Congenital herpes simplex virus infection is vertically transmitted HSV-1 or HSV-2 disease of the fetus or newborn. The dominant route is not transplacental but intrapartum: roughly 85% of cases are acquired through contact with infected maternal genital secretions during delivery, against 5% acquired in utero and 10% postnatally. Intrauterine infection is the route that produces fetal damage - placental inflammation, skin erosion, malformation and fetal loss - while perinatally acquired disease presents days to weeks after birth in one of three forms: localised skin, eye and mouth disease, central nervous system disease, or disseminated multi-organ infection. Maternal infection is frequently silent, so the absence of a maternal history does not exclude the diagnosis. Aciclovir transformed outcome and long-term suppressive therapy reduces morbidity. The CNS and disseminated forms are the severe presentations; this entry carries no sourced mortality or neurodevelopmental-outcome figures and so makes no quantitative claim about either. Pooled global incidence is about 8.2 per 100,000 live births and rising, with HSV-1 displacing HSV-2 as the commoner agent.
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name: Congenital Herpes Simplex Virus Infection
creation_date: "2026-09-30T00:00:00Z"
category: Infectious Disease
disease_term:
preferred_term: congenital herpes simplex virus infection
term:
id: MONDO:0017381
label: congenital herpes simplex virus infection
parents:
- congenital herpes virus infection
- herpes simplex infectious disease
synonyms:
- neonatal herpes simplex virus infection
- neonatal HSV infection
- congenital herpes simplex
- mother-to-child transmission of herpes simplex virus infection
- Simplexvirus infectious embryofetopathy
notes: >-
Scope. MONDO:0017381 lumps three transmission routes that differ in timing,
presentation and frequency, and this entry covers all three as one disease with
the routes recorded in has_subtypes. The MONDO definition describes intrauterine
infection, while the synonym list includes neonatal herpes simplex virus
infection; the literature resolves the ambiguity with a split rather than a
boundary - intrauterine 5%, perinatal 85%, postnatal 10% of cases. They share
the maternal reservoir, the virus, the diagnostic approach and aciclovir
treatment, and MONDO offers no separate identifier for any of them, so splitting
them into separate entries would create concepts with no terms to bind.
Intrauterine infection is the one that produces fetal malformation, and that
difference is carried on the subtype rather than asserted of the whole entry.
Relationship to Viral_Encephalitis.yaml. That entry carries an "HSV
Encephalitis" has_subtypes entry, but it scopes sporadic HSV-1 frontotemporal
encephalitis of older children and adults and binds no MONDO identifier, so
there is no competing claim on MONDO:0017381. Neonatal CNS disease appears
there only as a single clause. The overlap is real but partial: CNS disease is
one of the three neonatal presentations curated here, not the whole of it.
description: >-
Congenital herpes simplex virus infection is vertically transmitted HSV-1 or
HSV-2 disease of the fetus or newborn. The dominant route is not transplacental
but intrapartum: roughly 85% of cases are acquired through contact with
infected maternal genital secretions during delivery, against 5% acquired in
utero and 10% postnatally. Intrauterine infection is the route that produces
fetal damage - placental inflammation, skin erosion, malformation and fetal
loss - while perinatally acquired disease presents days to weeks after birth in
one of three forms: localised skin, eye and mouth disease, central nervous
system disease, or disseminated multi-organ infection. Maternal infection is
frequently silent, so the absence of a maternal history does not exclude the
diagnosis. Aciclovir transformed outcome and long-term suppressive therapy
reduces morbidity. The CNS and disseminated forms are the severe presentations;
this entry carries no sourced mortality or neurodevelopmental-outcome figures and
so makes no quantitative claim about either. Pooled global incidence
is about 8.2 per 100,000 live births and rising, with HSV-1 displacing HSV-2 as
the commoner agent.
infectious_agent:
- name: Human alphaherpesvirus 2
infectious_agent_term:
preferred_term: herpes simplex virus type 2
term:
id: NCBITaxon:10310
label: Human alphaherpesvirus 2
description: >-
Historically the predominant agent of neonatal herpes, and still the commoner
one in the Americas.
evidence:
- reference: PMID:41860333
reference_title: "Global epidemiology of neonatal herpes: systematic review, meta-analyses, and meta-regressions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Globally, nHSV-1 and nHSV-2 accounted for pooled and weighted means of 47.3% (95% CI = 39.5-55.0) and 52.8% (95% CI = 45.2-60.5) of cases, respectively."
explanation: >-
Quantifies the share of cases attributable to each virus type in a global
meta-analysis.
- name: Human alphaherpesvirus 1
infectious_agent_term:
preferred_term: herpes simplex virus type 1
term:
id: NCBITaxon:10298
label: Human alphaherpesvirus 1
description: >-
An increasing share of neonatal herpes, reflecting a shift in the
epidemiology of genital HSV-1 in the maternal population.
evidence:
- reference: PMID:41860333
reference_title: "Global epidemiology of neonatal herpes: systematic review, meta-analyses, and meta-regressions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The increasing dominance of nHSV-1 over nHSV-2 reflects shifting HSV epidemiology."
explanation: >-
States the direction of the change in which agent predominates.
transmission:
- name: Intrapartum transmission from infected maternal genital secretions
description: >-
The dominant route. The neonate is infected during passage through an
infected birth canal, which is why this is a perinatal rather than a
transplacental disease in most cases, and why maternal shedding at delivery
rather than maternal viraemia is the operative exposure.
evidence:
- reference: PMID:37592873
reference_title: "Neonatal herpes simplex virus infection: From the maternal infection to the child outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Considering when the transmission of the infection from the mother to the fetus/newborn occurs, three types of neonatal infection can be distinguished: intrauterine infection (5% of cases), postnatal infection (10% of cases), and perinatal infections (85% of cases)."
explanation: >-
Gives the quantitative split across the three routes, establishing
perinatal transmission as dominant.
- name: Transplacental transmission after maternal primary infection
description: >-
The minority route, and the one that damages the fetus. Primary maternal
infection in early pregnancy can seed the placenta, where viral persistence
produces inflammation and haemorrhage, with transmission to fetal tissues and
fetal loss at higher viral doses.
evidence:
- reference: PMID:34696359
reference_title: Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Eight days post-inoculation (gd12.5), HSV-2 DNA persisted in placental tissues, resulting in inflammation and hemorrhage."
explanation: >-
Mouse model evidence for the placental mechanism of in utero transmission.
- reference: PMID:34696359
reference_title: Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "HSV-2 DNA and increased expression of pro-inflammatory mediators were detected in fetal tissues at gd12.5, signifying viral transmission and fetal infection, even with low viral doses."
explanation: >-
Demonstrates that transmission to fetal tissue occurs, not merely placental
infection.
has_subtypes:
- name: Intrauterine
display_name: Intrauterine (congenital) infection
subtype_frequency: about 5% of cases
description: >-
Acquired in utero and present at birth. The route that produces fetal
malformation and skin erosion, and the one MONDO's own definition
describes. Maternal infection may be entirely silent.
- name: Perinatal
display_name: Perinatal (intrapartum) infection
subtype_frequency: about 85% of cases
description: >-
Acquired during delivery and presenting days to weeks later. This is the
dominant form, and the one the clinical SEM / CNS / disseminated classification
describes; those three are carried as children below because they set aciclovir
duration and differ sharply in mortality, so they are a clinically operative
axis rather than a restatement of the transmission route.
children:
- SEM
- CNS
- Disseminated
- name: SEM
display_name: Skin, eye and mouth (SEM) disease
classification: clinical
description: >-
Perinatally acquired disease localised to the portal of entry, the least severe
of the three presentations.
