HERPES SIMPLEX VIRUS
HUMAN IMMUNODEFICIENCY VIRUS
Sexually transmitted infections or diseases are among the most common of all infectious diseases encountered during pregnancy. Because they may be injurious to both mother and fetus, they should be aggressively sought and treated. Importantly, education, screening, treatment, and prevention are essential components of prenatal care (American Academy of Pediatrics and American College of Obstetricians and Gynecologists, 2012). Sexually transmitted infections (STIs) that affect pregnant women and potentially affect the fetus include syphilis, gonorrhea, trichomoniasis, and chlamydia, hepatitis B, human immunodeficiency virus (HIV), herpes simplex virus-1 and -2 (HSV-1, -2), and human papillomavirus (HPV) infections. Recommended therapy for most adhere to guidelines provided by the Centers for Disease Control and Prevention (CDC)(2010b). Treatment of most STIs is clearly associated with improved pregnancy outcome and prevention of perinatal mortality (Goldenberg, 2003, 2008; Ishaque, 2011; Koumans, 2012).
Despite the availability of adequate therapy for almost 70 years, syphilis remains a major issue for both mother and fetus. Syphilis rates reached an all-time low in 2000. But from 2001 through 2009 for the United States, there was a steady increase in primary and secondary syphilis rates, which then leveled in 2010 and 2011 (Centers for Disease Control and Prevention, 2013b). The primary and secondary syphilis rate among women in 2012 was 0.9 case per 100,000 persons, which is a 9-percent decrease from 2010. Congenital syphilis rates also decreased in 2012, mirroring the decline in primary and secondary syphilis rates among women since 2008. However, syphilis remains a significant global health problem, with many countries reporting high numbers of new infections (Lukehart, 2012).
Pathogenesis and Transmission
The causative agent for syphilis is Treponema pallidum. Minute abrasions on the vaginal mucosa provide an entry portal for the spirochete, and cervical eversion, hyperemia, and friability increase the transmission risk. Spirochetes replicate and then disseminate through lymphatic channels within hours to days. The incubation period averages 3 weeks—3 to 90 days—depending on host factors and inoculum size. The early stages of syphilis include primary, secondary, and early latent syphilis. These are associated with the highest spirochete loads and transmission rates of up to 30 to 50 percent. In late-stage disease, transmission rates are much lower because of smaller inoculum sizes.
The fetus acquires syphilis by several routes. Spirochetes readily cross the placenta to cause congenital infection. Because of immune incompetence prior to midpregnancy, the fetus generally does not manifest the immunological inflammatory response characteristic of clinical disease before this time (Silverstein, 1962). Although transplacental transmission is the most common route, neonatal infection may follow after contact with spirochetes through lesions at delivery or across the placental membranes. Increased maternal syphilis rates have been linked to substance abuse, especially crack cocaine; inadequate prenatal care and screening; and treatment failures and reinfection (Johnson, 2007; Lago, 2004; Trepka, 2006; Warner, 2001; Wilson, 2007). A report from Maricopa County, Arizona, also cited minority race or ethnicity as a risk factor (Kirkcaldy, 2011).
Maternal syphilis can cause preterm labor, fetal death, fetal-growth restriction, and neonatal infection (Krakauer, 2012; Saloojee, 2004). Any stage of maternal syphilis may result in fetal infection, but risk is directly related to maternal spirochete load (Fiumara, 1952; Golden, 2003). Maternal syphilis is staged according to clinical features and disease duration:
1. Primary syphilis is diagnosed by the characteristic chancre, which develops at the inoculation site. It is usually painless, with a raised, red, firm border and a smooth base (Fig. 65-1). Nonsuppurative lymphadenopathy may develop. A chancre will usually resolve spontaneously in 2 to 8 weeks, even if untreated. Multiple lesions may be found, predominantly in HIV-1 co-infected women.
2. Secondary syphilis is diagnosed when the spirochete is disseminated and affects multiple organ systems. Manifestations develop 4 to 10 weeks after the chancre appears and include dermatological abnormalities in up to 90 percent of women. A diffuse macular rash, plantar and palmar targetlike lesions, patchy alopecia, and mucous patches may be seen (Figs. 65-2 and 65-3). Condylomata lata are flesh-colored papules and nodules found on the perineum and perianal area. They are teeming with spirochetes and are highly infectious. Most women with secondary syphilis will also express constitutional symptoms such as fever, malaise, anorexia, headache, myalgias, and arthralgias. Up to 40 percent will have cerebrospinal fluid abnormalities, although only 1 to 2 percent will develop clinically apparent aseptic meningitis. Hepatitis, nephropathy, ocular changes, anterior uveitis, and periostitis may also develop.
3. Latent syphilis develops when primary or secondary syphilis is not treated. It is characterized by reactive serological testing, but resolved clinical manifestations. Early latent syphilis is latent disease acquired within the preceding 12 months. Disease diagnosed beyond 12 months is either late latent syphilis or latent syphilis of unknown duration.
