This virus poses a disproportionately higher risk to the newborn than to the mother. Thus, strategies in pregnancy aim to curb rates of vertical transmission.
Two types of herpes simplex viruses are distinguished based on immunological differences. Yet, the two viruses have significant DNA sequence homology, and thereby, prior infection with one type attenuates a primary infection with the other. Type 2 HSV is recovered almost exclusively from the genital tract and is usually transmitted by sexual contact. Type 1 is responsible for most nongenital infections and typically is acquired in childhood. However, more than half of new cases of genital herpes in adolescents and young adults are now caused by HSV-1 infection (Bernstein, 2013). This rise in the prevalence of HSV-1 genital disease is thought to stem from an increase in oral-genital sexual practices. Another explanation is that HSV-1 acquisition has declined in childhood as a result of improved living conditions and hygiene (Bradley, 2014; Xu, 2007). Without prior exposure, this renders young people without HSV-1 antibodies susceptible to genital acquisition of HSV-1 or -2.
Genital herpes simplex virus affects an estimated 50 million adolescents and adults (Workowski, 2015). Most women are unaware of their infection, but HSV-2 seroprevalence among non-Hispanic white females in the United States was 15.3 from 2007 to 2010 and among black females, it was 53 percent (Fanfair, 2014; Schulte, 2014). In one study of nearly 16,000 pregnant women from 2000 to 2010, the overall seroprevalence of HSV-2 was 16 percent, and for HSV-1, it was 66 percent (Delaney, 2014). Seronegative pregnant women have a 4 to 5 percent risk to acquire HSV-1 or -2 during pregnancy (Brown, 1997; Kulhanjian, 1992). For those who are HSV-1 seropositive, acquisition risk for HSV-2 approximates 2 percent (Brown, 1997).
Once transmitted by contact, HSV-1 or -2 replicates at the entry site. Following mucocutaneous infection, the virus moves retrograde along sensory nerves. It then remains latent in cranial nerves or dorsal spinal ganglia, but recurrences are common. HSV infections may be categorized into three groups.
First episode primary infection describes the case in which HSV-1 or 2 is isolated from a lesion in the absence of HSV-1 or -2 serological antibodies. The typical incubation period of 6 to 8 days (range 1 to 26 days) may be followed by a papular eruption with itching or tingling, which then becomes painful and vesicular. Multiple vulvar and perineal lesions may or may not coalesce, and then ulcerate (Fig. 65-5). Associated inguinal adenopathy can be severe. Many women do not present with typical lesions. Instead, a pruritic or painful abraded area or knife-cut may be found. Cervical involvement is common, although it may be inapparent clinically. Transient systemic influenza-like symptoms are frequent and are presumably caused by viremia. Some cases are severe enough to require hospitalization. Hepatitis, encephalitis, or pneumonia infrequently develop, and disseminated disease is rare. After 2 to 4 weeks, all signs and symptoms of infection disappear. Instead of these classic symptoms, the percentage of asymptomatic primary HSV-2 genital infections may be as high as 90 percent (Fanfair, 2013).
First-episode primary genital herpes simplex virus infection. Vesicles and knife-cut lesions are indicated by arrows. Small ulcers rim the anus. Similar lesions can typically be seen on the vulva.
First episode nonprimary infection is diagnosed when one HSV type is isolated from a lesion in a woman who has only the other serological HSV-type antibody present. In general, compared with primary infection, nonprimary infections are characterized by fewer lesions, less pain, fewer systemic manifestations, and briefer duration of lesions and viral shedding. This is likely because of some immunity from cross-reacting antibodies, for example, from childhood-acquired HSV-1 infection.
Recurrent disease is characterized by isolation of HSV-1 or -2 from the genital tract in women with the same serotype antibodies. During the latency period, in which viral particles reside in nerve ganglia, reactivation is common and mediated through poorly understood stimuli. The resulting lesions generally are fewer in number, are less tender, and shed virus for a shorter period than those of primary infection. Typically, they recur at the same sites. Genital disease recurrences are more frequently caused by HSV-2 compared with HSV-1. Recurrences are most frequent in the first year after initial infection, and rates slowly decline subsequently (Benedetti, 1999). Gravidas with a known prior history of genital HSV often experience recurrences (Sheffield, 2006).
Asymptomatic viral shedding is defined by the absence of clinical findings. Most infected women shed virus intermittently over time, and most HSV transmission to a partner occurs during these periods of asymptomatic viral shedding.
The virus can be passed to the fetus/neonate by three routes: (1) peripartum in 85 percent, (2) postnatal in 10 percent, or (3) intrauterine in 5 percent (James, 2015). As discussed in Chapter 18 (First-Trimester Spontaneous Abortion), evidence does not suggest an obvious link between HSV infection and miscarriage (Zhou, 2015).