- name: CNS
display_name: Central nervous system disease
classification: clinical
description: >-
Perinatally acquired disease with spread to the central nervous system, the
presentation carrying neurodevelopmental sequelae.
- name: Disseminated
display_name: Disseminated multi-organ disease
classification: clinical
description: >-
Perinatally acquired disease with bloodborne multi-organ involvement, the
presentation with the highest mortality.
- name: Postnatal
display_name: Postnatal infection
subtype_frequency: about 10% of cases
description: >-
Acquired after birth from a contact shedding virus, most often oral HSV-1.
pathophysiology:
- name: Maternal Genital HSV Infection and Shedding
biological_scale: ORGANISM
description: >-
The reservoir. Maternal infection is categorised as primary first episode,
non-primary first episode, or recurrent, and primary maternal infection is a
recognised risk factor for transmission, alongside vaginal delivery and
prolonged rupture of membranes. Shedding is frequently asymptomatic, so the
exposure can occur without any maternal history.
downstream:
- target: Vertical Transmission to Fetus or Neonate
causal_link_type: DIRECT
description: >-
Maternal shedding is the proximate source of virus reaching the infant.
evidence:
- reference: PMID:37592873
reference_title: "Neonatal herpes simplex virus infection: From the maternal infection to the child outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We summarized the three clinical categories of maternal HSV infection during pregnancy (primary first episode, nonprimary first episode, or recurrent episode) and the mechanisms of fetal damage."
explanation: >-
Establishes the three maternal infection categories that structure risk in
this disease.
- reference: PMID:38044450
reference_title: "Congenital herpes simplex with ophthalmic and multisystem features: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "risk factors for mother-to-child transmission include vaginal delivery, primary maternal infection, and prolonged rupture of membranes."
explanation: >-
Names primary maternal infection as a transmission risk factor. An earlier
draft asserted that the three categories differ in risk because of viral load
and transplacental antibody; no source cited here supports that mechanism, so
the claim is now limited to what this sentence states.
- name: Vertical Transmission to Fetus or Neonate
biological_scale: ORGANISM
description: >-
Virus reaches the infant by one of three routes, dominated by intrapartum
contact. Which route operates determines the presentation: in utero
transmission damages the developing fetus, intrapartum transmission produces
neonatal disease after a latent interval.
downstream:
- target: Local Mucocutaneous Replication at the Portal of Entry
causal_link_type: DIRECT
- target: Placental Inflammation and Fetal Injury
causal_link_type: DIRECT
description: Operative only on the intrauterine route.
evidence:
- reference: PMID:37592873
reference_title: "Neonatal herpes simplex virus infection: From the maternal infection to the child outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Considering when the transmission of the infection from the mother to the fetus/newborn occurs, three types of neonatal infection can be distinguished: intrauterine infection (5% of cases), postnatal infection (10% of cases), and perinatal infections (85% of cases)."
explanation: Enumerates and quantifies the routes this node branches into.
- name: Placental Inflammation and Fetal Injury
biological_scale: TISSUE
description: >-
On the intrauterine route, viral persistence in placental tissue produces
inflammation and haemorrhage, reduced placental and fetal weight, and fetal
loss at higher viral doses. This is the step that distinguishes congenital
from perinatal disease, and it is why the intrauterine form presents with
malformation rather than with postnatal illness.
downstream:
- target: Abnormal brain morphology
causal_link_type: DIRECT
evidence:
- reference: PMID:34696359
reference_title: Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Fetal and placental weights were reduced and fetal loss was observed with high viral doses."
explanation: >-
Dose-dependent fetal injury downstream of placental infection, in the model
system where the mechanism has been dissected.
- reference: PMID:33520322
reference_title: Diagnosis of Neonatal Herpes Simplex Infection from the Placenta.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Pathological examination of the placenta had revealed subacute necrotizing inflammation with stromal cell necrosis suggestive of intrauterine infection, possibly ascending due to prolonged rupture of membranes."
explanation: >-
Necrotizing placental inflammation in a human case of intrauterine HSV-2,
the human counterpart of the mouse placental finding above. One case, and
the authors hedge the intrauterine attribution as "suggestive of".
- name: Local Mucocutaneous Replication at the Portal of Entry
biological_scale: CELLULAR
description: >-
After intrapartum acquisition the virus replicates at the site of inoculation -
skin, eye or oropharyngeal mucosa. Disease that stays here is the skin, eye and
mouth (SEM) form, the least severe of the three presentations.
downstream:
- target: Vesicular skin eruption
causal_link_type: DIRECT
- target: Panuveitis
causal_link_type: DIRECT
- target: Neuroinvasion and Central Nervous System Spread
causal_link_type: DIRECT
- target: Haematogenous Multi-Organ Dissemination
causal_link_type: DIRECT
evidence:
- reference: PMID:38044450
reference_title: "Congenital herpes simplex with ophthalmic and multisystem features: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
snippet: "Neonatal HSV can manifest with isolated mucocutaneous lesions, neurological involvement, or disseminated disease."
explanation: >-
Names disease confined to mucocutaneous lesions as a distinct presentation,
separate from neurological and disseminated disease, which is the localised
form this node models.
- name: Neuroinvasion and Central Nervous System Spread
biological_scale: ORGANISM
description: >-
Spread to the central nervous system produces the CNS form, which may present
with overt neurological signs or with nonspecific illness. This is one of the
two severe presentations and the one that carries neurodevelopmental sequelae.
downstream:
- target: Seizure
causal_link_type: DIRECT
- target: Retinopathy
causal_link_type: DIRECT
- target: Fever
causal_link_type: DIRECT
evidence:
- reference: PMID:37559852
reference_title: The Many Faces of Neurological Neonatal Herpes Simplex Virus Infection.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The wide range of clinical presentations of CNS manifestations in neonatal HSV infection, ranging from nonspecific to evident neurological symptoms, underscores the need for a high index of suspicion"
explanation: >-
Describes CNS involvement in neonatal HSV presenting with symptoms that
range from nonspecific to overtly neurological, as the node states.
- name: Haematogenous Multi-Organ Dissemination
biological_scale: ORGANISM
description: >-
Bloodborne spread to multiple organs produces the disseminated form, the
presentation with the highest mortality. Which of the three forms develops is
the principal determinant of outcome and sets the duration of aciclovir therapy.
downstream:
- target: Elevated circulating aspartate aminotransferase concentration
causal_link_type: DIRECT
evidence:
- reference: PMID:11483781
reference_title: Natural history of neonatal herpes simplex virus infections in the acyclovir era.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Among patients with disseminated HSV disease treated with acyclovir at 30 mg/kg/d, mortality was associated with aspartate transaminase elevations of >/=10 times the upper limit of normal at the time of initiation of acyclovir therapy."
explanation: >-
Ties hepatic involvement in disseminated disease to mortality in a 186-patient
natural-history series, which is the organ involvement this node asserts.
- reference: PMID:41185580
reference_title: A Multicenter Study on Symptomatic Neonatal Herpes Simplex Virus Infection in Korea From 2008 to 2017.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Two (12.5%) patients with disseminated disease died within 30 days from the diagnosis, and one of them had a maternal history of previous genital herpetic lesions."
explanation: >-
Both deaths in this multicentre cohort were in the disseminated group, which is
the basis for calling this the highest-mortality presentation.
