Obstetrics and Gynecology
Genital Herpes Simplex Virus in pregnancy
- Genital Herpes Simplex Virus in Pregnancy
- 1. What every clinician should know
- 2. Diagnosis and differential diagnosis
- 3. Management
5. Prognosis and outcome
6. What is the evidence for specific management and treatment recommendations
Genital Herpes Simplex Virus in Pregnancy
1. What every clinician should know
Genital herpes is considered the most common ulcerative sexually transmitted disease in the United States and abroad. Although the true incidence of disease is unknown, it is believed that approximately 45 million Americans are infected with herpes simplex virus 2 (HSV2). Approximately 22% of pregnant women carry the virus.
The majority of genital herpes cases are caused by infection with HSV2, typically acquired through genital to genital contact. According to the Centers for Disease Control, the seroprevalence of HSV2 is approximately 16%, although population estimates have ranged upward to 26%. Estimates of seroprevalence are likely underestimated, as HSV2 is not a reportable disease.
In addition, it is estimated that 90% of individuals with genital herpes are unaware they carry the virus. Data suggest that the seroprevalence is greatest among women, with one in five women between the ages of 14-49 being affected. Non-Hispanic blacks are affected three times more than non-Hispanic whites. Not surprisingly, seroprevalence increases with age and number of lifetime sexual partners.
Further complicating the ability to fully understand the burden of genital herpes within the United States is the recent increase in the number of HSV1 cases of genital herpes. Although HSV1 was once thought to play a minor role in genital herpes, rates of disease from HSV1 have increased considerably. Currently it is thought that HSV1 accounts for approximately 20% of all genital herpes cases.
This is particularly true among the adolescent population. In fact, in this population the majority of new cases of genital herpes are thought to be secondary to HSV1 infection. It is important to note that genital herpes caused by HSV1 as compared to HSV2 is less likely to recur.
Because of the high incidence of genital herpes in the population, it is important to be knowledgeable about the herpes simplex viruses and their potential impact on pregnancy.
Approximately 10% of pregnant woman are at risk for acquisition of genital herpes. It is estimated that approximately 1-2% of pregnant women will newly acquire genital herpes during pregnancy. Most acquisition will occur during periods of asymptomatic shedding. Unfortunately most individuals with the disease are unaware of their disease status and are capable of passing along infection to their neonates without knowing it. These fetal and neonatal effects can be devastating and long lasting.
Herpes simplex virus is a double stranded DNA virus capable of causing herpes labialis, gingivostomatitis, keratoconjunctivitis and genital herpes, depending on the subtype implicated. HSV1 contains glycoprotein G1 in its lipid bilayer envelope, as opposed to HSV2, which consists of glycoprotein G2 within that same layer. In addition each subtype is further identified by the differing proteins within the viral protein coat.
Genital herpes can be caused by both HSV1 and HSV2. HSV2 is acquired by genital-to-genital contact and accounts for approximately 80% of genital herpes cases. Recently, the number of genital herpes cases caused by HSV1 has increased. Genital HSV1 is typically acquired by oral-genital contact. It is thought that approximately 20-30% of genital herpes cases are caused by HSV1.
In either case, the herpes simplex genome is able to gain access when the virus comes in contact with either mucosal surfaces or damaged epidermis. After exposure, the mean incubation period is approximately 4 days but can range between 2 to 12 days. After sufficient incubation, virus replicates in both the dermis and epidermis. After initial cellular damage and inflammation, virus is ultimately able to gain access to nueronal bodies.
In approximately 40% of individuals experiencing primary infection, infection will include systemic symptoms such as general malaise, low grade fevers, headaches and body aches. Concurrent with systemic symptoms, regional lymphadenopathy and localized pain occur with the onset of macules and papules. Depending on whether the route of acquisition is the oral route or genital route, pharyngitis and cervicitis or urethritis also may be observed.
During the course of the disease, the macules and papules transform to vesicles and pustules before ultimately crusting over and resolving. Risk factors for acquisition include female sex, duration of sexual activity, number of sex partners, previous genital infection, minority ethnicity and family income.
