intramuscular; IV, intravenous; PSF, pyrimethamine/sulfadiazine with folinic acid

15–30% of neonates with transplacental CMV infection are symptomatic to vaying degrees (eTable) (12). They carry a 35–50% risk of sensorineural hearing loss (SNHL) of 20 dB or more (detected with auditory brainstem evoked potentials, such as AABR or BERA) or neurocognitive impairment. Asymptomatic neonates with cCMV have a 7–14% risk of developing SNHL later in life. No definitive conclusions can be drawn about their neurological development (4, 11, 12). Follow-up care up to age 6 (e.g., brainstem audiometry, developmental tests) is needed for for asymptomatic CMV-infected children as well.

Postnatal treatment id intended to prevent the onset or progression of SNHV. Symptomatic neonates with moderate or severe manifestations (eTable) should be treated with valganciclovir for 6 months (Table 1). In a placebo-controlled, randomized trial, a 6-month course of valganciclovir yielded slightly better outcomes than a 6-week course with regard to hearing development and neurological condition at 12 and 24 months, although no differences were observed in the primary endpoint (hearing impairment at 6 months) (Tables 1, 4) (17). Treatment should be initiated within the first month after birth (18). CMV-infected infants who are asymptomatic except for an abnormal hearing test may have better hearing at 22 months if they are given a 6-week course of valganciclovir (n = 37; odds ratio [OR] 0.1, 95% confidence interval: [0.02; 0.45], p = 0.003) (Table 4) (19). It is unclear whether treating asymptomatic neonates with cCMV infection can prevent the development of hearing impairment over time, and such treatment is not recommended in clinical practice (4).

Parvovirus B19

Symptomatic B19V infection is estimated to affect fewer than 1 in 10,000 neonates per year (20–22). In Germany, approximately 35% of preschool children and 60–70% of young adults are seropositive (9, 22). The seroconversion rate during pregnancy is under 2% in endemic periods but can rise markedly during an epidemic. Information on epidemic clusters is available from the Robert Koch Institute (RKI) and reference laboratories (9, 20). In 2024, there was a marked rise in detected primary infections in pregnant women (Figure) all over Germany (eFigure). This observation may be related to altered epidemiologic features of B19V after measures related to the COVID pandemic.

Figure.

The demonstration of parvovirus B19 (B19V) DNA in the blood of pregnant women by PCR (1 specimen per case) from January 2016 to December 2024 (data from the routine diagnostic laboratory of Prof. Dr. G. Enders MVZ GbR, Stuttgart). Absolute case numbers and positivity rates (B19V virus count ≥ 10⁴ IU/mL) are shown.

eFigure.

The demonstration of parvovirus-B19 (B19V) DNA in the blood of pregnant women by PCR (1 specimen per case) from January 2016 to December 2024 (data from the routine diagnostic laboratory of Prof. Dr. G. Enders MVZ GbR. Stuttgart). The origin of each sample is shown by postal code region on the basis of the first digit of the postal code.

B19V is primarily transmitted via respiratory droplets (21). The infection is self-limiting in immunocompetent people; approximately half of the infected individuals develop symptoms such as a rash or transient arthropathy. The typical rash in affected children, called erythema infectiosum, bright red cheeks and a garland-like maculopapular rash.

Serological screening for B19V is not recommended in the maternal health guidelines (13), but seems reasonable for pregnant women with close contact to children of primary-school age, as these women are known to have a higher incidence of B19V (Table 3) (20). As far as is known, only a primary infection during pregnancy causes fetal complications. If the mother is B19V-IgG-positive and IgM-negative, she is considered protected. If abnormal ultrasound findings warrant further investigation, a B19V-PCR test should always be performed in addition to a positive B19V-IgG test. If both IgG and IgM are positive, B19V PCR and, if necessary, additional serological tests—such as IgG avidity or immunoblot—should be performed to confirm a recent infection (Table 3) (9).

In 30–50% of cases of primary infection, B19V is transmitted to the fetus. Infection from the 13th to the 20th week of gestation causes fetal anemia or hydrops fetalisin 7–8% of cases. Infection in the first trimester increases the risk of a non-hydropic spontaneous abortion (eTable) (9).

As 85–95% of complications arise within 10 weeks of maternal infection (22), regular ultrasound or Doppler ultrasound examinations are recommended after confirmation of an infection (9). The flow velocity in the middle cerebral artery should be followed over time for the early detection of anemia before hydrops develops. Aside from anemia, other contributing factors to the development of hydrops may include endothelial damage to the capillary barrier and cardiomyopathy due to myocarditis (9). Hydrops elevates fetal and perinatal mortality to approximately 30%, compared to 4% in cases of anemia without hydrops (23). Among surviving neonates with hydrops, 10% suffer from long-term neurological impairment, presumably because of transient intrauterine oxygen deprivation (24). The standard treatment for severe fetal anemia is intrauterine transfusion, which gains time until normal erythropoiesis is restored (Tables 1 and 4) (9, 25).