Peripartum transmission is by far the more frequent route of infection, and the fetus is exposed to virus shed from the cervix or lower genital tract. HSV-1 or -2 invades the uterus following membrane rupture or is transmitted by contact at delivery. The newborn is mainly infected, but rare cases of maternal endometritis have been described (Hollier, 1997; McGill, 2012). Neonatal manifestations vary. First, infection may be localized to the skin, eye, or mouth—SEM disease—in approximately 40 percent of cases. Second, central nervous system disease with encephalitis is seen in 30 percent. Last, disseminated disease with involvement of multiple major organs is found in 32 percent. Localized infection is usually associated with a good outcome. Conversely, even with acyclovir treatment, disseminated infection has a mortality rate of nearly 30 percent (Corey, 2009; Kimberlin, 2011). Of disseminated or cerebral infection survivors, serious developmental and central nervous system morbidity is seen in 20 to 50 percent.
The neonatal infection rate is 0.5 to 1 per 10,000 births in the United States (Flagg, 2011; Mahnert, 2007). Most infected newborns are born to mothers with no reported history of HSV infection (Gardella, 2010). The risk of neonatal infection correlates with the presence of HSV in the genital tract, the HSV type, invasive obstetrical procedures, and stage of maternal infection (Brown, 2005, 2007). For example, neonates born to women who acquire genital HSV near the time of delivery have a 30- to 50-percent risk of infection. This is attributed to higher viral loads and the lack of transplacental protective antibodies (Brown, 1997, 2000). Women with recurrent HSV have less than a 1-percent risk of neonatal infection (Pasternak, 2010; Prober, 1987).
Postpartum transmission is uncommon and passed to the newborn by contact with an infected mother, family member, or health-care worker. The clinical presentation mirrors that with peripartum transmission.
In utero transmission of HSV-1 or HSV-2 is rare and is part of the TORCH (toxoplasmosis, other, rubella, cytomegalovirus, herpes virus) collection of infections. Intrauterine HSV infection classically leads to disease involving the skin (blisters, scarring), the central nervous system (hydranencephaly, microcephaly, intracranial calcification), or the eyes (chorioretinitis, microphthalmia) (Hutto, 1987). Bone and viscera can be involved (Marquez, 2011). If seen sonographically, findings should prompt viral serological testing as described next. PCR analysis of an amniocentesis sample is another potential tool (Diguet, 2006).
Several organizations recommend against routine serological HSV screening in asymptomatic gravidas (American College of Obstetricians and Gynecologists, 2016b; Workowski, 2015; U.S. Preventive Services Task Force, 2016). However, for those with a clinically suspicious lesion, a diagnosis should be confirmed by laboratory testing. Available HSV tests are either virological or type-specific serological tests.
Direct virological tests are can be performed on a specimen from the mucocutaneous lesion. PCR or culture of the sample is a testing option. Of the two, PCR assays are more sensitive, the results generally are available in 1 to 2 days, and specimen handling is easier. In contrast, for viral culture, the sensitivity of HSV isolation is relatively low as vesicular lesions ulcerate and then crust. Also, results sometimes are not available for 7 to 14 days (Strick, 2006). Regardless of the test performed, HSV viral types should be differentiated (LeGoff, 2014). Importantly, a negative culture or PCR result does not exclude infection. In contrast, false-positive results are rare.
Serological assays are available to detect antibodies produced against specific HSV glycoproteins, G1 and G2. These proteins evoke type-specific antibody responses to HSV-1 and HSV-2 infection, respectively, and they reliably differentiate the two. IgG antibodies develop 1 to 2 weeks after a primary infection and then persist. This permits confirmation of clinical infection and identification of asymptomatic carriers. Providers should request type-specific glycoprotein G-based assays when serology is being performed. Sensitivity approaches 90 to 100 percent, and specificity is 99 to 100 percent (Wald, 2002). IgM antibody detection is not a useful test.
In nonpregnant patients, antiviral therapy with acyclovir, valacyclovir, or famciclovir is used to treat first-episode genital herpes. Oral or parenteral preparations attenuate clinical infection and viral shedding duration. Suppressive therapy is also an option to limit recurrent infections and to reduce heterosexual transmission (Corey, 2004).
In pregnant women, acyclovir is safe (Briggs, 2015). Through 1999, the manufacturers of acyclovir and valacyclovir maintained a registry of outcomes following exposure to these drugs during pregnancy. More than 700 neonates exposed during the first trimester were evaluated, and there were no adverse effects attributable to acyclovir (Stone, 2004). At this time, data are insufficient regarding famciclovir exposure, although a pregnancy registry is being maintained (1–888–669–6682).