4. Tertiary or late syphilis is a slowly progressive disease affecting any organ system but is rarely seen in reproductive-aged women.
FIGURE 65-1 Primary syphilis. Photograph of a chancre with a raised, firm border and smooth, red base.
FIGURE 65-2 Target lesions on the palms of a pregnant woman with secondary syphilis.
FIGURE 65-3 Mucous patches around the mouth of a pregnant woman with secondary syphilis.
As noted, congenital infection is uncommon before 18 weeks. Once fetal syphilis develops, however, it manifests as a continuum of involvement. Fetal hepatic abnormalities are followed by anemia and thrombocytopenia, then ascites and hydrops (Hollier, 2001). Stillbirth remains a major complication (Di Mario, 2007; Hawkes, 2011; Rac, 2014b). The newborn may have jaundice with petechiae or purpuric skin lesions, lymphadenopathy, rhinitis, pneumonia, myocarditis, nephrosis, or long-bone involvement.
With syphilitic infection, the placenta becomes large and pale (Fig. 65-4). Microscopically, villi lose their characteristic arborization and become thicker and clubbed (Kapur, 2004). Sheffield and colleagues (2002c) described such large villi in more than 60 percent of syphilitic placentas. Blood vessels markedly diminish in number, and in advanced cases, they almost entirely disappear as a result of endarteritis and stromal cell proliferation. Likely related, Lucas and coworkers (1991) demonstrated increased vascular resistance in uterine and umbilical arteries of infected pregnancies. In a study of 25 untreated women, Schwartz and associates (1995) reported that necrotizing funisitis was present in a third. Spirochetes were detected in almost 90 percent using silver and immunofluorescent staining.
FIGURE 65-4 Congenital syphilis. A. Fetogram of a stillborn infant infected with syphilis showing the “moth-eaten” appearance of the femurs (arrow). B. Enlarged hydropic placenta of a syphilis-infected neonate.
The United States Preventative Services Task Force has reaffirmed its recommendation that clinicians screen all pregnant women for syphilis to treat and prevent congenital infection (Wolff, 2009). Testing is now required by law in all states and should be performed at the first prenatal visit. In populations in which the prevalence of syphilis is high, serological testing should be performed in the third trimester and again at delivery (Centers for Disease Control and Prevention, 2010b).
Treponema pallidum cannot be cultured from clinical specimens. Definitive diagnosis of early-stage lesions is made using dark-field examination and direct immunofluorescent antibody staining of lesion exudates (Centers for Disease Control and Prevention, 2010b). In asymptomatic patients or for screening purposes, serological testing is used. There are two types. The first type is nontreponemal testing that includes the Venereal Disease Research Laboratory (VDRL) and the rapid plasma reagin (RPR). These tests are quantified and expressed as titers. Because titers reflect disease activity, they increase during early syphilis and often exceed levels of 1:32 in secondary syphilis. Following treatment of primary and secondary syphilis, serological testing at 3 to 6 months usually confirms a fourfold drop in VDRL or RPR titers (Rac, 2014a). Those with treatment failure or reinfection may lack this decline. Because VDRL titers do not correspond directly to RPR titers, consistent use of the same test for surveillance is recommended.
The other type of testing is treponemal-specific and includes the fluorescent treponemal-antibody absorption tests (FTA-ABS), the microhemagglutination assay for antibodies to T pallidum (MHA-TP), or the Treponema pallidumpassive particle agglutination (TP-PA) test. These treponemal-specific tests generally remain positive throughout life.
Each of the serological tests has limitations including false-positive results. Traditionally, nontreponemal tests have been used for screening in the United States, and results are then confirmed by a specific treponemal test. Several laboratories have recently implemented a reverse screening algorithm, that is, screening with a treponemal test (Binnicker, 2012; Park, 2011). Both approaches are effective if appropriate screening, follow-up, and treatment are implemented. Patel and colleagues (2012) described missed opportunities for preventing and treating congenital syphilis in New York City. They found that 63 percent of mothers with newborns diagnosed with congenital syphilis had a missed opportunity for prevention. Most of these did not receive serological testing.
Rapid syphilis testing for “point of care” diagnosis is currently being developed and may be useful in settings with limited prenatal care (Centers for Disease Control and Prevention, 2010b; Greer, 2008). Treponemal immunochromatographic strip (ICS) tests and enzyme immunoassays (EIAs) are increasingly being used for screening and confirmatory testing (Henrich, 2011; Lukehart, 2012).