Toxoplasmosis

The Robert Koch Institute receives 6–23 reports of congenital toxoplasmosis per year; the actual number of infected children is likely higher and is estimated at 350 symptomatic and 1,300 asymptomatic newborns per year (26). The intracellular protozoon Toxoplasma gondii is ubiquitous and can infect almost all domestic and wild animals; domestic cats, which excrete oocysts, are the definitive hosts. In Germany, the main risk factors for Toxoplasma infection are raw meat consumption and the presence of cats in the household. As a rule, only primary infection during pregnancy leads to transplacental infection (exception: severe immunosuppression). In this process, multiplying tachyzoites released from placental foci cross into the fetal compartment (26).

Infections increase the risk of miscarriage in early pregnancy and can lead to the classic triad of retinochoroiditis, cerebral calcifications, and hydrocephalus. With antenatal antiparasitic treatment, the pre- and postnatal risk of hydrocephalus is 0–4% (27–30). Retinochoroiditis affects approximately 15–30% of children and may not manifest until preschool age or later, sometimes with marked impairment of vision (5, 30–33).

Women should be told about the risk of toxoplasmosis as early in pregnancy as possible (26). Because the infection is almost always asymptomatic in pregnant women, transplacental transmission can only be diagnosed by the detection of specific IgM and IgG antibodies and treated with the appropriate antiparasitic drugs (eTable) (26).

In cases of latent infection, IgM detectability can persist for years; therefore, if IgM is positive, the antigen-binding strength of IgG antibodies (IgG avidity), which increases the longer the infection has been present, is determined as well. High IgG avidity suggests that the infection occurred weeks to months ago (the test manufacturer’s instructions should be followed in this regard). Low IgG avidity is of limited diagnostic value and necessitates further follow-up testing and the measurement of other parameters (e.g., IgA, IgM) to assess the timing of infection (Table 3).

In cases of primary infection transmission is prevented by continuous antiparasitic therapy, which is begun with spiramycin only (3.0 g = 9 million IU/day) up to gestational week 15+0, because of the teratogenicity of pyrimethamine. From gestational week 15+0 onward, pyrimethamine (50 mg on the first day, 25 mg starting on day 2) is given for at least four weeks in combination with sulfadiazine (50 mg/kg body weight/day, maximum 4 g/day) and folinic acid (10–15 mg/day; discontinue folic acid supplementation from then onward) to lessen the risk of the risk of bone marrow toxicity (25). Through treatment of toxoplasmosis can lower the risk of long-term damage (Table 1) (5, 32–35). A French study of 2455 mother-child pairs that was conducted after the introduction of screening in 1992 showed a downward secular trend in clinical symptoms in the affected children after treatment of the primary infection (26/177, 14.7%, 2009–2021 versus 55/193, 28.5%, 1992–2008; OR 0.49, [0.28; 0.85]), although retinochoroiditis cannot be completely prevented (13 versus 34 affected children) (35). The need for amniocentesis for the detection of fetal infection after successful treatment is debated. It should be performed no earlier than four weeks after maternal infection and not before 18 weeks of gestation (26). If the pathogen is detected by PCR, treatment is recommended until the child is born. Amniotic fluid PCR is 70–90% sensitive and 98–100% specific; thus, a negative PCR finding does not rule out infection.

The detection of specific IgM and/or IgA antibodies in the blood of the neonate indicates a congenital infection. Its sensitivity, however, is only 40–50% and is especially low in asymptomatic children whose mothers were treated prenatally. Therefore, a comparative immunoblot (parallel testing of infant and maternal serum) or pathogen detection via PCR in EDTA-treated blood or cerebrospinal fluid is recommended as well. As there is no diagnostic test that can definitively rule out a congenital infection, regular serological follow-up is advised until maternal antibodies have are no longer present (Table 3).

For infected but clinically asymptomatic neonates or children in congenital toxoplasmosis is only diagnosed later on follow-up laboratory testing (specifically, when specific IgG levels do not continue to decline or begin to rise), no clear treatment recommendation can be made, because of insufficient evidence. Parents should receive individualized counseling, including the recommendation that the child should be examined regularly by an ophthalmologist (Tables 1 and 4).

In symptomatic neonates, after a cerebrospinal fluid examination, combination therapy with pyrimethamine, sulfadiazine, and folinic acid should be initiated within five days (pyrimethamine: 1 mg/kg body weight/day, sulfadiazine 100 mg/kg body weight/day in two divided doses, and folinic acid 10 mg 3 times/week or 50 mg once/ week, depending on the regimen). Treatment for symptomatic congenital toxoplasmosis is typically given for 12 months, with regular clinical follow-up (5, 33–35).