First episode non-primary infection
Those experiencing first episode non primary infection have symptoms similar to those experiencing primary disease, although the clinical course is often less acute. These infections are typically less severe, with fewer lesions, and clinical symptoms are shorter in duration. In addition, systemic symptoms in such individuals are less common and only occur in approximately 16% of this population as compared to more than 60% in those with primary disease. Symptoms typically last an average of 9 days.
Recurrent disease occurs when the latent virus within the neuronal bodies reactivates and results in symptomatic or asymptomatic disease. Although cellular and humoral immunity is responsible for keeping the virus in check in immunocompetent individuals, recurrences do occur. After the first recognized infection with HSV2, approximately 90% of individuals will have at least one recurrence. And 38% of individuals with have at least 6 recurrences. The average number of recurrences within the first year of infection is four.
While recurrent genital disease does occur with HSV1 infection, recurrence rates tend to be lower than that of HSV2. Individuals experiencing recurrent disease often experience prodromal symptoms described as tingling in the genital region. This may be present up to 48 hours before lesions occur. Similar to non-primary disease, symptoms are typically much milder, without associated systemic symptoms. In some cases recurrent disease may be virtually asymptomatic.
Transmission of disease
Both HSV1 AND HSV2 can be transmitted during times of symptomatic disease as well as during times of asymptomatic shedding. In fact, although transmission of disease occurs more easily during times of active infection, much (70%) of HSV transmission occurs during periods of asymptomatic viral shedding. This seems to be the case because of the significant amount of time that asymptomatic shedding is occurring.
2. Diagnosis and differential diagnosis
Establishing the diagnosis
Diagnosis of herpes simplex virus involves careful history taking, physical examination and laboratory evaluation. Although genital herpes is classically characterized by painful labial and vaginal ulcerations, the presentation of herpes simplex virus is quite variable depending on type of infection.
In evaluating individuals suspected of having genital herpes particular emphasis should be placed on obtaining an accurate sexual history. This involves number of partners as well as known partners with disease. This is particularly important because it is estimated that 10% of pregnant women are in discordant relationships and are at the greatest risk for acquisition of genital herpes secondary to HSV2.
Other elements essential to obtaining a useful history include the presence of prodromal symptoms such as burning or tingling of the vulva, general malaise and headaches. It is also important to elicit the character and chronicity of the lesions. Determining whether this is the first occurrence or recurrence is also helpful in guiding therapy and counseling of the pregnant woman.
Primary herpes infection is the resulting infection in an individual who has no prior exposure to either HSV1 or HSV2 infection.
Symptoms caused by primary infection are the most significant of any herpetic symptoms. Symptoms in people experiencing primary disease are often systemic and may include headache, general malaise, fever, lymphadenopathy, vaginal discharge, voiding difficulties or dysuria, and the typical painful burning genital ulcerations. Examination of these individuals may reveal numerous bilateral lesions involving the external genitals, the vagina, and in some cases lesions will be found on the cervix. Symptoms may persist from days to weeks. Viral shedding typically lasts approximately 15 days.
Culture or polymerase chain reaction test (PCR) positive for HSV1 or HSV2. Serologic tests are initially negative.
Non-primary first occurrence
This type of infection typically occurs when an individual is previously immune to HSV1 and therefore has some immunity to HSV2, leading to less virulent infection.
Individuals experiencing non primary, first occurrence disease typically have less severe symptoms than those with a primary infection. Symptoms typically mimic those of primary infection, although may not persist for as long.
Culture or PCR positive for HSV2. Serologic tests are positive for HSV1.
Recurrent disease is defined as reactivation of herpes virus in individuals with known prior HSV1 or HSV2 who have experienced symptomatic disease in the past.
Recurrent herpes may simply present as a single or few lesions that may or may not be symptomatic. While symptoms of burning and itching may be present, symptoms often are more localized. In the case of recurrent disease, lesions are usually present for a shorter duration. Frequency of recurrences vary, although the number of annual recurrences decreases over time. Those individuals with HSV2 do tend to have a greater recurrence rate than those with HSV1. It is estimated that 90% with genital herpes secondary to HSV2 will have at least one recurrence in the first year of infection versus only 60% of women with HSV1 genital herpes.