The prenatal diagnosis of congenital syphilis is difficult because an infected fetus often has a normal sonographic examination. Some findings, however, may be suggestive or even diagnostic—hydrops fetalis, ascites, hepatomegaly, placental thickening, elevated middle cerebral artery Doppler velocimetry measurements, and hydramnios all suggest infection (Rac, 2014b). Polymerase chain reaction (PCR) is specific for detection of T pallidum in amnionic fluid, and treponemal DNA has been found in 40 percent of pregnancies infected before 20 weeks (Nathan, 1997; Wendel, 1991). Fetal syphilis has also been verified by amnionic fluid dark-field examination or rabbit infectivity testing in 64 percent of a cohort of women with untreated syphilis (Hollier, 2001). Although prenatal diagnosis can be made by funipuncture or amniocentesis, its clinical utility is not clear.
Syphilis therapy during pregnancy is given to eradicate maternal infection and to prevent or treat congenital syphilis. Parenteral penicillin G remains the preferred treatment for all stages of syphilis during pregnancy. Currently recommended treatment guidelines are shown in Table 65-1 and are the same as for nonpregnant adults. For pregnant women, authorities recommend that a second dose of benzathine penicillin G be given 1 week after the initial dose.
TABLE 65-1. Recommended Treatment for Pregnant Women with Syphilis
In retrospective analyses, benzathine penicillin G has been shown to be highly effective for early maternal infection. In a study of 340 pregnant women so treated, Alexander and associates (1999) reported six cases—1.8 percent—of congenital syphilis. Four of these six neonates were from a group of 75 women with secondary syphilis. The other two were identified in those delivered from a group of 102 women with early latent syphilis. Congenital syphilis was generally confined to neonates of women treated after 26 weeks and is likely related to the duration and severity of fetal infection. Sheffield and coworkers (2002b) reported that high maternal serological titers, preterm delivery, and delivery shortly after antepartum therapy are all risks for failure of maternal treatment to prevent neonatal infection. There are no proven alternatives to penicillin therapy during pregnancy. Erythromycin and azithromycin may be curative for the mother, but because of limited transplacental passage, these drugs do not prevent all congenital disease (Berman, 2004; Centers for Disease Control and Prevention, 2010b; Wendel, 1988; Zhou, 2007). In several countries, macrolide resistant strains of T pallidum are now prevalent (Stamm, 2010). Cephalosporins may prove useful, but data are limited (Augenbraun, 1999, 2002; Zhou, 2007). Tetracyclines, including doxycycline, are effective for treatment of syphilis in the nonpregnant woman. These are generally not recommended during pregnancy, however, because of the risk of yellow-brown discoloration of fetal deciduous teeth (Chap. 12, p. 248).
Women with a history of penicillin allergy should have either a oral stepwise penicillin dose challenge or skin testing performed to confirm the risk of immunoglobulin E (IgE)-mediated anaphylaxis. If confirmed, penicillin desensitization is recommended, as shown in Table 65-2, and then followed by benzathine penicillin G treatment (Chisholm, 1997; Wendel, 1985).
TABLE 65-2. Penicillin Allergy—Oral Desensitization Protocol for Patients with a Positive Skin Test
In most women with primary syphilis and approximately half with secondary infection, penicillin treatment causes a Jarisch-Herxheimer reaction. Uterine contractions frequently develop with this reaction and may be accompanied by decreased fetal movement and late fetal heart rate decelerations (Klein, 1990). In a study of 50 pregnant women who received benzathine penicillin for syphilis, Myles and colleagues (1998) reported a 40-percent incidence of a Jarisch-Herxheimer reaction. Of the 31 women monitored electronically, 42 percent developed regular uterine contractions with a median onset of 10 hours, and 39 percent developed variable decelerations with a median onset of 8 hours. All contractions resolved within 24 hours of therapy. Lucas and associates (1991) used Doppler velocimetry and demonstrated acutely increased vascular resistance during this time. Beta-lactam antibiotics for group B streptococcus intrapartum prophylaxis can also trigger this reaction in a woman with untreated syphilis (Rac, 2010).
All women with syphilis should be offered counseling and testing for HIV (Koumans, 2000). For women with concomitant HIV infection, the Centers for Disease Control and Prevention (2010b) recommend the same treatment as for HIV-negative persons. Clinical and serological surveillance to detect treatment failures is also recommended at 3, 6, 9, 12, and 24 months in HIV-positive patients.
Gonorrhea remains the second most commonly reported notifiable disease in the United States. The incidence of gonorrhea in the United States for 2012 was 107.5 cases per 100,000 persons, which is an increase of 4 percent since 2011 (Centers for Disease Control and Prevention, 2013b). The highest rates in women of any ethnicity were in the groups aged 20 to 24 years (578.5) and 15 to 19 years (521.2). Its prevalence in prenatal clinics in 2011 among women aged 15 to 24 years was 0.8 percent, although inner-city STI clinics have reported a prenatal prevalence of 5 to 10 percent (Berggren, 2011; Johnson, 2007). Risk factors include single marital status, adolescence, poverty, drug abuse, prostitution, other STIs, and lack of prenatal care (Berggren, 2011; Gorgos, 2011). Gonococcal infection is also a marker for concomitant chlamydial infection in up to 40 percent of infected women (Christmas, 1989; Miller, 2004). In most pregnant women, gonococcal infection is limited to the lower genital tract—the cervix, urethra, and periurethral and vestibular glands. Acute salpingitis is rare in pregnancy, but pregnant women account for a disproportionate number of disseminated gonococcal infections (Bleich, 2012; Ross, 1996; Yip, 1993).