Syphilis

The reported incidence of syphilis in Germany is steadily rising, but the incidence of congenital syphilis steadily remains low (for example, 8 cases in 2024) (36). In the United States, there has been a marked increase in congenital cases because of lack of access to healthcare (8). Syphilis is almost exclusively transmitted by sexual contact (36). Aside from transplacental transmission, syphilis can rarely be transmitted to an infant peri- or postnatally either during vaginal delivery or through breastfeeding if the mother has syphilitic lesions on her breasts.

Syphilis is a systemic infection with a primary stage (painless chancre at the inoculation site), a secondary stage approximately six weeks later with generalized symptoms (e.g., maculopapular rash, lymphadenopathy, alopecia, hepatitis, meningitis), an early latent stage (up to one year after infection), and a late latent stage (more than one year after infection) (8). 70% of untreated infections remain latent, while 30% of untreated patients develop tertiary syphilis 10 to 30 years after the initial infection (37).

In a pregnant woman with untreated or inadequately treated syphilis, there is a risk of transplacental infection. Transmission to the fetus can occur at any stage of pregnancy but is most likely to occur after the 16th week of gestation; if the mother has sustained a primary infection during early pregnancy, the probability of transmission is 50–70% (eTable) (8). In women with late-stage latent syphilis, the risk of transmission is lower, but still substantial. Intrauterine infection can lead to miscarriage, stillbirth, or preterm birth (8). According to the German maternity protection guideline, a syphilis screening test (SST) should be performed as early as possible in pregnancy and documented in the prenatal care record. The SST detects Treponema pallidum-specific IgM and IgG antibodies, typically yielding a positive result 2–3 weeks after infection. As coinfection is common, an HIV test should also be performed if syphilis is detected. This must be confirmed by a second pathogen-specific antibody test. The activity of the infection is tested with Treponema-pallidum-IgM tests (e.g., 19S-IgM-FTA-ABS, IgM-Immunoblot, IgM-EIA) und non-pathogen-specific cardiolipin antibody tests (e.g., VDRL, RPR) (Table 2). Screening and treatment of infected pregnant women (if the infection has been present for less than one year, benzathine penicillin G 2.4 million IU as a single intramuscular injection; if it has ben present for more than one year or for an unknown period of time, benzathine penicillin G 2.4 million IU intramuscularly on days 1, 8, and 15) lower the risk of an adverse outcome of pregnancy and can prevent more than 95% of cases of congenital syphilis (Table 1) (8).

Congenital syphilis is classified into an early stage (lues connata praecox) in the first two years of life and a late stage (lues connata tarda) thereafter, with differing manifestations. Half of the infected neonates are asymptomatic at birth. The first symptom is often rhinitis with thick secretions. The early stage is characterized by respiratory problems, a maculopapular, sometimes vesicular rash (palms, soles, face, and buttocks), bone changes (periostitis, osteitis), nephritis, and hepatobiliary dysfunction. 30–60% of cases have manifestations in the nervous system including meningitis, seizures, stroke, and cranial nerve deficits. Comprehensive organ function tests and imaging should be performed when there is a corresponding clinical suspicion. Typical findings of a late manifestation include the Hutchinson triad, which consists of keratitis (from age 4 onward), barrel-shaped permanent teeth, and sensorineural hearing loss (from age 10 onward). Further indicative changes are seen in the bones, cartilage, and joints (“sword-shaped tibia,” “saddle nose”); perforation of the palate is pathognomonic (eTable) (8).

The diagnosis of congenital syphilis is complex and is based on information about the treatment of the maternal infection, the infant’s symptoms, and laboratory findings. All infants born to mothers with syphilis should undergo postnatal testing for Treponema-specific antibodies and cardiolipin antibodies. The detection of specific IgM antibodies suggests that the infant has developed an immune response to Treponema pallidum. A Venereal Disease Research Laboratory (VDRL) test or a cardiolipin microagglutination test (CMT) showing a ≥ 4-fold increase in the maternal titer likewise strongly suggests intrauterine exposure. Cerebrospinal fluid analysis is indicated for all symptomatic neonates as well as for asymptomatic neonates with abnormal laboratory findings or after inadequate treatment during pregnancy. Children with a potential prenatal exposure should be monitored until maternal antibodies are no longer detectable (Table 2) (40).

