Congenital herpes simplex (CHS) is a rare disease affecting neonates born to mothers infected with herpes simplex virus. Women who acquire the disease during the third trimester of pregnancy are most likely to transmit the virus to their unborn child. An intrauterine infection with herpes simplex viruses of either type may cause abortion, stillbirth or perinatal death, growth retardation and developmental delays. Due to the profound impact of the disease on the child's quality of life, adequate measures should be taken to prevent infections with herpes simplex virus during pregnancy and to avoid the vertical transmission of the pathogen, e.g., by avoidance of certain sexual activities, antiviral therapy, and preference of caesarean section over vaginal delivery.
Very few fetuses survive an intrauterine herpes simplex virus infection if it takes places during the first trimester of pregnancy. Such an infection usually results in spontaneous abortion, stillbirth or perinatal death. However, those that do survive may present with symptoms of severe intrauterine growth retardation and developmental delay . Microcephaly has repeatedly been described in CHS patients, but patients may also suffer from encephalomalacia and intracranial calcifications that are not recognizable without applying imaging techniques. Cranial and central nervous system malformations may also provoke seizures. Affected infants are unlikely to reach pyschomotor developmental milestones in a timely manner. Besides neurological damage, eye and skin lesions are characteristic of CHS. Microphthalmia, cataract, chorioretinitis, and optic atrophy are common findings and neonates often have a vesicular rash. Atypical skin lesions observed in CHS patients comprise erythematous, erosive, ulcerative, and even atrophic patches  . Additionally, aplasia cutis may be seen and infants may present areas of hypo- or hyperpigmentation . Pathogen dissemination is possible and may entail multiple organ failure and death .
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Eczema herpeticum in children: clinical features and factors predictive of hospitalization. J Pediatr. 2012 Oct. 161 (4):671-5. [Medline]. Hsu DY, Shinkai K, Silverberg JI. Epidemiology of Eczema Herpeticum in Hospitalized U.S. [emedicine.medscape.com]
Babies born to women with a known herpes simplex virus infection should be examined thoroughly for any symptoms that may indicate that vertical transmission has occurred. Positive findings should prompt the immediate initiation of antiviral treatment. To treat possibly underlying bacterial diseases and to avoid secondary infections of skin lesions, antiviral agents are usually combined with antibiotics.
In any case, skin swabs and serum samples should always be obtained from neonates at high risk of having acquired the disease and from symptomatic ones, independent of the medical history of their mother. They should be tested both immunohistochemically and by means of polymerase chain reaction for the presence of HSV-1 and HSV-2. It should be noted, though, that false-negative results may be obtained, especially if the mother has been treated with antiviral agents . If the infant continues to be suspicious for CHS, the respective studies have to be repeated with new samples at a later point in time . Finally, if herpes simplex virus is detected, similar test should be run on cerebrospinal fluid samples to assess whether the infection has stread to the central nervous system. An electroencephalogram may be recorded to better evaluate brain function .
Skin biopsies may be obtained and histopathologically examined to rule out differential diagnoses. This procedure should also be considered if the patient assumed to suffer from CHS does not respond to antiviral therapy.
Because CHS is often associated with eye disease, CHS patients should undergo an ophthalmological examination. Additionally, brain imaging may be helpful to evaluate the degree of brain damage.
Therapy is based on antiviral compounds like acyclovir. The most common treatment regimen comprises the application of 60 mg acyclovir per kg body weight and day, divided in three doses . Besides acyclovir, vidarabine has been used to treat CHS. However, acyclovir is considered to be superior to vidarabine . Nevertheless, vidarabine may be administered in case of resistance to acyclovir . Foscarnet has been proposed as another alternative . Fortunately, few cases of CHS refractory to acyclovir treatment have been reported to date   .
Parenteral treatment is typically continued for two to three weeks. At this point, it is recommended to re-test serum and possibly cerebrospinal fluid samples to confirm the absence of viremia and central nervous system infection. If those tests yield negative results, parenteral treatment is replaced by suppressive oral therapy. The latter needs to be continued for another six months. The corresponding dose of acyclovir is 900 mg per square meter of body surface area, divided in three doses . However, recurrence during the first year of life is not uncommon and warrants further parenteral therapy .
During antiviral therapy, absolute neutrophil counts should be assessed repeatedly: twice weekly while the antiviral agent is applied parenterally, and monthly during suppressive oral therapy. If absolute neutrophil counts remain below 500/µl for a prolonged period of time, it may be necessary to reduce the dosage of acyclovir or to administer granulocyte colony-stimulating factor .
CHS has long since been associated with substantial morbidity and mortality in affected infants. Due to advances in diagnosis and treatment, CHS patients have a better prognosis today. Still, invasive and disseminated forms of the disease may entail neurological long-term sequelae and death . Even though normal development is likely if the disease is treated early on, skin lesions may heal with scarring .
CHS may result from the vertical transmission of herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2) . CHS is considered to be the most devastating consequence of genital herpes and it should be noted that both virus strains may trigger this disease, even though it is more commonly attributed to HSV-2 .
Both HSV-1 and HSV-2 belong to the family of Herpesviridae and their genomes show about 50% homology. Homologous DNA sequences encode for proteins that can hardly be assigned to a specific type of virus, but both of them are known to produce type-specific glycoproteins, too. The latter can be detected applying immunological assays. Furthermore, molecular biological approaches allow for the differentiation of type 1 and type 2 virus strains.