Culture or PCR positive for HSV1 or HSV2. Serologic tests are positive for the same serotype.
Once genital herpes is suspected a number of methods exist to confirm infection with HSV. Diagnosis may include direct viral identification as well as subtype specific serology in order to determine the type of infection.
Three methods exist for viral identification. These include viral culture, direct antibody studies to viral proteins and PCR to identify viral DNA.
Viral culture with typing is useful in discriminating type 1 and type 2 disease. Culture can be used in the setting of acute or recurrent disease when vesicles, pustules or ulcers are present. The technique involves unroofing the lesion and obtaining the fluid within it. However, the culture is most sensitive when performed on "wet" lesions during primary infection (80% vs. 40%).
PCR is similar to viral culture in that it is able to discriminate between HSV1 and HSV2. This technique has in many settings replaced viral culture as it does appear to have increased sensitivity. PCR can additionally be performed on both wet or crusting lesions with good sensitivity. Because amplification of RNA/DNA occurs prior to identification, PCR does not require unroofing the lesion and can be performed on crusting lesions. Unfortunately, PCR is not FDA approved for use with genital lesions and individual assays may vary in the risk of false positive results.
Although immunoflourescent staining is capable of identifying herpes virus, it is less sensitive than both viral culture and PCR. For this reason it is less useful than the other modalities used in viral identification. Its performance is particularly poor in the setting of recurrent disease but may be useful in tissue stains, particularly of placenta or endometrium when a diagnosis is unclear.
The Tzank smear involves obtaining scrapings at the base of a vesicular lesion and examining for the presence of multinucleated giant cells. The Tzank smear is unable to identify herpes virus but rather is useful identifying cells consistent with herpes viral infection.
Current serologic tests are aimed at detecting IgG antibodies to either HSV1 glycoprotein (gG1) or HSV2 glycoprotein (gG2). Antibodies to the herpes virus can be found in an individual's serum within the first couple of weeks of infection and increase up until approximately 12 weeks. Once present, herpes IgG remains persistent in an individual’s serum.
Serologic testing is particularly helpful in trying to discriminate between primary, non primary first episode and recurrent disease. It is additionally useful when the viral identification methods described above are unsuccessful or when lesions have already resolved at the time of presentation to a health care provider. Sensitivity of current serologic methods (ELISA and immunoblot) range between 93-100% with a specifity of 93-98%.
While most experts agree on the need to prevent HSV acquisition during pregnancies, no guidelines exists for routine screening or preventative measures. Advocates for and against universal screening have been quite vocal. However, a number of strategies have been proposed to decrease neonatal acquisition. These include recommending abstinence for all women during pregnancy, recommending routine serologic screening with plan for abstinence and safe sex practices for seronegative woman and suppression in seropositive woman.
In addition, recommendations have been made to identify discordant couples for treatment of the seropositive male to decrease transmission to the seronegative pregnant female. These suggestions have been the subject of controversy and, for a variety of reasons including lack of proven benefit in pregnancy, have not been widely accepted or become the standard of care. It would, however, be erroneous to state that advocates in support of routine screening do not exist.
Recently, the University of Washington in Seattle proposed that all pregnant women undergo testing of vaginal secretions at the time of labor and delivery with reflex serologic testing in those with positive secretions in order to determine primary or recurrent disease. Those women with primary disease would be offered cesarean delivery because these authors suggest that the number needed to treat is only two cesareans in order to prevent one case of neonatal disease with this strategy. There is insufficient evidence at this time to make a recommendation for this approach but further research is necessary on this topic.
Management of those with recurrent disease is more complicated. Suggested strategies include acyclovir prophylaxis during labor and delivery, increased neonatal surveillance and antiviral prophylaxis for the neonate. The optimal strategy will minimize the risk of neonatal disease while also avoiding many unnecessary cesarean deliveries being performed in this population.