A possible infection cannot be ruled out if the mother was treated inadequately or only in the last 30 days of pregnancy, or if adherence to follow-up care is uncertain. In cases of probable or possible infection, the infant is treated with penicillin G 50,000 IU/kg IV twice daily (first week of life), three times daily (weeks 2–4), and finally four to six times daily for 10 days (starting in week 5)(Tables 1 and 3) (8, 39). Children in the early stages of the disease are contagious via their nasal secretions and skin lesions. The risk of transmission ceases just 24 hours after the initiation of treatment.

Overview

Preventing transplacental infections through education and counseling (hygiene, exposure prophylaxis) has high priority. In addition to the screening tests recommended in the German maternal protection guideline, serological testing should be performed liberally in case of exposure to pathogens known to cause transplacental infection and should be repeated during pregnancy if clinical suspicion arises. Secondary preventive measures include anti-infective treatment of the pregnant woman to lower the risk of transmission. Decisions about postnatal treatment of affected neonates should be made in consideration of the timing of the infection, the treatment that the mother has undergone during gestation, and the child’s clinical manifestations.

Further information on CME.

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Questions on this article: Participation is possible at cme.aerzteblatt.de. The submission deadline is 28 May 2027.

Only one answer is possible per question. Please select the answer that is most appropriate.

• Question 1

  What is the approximate prevalence of CMV among pregnant women in Germany?

  1. 5-10%
  2. 20-30%
  3. 40-50%
  4. 60-80%
  5. nearly 95%

• Question 2

  Which measure is highlighted in the article as a key primary strategy for avoiding transplacental infections?

  1. counseling and education on hygiene and exposure prophylaxis
  2. routine monthly serological testing of all pregnant women
  3. prophylactic antiviral therapy in the second and third trimesters for seronegative pregnant women
  4. a general ban on work in any job for seronegative pregnant women
  5. prophylactic antibiotics for pregnant women who have eaten potentially contaminated food

• Question 3

  For which of the following transplacental infections does primary infection in adulthood occur almost exclusively through sexual contact?

  1. listeriosis
  2. CMV infection
  3. toxoplasmosis
  4. parvovirus B19 infections
  5. syphilis

• Question 4

  Which statement is true of cCMV in Germany?

  1. Severe congenital CMV infections are only possible with primary infection.
  2. A congenital CMV infection affects 1 in 10,000 newborns.
  3. A high IgG avidity test suggests an infection that occurred 1-2 weeks ago.
  4. Valaciclovir therapy for primary infection in the first trimester can lower the rate of transmission to the fetus.
  5. Primarily asymptomatic neonates with congenital CMV infection do not need any specific follow-up care.

• Question 5

  What is recommended for the postnatal treatment of symptomatic congenital CMV infection?

  1. For newborns with symptomatic, severe congenital CMV infection, a 6-month course of valganciclovir is indicated.
  2. The standard duration of antiviral therapy for symptomatic neonates with severe findings is 6 weeks.
  3. A combination of valganciclovir and CMV hyperimmunoglobulin is the recommended standard treatment.
  4. Because of its severe side effects, antiviral therapy should not be initiated until after the third month of life.
  5. Antiviral therapy for infants is indicated only when there is clear evidence of severe cerebral calcification.

• Question 6

  What is the typical clinical manifestation of a primary parvovirus B19 infection in young children?

  1. rubella
  2. fifth disease
  3. chickenpox
  4. measles
  5. tertian fever

• Question 7

  What is the standard treatment for severe fetal anemia due to a B19V infection?

  1. hyperimmunoglobulin therapy
  2. antiviral therapy
  3. intrauterine transfusion
  4. corticosteroid administration
  5. erythropoietin administration

• Question 8

  According to the article, what is the recommended treatment for a primary Toxoplasma infection before 15 + 0 weeks of gestation?

  1. a combination of pyrimethamine, sulfadiazine, and folinic acid
  2. spiramycin as monotherapy
  3. valaciclovir
  4. benzathine penicillin G
  5. watchful waiting without drug treatment until amniocentesis

• Question 9

  In asymptomatic children whose mothers were treated prenatally for toxoplasmosis, blood can be tested for toxoplasmosis-specific IgA and IgM antibodies. What is the sensitivity of the antibody test in this case?

  1. 20–30%
  2. 40–50%
  3. 60–70%
  4. 80–90%
  5. 95–100%

• Question 10

  Which approach most closely corresponds to the recommended diagnostic procedure for neonates born to mothers with syphilis?

  1. Measurement of Treponema-specific IgG antibodies alone is sufficient.
  2. Serological testing is indicated only for clinically symptomatic neonates.
  3. All neonates born to mothers with syphilis should be tested postnatally for both Treponema-specific and non-pathogen-specific cardiolipin antibodies.
  4. A cerebrospinal fluid examination is mandatory for all exposed neonates.
  5. Serological testing is only recommended from age three months onward.