For a primary outbreak during pregnancy, women may be given antiviral therapy to attenuate and decrease the duration of symptoms and viral shedding (Table 65-4). Women with HIV co-infection may require a longer duration of treatment. Those with severe or disseminated HSV are given IV acyclovir, 5 to 10 mg/kg every 8 hours for 2 to 7 days until clinically improved. This is followed by oral antiviral drugs to complete at least 10 days of total therapy (Workowski, 2015). For intense discomfort, oral analgesics and topical anesthetics may provide some relief, and comorbid urinary retention is treated with an indwelling bladder catheter.
TABLE 65-4Oral Antiviral Medications for Herpesvirus Infection in Pregnancya ||Download (.pdf) TABLE 65-4 Oral Antiviral Medications for Herpesvirus Infection in Pregnancya
|Indication ||Pregnancy Recommendation |
|Primary or first episode infection ||Acyclovir, 400 mg three times daily for 7–10 d |
Valacyclovir, 1 g twice daily for 7–10 days
|Symptomatic recurrent infection (episodic therapy) ||Acyclovir, 400 mg three times daily for 5 days |
Acyclovir, 800 mg twice daily for 5 days
Acyclovir, 800 mg three times daily for 2 d
Valacyclovir, 500 mg twice daily for 3 days
Valacyclovir, 1 g once daily for 5 days
|Daily suppression ||Acyclovir, 400 mg three times daily from 36 weeks until delivery |
Valacyclovir, 500 mg twice daily from 36 weeks until delivery
For recurrent HSV infections during pregnancy, antiviral treatment is provided mainly for symptom relief (see Table 65-4). Although uncommon, acyclovir resistance has been reported, predominantly with HSV-2 and in immunocompromised patients (Andrei, 2013).
During pregnancy, amniocentesis, percutaneous cord blood sampling, or transabdominal chorionic villus sampling may be performed even with active genital lesions. With active lesions, however, internal electronic monitoring during labor is not recommended. Transcervical procedures may best be delayed until lesions have resolved (American College of Obstetricians and Gynecologists, 2016b).
Peripartum Shedding Prophylaxis
To diminish vertical transmission risks, cesarean delivery is indicated for women with active genital lesions or prodromal symptoms (American College of Obstetricians and Gynecologists, 2016b). Several studies have shown that acyclovir or valacyclovir suppression initiated at 36 weeks’ gestation for gravidas with recurrences during pregnancy lowers the number of HSV outbreaks at term. The goal is to decrease the need for cesarean delivery (Hollier, 2008). This suppressive therapy will also decrease viral shedding (Scott, 2002; Sheffield, 2006; Watts, 2003). One systematic review evaluated acyclovir prophylaxis given from 36 weeks to delivery to women with HSV recurrence during pregnancy. Sheffield and colleagues (2003) found that suppressive therapy was associated with significantly lower rates of clinical HSV recurrence, cesarean deliveries for HSV recurrences, total HSV detection, and asymptomatic shedding. Subsequent studies using valacyclovir suppression have shown similar results (Andrews, 2006; Sheffield, 2006). Because of these studies, the American College of Obstetricians and Gynecologists (2016b) recommends viral therapy at or beyond 36 weeks for women who had primary genital herpes infection or active recurrent genital herpes during pregnancy. It is unclear whether suppression is needed for women with outbreaks before but not during pregnancy. Notably, despite maternal antiviral suppression, several cases of atypical neonatal herpes infection have been reported (Pinninti, 2012).
On presentation for delivery, a woman with a history of HSV should be questioned regarding prodromal symptoms such as vulvar burning or itching. A careful examination of the vulva, vagina, and cervix is performed, and women without genital lesions may proceed with labor and delivery. Use of a fetal scalp electrode can raise the transmission risk. But, electrode placement is reasonable if needed in the absence of active lesions (American College of Obstetricians and Gynecologists, 2016b).
Suspicious lesions should be cultured or PCR tested. Cesarean delivery is indicated for women with genital lesions or prodromal symptoms. It is not recommended for women with a history of HSV infection but no active genital disease at the time of delivery. Moreover, an active lesion in a nongenital area is not an indication for cesarean delivery. Instead, an occlusive dressing is placed, and vaginal delivery is allowed.
With preterm ruptured membranes, no evidence suggests that external lesions cause ascending fetal infection. Major and associates (2003) described expectant management of preterm premature membrane rupture in 29 women at gestational ages <31 weeks. There were no cases of neonatal HSV, and the maximum infection risk was calculated to be 10 percent. Antiviral treatment is recommended. For women with a clinical recurrence at delivery, there is not an absolute duration of membrane rupture beyond which the fetus would not benefit from cesarean delivery (American College of Obstetricians and Gynecologists, 2016d).
Women with active HSV may breastfeed if there are no active breast lesions. Strict hand washing is essential. Valacyclovir and acyclovir may be used for symptomatic maternal lesions during breastfeeding, as drug concentrations in breast milk are low. One study found the acyclovir concentration to be only 2 percent of that used for therapeutic dosing of the neonate (Sheffield, 2002a).