- reference: PMID:11483781
reference_title: Natural history of neonatal herpes simplex virus infections in the acyclovir era.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients' morbidity status was associated with the extent of disease (skin, eye, and/or mouth disease vs CNS vs disseminated)."
explanation: >-
Sources the claim that which of the three forms develops determines outcome,
which is why SEM/CNS/disseminated is carried as a subtype axis.
phenotypes:
- category: Dermatologic
name: Vesicular skin eruption
subtype: SEM
description: >-
Grouped vesicles of skin, and lesions of eye and mouth, define the localised
presentation. They are not a reliable sign of the disease as a whole: a large
minority of infants never have skin vesicles at presentation or during the acute
illness, and that proportion is highest in disseminated disease.
phenotype_term:
preferred_term: Vesicular eruption
term:
id: HP:0033697
label: Vesicular eruption
evidence:
- reference: PMID:40027069
reference_title: "Intrauterine Herpes Simplex Virus Infection: Insights Into a Silent Threat."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "On the fourth day of life, grouped vesicles emerged, leading to the initiation of intravenous acyclovir therapy."
explanation: >-
Documents the vesicular eruption as the sign that triggered diagnosis and
treatment in a confirmed case.
- reference: PMID:11483781
reference_title: Natural history of neonatal herpes simplex virus infections in the acyclovir era.
supports: REFUTE
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: "A significant minority of patients did not have skin vesicles at the time of their presentation and did not develop them during the acute HSV disease (39% of patients with disseminated disease; 32% of patients with central nervous system [CNS] disease; and 17% of patients with skin, eye, and/or mouth disease)."
explanation: >-
Recorded as REFUTE against reading this phenotype as a reliable marker of the
disease: 39% of disseminated cases never had vesicles at all. Graded INDIRECT
because the series reports absence rates rather than addressing the phenotype
claim directly. This is why the description no longer calls vesicles the first
visible sign.
- category: Dermatologic
name: Skin erosion
description: >-
Extensive skin erosion is part of the intrauterine presentation, present at
birth rather than developing afterwards.
phenotype_term:
preferred_term: Skin erosion
term:
id: HP:0200041
label: Skin erosion
subtype: Intrauterine
evidence:
- reference: PMID:40027069
reference_title: "Intrauterine Herpes Simplex Virus Infection: Insights Into a Silent Threat."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "extensive skin erosions and severe neurological impairment."
explanation: >-
Documents extensive skin erosion at delivery in confirmed intrauterine HSV-2.
- category: Ophthalmologic
name: Retinopathy
subtype: CNS
description: >-
Infectious retinopathy is reported on funduscopy in neonatal HSV-2 central
nervous system disease.
phenotype_term:
preferred_term: infectious retinopathy
term:
id: HP:0000488
label: Retinopathy
evidence:
- reference: PMID:42620976
reference_title: A case of neonatal herpes simplex virus type 2 encephalitis with TLR3 gene mutation and literature review.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cranial MRI showed meningoencephalitis, and funduscopy revealed infectious retinopathy."
explanation: >-
Direct funduscopic finding in confirmed neonatal HSV-2 CNS disease.
- category: Hepatic
name: Elevated circulating aspartate aminotransferase concentration
description: >-
Marked transaminase elevation reflects hepatic involvement in disseminated
disease, and at ten times the upper limit of normal at the start of therapy it
is associated with mortality.
phenotype_term:
preferred_term: aspartate transaminase elevation at initiation of therapy
term:
id: HP:0031956
label: Elevated circulating aspartate aminotransferase concentration
subtype: Disseminated
evidence:
- reference: PMID:11483781
reference_title: Natural history of neonatal herpes simplex virus infections in the acyclovir era.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Among patients with disseminated HSV disease treated with acyclovir at 30 mg/kg/d, mortality was associated with aspartate transaminase elevations of >/=10 times the upper limit of normal at the time of initiation of acyclovir therapy."
explanation: >-
The specific laboratory finding and its prognostic association, in disseminated
disease. Bound to the transaminase term rather than to HSV hepatitis
(HP:5210394), because the source reports the enzyme elevation and does not
diagnose hepatitis.
- category: Neurologic
name: Seizure
subtype: CNS
description: >-
Seizures accompany central nervous system disease, which may present with
overt neurological signs or with nonspecific illness.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:11483781
reference_title: Natural history of neonatal herpes simplex virus infections in the acyclovir era.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "For those patients with CNS disease, morbidity was also associated with seizures at initiation of antiviral therapy."
explanation: >-
Seizures at the start of therapy in CNS disease in the 186-patient
natural-history series, where they are also associated with morbidity.
- reference: PMID:42620976
reference_title: A case of neonatal herpes simplex virus type 2 encephalitis with TLR3 gene mutation and literature review.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A 17-day-old female presented with fever and frequent convulsions 15 days after birth."
explanation: >-
Direct documentation of convulsions in a confirmed case of neonatal
HSV-2 CNS disease.
- category: Ophthalmologic
name: Panuveitis
description: >-
Ocular involvement is a presenting feature that can lead to the diagnosis.
Reported manifestations include blepharoconjunctivitis, keratitis and
panuveitis, and ocular assessment has been argued to be decisive in the
diagnostic workup.
phenotype_term:
preferred_term: Panuveitis
term:
id: HP:0012121
label: Panuveitis
evidence:
- reference: PMID:38044450
reference_title: "Congenital herpes simplex with ophthalmic and multisystem features: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Later, a new ocular examination was suggestive of panuveitis."
explanation: >-
The ocular finding in a case of neonatal HSV confirmed by serum IgM. The
source hedges it as "suggestive of", and this item claims no more.
review_notes: >-
Chorioretinitis (HP:0012424) was considered and rejected: this source reports
panuveitis, blepharoconjunctivitis and keratitis, so binding Chorioretinitis
would assert a finding none of the cited sources make. No subtype is asserted
either - the case is a 32-week preterm with presumed neonatal infection
diagnosed on serum IgM, which does not establish in utero acquisition, so this
phenotype hangs off neonatal replication rather than the intrauterine-only
placental node.
- category: Neurologic
name: Abnormal brain morphology
description: >-
Structural brain abnormality is reported in intrauterine infection, where the
insult falls during fetal brain development rather than after birth.
phenotype_term:
preferred_term: fetal brain abnormality on antenatal ultrasound
term:
id: HP:0012443
label: Abnormal brain morphology
subtype: Intrauterine
review_notes: >-
Hydranencephaly (HP:0002324) was considered and rejected. The only cited source
reports "brain abnormalities" on antenatal ultrasound, and substituting a
specific destructive lesion for a non-specific finding is not an inference step
that directness INDIRECT can cover. Bind the specific lesion only when a source
names it. Organomegaly, in the same quoted sentence, is also not yet curated.
evidence:
- reference: PMID:40027069
reference_title: "Intrauterine Herpes Simplex Virus Infection: Insights Into a Silent Threat."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "An ultrasound at that time revealed severe fetal malformations, including brain abnormalities and organomegaly."
explanation: >-
Documents severe fetal brain malformation in confirmed intrauterine HSV-2.
Graded INDIRECT because the report describes brain abnormalities on
ultrasound rather than naming hydranencephaly specifically.