Gonococcal infection may have deleterious effects in any trimester. There is an association between untreated gonococcal cervicitis and septic abortion as well as infection after voluntary abortion (Burkman, 1976). Preterm delivery, prematurely ruptured membranes, chorioamnionitis, and postpartum infection are reported to be more common in women infected with Neisseria gonorrhoeae (Alger, 1988; Johnson, 2011). Bleich and coworkers (2012) reviewed outcomes of 32 pregnant women admitted to Parkland Hospital for disseminated gonococcal infection. Although all the women promptly responded to appropriate antimicrobial therapy, one stillbirth was attributed to gonococcal sepsis.
Screening and Treatment
The U.S. Preventative Services Task Force recommends gonorrhea screening for all sexually active women, including pregnant women, if they are at increased risk (Meyers, 2008). Risk factors include age < 25 years, prior gonococcal infection, other STIs, prostitution, new or multiple sexual partners, drug use, and inconsistent condom use. For women who test positive, screening for syphilis, Chlamydia trachomatis, and HIV should precede treatment, if possible. If chlamydial testing is unavailable, presumptive therapy is given. Screening for gonorrhea in women is by culture or nucleic acid amplification tests (NAATs). Rapid tests for gonorrhea, although available, do not yet reach the sensitivity or specificity of culture or NAAT (Greer, 2008).
Gonorrhea treatment has evolved during the past decade due to the ability of N gonorrhoeae to rapidly develop antimicrobial resistance (Centers for Disease Control and Prevention, 2011b,c; Dionne-Odom, 2011; Ram, 2012; Unemo, 2011). Rapid development of fluoroquinolone resistance caused the CDC to remove that therapeutic class from its treatment guidelines in 2007. The Gonococcal Isolate Surveillance Project, a national sentinel surveillance system established to monitor trends in gonococcal antimicrobial resistance, has reported decreasing susceptibility to cephalosporins. This is the one remaining class of antimicrobial agents currently recommended for gonorrhea treatment (Bolan, 2012; Centers for Disease Control and Prevention, 2010b, 2012). This global public health threat has led the CDC in 2012 to change the gonorrhea treatment recommendations.
Listed in Table 65-3 are the updated recommendations for treatment of uncomplicated gonococcal infection during pregnancy. The increased ceftriaxone dose of 250 mg should be given along with 1 gram of azithromycin. The latter provides another drug with a different mechanism of action against N gonorrhoeae and treats chlamydial co-infections. Cefixime tablets should be reserved for situations that preclude ceftriaxone treatment. If they are used, a test-of-cure should be performed 1 week after treatment. Azithromycin, 2 grams orally as a single dose, can be used in cephalosporin-allergic women. However, this treatment should be limited due to emerging macrolide resistance (Centers for Disease Control and Prevention, 2011c). Treatment is also recommended for sexual contacts. A test-of-cure is unnecessary if symptoms resolve, but because gonococcal reinfection is common, a second screening in late pregnancy should be considered for women treated earlier (Blatt, 2012).
TABLE 65-3. Treatment of Uncomplicated Gonococcal Infections During Pregnancy
Ceftriaxone, 250 mg intramuscularly as a single dose
Azithromycin, 1 gram orally as a single dose
From the Centers for Disease Control and Prevention, 2010b.
Disseminated Gonococcal Infections (DGI)
Gonococcal bacteremia may cause disseminated infections that manifest as petechial or pustular skin lesions, arthralgias, septic arthritis, or tenosynovitis. For treatment, the Centers for Disease Control and Prevention (2010b) has recommended ceftriaxone, 1000 mg intramuscularly or intravenously (IV) every 24 hours. Treatment should be continued for 24 to 48 hours after improvement, and therapy is then changed to an oral agent to complete 1 week of therapy. Prompt recognition and antimicrobial treatment will usually result in favorable outcomes in pregnancy (Bleich, 2012). Meningitis and endocarditis rarely complicate pregnancy, but they may be fatal (Bataskov, 1991; Burgis, 2006; Ram, 2012). For gonococcal endocarditis, ceftriaxone 1000 to 2000 mg IV every 12 hours should be continued for at least 4 weeks, and for meningitis, 10 to 14 days (Centers for Disease Control and Prevention, 2010b).
