We discuss the types of maternal and neonatal HSV infection, strategies for risk reduction, and evaluation of infants born to mothers with HSV. We are joined by Chelsea Anderson, MD, MHS, Assistant Professor of Neonatal-Perinatal Medicine at the University of Texas Southwestern Medical Center.
Dr. Neeta Goli :
Welcome to Newborn News, a podcast where we discuss educational topics for medical professionals who care for newborns. I'm your host, Dr. Neeta Goli, a pediatrician in the UT Southwestern newborn nursery. Welcome back to the podcast. Today, we'll be discussing the herpes simplex virus, or HSV. We are recording remotely, due to the COVID pandemic. We are joined today by Dr. Chelsea Anderson, Assistant Professor in the UT Southwestern Division of Neonatal-Perinatal Medicine.
Dr. Chelsea Anderson:
Hello.
Dr. Neeta Goli :
Hi, Dr. Anderson, thanks for joining us today.
Dr. Chelsea Anderson:
Hi, it's great to be here and I hope to be able to make my audience cringe at least once during my discussion.
Dr. Neeta Goli :
Uh oh, all right. Well, looking forward to that. So, let's get started. Neonatal HSV from perinatal acquisition carries a significant risk of neonatal morbidity and mortality, and generally gives us as general pediatricians nightmares. It can manifest in three different forms. So, there's disseminated, CNS disease, and SEM disease, which Dr. Anderson will get into in just a minute, what that is. Presentation is typically in the first six weeks of life, usually occurs in the first month of life. As you might remember, not all maternal HSV infections carry the same risk to the neonate. Please can you remind us of the different categories of maternal infection and the risk posed to the infant from each?
Dr. Chelsea Anderson:
Yes. Before I begin, I'd just like to provide a little introduction to HSV, and at what time period most infections occur. HSV is a large, enveloped double-stranded DNA virus from the family Herpesviridae. The incidence of neonatal infection ranges from one in 2000 to 3000 live births in the United States. It's important to know that maternal antibodies develop within 12 weeks after an infection and persist indefinitely. Most transmissions occur during the birth process through contact within an infected maternal genital tract, but can also occur by ascending infection through ruptured or in some cases, intact amniotic membranes. 85% of transmission occur in this manner, in the intrapartum period. However, 10% of neonates acquire a postnatal infection from either a maternal or a non-maternal source. 5% of infections occur in-utero, either transplacentally or trans-cervically, and these are associated with congenital abnormalities.
Dr. Chelsea Anderson:
In regard to maternal infection and infant risks, there are three categories of maternal infection, and each is associated with a unique infant risk. The first is a primary maternal infection. This is the first occurrence of genital HSV in a patient with no pre-existing HSV antibodies. So, again, this will be a mother who has a positive PCR for either HSV 1 or 2, from a genital lesion, in the absence of HSV 1 or 2 serologies. This scenario presents the highest risk for the infant, especially in of a setting of an infection that's acquired near the time of delivery. The transmission to the neonate can range from 25-60% of cases, and that's a 10 to 30 times greater risk compared with recurrent HSV infections.
Dr. Neeta Goli :
To clarify for our listeners, when you said the absence of serology, you're referring to mom does not have IgG towards HSV one or two at the time of the infection?
Dr. Chelsea Anderson:
That's correct. Negative HSV 1 or HSV 2 IgG. Yes. So, the higher risk that occurs in primary infection is due to a lack of maternal neutralizing antibody and greater concentration and duration of genital tract viral shedding.
Dr. Neeta Goli :
Okay.
Dr. Chelsea Anderson:
The second category of maternal infection is a first episode non-primary infection, and this occurs when a patient has a first occurrence of a genital HSV lesion, but has pre-existing antibodies to a different HSV type. So, an example of this would be a genital lesion, which swabbed positive for HSV 1 PCR and maternal serologies, which show a positive HSV 2 IgG antibody and a negative HSV 1 IgG antibody. This references a new infection. Especially if the infection is at the time of delivery, this presents a serious risk to the neonate, though there is slightly lower risk of transmission, compared to a first episode, primary infection.