Because of the lack of current data for routine screening, ACOG recommends against universal screening at this time. While it is true that the majority of neonatal herpes occurs in neonates of asymptomatic women, there is currently not enough data to support routine screening. Benefit from routine screening has yet to be proven.
Additionally, cost-effective strategies have not been found. It is estimated that the cost to prevent one case of neonatal herpes could be as high as $4,000,000. For these reasons, routine screening for herpes is not recommended. Further studies evaluating potential strategies to prevent neonatal disease are necessary.
Although uncommon, newly acquired or reactivated HSV is capable of causing disseminated disease during pregnancy. Disseminated disease can present with or without identified usual vesicular lesions. Usual presenting manifestations include general malaise, fever of unknown origin and leukocytosis, with eventual progression to symptoms specific to the involved organ systems.
Successful diagnosis involves having a high index of suspicion coupled with careful and thorough evaluation. Initial evaluation should include a thorough history and physical exam followed by those studies typically ordered in evaluating fever of unknown origin, including complete blood counts, chemistries, liver function tests and cultures. Imaging studies should be performed in accordance to symptoms.
In the presence of vesicular lesions, culture should be completed. Pap smears and cervical and vaginal scrapings have also been useful in identifying disease. In the absence of lesions but in individuals suspected of having HSV, serologic studies should be performed.
Virtually all organ systems can become involved in disseminated disease. Pancreatitis, esophagitis, myocarditis, arthritis and hematologic abnormalities have all been described, although pneumonitis, hepatitis and aseptic meningitis/encephalitis are most often noted. Herpes pneumonitis often presents with fever and cough. Herpes hepatitis presents with fever, abdominal pain and markedly elevated transaminases. Encephalitis can present with fevers, headache and new onset seizures. Central nervous system involvement can also present as transverse myelitis or sacral radiculopathy.
Autonomic dysfunction exhibited by urinary retention, constipation, and anesthesia or hyperesthesia of the perineum, lower back and sacrum have all been described. Definitive diagnosis of central nervous system infection involves PCR confirmation of herpes virus within the cerebrospinal fluid.
In the case of any of the above, prompt diagnosis and treatment is critical. Disseminated disease is associated with increased risk of maternal and fetal morbidity and mortality. Mortality rates can be as high as 40%. Intravenous Acyclovir 5-10mg/kg every 8 hours until resolution of fever followed by oral therapy twice daily for a total 10-day course is the usual first line treatment in cases of disseminated disease. Consultation with an Infectious disease specialist is recommended early in the course of disease as more aggressive therapy may be indicated.
Imaging studies are not typically necessary in the diagnosis of genital herpes. In the rare instance of disseminated disease, additional imaging studies may be indicated.
Because the presentation of herpes simplex virus can vary considerably, many individuals will confuse infection with a variety of other etiologies including:
Other ulcerative STIs (syphilis, chancroid)
Non-infectious ulcerations (Behcet's syndrome)
Other vaginitis (yeast, bacterial vaginosis)
Other GU infection (urinary tract infection)
Contact allergies (clothing, semen, spermicides)
HSV and HIV transmision
Studies in non-pregnant individuals have shown that transmission of HIV increased in the presence of any ulcerative disease. This is, however, secondary to high titers of HIV found in genital ulcerations. Furthermore and perhaps more importantly in the current review, studies have shown an increased risk of perinatal transmission of HIV in individuals with an episode of genital herpes during pregnancy.
Because of this association, some advocate suppression throughout pregnancy in this population. This approach is also supported by a French study by Nagot et al. In suppressed individuals, valacyclovir has been associated with lower genital and plasma viral loads of HIV1. Unfortunately studies have failed to show a decreased risk of HIV transmission among a non-pregnant population receiving acyclovir suppression.