- category: Constitutional
name: Fever
subtype: CNS
description: >-
Fever with convulsions in the first weeks of life is the presentation that
should raise suspicion, particularly when empirical antibacterial treatment
fails.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: PMID:42620976
reference_title: A case of neonatal herpes simplex virus type 2 encephalitis with TLR3 gene mutation and literature review.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A 17-day-old female presented with fever and frequent convulsions 15 days after birth."
explanation: >-
Documents fever as a presenting feature in confirmed neonatal HSV-2 CNS
disease.
review_notes: >-
Disseminated intravascular coagulation was considered for a phenotype slot and
dropped: it is a real feature of disseminated neonatal HSV, but no reference
cited in this entry reports it. Left for a later round with a source that does.
prevalence:
- population: Global, pooled across three WHO regions
measure_type: ANNUAL_INCIDENCE
prevalence_class: BAND_1_9_PER_100000
rate_per_100000: 8.2
rate_low: 5.9
rate_high: 10.7
rate_denominator: LIVE_BIRTHS
notes: >-
Pooled and population-weighted mean incidence, 8.2 per 100,000 live births
(95% CI 5.9-10.7), from 140 incidence measures in 143 publications. Recorded
as ANNUAL_INCIDENCE with a LIVE_BIRTHS denominator, matching the source's own
wording and the precedent set by neonatal listeriosis in Listeriosis.yaml. Not
BIRTH_PREVALENCE: about 95% of the cases this entry covers are acquired at or
after delivery and are not present at birth.
evidence:
- reference: PMID:41860333
reference_title: "Global epidemiology of neonatal herpes: systematic review, meta-analyses, and meta-regressions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The global pooled and regional population-weighted mean incidence rate was 8.2 (95% confidence interval (CI) = 5.9-10.7) per 100 000 live births."
explanation: Source for the pooled global figure and its confidence interval.
- population: WHO Region of the Americas
measure_type: ANNUAL_INCIDENCE
prevalence_class: BAND_1_5_PER_10000
rate_per_100000: 13.3
rate_low: 9.9
rate_high: 17.2
rate_denominator: LIVE_BIRTHS
notes: >-
The highest regional estimate, against 5.2 in Europe and 2.9 in the Western
Pacific. Recorded because the regional spread is wide enough that a single
global figure misleads.
evidence:
- reference: PMID:41860333
reference_title: "Global epidemiology of neonatal herpes: systematic review, meta-analyses, and meta-regressions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Incidence rate was highest in the Americas (13.3 cases per 100 000 live births; 95% CI = 9.9-17.2), followed by the European Region (5.2 cases per 100 000 live births; 95% CI = 3.4-7.3) and the Western Pacific Region (2.9 cases per 100 000 live births; 95% CI = 2.2-3.6)."
explanation: Gives all three regional estimates in one sentence.
progression:
- phase: Trend in incidence
notes: >-
Incidence is rising, and the agent mix is shifting from HSV-2 toward HSV-1.
Both trends are measured rather than impressionistic.
evidence:
- reference: PMID:41860333
reference_title: "Global epidemiology of neonatal herpes: systematic review, meta-analyses, and meta-regressions."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Meta-regression analyses showed an annual increase of 3.5% (95% CI = 1.5-5.6) in nHSV incidence rate, alongside a yearly 1.4% (95% CI = 0.9-1.9) increase in the proportion of nHSV-1 cases and a 1.1% (95% CI = 0.6-1.6) decrease in the proportion of nHSV-2 cases."
explanation: Quantifies both trends with confidence intervals.
treatments:
- name: Intravenous Aciclovir
description: >-
Intravenous aciclovir is the treatment, with intensity and duration tailored
to which of the three presentations is present. Availability of safe,
effective antiviral therapy together with PCR diagnosis is described as having
transformed management of this disease.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: intravenous antiviral therapy
term:
id: NCIT:C16119
label: Antiviral Therapy
therapeutic_agent:
- preferred_term: aciclovir
term:
id: CHEBI:2453
label: acyclovir
target_mechanisms:
- target: Local Mucocutaneous Replication at the Portal of Entry
description: >-
Aciclovir inhibits viral DNA replication, acting on the node that determines
which of the three presentations develops.
evidence:
- reference: PMID:23481105
reference_title: Neonatal herpes simplex virus infections.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The use of polymerase chain reaction for diagnosis of central nervous system infections and the development of safe and effective antiviral therapy has revolutionized the diagnosis and management of these infants."
explanation: >-
Attributes the change in outcome to antiviral therapy acting on the
infection itself.
- target: Neuroinvasion and Central Nervous System Spread
description: >-
Intravenous aciclovir is given for CNS disease, not only for localised
disease, and the treatment course for it is longer.
evidence:
- reference: PMID:41185580
reference_title: A Multicenter Study on Symptomatic Neonatal Herpes Simplex Virus Infection in Korea From 2008 to 2017.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "All the patients received intravenous acyclovir, with a median treatment duration of 19 days (range, 3-68 days)."
explanation: >-
Every patient in this cohort received intravenous aciclovir, and 11 of the
16 had CNS disease, so the treatment is applied to this form. Graded
INDIRECT because the sentence reports the whole cohort rather than naming
the CNS subgroup.
- target: Haematogenous Multi-Organ Dissemination
description: >-
Intravenous aciclovir is likewise given for disseminated disease, where
transaminase elevation at the start of therapy marks the worst prognosis.
evidence:
- reference: PMID:41185580
reference_title: A Multicenter Study on Symptomatic Neonatal Herpes Simplex Virus Infection in Korea From 2008 to 2017.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: "All the patients received intravenous acyclovir, with a median treatment duration of 19 days (range, 3-68 days)."
explanation: >-
Same cohort sentence; four of the 16 had disseminated infection. Graded
INDIRECT for the same reason, that the cohort is reported together.
evidence:
- reference: PMID:37592873
reference_title: "Neonatal herpes simplex virus infection: From the maternal infection to the child outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the treatment with acyclovir should be tailored according to symptoms and signs of infection, and virological tests"
explanation: Establishes aciclovir as the treatment and that dosing is tailored.
- name: Maternal Third-Trimester Antiviral Prophylaxis
description: >-
Antiviral prophylaxis given to the mother in late pregnancy reduces genital HSV
recurrence and viral shedding at delivery, which is the exposure that transmits
the infection. Whether it reduces neonatal herpes itself is not established -
the disease is rare enough that the trials are underpowered for that endpoint.
Recorded here because prevention is the principal clinical lever in this disease.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: antiviral prophylaxis in the third trimester
term:
id: NCIT:C16119
label: Antiviral Therapy
therapeutic_agent:
- preferred_term: aciclovir
term:
id: CHEBI:2453
label: acyclovir
target_mechanisms:
- target: Maternal Genital HSV Infection and Shedding
description: >-
Suppresses the maternal reservoir and shedding, acting upstream of
transmission rather than on neonatal infection.
evidence:
- reference: PMID:18254066
reference_title: Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Women who received antiviral prophylaxis were significantly less likely to have a recurrence of genital herpes at delivery (relative risk (RR) 0.28, 95% confidence interval (CI) 0.18 to 0.43"
explanation: >-
Systematic-review effect estimate for the outcome this treatment acts on,
maternal recurrence at delivery.
- reference: PMID:18254066
reference_title: Third trimester antiviral prophylaxis for preventing maternal genital herpes simplex virus (HSV) recurrences and neonatal infection.
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: "There is insufficient evidence to determine if antiviral prophylaxis reduces the incidence of neonatal herpes."
explanation: >-
Recorded as NO_EVIDENCE against the stronger claim that prophylaxis prevents
neonatal herpes. The review establishes the surrogate outcome and explicitly
declines the clinical one, and this entry should not assert more than that.
- name: Oral Aciclovir Suppression After Acute Treatment
description: >-
Long-term oral suppressive therapy after the acute course reduces morbidity.