Dr. Chelsea Anderson:
Lastly, your third category is recurrent infection, and this is when the HSV type from the genital lesion is the same as the pre-existing serum antibody. As a note, this may be the first recognized episode for the patient, who had a previously asymptomatic infection. Testing of the mother will reveal a positive HSV PCR from the genital lesion in the presence of a positive HSV antibody of the same corresponding serotype in maternal serum. For an infant born to a mother with an outbreak at delivery, this is the most favorable scenario. The risk of transmission is less than 2%, and this risk category also includes mothers who acquire infection in the first half of pregnancy, and then have a reactivation near delivery.
Dr. Chelsea Anderson:
In a large landmark study assessing the influence of the type of maternal infection on neonatal transmission, the study showed that 50% of infants develop neonatal disease who are born to mothers with a first episode, primary infection, compared to 25% of affected infants with a first episode, non-primary infection. 2% of infants were infected who were delivered to women with recurrent HSV disease.
Dr. Neeta Goli :
Was that with lesions at the time of delivery?
Speaker 3:
Actually, these women were asymptomatic.
Dr. Neeta Goli :
Okay. Then, so if a mom has a known history of HSV, what is the ideal management while she is pregnant?
Speaker 3:
Yes. HSV is incredibly common among the US population and among pregnant women. The seroprevalence for HSV 1 among pregnant women is estimated to be 59% and HSV 2, 21%. So, this is a very key issue that our OB colleagues deal with. There are five factors that influence the transmission, and this includes the type of maternal infection and maternal HSV antibody status. So, those two we've previously discussed in our last question. The other factors include the duration of rupture of membranes, the integrity of the infant’s mucocutaneous barrier. So, for example, whether a fetal scalp electrode was used, or if there's an abrasion due to a forceps- or vacuum-assisted delivery, as well as the mode of delivery, whether it's C-section or vaginal. These factors can be addressed to reduce risk.
Speaker 3:
Also, there are factors that can be addressed to reduce the risk of transmission. A number of those would include antiviral therapy for the mothers. So, antiviral therapy is recommended for women when they do have symptoms of their primary HSV infection, as this can reduce viral shedding. Then suppressive therapy is recommended at 36 weeks until the onset of labor. This is to reduce the frequency of recurrences and reduce viral shedding. Though suppression does not completely eliminate viral shedding. A C-section should be performed for women with active genital lesions or prodromal symptoms at delivery, and may be offered to women with a primary or a first episode non-primary infection, who present with infection and symptoms during the third trimester. This is due to prolonged viral shedding in this population. Then lastly, limiting when possible, interventions which may compromise the integrity of the infant's mucocutaneous barrier on a case-to-case scenario.
Dr. Neeta Goli :
So, if an infant is born to a mother with recurrent HSV lesions at the time of delivery, how should we manage that infant? A note for our listeners, we are recording this in October of 2020, so if you are listening to this a long time from now, make sure that you're double- checking the current guidelines to make sure they're in line with what we're discussing right now.
Dr. Chelsea Anderson:
Excellent. We have clear guidance from the Red Book, which is our authority on pediatric infectious disease on this topic. As a note, this does require access of your hospital to PCR assays and HSV type-specific serologic tests. This algorithm, again, only applies to asymptomatic neonates following either vaginal or C-section delivery to a mother with active genital HSV lesions. If at any time, the neonate develops concerning symptoms, a full diagnostic evaluation should be undertaken and IV acyclovir should be initiated. If an infant develops symptoms, full diagnostic evaluation and IV acyclovir therapy should be initiated. In addition, immediate evaluation and treatment can be considered if there is prolonged rupture of membranes greater than four to six hours, or if the infant is premature.