Chlamydia trachomatis is an obligate intracellular bacterium that has several serotypes, including those that cause lymphogranuloma venereum. The most commonly encountered strains are those that attach only to columnar or transitional cell epithelium and cause cervical infection. It is the most commonly reported infectious disease in the United States, with 1.4 million cases reported in 2012. It is estimated, however, that there are approximately 2.8 million new cases annually, although most are undiagnosed (Centers for Disease Control and Prevention, 2008). In 2012, the incidence of chlamydial infection among women was 2Δ times greater than among men. Selective prenatal screening clinics in 2011 reported a median chlamydial infection rate of 7.7 percent (Centers for Disease Control and Prevention, 2013b).
Although most pregnant women have asymptomatic infection, a third have urethral syndrome, urethritis, or Bartholin gland infection (Peipert, 2003). Mucopurulent cervicitis may be due to chlamydial or gonococcal infection or both. It may also represent normal, hormonally stimulated endocervical glands with abundant mucus production. Other chlamydial infections not usually seen in pregnancy are endometritis, salpingitis, peritonitis, reactive arthritis, and Reiter syndrome.
The role of chlamydial infection in pregnancy complications remains controversial. A few studies have reported a direct association between C trachomatis and miscarriage, whereas most show no correlation (Baud, 2011; Coste, 1991; Paukku, 1999; Sugiura-Ogasawara, 2005). It is disputed whether untreated cervical infection increases the risk of preterm delivery, preterm ruptured membranes, and perinatal mortality (Andrews, 2000, 2006; Baud, 2008; Blas, 2007; Silva, 2011). Johnson and colleagues (2011) reported a twofold risk for low-birthweight infants.
Chlamydial infection has not been associated with an increased risk of chorioamnionitis or with pelvic infection after cesarean delivery (Blanco, 1985; Gibbs, 1987). Conversely, delayed postpartum uterine infection has been described by Hoyme and associates (1986). The syndrome, which develops 2 to 3 weeks postpartum, is distinct from early postpartum metritis. It is characterized by vaginal bleeding or discharge, low-grade fever, lower abdominal pain, and uterine tenderness.
There is vertical transmission to 30 to 50 percent of neonates delivered vaginally from infected women. Perinatal transmission to newborns can cause pneumonia. Moreover, C trachomatis is the most commonly identifiable infectious cause of ophthalmia neonatorum (Chap. 32, p. 631).
Screening and Treatment
Prenatal screening for C trachomatis is a complex issue, although there is little evidence for its effectiveness in asymptomatic women who are not in high-risk groups (Kohl, 2003; Meyers, 2007; Peipert, 2003). Identification and treatment of asymptomatic infected women may prevent neonatal infections, but evidence of adverse pregnancy outcome prevention is lacking. Currently, the U.S. Preventive Services Task Force (2007) and the CDC recommend prenatal screening at the first prenatal visit for women at increased risk for chlamydial infection, and again during the third trimester if high-risk behavior continues. In a systematic review of repeat chlamydial infection among women, Hosenfeld and coworkers (2009) reported a reinfection rate of 14 percent, and most recurred within the first 8 to 10 months. Interestingly, in another study, Sheffield and colleagues (2005) found that almost half of pregnant women with asymptomatic cervical chlamydia underwent spontaneous resolution of infection.
Diagnosis is made predominantly by culture or NAAT. Cultures are more expensive and less accurate than newer NAATs, including PCR (Greer, 2008). Roberts and associates (2011) evaluated nucleic acid amplification testing of urine compared with cervical secretions in more than 2000 pregnant women and found them to be equivalent.
Currently recommended treatment regimens for chlamydial infections are shown in Table 65-4. Azithromycin is first-line treatment and has been found to be safe and effective in pregnancy. The fluoroquinolones and doxycycline are avoided in pregnancy, as is erythromycin estolate because of drug-related hepatotoxicity. Repeat chlamydial testing 3 to 4 weeks after completion of therapy is recommended.
TABLE 65-4. Treatment of Chlamydia trachomatis Infections During Pregnancy
L1, L2, and L3 serovars of C trachomatis cause lymphogranuloma venereum (LGV). The primary genital infection is transient and seldom recognized. Inguinal adenitis may develop and at times lead to suppuration. It may be confused with chancroid. Ultimately, the lymphatics of the lower genital tract and perirectal tissues may be involved. Here, sclerosis and fibrosis can cause vulvar elephantiasis and severe rectal stricture. Fistula formation involving the rectum, perineum, and vulva also may evolve.
For treatment during pregnancy, erythromycin base, 500 mg orally four times daily, is given for 21 days (Centers for Disease Control and Prevention, 2010b). Although data regarding efficacy are scarce, some authorities recommend azithromycin, 1000 mg orally weekly for 3 weeks.