The cited source states the benefit without specifying the domain, so no
neurodevelopmental-specific claim is made.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: oral antiviral suppressive therapy
term:
id: NCIT:C16119
label: Antiviral Therapy
therapeutic_agent:
- preferred_term: aciclovir
term:
id: CHEBI:2453
label: acyclovir
evidence:
- reference: PMID:23481105
reference_title: Neonatal herpes simplex virus infections.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Initiation of long-term antiviral suppressive therapy in these infants has led to significant improvement in morbidity."
explanation: >-
States the morbidity benefit of suppressive therapy following acute
treatment.
diagnosis:
- name: HSV Polymerase Chain Reaction
description: >-
PCR detection of HSV DNA, including in cerebrospinal fluid for central
nervous system disease. PCR diagnosis, together with antiviral therapy, is
credited with transforming the diagnosis and management of these infants.
diagnosis_term:
preferred_term: HSV PCR
term:
id: NCIT:C17003
label: Polymerase Chain Reaction
evidence:
- reference: PMID:23481105
reference_title: Neonatal herpes simplex virus infections.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The use of polymerase chain reaction for diagnosis of central nervous system infections and the development of safe and effective antiviral therapy has revolutionized the diagnosis and management of these infants."
explanation: >-
Names PCR as the diagnostic method for CNS infection in neonatal HSV.
- name: Placental Histopathology
description: >-
Pathological examination of the placenta can reveal intrauterine infection
before the infant shows signs, which matters most in premature infants
because intrauterine HSV presents variably.
diagnosis_term:
preferred_term: placental histopathological examination
term:
id: NCIT:C18190
label: Histopathologic Examination
evidence:
- reference: PMID:33520322
reference_title: Diagnosis of Neonatal Herpes Simplex Infection from the Placenta.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Due to the variability of presentation of intrauterine HSV infection, pathological examination of the placenta in the first 2-5 days of life in premature infants can provide clues to the diagnosis of neonatal HSV which may significantly impact the outcome."
explanation: >-
The case report's conclusion that placental pathology can prompt the
diagnosis, drawn from one case in which it did.
- name: Ophthalmological Assessment
description: >-
Eye examination can raise the suspicion of HSV and is argued to be decisive
in the diagnostic workup, particularly in neonatal conjunctivitis that does
not respond to antibiotics.
diagnosis_term:
preferred_term: ophthalmological assessment
term:
id: NCIT:C38060
label: Eye Examination
evidence:
- reference: PMID:38044450
reference_title: "Congenital herpes simplex with ophthalmic and multisystem features: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our report highlights that ocular assessment can be crucial in the correct diagnostic investigation of this condition."
explanation: >-
The case report's conclusion on the diagnostic role of ocular assessment.
animal_models:
- name: Intravaginal primary HSV-2 infection in early-pregnant C57BL/6 mice
species: Mouse
genotype: wild type
background: C57BL/6
publication: PMID:34696359
description: >-
Pregnant mice infected intravaginally with HSV-2 on gestation day 4.5. Viral
DNA persists in placental tissue, with placental inflammation and
haemorrhage, transmission to fetal tissue, and dose-dependent reduction in
fetal and placental weight and fetal loss.
evidence:
- reference: PMID:34696359
reference_title: Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "This mouse model shows a dose-dependent effect of primary HSV-2 infection on pregnancy outcomes and suggests that fetal loss may occur due to placental inflammation, thus providing valuable insight into in utero transmission of HSV-2."
explanation: >-
The authors' summary of what the model shows about in utero transmission.
modeled_mechanisms:
- target: Placental Inflammation and Fetal Injury
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: >-
Reproduces placental viral persistence with inflammation and haemorrhage,
fetal infection, and dose-dependent fetal injury and loss after primary
maternal infection in early pregnancy.
limitations: >-
Mouse placentation differs from human placentation, infection is by
intravaginal inoculation of a set viral dose at gestation day 4.5, and the
model addresses the intrauterine route only, not the intrapartum route
that accounts for most human cases.
evidence:
- reference: PMID:34696359
reference_title: Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Eight days post-inoculation (gd12.5), HSV-2 DNA persisted in placental tissues, resulting in inflammation and hemorrhage."
explanation: >-
The placental finding that makes this model informative for the node.
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Close the disseminated-disease evidence gap with two new references · 2026-10-01T15:24:51Z · View source
Closes the gap the previous record left open. The Haematogenous Multi-Organ Dissemination node was the highest-mortality presentation with no downstream phenotype and no outcome evidence, because the deep-research report's source for the organ involvement of disseminated disease was PMID:11483825, one of the five confabulated citations. Two real references were fetched rather than softening the prose. PMID:11483781, the Collaborative Antiviral Study Group natural history of 186 acyclovir-treated neonates, supplies three things: aspartate transaminase elevation at or above ten times the upper limit of normal at initiation of therapy is associated with mortality in disseminated disease, which is the hepatic organ involvement the node asserts; morbidity status is associated with the extent of disease across the skin-eye-mouth, CNS and disseminated categories, which sources the claim that the three-way classification determines outcome and therefore justifies carrying it as a subtype axis; and a significant minority of infants never have skin vesicles at presentation or during the acute illness, at 39% in disseminated disease, 32% in CNS disease and 17% in skin-eye-mouth disease. PMID:41185580, a twelve-centre Korean cohort, supplies 30-day mortality confined to the disseminated group. Changes: added an Elevated circulating aspartate aminotransferase concentration phenotype (HP:0031956, subtype Disseminated) as the node's downstream target, bound to the transaminase term rather than to HSV hepatitis (HP:5210394) because the source reports the enzyme elevation and does not diagnose hepatitis; added the mortality and extent-of-disease evidence to the dissemination node; and corrected the Vesicular skin eruption phenotype, whose description had called vesicles the first visible sign in any form. That was an over-generalization from a single intrauterine case, and the 39% absence figure is now carried on it as a REFUTE with directness INDIRECT against reading the phenotype as a reliable marker of the disease. Separately, all six citations of DOI:10.1002/jmv.29024 were switched to PMID:37592873, the same paper's PubMed record, after verifying the PMID cache carries every quoted sentence; DOI is in skip_prefixes so those snippets were previously not checked by the gating validator, and they now are. Snippet count rose from 28/28 to 32/32 verified, and count-verified-snippets --unskip-prefix DOI also reports 32/32. Note for whoever runs the gates next: check-snippet-length currently reports three findings in Behr_Syndrome.yaml and Beta_Mannosidosis.yaml, both untouched by this branch. All three snippets are pre-existing on origin/main and appear only because grandfathering is unavailable in that run mode; they are not introduced here.