Dr. Chelsea Anderson:
Otherwise, in an asymptomatic neonate, born to a mother with recurrent HSV, at 24 hours, the pediatric providers will obtain HSV surface cultures and PCRs, in addition to an HSV blood PCR. The surface culture sites include the infant's conjunctiva, mouth, nasopharynx, rectum, and a scalp electrode site if that is present. It's important to take the cultures after 24 hours to allow the test to be a better indication of viral replication, instead of contamination from maternal fluid. The infant may be cleared for discharge after 48 hours of negative HSV cultures and PCRs, and in addition, if other discharge criteria are met and there is access to medical care or a caregiver who is able to comply with instructions for home observation. If these conditions are not met, the infant should be kept for a longer observation period, as an inpatient, until the cultures are finalized as negative, or they've been negative for 96 hours, whichever is shorter. If a surface culture PCR or blood PCR returns positive, a diagnostic workup should follow, including CSF studies, ALT, and IV acyclovir should be initiated.
Dr. Neeta Goli :
Did you say we keep them until the cultures are turned negative or the PCRs are turned negative?
Dr. Chelsea Anderson:
Per our guidelines, culture is actually the gold standard. This may be done in conjunction with PCRs, and you should have your PCRs returned negative and your cultures negative at the time of discharge. If you have a good follow-up, this can be negative at 48 hours. If there's a question, then we should have cultures that are read as negative at 96 hours, whichever course would be shorter.
Dr. Neeta Goli :
Okay. Then, so that was the management of moms with recurrent. Now what about if we have an infant born to a mother with either primary or a non-primary HSV lesion at the time of delivery? How should we manage that infant?
Dr. Chelsea Anderson:
Yes, as we discussed earlier, these infants are at much higher risk for transmission. So, at 24 hours, a more complete workup is obtained. So, we start with the same HSV cultures and PCRs and HSV blood PCR. But in addition, CSF cell count chemistries and an HSV PCR from CSF is obtained in addition to a serum ALT. The infant is initiated on acyclovir, while awaiting these studies. While these studies are cooking, it's important to determine the true HSV classification of the mother. So, OB will have her labs sent. If it is determined that this is truly a recurrent episode, then the same policies as we covered in the previous case will take effect.
Dr. Chelsea Anderson:
If this is a true primary or first episode, non-primary, further treatment is required. So, if the infant is asymptomatic and the CSF indices are reassuring, the CSF and blood PCR are negative, and the ALT is normal, the infant may be given preemptive therapy of infection, which includes 10 days of acyclovir. If any of the labs are concerning for infection, the infant will then receive treatment for infection and proven disease. This will include 14 days of acyclovir, if there is a skin eye and mouth classification, or 21 days for a CNS or a disseminated classification. If there is evidence of CNS disease, it's necessary to repeat a CSF HSV PCR at the end of the treatment course. If this PCR returns positive, the acyclovir course will be extended for an additional seven days. IV antiviral therapy should not be stopped until the CSF HSV PCR is negative.
Dr. Neeta Goli :
Then, you just actually touched on the treatment of each of the three different types of HSV, but let's get into the symptoms. Can you describe each of the three different types of HSV manifestations in a neonate?
Dr. Chelsea Anderson:
Yes. There are three neonatal HSV manifestations, which you mentioned earlier. Skin, eye and mouth is a localized disease to exactly that. The skin, eyes, or mouth, and this represents 45% of neonatal manifestation. Disseminated disease involves multiple organs, especially the liver and lungs and represents 25% of neonatal cases. CNS disease can occur with or without skin, eye, mouth involvement, and this occurs in 30% of neonatal HSV cases. The initial signs and symptoms of neonatal HSV can occur anywhere between birth and six weeks of age, but the presentation just varies based on the classification of HSV.
Dr. Chelsea Anderson:
I'll go a little more in-depth into skin eye and mouth first. So this will be when we get the characteristic, localized clustering of vesicles on an erythematous base. This includes any site of trauma or a presenting body part of the infant. 80% of neonates with skin eye and mouth presentation will have skin vesicles. Otherwise, in rarer cases, the presentation may be limited to the eyes or oral mucosa. Eye involvement may present as a persistent watering or conjunctival injection. The HSV-induced keratoconjunctivitis can progress to cataract or chorioretinitis without treatment. Mouth involvement usually presents with ulcerations to the mouth, palate, or tongue. The outcome of this presentation is favorable if caught and treated early, and the presentation tends to be earlier, so usually at 1-2 weeks of life.