HERPES SIMPLEX VIRUS
Genital herpes simplex virus infection is one of the most common sexually transmitted diseases according to the Centers for Disease Control and Prevention (2010a,b). An estimated 50 million adolescents and adults are currently affected. In 2012, there were 228,000 initial office visits for genital herpes (Centers for Disease Control and Prevention, 2013b). Although most women are unaware of their infection, approximately one in six has serological evidence for HSV-2 infection. This incidence is as high as one in two for non-Hispanic black pregnant women (Corey, 2012). As most cases of HSV are transmitted by persons who are asymptomatic or unaware of their disease, herpes infections have become a major public health concern. It is estimated that 0.5 to 2 percent of pregnant women acquire HSV-1 or -2 during pregnancy (Brown, 1997).
Pathogenesis and Transmission
Two types of HSV have been distinguished based on immunological and clinical differences. Type 1 is responsible for most nongenital infections. However, more than half of new cases of genital herpes in adolescents and young adults are caused by HSV-1 infection. This is thought to be due to an increase in oral-genital sexual practices (Mertz, 2003; Pena, 2010; Roberts, 2003). Type 2 HSV is recovered almost exclusively from the genital tract and is usually transmitted by sexual contact. Most recurrences—greater than 90 percent—are secondary to HSV-2. There is a large amount of DNA sequence homology between the two viruses, and prior infection with one type attenuates a primary infection with the other type.
Neonatal transmission is by three routes: (1) intrauterine in 5 percent, (2) peripartum in 85 percent, or (3) postnatal in 10 percent (Kimberlin, 2004b). The fetus becomes infected by virus shed from the cervix or lower genital tract. It either invades the uterus following membrane rupture or is transmitted by contact with the fetus at delivery. The overall transmission rate is 1 in 3200 to 1 in 30,000 births depending on the population studied (Corey, 2012; Mahnert, 2007; Whitley, 2007). Neonatal herpes is caused by both HSV-1 and HSV-2, although HSV-2 infection predominates. Most infected infants 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). Infants 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; Brown, 2000). Women with recurrent HSV have less than a 1-percent risk of neonatal infection (Pasternak, 2010; Prober, 1987).
Once transmitted by genital-genital or oral-genital 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. HSV infections may be categorized into three groups:
1. First episode primary infection describes cases in which HSV-1 or -2 is isolated from genital secretions in the absence of HSV-1 or -2 antibodies. Only a third of newly acquired HSV-2 genital infections are symptomatic (Langenberg, 1999). The typical incubation period of 6 to 8 days (range 1 to 26 days) may be followed by a “classic presentation.” This is characterized by a papular eruption with itching or tingling, which then becomes painful and vesicular. Multiple vulvar and perineal lesions may coalesce, and inguinal adenopathy may be severe (Fig. 65-5). Transient systemic influenza-like symptoms are common and are presumably caused by viremia. Hepatitis, encephalitis, or pneumonia may develop, although disseminated disease is rare. Cervical involvement is common, but it may be inapparent clinically. Some cases are severe enough to require hospitalization. In 2 to 4 weeks, all signs and symptoms of infection disappear. Many women do not present with the typical lesions—instead, a pruritic or painful abraded area or knife-slit may be present. The incidence of asymptomatic primary infections may be as high as 80 percent (Centers for Disease Control and Prevention, 2010a,b).
2. First episode nonprimary infection is diagnosed when HSV is isolated in women who have only the other serum HSV-type antibody present. For example, HSV-2 is isolated from genital secretions in women already expressing serum HSV-1 antibodies. In general, these infections are characterized by fewer lesions, fewer systemic manifestations, less pain, 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. In many cases, it may be impossible to differentiate clinically between the two types of first infection. Thus, serological confirmation may be beneficial.
3. Reactivation 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 variable but poorly understood stimuli. Reactivation is termed recurrent infection and results in herpes-virus shedding. Most recurrent genital herpes is caused by type 2 virus (Centers for Disease Control and Prevention, 2010a,b; Corey, 2012). These lesions generally are fewer in number, are less tender, and shed virus for shorter periods—2 to 5 days—than those of primary infection. Typically, they recur at the same sites. Recurrences are most common in the first year after initial infection, and rates slowly decline over several years.
FIGURE 65-5 First-episode primary genital herpes simplex virus infection. On the left labium majora and mons, both vesicles and ulcers are seen.
Asymptomatic viral shedding is defined by HSV as detected by culture or PCR in the absence of clinical findings. Most infected women shed virus intermittently, and most HSV transmission to a partner occurs during periods of asymptomatic viral shedding. Gardella and coworkers (2005) reported an HSV culture-positive rate of 0.5 percent and a PCR-positive rate of 2.7 percent in asymptomatic women presenting for delivery. More data are needed to determine the effect of asymptomatic shedding on neonatal transmission.
Most primary and first-episode infections in early pregnancy are probably not associated with an increased rate of spontaneous abortion or stillbirth (Eskild, 2002). In their review, Fagnant and Monif (1989) found only 15 cases of congenital herpetic infection that were acquired during early pregnancy. Brown and Baker (1989) reported that late-pregnancy primary infection may be associated with preterm labor and fetal-growth restriction.