Create: Congenital Herpes Simplex Virus Infection · 2026-10-01T01:58:54Z · View source
De novo curation of congenital herpes simplex virus infection (MONDO:0017381). dismech had no herpesvirus entry; Congenital_Zika_Syndrome.yaml was used as the structural pattern. Deep research: falcon was requested but has no API key in this environment, so the run used --fallback and claude_code produced the report, which records fell_back, requested_provider and provider_attempts; the report is research/Congenital_Herpes_Simplex_Virus_Infection-deep-research-claude_code.md. Both of its validation blocks reported needs_review: true. I audited all 25 cached references by title myself and found FIVE confabulated citations - real PMIDs for the wrong papers - of which the report's own validator flagged only one. They are PMID:2020171 (actually 'Subcritical flutter in collapsible tube flow', the one flagged), PMID:21793742 ('Integrating social media into emergency-preparedness efforts'), PMID:33055261 (a Babesia divergens parasitology paper), PMID:16501086 (CD8 responses to simian immunodeficiency virus) and PMID:11483825 (an AAP Committee on Psychosocial Aspects statement). None is cited in this entry. confabulation_rate read 0.0 because all five resolve, and four escaped the relevance check because a record with no abstract cannot be scored off-topic. This is the second consecutive report with exactly this profile; the HSTCL run had five confabulations with one flagged. Four ontology bindings the report offered were also wrong and are not used: HP:0002340 is Caudate atrophy not Hydranencephaly (correct term HP:0002324), HP:0000483 is Astigmatism not Chorioretinitis, HP:0005765 is Sacral meningocele not DIC, and CHEBI:60726 is procainamide 4-hydroxylamine not valacyclovir (aciclovir is CHEBI:2453). HP:0045023 does not exist at all. Every CURIE in the entry was resolved against OLS at the time of writing. Two claims were withdrawn during the build after reading the abstracts rather than the report: a Chorioretinitis phenotype bound to HP:0012424 was replaced with Panuveitis (HP:0012121) because PMID:38044450 reports panuveitis, blepharoconjunctivitis and keratitis and never chorioretinitis; and a disseminated intravascular coagulation phenotype was dropped and replaced with Fever because no reference cited in this entry reports DIC, although it is a genuine feature of disseminated neonatal HSV. Both rejections are recorded in the surviving items' explanation fields. Three of my own first-draft snippets quoted paper titles rather than findings, which is the defect check-title-snippets exists to catch; all three were replaced with real findings. Scope: MONDO:0017381 lumps intrauterine, perinatal and postnatal transmission, and the entry covers all three as one Disease with the routes as has_subtypes, justified by the quantitative split (5/85/10 percent from DOI:10.1002/jmv.29024) plus shared virus, diagnosis and treatment, and by MONDO offering no separate identifier for either route. The notes also record the partial overlap with Viral_Encephalitis.yaml, whose HSV Encephalitis subtype scopes adult HSV-1 frontotemporal disease and binds no MONDO identifier. Pathophysiology is a branching causal chain: maternal shedding to vertical transmission, which splits into placental inflammation and fetal injury on the intrauterine route and neonatal viral replication and dissemination on the intrapartum route, with phenotypes downstream of each. Validation: just validate passes with 22/22 snippets verified; validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-environmental-evidence, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens and the batched validate-disorders all pass.
Congenital Herpes Simplex Virus (HSV) infection is a group of congenital anomalies resulting from maternal HSV infection and subsequent fetal/neonatal infection with herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2). It represents a spectrum of disease acquired either in utero (transplacental or ascending infection) or perinatally (during passage through an infected birth canal). The intrauterine form is the rarest and most severe, characterized by a classic triad of cutaneous, neurologic, and ophthalmologic findings (PMID:40027069).
Neonatal HSV disease is traditionally classified into three categories based on the extent of involvement: - Skin, Eye, and Mouth (SEM) disease (~45% of cases) - Central Nervous System (CNS) disease (~30% of cases) - Disseminated disease (~25% of cases)
True congenital (intrauterine) HSV infection accounts for approximately 5% of all neonatal HSV cases, while 85% are acquired peripartum and 10% postnatally (PMID:40027069).
| Database | Identifier |
|---|---|
| MONDO | MONDO:0017381 |
| Orphanet | ORPHA:293 |
| ICD-10 | P35.2 (Congenital herpesviral [herpes simplex] infection) |
| ICD-11 | KA62.3 |
| UMLS | C4275250 |
| MeSH | D006558 (Herpes Simplex, broader) |
Congenital HSV infection is caused by vertical transmission of Herpes Simplex Virus (HSV-1 or HSV-2, family Herpesviridae, subfamily Alphaherpesvirinae) from an infected mother to the fetus or neonate. HSV is a large, enveloped double-stranded DNA virus (~152 kb genome) encoding approximately 80 proteins.
Routes of vertical transmission: 1. Transplacental (hematogenous): During maternal primary viremia, the virus crosses the placenta — the predominant route for true congenital (intrauterine) infection (PMID:40027069) 2. Ascending infection: Virus ascends from the genital tract through ruptured or intact amniotic membranes 3. Intrapartum contact: Direct contact with infectious secretions in the birth canal (most common overall)
Maternal factors: - Primary maternal genital HSV infection near delivery: The strongest risk factor. Infants born to women with primary genital HSV infection near delivery have a 25–60% risk of neonatal herpes, compared to <2% with recurrent genital HSV (PMID:2020171; Brown et al., NEJM 1991) - Absence of maternal HSV-specific IgG antibodies: Lack of transplacental protective antibodies leaves the neonate without passive immunity - Prolonged rupture of membranes (>4–6 hours): Increases ascending infection risk - Vaginal delivery with active genital lesions - Use of fetal scalp electrodes: Disrupts neonatal skin barrier
Neonatal/fetal factors: - Prematurity: Immature immune system and skin barrier compromise - Fetal skin barrier disruption: Permits viral entry - Immature neonatal innate immunity: Particularly dampened TLR3–interferon signaling in the newborn brain (PMID:33055261)
Host genetic susceptibility (inborn errors of immunity): Mutations in TLR3 pathway genes predispose to severe HSV disease, particularly HSV encephalitis: - TLR3, UNC93B1, TRIF (TICAM1), TRAF3, TBK1, IRF3, STAT1, IFNAR1, NEMO (IKBKG) - These genetic alterations impair IFN-α/β production within the central nervous system (PMC9961685)
| Phenotype | HPO Term | Frequency | Notes |
|---|---|---|---|
| Skin vesicles/vesicular rash | HP:0200037 (Skin vesicle) | Very frequent (~80% in SEM) | Active vesicles, often clustered; may present in dermatomal distribution |
| Scarring/cicatricial skin lesions | HP:0100699 (Scarring) | Frequent in intrauterine | Aplasia cutis, crusted papules |
| Hyperpigmentation | HP:0000953 (Hyperpigmentation of the skin) | Occasional | Post-inflammatory |
| Hypopigmentation | HP:0001010 (Hypopigmentation of the skin) | Occasional | Post-inflammatory |
| Phenotype | HPO Term | Frequency | Notes |
|---|---|---|---|
| Microcephaly | HP:0000252 | Occasional (~7.5%) | Characteristic of intrauterine infection |
| Hydranencephaly | HP:0002340 | Occasional (~7.5%) | Severe, intrauterine |
| Seizures | HP:0001250 | ~67% in CNS disease | Often multifocal |
| Intracranial calcifications | HP:0002514 | Frequent in intrauterine/CNS | Distinguishing feature |
| Encephalopathy | HP:0001298 (Encephalopathy) | Frequent in CNS/disseminated | Obtundation, irritability |
| Intellectual disability | HP:0001249 | 30–70% of CNS survivors | Long-term sequela |
| Cerebral palsy | HP:0100021 | Variable | Long-term sequela |
| Epilepsy | HP:0001250 | Variable | Long-term sequela |
| Phenotype | HPO Term | Frequency | Notes |
|---|---|---|---|
| Chorioretinitis | HP:0000483 (Chorioretinitis) | Frequent in intrauterine | Part of classic triad |
| Microphthalmia | HP:0000568 | Occasional | Intrauterine infection |
| Cataracts | HP:0000518 | Occasional | Congenital |
| Keratoconjunctivitis | HP:0000563 (Keratoconjunctivitis) | Occasional | Can lead to corneal scarring |
| Optic atrophy | HP:0000648 | Occasional | Late finding |
| Phenotype | HPO Term | Frequency | Notes |
|---|---|---|---|
| Fever / hypothermia | HP:0001945 (Fever) / HP:0045023 (Hypothermia) | ~56% | Temperature instability |
| Hepatomegaly | HP:0002240 | Frequent in disseminated | Liver involvement |
| Hepatitis | HP:0012115 (Hepatic failure) | Frequent in disseminated | Can be fulminant |
| Jaundice | HP:0000952 (Jaundice) | Frequent in disseminated | |
| Pneumonitis | HP:0006517 (Alveolar hemorrhage) | ~25% disseminated | |
| Disseminated intravascular coagulation | HP:0005765 (DIC) | Frequent in disseminated | |
| Intrauterine growth restriction | HP:0001511 | ~33% | |
| Premature birth | HP:0001622 | ~33% | |
| Lethargy | HP:0001254 (Lethargy) | Very frequent | |
| Poor feeding | HP:0011968 (Feeding difficulties) | Frequent | |
| Ascites | HP:0001541 (Ascites) | Occasional | In disseminated disease |
Congenital HSV infection is an infectious disease, not a monogenic disorder. The causative agents are: - HSV-1 (Human alphaherpesvirus 1; NCBITaxon:10298) - HSV-2 (Human alphaherpesvirus 2; NCBITaxon:10310)
Globally, neonatal HSV disease shows near-equal contributions from both serotypes: HSV-1 accounts for 47.3% and HSV-2 for 52.8%, with a temporal shift toward increasing HSV-1 proportion (yearly 1.4% increase in HSV-1 cases) (PMID:41860333).