Dr. Chelsea Anderson:
Disseminated HSV occurs, as I mentioned before, these infants present with a sepsis-like picture with negative bacterial cultures. They may have hepatitis or severe liver dysfunction, a consumptive coagulopathy, a viral pneumonia, or pneumonitis. They may also present with myocarditis findings, a necrotizing enterocolitis, or adrenal and kidney involvement. The symptoms that we see clinically for these infants include temperature instability, apnea, respiratory distress, abdominal distension, and hepatomegaly. The presentation for these cases is like SEM, typically earlier, around 1-2 weeks of life, and the mortality is greater than 80% for untreated disseminated HSV, unfortunately. There is quite a lot of overlap between the different manifestations. In infants with a disseminated HSV, 60-75% of cases can also have involvement of the CNS. This is usually due to seeding of the CNS via hematogenous spread. Two-thirds of infants will have skin lesions, though they may not always be present at the time of symptom onset.
Dr. Chelsea Anderson:
The third manifestation will be a CNS disease with, or without skin, eye, and mouth involvement. These infants, their presentation will generally be with symptoms of lethargy, irritability, tremors, temperature instability, poor feeding, or a full anterior fontanelle. Half of the affected infants will have CNS involvement and two-thirds of infants again, will have skin lesions, though not necessarily at the time of symptom onset. So again, some variability in the presentation, some overlap between presentations. These infants usually present slightly later than the other two, at 2-3 weeks of life. A CT or MRI may be normal early in the case, and then go on to develop edema and hemorrhage, which is characteristic. CSF studies may show a mononuclear cell pleiocytosis, a normal to low CSF glucose, and a mildly elevated CSF protein. An EEG may show periodic epileptiform discharges. Any infant surviving any classification of HSV infection should receive oral acyclovir suppression for six months after completion of their parenteral therapy. So, that was just a review of the different manifestations of neonatal HSV.
Dr. Neeta Goli :
Then, so if we're sending home a baby born to a mother with a history of HSV, no active lesions at the time of delivery, the baby has had a routine normal newborn course while with us, what precautions do we need to give the mother at discharge?
Dr. Chelsea Anderson:
Yes. Education of families is very important. We need to spend a special amount of time educating mothers who have lesions at delivery to observe their infants at home, to continue that observation at home. But, in addition, mothers with recurrent HSV, without genital lesions at delivery also need this education, even though these infants are in a low-risk category. We should educate parents to observe for vesicular lesions on the skin, respiratory distress, fever, poor feeding, and lethargy. These families should present to the ER if symptoms do occur and make the ER providers aware of the HSV history. In addition, mothers or family members with cold sores should avoid nuzzling or kissing their infants until those lesions have healed and be diligent about hand hygiene during that time.
Dr. Neeta Goli:
To end today's episode, what advice do you have for our listeners while they care for newborns?
Dr. Chelsea Anderson:
I would say that transmission of HSV to a neonate is a rare occurrence and that we need to be very diligent in reviewing the maternal history and very diligent during our newborn physical exam to pick up any concerning findings. HSV should be detected as early as possible and treated, to prevent complications.
Dr. Neeta Goli :
Thank you so much, Dr. Anderson for joining us today. I appreciate your time.
Dr. Chelsea Anderson:
Thank you.
Dr. Neeta Goli :
Thanks for listening to Newborn News. We hope you join us next time. If you like what you hear, make sure to subscribe and leave us a review. If you have questions, comments, feedback, or suggestions for future episodes, please email me at NewbornNews@utsouthwestern.edu. As a reminder, this content is educational and is not meant to be used as medical advice. Views or opinions expressed in this podcast are those of myself and my guests and do not necessarily reflect the views of the University.