Similar to other members of the family of Herpesviridae, herpes simplex viruses are able to replicate within host cells, destroy them, and penetrate into other cells. They may also infect neurons and remain inactive inside those cells for years, possibly establishing lifelong latency. Contrary to epithelial cells involved in the actual replication cycle, infected neurons usually maintain their integrity during a latent infection.
Intrauterine transmission of herpes simplex virus is rare and has been estimated to occur in 1 of 300,000 births . CHS accounts for only 5% of herpes simplex virus infections in neonates . This may come as a surprise, considering the high prevalence of herpes simplex viruses among the population of industrialized and developing countries: According to the World Health Organization, about two thirds of the global population had prevalent HSV-1 infection in 2012 and approximately 400 million people were living with HSV-2  .
Neonatal herpes simplex virus infections most commonly result from exposure to the causative agent during delivery. Intrauterine infections are uncommon but may be facilitated by a variety of factors: On the one hand, first-episode
primary infections are associated with a particularly high viral burden. By contrast, viremia is not to be expected in case of latent infections, when virus particles can only be detected in ganglion neurons . On the other hand, both the pregnant woman and her unborn child will show a limited immune response when exposed to the pathogen.
It has been shown that women who contract infections with HSV-1 or HSV-2 during third trimester of pregnancy are at greater risk of transmitting their disease than those with long-standing herpes simplex infections. In detail, the risk of transmission is 25-50% in case of newly acquired genital herpes, but <1% in women with long-standing disease . Therefore, preventive measures focus on avoiding infections during pregnancy, i.e, by abstinence from oral sex, the use of condoms, and avoidance of direct or indirect oral contact with people suffering from symptomatic herpes labialis.
Women with a known herpes simplex infection - whether or not it has been acquired in pregnancy - should inform their gynecologist accordingly so that adequate measures can be taken to minimize the risk of vertical transmission. However, herpes simplex infections are often asymptomatic and available data show that 80% of women who vertically transmit the virus to their unborn child have no known history of symptomatic genital herpes . In this context, risk factors should be assessed by the treating gynecologist and if suspicion of a herpes simplex infection arises, virological and serological tests should be performed to assess the status of the mother.
Both recurrent and newly acquired herpes simplex infections may be managed with antiviral medication and may eventually justify the decision for a caesarean section. Antiviral therapies are usually based on the application of acyclovir or other antiviral agents from week 36 until delivery. Those compounds may be administered earlier in case of very serious events in the mother or if there is an increased risk of preterm delivery, though. If the risk of transmission is particularly high, as is the case in women with recently acquired infections, antiviral treatment may be continued in the newborn .
CHS is a form of neonatal herpes simplex virus infection. The latter term may also refer to infections acquired in the peripartum or postpartum period. The unborn child or neonate may contract the disease due to maternal viremia, via an ascending transplacental infection or by retrograde spread through the amniotic membranes . But despite the high worldwide prevalence of herpes simplex virus infections, intrauterine transmission of the causative agent and CHS are considered rare occurrences.
CHS-related symptoms are present at birth. The disease is characterized by a triad of clinical manifestations, namely by neurological, ocular and cutaneous findings . Affected neonates often suffer from microcephaly and distinct malformations of the central nervous system. They may present with microphthalmia and and anomalies of different ocular tissues, and while these symptoms are commonly associated with a vesicular rash, atypical skin lesions have been reported on numerous ocasions. Virus dissemination is the most dreaded complication of CHS since it may lead to multiple organ failure and death.
Treatment mainly consists in the application of antiviral agents like acyclovir. Ideally, herpes simplex virus infections are recognized and treated in the mother. If the mother hasn't been treated or if the unborn child has acquired the disease despite maternal therapy, antiviral compounds have to be administered to the newborn for prolonged periods of time. The child's prognosis for normal psychomotor development is favorable if virus dissemination can be avoided and if the causative agent is not resistant to the antiviral compound applied. Otherwise, there is a high risk of neurological long-term sequelae and death.
Herpes simplex virus is a widely distributed pathogen best known for causing herpes labialis and genital herpes. In fact, it has been estimated that about two thirds of the world's population are infected with this virus. Most people don't know about it, though, because the virus tends to remain in an inactive state and to hide in ganglion neurons: Affected individuals don't typically experience any complaints. However, herpes simplex virus may occasionally be transmitted from a mother to her unborn child. This is most likely if the mother first aquires a herpes simplex virus infection during pregnancy, but it may also happen in case of long-standing infections.
If an intrauterine herpes simplex virus infection takes places during early pregnancy, it often leads to spontaneous abortion or stillbirth. If it occurs in late pregnancy, it may provoke severe intrauterine growth retardation and developmental delay. Affected neonates may suffer from cranial and central nervous system malformations, may have seizures, ocular defects and skin lesions. These babies require antiviral treatment in order to fight the infection. Unfortunately though, virus dissemination cannot always be prevented and some infants die of congenital herpes simplex.
Disease prevention is the best medicine. Pregnant women are highly recommended to inform their gynecologist about a possible history of genital herpes. Even if corresponding symptoms have never been observed, certain risk factors may prompt the practitioner to run some tests on blood samples to assess the woman's health status. If the woman is not infected with herpes simplex virus, she may adopt certain behaviors to increase the likelihood that it remains this way, e.g., abstinence from oral sex, use of condoms, and avoidance of direct or indirect oral contact with people suffering from symptomatic herpes labialis. In case of positive findings, antiviral treatment may be indicated and a caesarean section may preferred over vaginal delivery.
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