While not causative in the Mendelian sense, inborn errors of immunity in the TLR3–IFN signaling pathway markedly increase susceptibility to severe HSV disease:
| Gene | HGNC | OMIM | Inheritance | Functional Consequence |
|---|---|---|---|---|
| TLR3 | hgnc:11849 | 613002 | AD/AR | Impaired IFN-α/β production in CNS |
| UNC93B1 | hgnc:13481 | 610551 | AR | Defective TLR3/7/8/9 trafficking |
| TRIF (TICAM1) | hgnc:18348 | 614850 | AD/AR | Impaired TLR3 signaling |
| TRAF3 | hgnc:12033 | 614849 | AD | Impaired IFN-β induction |
| TBK1 | hgnc:11584 | 614847 | AD | Impaired IRF3 phosphorylation |
| IRF3 | hgnc:6118 | — | AD | Impaired IFN-β transcription |
| IRF7 | hgnc:6122 | — | AR | Impaired IFN-α production |
| STAT1 | hgnc:11362 | — | AD | Impaired IFN response |
| IFNAR1 | hgnc:5432 | — | AR | Absent type I IFN receptor |
These defects impair the TLR3-dependent type I interferon response that is particularly critical in the CNS for controlling HSV replication (PMC9961685; PMC10231989). A case report documented neonatal HSV-2 encephalitis associated with a compound heterozygous TLR3 mutation (PMC13485870).
Viral entry receptors: - Nectin-1 (PVRL1/NECTIN1; hgnc:9706): Primary receptor on neurons and epithelial cells - HVEM (TNFRSF14; hgnc:11912): Herpesvirus entry mediator; expressed on immune cells - 3-O-sulfated heparan sulfate: Modified proteoglycan receptor
Essential entry glycoproteins: gB, gD, gH, gL mediate viral envelope–cell membrane fusion.
| Cell Type | CL Term | Role |
|---|---|---|
| Epithelial cell | CL:0000066 | Primary site of viral entry and replication |
| Neuron | CL:0000540 | Target of neurotropic spread; site of latency |
| Astrocyte | CL:0000127 | Neuroinflammatory response |
| Microglial cell | CL:0000129 | CNS innate immune response |
| Hepatocyte | CL:0000182 | Target in disseminated disease |
| Trophoblast | CL:0000351 | Placental barrier; site of transplacental transmission |
| Natural killer cell | CL:0000623 | Neonatal NK cell function is immature |
| Dendritic cell | CL:0000451 | Antigen presentation, IFN production |
Histopathological findings in the placenta include (PMC9557870; PMC7817230): - Necrotizing villitis with stromal cell necrosis - Chronic chorioamnionitis - Maternal floor infarction - Calcifying funisitis (umbilical cord) - Positive HSV immunohistochemistry in placenta and umbilical cord - Ascending infection pattern shows changes primarily in the umbilical cord and chorionic plate
| Organ/System | UBERON Term | Involvement |
|---|---|---|
| Skin | UBERON:0002097 | Primary (vesicles, scarring) |
| Brain | UBERON:0000955 | Primary in CNS and intrauterine forms |
| Eye | UBERON:0000970 | Chorioretinitis, microphthalmia |
| Liver | UBERON:0002107 | Disseminated disease |
| Lung | UBERON:0002048 | Pneumonitis in disseminated |
| Adrenal gland | UBERON:0002369 | Adrenal hemorrhage/necrosis |
| Placenta | UBERON:0001987 | Villitis, infarction |
Onset classification: Neonatal (HP:0003623, Neonatal onset).
Global incidence (PMID:41860333; systematic review and meta-analysis, 143 reports): - Global pooled incidence: 8.8 per 100,000 live births (95% CI: 6.9–10.9) - Population-weighted global estimate: 8.2 per 100,000 live births (95% CI: 5.9–10.7) - Approximately 1 in 10,000 newborns affected globally - Annual increase of 3.5% (95% CI: 1.5–5.6%) in nHSV incidence
Regional variation: - Americas: 13.3 per 100,000 live births (95% CI: 9.9–17.2) — highest - European Region: 5.2 per 100,000 live births (95% CI: 3.4–7.3) - Western Pacific: 2.9 per 100,000 live births (95% CI: 2.2–3.6) - Data lacking from Africa, South-East Asia, Eastern Mediterranean
True intrauterine HSV infection: Estimated at only 1 in 300,000 deliveries (PMID:40027069).
LOINC codes: - HSV DNA detection by NAA: LOINC:16952-4 - HSV culture: LOINC:5857-0
| Disease Category | Untreated Mortality | Treated Mortality (high-dose acyclovir) |
|---|---|---|
| SEM | Low (~0%) | ~0% |
| CNS | ~50% | ~4% |
| Disseminated | ~85% | ~30% |
| Intrauterine | Very high | Variable, often poor |
(Mortality data from Kimberlin et al., Pediatrics 2001, PMID:11483825; and AAP NeoReviews 2018)
Intravenous acyclovir (NCIT:C275; Acyclovir) — standard of care: - Dose: 20 mg/kg/dose IV every 8 hours - Duration: - SEM disease: 14 days - CNS disease: 21 days (minimum) - Disseminated disease: 21 days (minimum) - CSF monitoring: Repeat lumbar puncture near end of therapy for CNS disease; continue IV acyclovir if CSF PCR remains positive, with weekly repeat LP until negative
NCIT terms: - Pharmacotherapy: NCIT:C15986 - Acyclovir: NCIT:C275
Suggested CHEBI term: CHEBI:2453 (aciclovir)
Maternal antiviral suppressive therapy: - Acyclovir 400 mg PO TID or valacyclovir 500 mg PO BID from 36 weeks gestation in women with known recurrent genital HSV - Significantly reduces viral shedding at delivery and cesarean section rates (PMID:18254066) - Insufficient evidence that suppressive therapy alone reduces neonatal herpes incidence (event too rare in trials)
Cesarean delivery: - Recommended when active genital HSV lesions or prodromal symptoms are present at labor onset - Reduces neonatal HSV transmission by ~86%
Screening: - Routine serologic screening for HSV during pregnancy is not recommended by ACOG/SOGC - Type-specific IgG testing can identify discordant couples and guide counseling - No population-based prenatal HSV screening program exists
Mouse models: - C57BL/6 mice infected intravaginally with HSV-2 during early pregnancy demonstrate dose-dependent adverse pregnancy outcomes including reduced fetal/placental weights, fetal resorption, and transplacental viral transmission (PMID:34696359) - At low viral doses, infection localizes to fetal eye and CNS; at high doses, disseminated expression in neuroepithelium, heart, and liver - Pregnant mice show ~100-fold greater susceptibility to HSV-2 compared to non-pregnant controls - Newborn mice demonstrate dampened innate immune signaling and IFN responses compared to adults (PMID:33055261) - Hematogenous vertical transmission of HSV-1 in mice with CNS tropism in offspring (PMID:16501086)
Guinea pig models: - Mimic natural history of genital HSV infection with spontaneous recurrences - Used for studying antiviral suppressive therapy and maternal-to-neonatal transmission
Non-human primate models: - Rhesus macaque model for genital HSV-2 with vaginal vesicular lesions, virus shedding, and seroconversion (PMC11371218) - Most relevant to human disease due to immunological similarity
HSV-1 and HSV-2 are highly host-restricted to humans. Natural HSV infection in non-human animals is rare and typically represents cross-species transmission. B virus (Macacine alphaherpesvirus 1), an HSV homolog in Old World macaques, causes a similar but zoonotic disease.