Newborn infection may manifest in a number of ways. Infection may be localized to the skin, eye, or mouth—SEM disease—in about 40 percent of cases. Central nervous system disease with encephalitis is seen in 30 percent of cases. Disseminated disease as shown in Figure 65-6 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, 2004a,b, 2011). Importantly, serious developmental and central nervous system morbidity is seen in 20 to 50 percent of survivors with disseminated or cerebral infection.
FIGURE 65-6 Cross-section showing necrotic brain tissue from a newborn who died from disseminated herpesvirus infection.
According to the Centers for Disease Control and Prevention (2010a), clinical diagnosis of genital herpes is both insensitive and nonspecific and should be confirmed by laboratory testing. HSV tests available are either virological or type-specific serological tests.
Virological tests are performed on a specimen from a mucocutaneous lesion. Cell culture and PCR are the preferred tests. The sensitivity of HSV isolation is relatively low for viral culture as vesicular lesions ulcerate and then crust. Viral isolation results sometimes are not available for 1 to 2 weeks. PCR assays are more sensitive, the results generally are available in 1 to 2 days, and specimen handling is easier. The major limitation of PCR is cost and laboratory availability. The PCR assay is the preferred test for HSV detection in spinal fluid. Regardless of the test performed, HSV viral type should be differentiated because HSV type influences counseling and long-term prognosis. A negative culture or PCR result does not exclude infection. False-positive results are rare.
Several serological assay systems are available to detect antibody to HSV glycoproteins G1 and G2 (Anzivino, 2009; Centers for Disease Control and Prevention, 2010a). These proteins evoke type-specific antibody responses to HSV-1 and HSV-2 infection, respectively, and they reliably differentiate the two. This permits confirmation of clinical infection and identification of asymptomatic carriers. The Food and Drug Administration (FDA) has approved type-specific tests that are enzyme-linked immunosorbent assay (ELISA) or blot-style tests. Providers should request type-specific glycoprotein G-based assays when serology is being performed. Sensitivity approaches 90 to 100 percent and specificity 99 to 100 percent (Wald, 2002). IgG antibodies usually are detected 1 to 2 weeks after a primary infection. IgM antibody detection is not a useful test.
Point-of-care testing is being increasingly requested by practitioners to help guide management intrapartum or near delivery. There are type-specific serological tests available that use capillary blood or serum. Sensitivity varies from 80 to 98 percent with specificity ≥ 96 percent. False-positive and false-negative results may occur. Real-time quantitative PCR of genital tract secretions has recently been developed by Gardella and colleagues (2010). They reported sensitivity of 99.6 percent and specificity of 96.7 percent with a turnaround time of 2 hours. These features would prove valuable to guide clinical decision making at delivery.
Routine serological screening for herpes in pregnancy is not recommended by the American College of Obstetricians and Gynecologists (2012) due to cost and limited data on efficacy in reducing the incidence of neonatal herpes. Cost-decision analysis for prenatal type-specific antibody screening and suppressive therapy for partners has been found to be unacceptably expensive (Barnabas, 2002; Rouse, 2000; Thung, 2005). In contrast, it was found to be potentially cost-effective by Baker and associates (2004). Cleary and coworkers (2005) calculated that universal prenatal screening would reduce rates of perinatal death and severe sequelae from neonatal HSV. But they also found that it would require treatment of 3849 women to prevent one case of neonatal death or disease with severe sequelae. Universal screening would identify previously undiagnosed women who could then be counseled regarding safe practices and antepartum antiviral suppression, but a concrete benefit remains unproven.
Antiviral therapy with acyclovir, famciclovir, or valacyclovir has been used for treatment of first-episode genital herpes in nonpregnant patients. Oral or parenteral preparations attenuate clinical infection and the viral shedding duration. Suppressive therapy has also been given to limit recurrent infections and to reduce heterosexual transmission (Corey, 2004, 2012). For intense discomfort, oral analgesics and topical anesthetics may provide some relief, and urinary retention is treated with an indwelling bladder catheter. Acyclovir appears to be safe for use in pregnant women (Briggs, 2011; Stone, 2004). The manufacturers of acyclovir and valacyclovir, in cooperation with the Centers for Disease Control and Prevention, maintained a registry of outcomes following exposure to these drugs during pregnancy through 1999. More than 700 neonates exposed during the first trimester were evaluated, and no increased adverse effects were found (Stone, 2004). At this time, there are insufficient data with famciclovir exposure, although a pregnancy registry is being maintained (1-888-669-6682).