-should be prescribed during wet phase
Local and oral analgesics
cold compresses, oatmeal baths,xylocaine jelly
Acyclovir 400mg orally TID x 7-10days
Famcyclovir 250mg orally TID x 7-10days
Valacyclovir 1gram orally BID x 7-10days
-should be prescribed during prodrome
Acyclovir 400mg oraly TID X 5days
Acyclovir 800mg orally BID x 5days
Famcyclovir 125mg orally BID 5days
Valacyclovir 1g orally daily x 3-5days
indicated for patients with more than six recurrences per year.
indicated for all pregnant women and initiated by 36 weeks (sooner if obstetrically indicated).
indicated in immunocompromised individuals .
indicated in individuals with significant complications with outbreaks
indicated in known discordant partners
Acyclovir 400mg orally TID
Famcyclovir 250mg orally daily
Valacyclovir 500mg orally daily/BID
Valacyclovir 1gram orally daily
Notes: (1) Limited data on famcyclovir in pregnancy; (2) rare instances of resistance to acyclovir. Usually susceptible to foscarnet and cidofovir.
Role of vaccination
Vaccinatons against herpes viruses have been largely ineffective. There is questionable utility and practice of HSV2 glycoprotein-D-subunit vaccine. This vaccine has been found to be 75% effective in women who are seronegative for both HSV1 and HSV2. Otherwise it is non-effective in women who are seropositive for HSV1 and in men. Because of the lack of data showing benefit, vaccination has not played a significant role in the prevention of genital herpes.
The primary goal of therapy in pregnancy is to reduce the risk of vertical transmission. It is estimated that 22% percent of reproductive age women are seropositive for HSV2, 63% are seropositive for HSV1 virus. Approximately 1-2% of pregnant women will acquire genital herpes. In pregnant women who carry the diagnosis of genital herpes, symptom assessment throughout pregnancy is warranted and is particularly important during the last trimester of pregnancy and at the time of labor and delivery. This includes asking patients about the presence of prodromal symptoms in addition to careful examination for genital lesions. Examination should involve careful exam of the cervix, vagina and vulva.
In pregnant women with a known history of genital herpes, suppressive therapy is recommended. Data suggest that in all women with recurrent genital herpes or primary infection during the last trimester, suppression should be initiated at 36 weeks gestation. In treating such women, the risk of recurrent disease is decreased by 75%. In addition, the rate of cesarean delivery secondary to recurrent disease was reduced by 40%. Results are similar with the use of either acyclovir or valacyclovir suppression.
Unfortunately despite screening and suppressive therapy, patients will still present with active disease in labor. In order to reduce the risk of perinatal transmission in this population, elective cesarean delivery is recommended in all women who have had active disease or signs or prodromal symptoms at the time of presentation for delivery. Brown et al has shown that cesarean delivery is protective against neonatal infection in woman in whom HSV is isolated at the time of delivery (1.2% vs 7.7%, p=0.47).
It is important to note that while cesarean delivery is indicated in women with genital lesions, the presence of non-genital lesions is not an indication for cesarean delivery. This includes lesions on the buttocks, thighs or back. It is, however, recommended that these lesions be covered.
In those individuals with a history of genital herpes but without active disease, there is no role for cesarean delivery and cesarean section should be reserved for usual obstetric indications.
Premature rupture of membranes (PROM) and HSV
The case of active herpes simplex lesions in the setting of PROM and PTL requires careful consideration. In pregnancies at or near term immediate cesarean delivery should be undertaken. In those cases of preterm PROM (PPROM) with active lesions remote from term, it is necessary to weigh risk of prematurity against risk for neonatal transmission.
Experts agree that delay for the administration of corticosteroids for lung maturity along with antiviral therapy is indicated. In cases of extreme prematurity, expectant management beyond 48 hours is also widely accepted. In fact, in two small case series of 29 and three patients with recurrent disease, no cases of neonatal herpes were observed. Although it would be expected that the risk of neonatal infection would be higher in cases of primary infection and PPROM, only isolated case reports exist and therefore no standard of care exists.
In women with a history of PPROM without active genital lesions, suppressive therapy should be immediately initiated. Recommendations for corticosteroids for lung maturity, antibiotics for latency and magnesium sulfate for neuroprotection should follow typical standards for PPROM.