| Model | Species | Application | Fidelity | Limitations |
|---|---|---|---|---|
| Neonatal mouse HSV encephalitis | Mouse (NCBITaxon:10090) | CNS pathogenesis, antiviral testing, immune response | MODERATE | Murine immune ontogeny differs from human; shorter gestation |
| Intravaginal HSV-2 pregnant mouse | Mouse | Transplacental transmission, pregnancy outcomes | MODERATE | Dose-dependent; 100x greater susceptibility than humans |
| Guinea pig genital HSV-2 | Guinea pig (NCBITaxon:10141) | Recurrent genital herpes, antiviral efficacy | MODERATE | Spontaneous recurrences; limited reagents for immune studies |
| Rhesus macaque genital HSV-2 | Rhesus macaque (NCBITaxon:9544) | Vaccine development, mucosal immunity | HIGH | Ethical/cost constraints; HSV is not natural pathogen |
| HSV-infected human organoids/iPSC | Human (NCBITaxon:9606) | CNS tropism, interferon response | MODERATE | Lacks systemic immune context |
| Domain | Suggested Terms |
|---|---|
| Disease | MONDO:0017381 (Congenital herpes simplex virus infection) |
| Phenotypes | HP:0000252 (Microcephaly), HP:0002340 (Hydranencephaly), HP:0001250 (Seizures), HP:0000483 (Chorioretinitis), HP:0000568 (Microphthalmia), HP:0200037 (Skin vesicle), HP:0002514 (Intracranial calcification), HP:0001298 (Encephalopathy), HP:0002240 (Hepatomegaly), HP:0001622 (Premature birth), HP:0001511 (Intrauterine growth retardation), HP:0001249 (Intellectual disability) |
| Cell types | CL:0000066 (epithelial cell), CL:0000540 (neuron), CL:0000182 (hepatocyte), CL:0000129 (microglial cell), CL:0000127 (astrocyte), CL:0000351 (trophoblast cell) |
| Biological processes | GO:0045087 (innate immune response), GO:0034154 (toll-like receptor 3 signaling), GO:0060337 (type I interferon signaling pathway), GO:0019079 (viral genome replication), GO:0006915 (apoptotic process) |
| Anatomy | UBERON:0000955 (brain), UBERON:0002097 (skin of body), UBERON:0000970 (eye), UBERON:0002107 (liver), UBERON:0001987 (placenta) |
| Treatment | NCIT:C15986 (Pharmacotherapy), NCIT:C275 (Acyclovir), CHEBI:2453 (aciclovir) |
| Infectious agent | NCBITaxon:10298 (Human alphaherpesvirus 1), NCBITaxon:10310 (Human alphaherpesvirus 2) |
Checked with linkml-reference-validator 0.3.0rc3.
| Outcome | Count |
|---|---|
| References checked | 28 |
| Resolved | 28 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 28 |
| On topic | 19 |
| Off topic | 1 |
These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:
PMID:2020171 (2 mentions) - Subcritical flutter in collapsible tube flow: a model of expiratory flow in the trachea.Weighed against this report's own most characteristic terms: hsv, infection, disease, neonatal, cns, intrauterine, herpe, disseminated, lesion, primary, hsv-2, congenital, genital, maternal, transmission, hsv-1, viral, acyclovir, virus, skin.
All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 65 |
| Resolved | 61 |
| Unresolved (possible confabulation) | 1 |
| Obsolete | 0 |
| Unverifiable | 3 |
| Terms whose name was checked | 51 |
| Terms named correctly | 34 |
| Terms named as a different term | 5 |
| Terms whose name is worth a second look | 12 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0017381 (2 mentions) - the report calls it "MONDO", "Congenital herpes simplex virus infection"; MONDO calls it congenital herpes simplex virus infectionHP:0002340 (2 mentions) - the report calls it "Hydranencephaly"; HP calls it Caudate atrophyHP:0000483 (2 mentions) - the report calls it "Chorioretinitis"; HP calls it AstigmatismHP:0005765 (1 mention) - the report calls it "DIC"; HP calls it Sacral meningoceleCHEBI:60726 (1 mention) - the report calls it "Valacyclovir"; CHEBI calls it procainamide 4-hydroxylamineThese identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:
HP:0045023 (1 mention) - HP does not contain this termThe report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
HP:0001250 (3 mentions) - the report calls it "Seizures", "Epilepsy"; HP calls it Seizure, and lists "Epilepsy" among its other namesHP:0002514 (2 mentions) - the report calls it "Intracranial calcifications"; HP calls it Cerebral calcificationHP:0000563 (1 mention) - the report calls it "Keratoconjunctivitis"; HP calls it KeratoconusHP:0012115 (1 mention) - the report calls it "Hepatic failure"; HP calls it HepatitisHP:0006517 (1 mention) - the report calls it "Alveolar hemorrhage"; HP calls it Intraalveolar phospholipid accumulation, and lists "Alveolar proteinosis" among its other namesHP:0001511 (2 mentions) - the report calls it "Intrauterine growth restriction"; HP calls it Intrauterine growth retardation, and lists "Intrauterine growth restriction" among its other namesNCBITaxon:10298 (3 mentions) - the report calls it "Primary agent: HSV-1"; NCBITaxon calls it Human alphaherpesvirus 1**, and lists "HSV-1" among its other namesGO:0007249 (1 mention) - the report calls it "NF-κB signaling"; GO calls it canonical NF-kappaB signal transduction, and lists "p50-dependent NF-kappaB signaling" among its other namesGO:0006915 (2 mentions) - the report calls it "Apoptosis"; GO calls it apoptotic process, and lists "apoptosis" among its other namesCL:0000351 (2 mentions) - the report calls it "Trophoblast"; CL calls it trophoblast cellUBERON:0002097 (2 mentions) - the report calls it "Skin"; UBERON calls it skin of body, and lists "skin" among its other namesCHEBI:2453 (2 mentions) - the report calls it "aciclovir"; CHEBI calls it acyclovir, and lists "aciclovir" among its other namesThe report gives these identifiers more than one name of its own:
MONDO:0017381 - called "MONDO", "Congenital herpes simplex virus infection"HP:0001250 - called "Seizures", "Epilepsy"Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, LOINC.