Some investigators have questioned the importance of intrauterine HSV disease.26
Avgil and Ornoy4
stated that “in utero infection by HSV bears relatively little danger for significant fetal damage ... and has weak teratogenic potential.” While not a common entity, the cases of intrauterine HSV infection reviewed in this work demonstrate HSV is clearly a teratogen.
A case definition of intrauterine HSV infection has been attempted previously. Baldwin and Whitley3
described a case as having: (1) evidence of infection in the first 48 hours of life, (2) virologic confirmation, and (3) exclusion of other illnesses. Fagnant's39
group asserted that a case includes: (1) evidence of an effect on embryogenesis, (2) virologically or histologically demonstrated herpetic infection within 24 hours of rupture of membranes, and (3) evidence of viral placentitis. Lastly, Monif40
required evidence of disease within 48 hours of rupture of membranes and a lesion older than what could be accounted for by ascending infection.
Our case definition did not include exclusion of other illnesses because this information was not available in the literature. While conformation of HSV disease was a prerequisite, some patients had delayed identification of virus raising the possibility of inclusion of cases of acquired disease.
There are deficiencies in published reports of intrauterine HSV; single case reports or small case series are limited by inconsistent definitions of intrauterine disease and misclassification of intrapartum cases as intrauterine. To date, there is no extensive review of reported cases of intrauterine HSV infection.
Our review significantly expands the limited literature on the disease. The largest published series by Hutto et al41
in 1987 described 13 infants with intrauterine HSV infection. It did not include descriptions of individual cases, rendering it impossible to analyze within our database. However, we found similarities in cutaneous involvement (95% vs. 92%), visceral involvement (34% vs. 31%), and prematurity (64% vs. 69%), but lower rates of CNS (67% vs. 92%) and ophthalmologic (39% vs. 69%) involvement.
HSV 2 accounts for 75% of all cases of intrapartum and postnatal disease.2
suggested HSV 2 may account for 90% of cases of intrauterine HSV infection. Of the 64 cases presented and reviewed in this report, 46 reported HSV serotype; 36 (78%) were HSV 2, similar to what is seen in intrapartum and postnatal HSV disease.
In our review, more deaths occurred with HSV 2. Prematurity occurred in 64% of infants compared with 40% to 50% previously reported in the literature.2
It is unclear whether prematurity is a consequence of maternal or fetal disease.
Baldwin and Whitley3
reported that 50% of cases of intrauterine HSV infection had CNS, cutaneous and ophthalmologic involvement. Johansson23
reported the triad in 39% of cases, similar to our figure of 30%. We report that intrauterine infection is not limited to the typical clinical triad. Prematurity, visceral involvement, limb and bone abnormalities, altered fetal growth, hydrops, and intrauterine demise are part of the clinical spectrum of intrauterine HSV infection.
Several factors could lead to under recognition of intrauterine HSV, including variations in or absence of cutaneous disease. The expected natural progression of herpetic lesions is to evolve from vesicle to ulcer, crust and then heal. Infants with intrauterine infection have a variety of cutaneous presentations, depending on the stage of the eruption at the time of birth. Secondary skin findings such as erosions or scarring, likely evidence of earlier vesicles, are important to recognize as potential signs of intrauterine disease. Additionally, HSV can mimic other diseases such as epidermolysis bullosa, aplasia cutis congenita, and incontinentia pigmenti. Confirming HSV disease by viral culture can be difficult. In 15 cases where lesions were present at birth, culture confirmation was delayed beyond 72 hours of life. Contributing factors included: (1) false-negative cultures, (2) deferral of culture despite the presence of vesicles, and (3) lesions such as plaques or scars that were not amenable to culture. Older lesions and poor quality specimens result in low culture yield. Several cases required more than 1 culture for confirmation; detecting the virus in culture was facilitated by a recurrence of skin disease, which is anticipated in intrauterine HSV infection. If the index of suspicion for intrauterine HSV infection is high, isolation of virus can be optimized by culturing other sites, such as conjunctiva, nasopharynx, and rectum.
Initiation of antiviral therapy should not be delayed if there is clinical suspicion of HSV disease. In addition, caution should be exercised in discontinuing antiviral therapy in the setting of negative cultures. Treatment will not reverse the organ injury sustained in utero. However, it may prevent progression of disease in a subset of patients with intrauterine HSV infection who do not have neurologic involvement at the time of birth. Thus, treatment aims to prevent CNS and possibly disseminated disease.
Our data are consistent with prior reports where 60% to 80% of mothers with infants who develop neonatal HSV disease have no symptoms at the time of delivery nor a history of genital herpes.2
An infant is at highest risk for neonatal HSV disease if the mother has primary disease during the pregnancy. However, reports of intrauterine disease in mothers with past herpes infection exist, and this series includes 2 mothers who had primary herpetic lesions prior to their pregnancy. Intrauterine infection is thought to occur via 2 routes—transplacental infection and ascending infection, even in the absence of rupture of membranes.
Data from the early 1980s suggest that intrauterine HSV accounts for nearly 5% of all neonatal disease.41
New data are needed to determine if that figure prevails today. The incidence of intrauterine HSV infection cannot be inferred from the cases we have reviewed. However, we confirm that maternal HSV infection can result in significant neonatal morbidity and mortality.