5. Prognosis and outcome
The goal of therapy in pregnant women is to reduce the risk of fetal transmission and neonatal disease.
Although most cases of neonatal disease are acquired during labor and delivery, fetal transmission, though rare, has been described. Congenital herpes occurs most frequently as a result of first trimester primary infection. In these infections, the HSV virus is able to cross the placenta, leading to a number of effects. These neonates typically exhibit neonatal chorioretinitis, microcephaly and skin lesions.
One of the most devastating sequelae of maternal HSV is neonatal HSV. The diagnosis is made when disease is diagnosed within the first 28 days of life. The reported incidence ranges between 1/1,700-1/3,200. Unfortunately, rates of neonatal herpes have remained constant. Neonatal HSV results from maternal to fetal/neonatal vertical transmission during the intrapartum period. Common routes of entry include the eyes, nasopharynx and traumatized scalp.
Neonates born to mothers experiencing primary infection during pregnancy, particularly in the third trimester, are at greatest risk. The risk of transmission with active primary disease at the time of labor and delivery has been estimated to be 30-60%. This is in contrast to neonates born to mothers experiencing recurrent disease during labor and delivery, where the risk is estimated to be approximately 1-3%. The wide discrepancy between the two populations is thought secondary to passive immunity from maternal antibodies that are capable of crossing the placenta. Unfortunately up to 80% of affected neonates are born to mothers without known or clinically apparent disease.
The clinical manifestations of neonatal disease does vary and disease is classified by the major systems affected.
Skin, eye and mouth diseaseis thought to represent 45% of neonatal disease. These neonates usually exhibit the typical vesicular skin lesion. These lesions can, however, be accompanied by general malaise and irritability. With early antiviral therapy, progression to disseminated disease is unlikely to occur. Long term outcomes with localized disease is good, although recurrences with cutaneous lesions can occur throughout childhood.
Central nervous system (CNS) disease represents approximately 33% of neonatal disease. Neonates with CNS disease often experience fever, lethargy, irritability, seizure activity, poor feeding and temperature instability. HSV DNA present in cerebrospinal fluid is diagnostic. Despite therapy there is a 6% mortality rate, and 50% of surviving neonates will have at least moderate neurologic sequelae. Long term neurologic outcomes are more common in those with HSV2 disease compared to HSV1 infection. Outcomes may include epilepsy, blindness, as well as cognitive and developmental disability.
Finally, disseminated disease accounts for approximately 25% of neonatal disease. Unfortunately neonates with disseminated disease can experience involvement of all viscera resulting in pneumonitis, hepatitis and disseminated intravascular coagulopathy, resulting in eventual death. Despite treatment, mortality rates are at least 30%.
Both HSV1 and HSV2 are capable of causing neonatal disease. In recent years there has been an increase in cases caused by HSV1. This increase seems to mirror the overall increase in genital herpes caused by HSV1. There does also seem to be a slight difference in transmission rates between HSV1 and HSV2. Although HSV1 is overall less likely to reactivate, it may be more easily acquired by the neonate when reactivation does recur. HSV1 tends to result in more localized disease as opposed to HSV2, which is more commonly implicated in CNS and disseminated disease resulting in long term developmental sequelae.
Mortality rates from all forms of neonatal disease ranges from 4-at least 30%, depending on severity of disease. Neonates with disseminated disease have the highest risk of morbidity and mortality. Before the advent of early antiviral therapy, disease mortality in individuals with disseminated disease exceeded 50%. In light of the high mortality with advanced disease, early aggressive therapy with IV acyclovir 20mg/kg has become the norm. Obstetricians should inform their pediatric colleagues if transmission risk exists. PCR is often the laboratory evaluation of choice in this population, given its quick turn around time. Treatment, however, is often initiated based on suspicion alone, frequently before diagnostic results are available.
6. What is the evidence for specific management and treatment recommendations
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Nagot, N, Ouedrago, A, Foulongne, V. "Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus". N Engl J Medicine. vol. 356. 2007. pp. 790-9.
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