Women with a primary outbreak during pregnancy may be given antiviral therapy to attenuate and decrease the duration of symptoms and viral shedding (Table 65-5). 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 therapy to complete at least 10 days of total therapy (Centers for Disease Control and Prevention, 2010b). Recurrent HSV infections during pregnancy are treated for symptomatic relief only (see Table 65-5). Acyclovir resistance has been reported, predominantly with HSV-2 and in immunocompromised patients (Corey, 2012).
TABLE 65-5. Antiviral Medications for Herpesvirus Infection in Pregnancy
Peripartum Shedding Prophylaxis
Several studies have shown that acyclovir or valacyclovir suppression initiated at 36 weeks’ gestation will decrease the number of HSV outbreaks at term, thus decreasing the need for cesarean delivery (Hollier, 2008). Such suppressive therapy will also decrease viral shedding defined by both culture and PCR techniques (Scott, 2002; Sheffield, 2006; Watts, 2003). A systematic review of studies of acyclovir prophylaxis given from 36 weeks to delivery was reported by Sheffield and colleagues (2003). They found that delivery suppressive therapy was associated with significantly decreased 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 (2012) recommends viral therapy at or beyond 36 weeks for women who have any recurrence during pregnancy. It is unclear whether suppression is needed for women with outbreaks before but not during pregnancy. There have been several case reports of atypical neonatal herpes disease following maternal antiviral suppression. Thus, suppression does not prevent all cases of neonatal disease (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 should be performed, and suspicious lesions should be cultured or PCR tested. Currently, there is no approved point-of-care test to guide management. Cesarean delivery is indicated for women with active genital lesions or prodromal symptoms (American College of Obstetricians and Gynecologists, 2012). Of note, 10 to 15 percent of neonates with HSV are born to women undergoing cesarean delivery. Cesarean delivery 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.
There is no evidence that external lesions cause ascending fetal infection with preterm ruptured membranes. Major and associates (2003) described expectant management of preterm premature membrane rupture in 29 women < 31 weeks. There were no cases of neonatal HSV, and the maximum infection risk was calculated to be 10 percent. Antiviral treatment use in this setting is reasonable, but of unproven efficacy. 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, 2013). Women with active HSV may breast feed if there are no active HSV breast lesions. Strict hand washing is advised. Valacyclovir and acyclovir may be used during breast feeding, 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).
Other antiviral agents are under development. One is pritelivir, a viral helicase-primase complex that reduces HSV-2 shedding (Wald, 2014). Also, HSV-2 vaccine development is currently being aggressively pursued. Two glycoprotein D-based subunit vaccine trials have shown benefit in discordant couples by decreasing HSV-2 acquisition (Stanberry, 2002). Interestingly, a recent randomized controlled trial of a newer glycoprotein D-based HSV-2 vaccine showed it to be effective in women in preventing HSV-1, but not HSV-2, genital disease (Belshe, 2012). Further research is needed to better understand these challenging and contradictory results (Johnson, 2011).
Haemophilus ducreyi can cause painful, nonindurated genital ulcers termed soft chancres that at times are accompanied by painful suppurative inguinal lymphadenopathy. Although common in some developing countries, it had become rare in the United States by the 1970s. There was an increase in the late 1980s, but only fifteen cases were reported in the United States in 2012. This marked decrease likely represents a true decline as well as diagnostic difficulties that led to underdiagnosis (Centers for Disease Control and Prevention, 2013b). Importantly, the ulcerative lesion is a high-risk cofactor for HIV transmission.
Diagnosis by culture is difficult because appropriate media are not widely available. Instead, clinical diagnosis is made when typical painful genital ulcer(s) are dark-field negative for spirochetes and herpes-virus test results are negative. No FDA-cleared PCR test is yet available. Recommended treatment in pregnancy is azithromycin, 1 g orally as a single dose; erythromycin base, 500 mg orally three times daily for 7 days; or ceftriaxone, 250 mg in a single intramuscular dose (Centers for Disease Control and Prevention, 2010b).
Human papillomavirus (HPV) is one of the most common sexually transmitted infections, and more than 40 types infect the genital tract. Most reproductive-aged women become infected within a few years of becoming sexually active, although most infections are asymptomatic and transient. Oncogenic or high-risk HPV types 16 and 18 are associated with dysplasia and are discussed in Chapter 63 (p. 1222). Mucocutaneous external genital warts termed condyloma acuminata are usually caused by HPV types 6 and 11 but may also be caused by intermediate-and high-oncogenic-risk HPV.
The National Health and Nutrition Examination Survey (NHANES) 2003 to 2006 reported an overall HPV prevalence of 43 percent in females aged 14 to 59 years (Hariri, 2011). A 27-percent seroprevalence was also reported for subjects 18 through 25 years in the National Longitudinal Study of Adolescent Health (Manhart, 2006). Similar rates of HPV positivity have been reported for pregnant women (Aydin, 2010; Gajewska, 2005; Hernandez-Giron, 2005; Rama, 2010). Prevalence is highest in younger age groups.
External Genital Warts—Condyloma Acuminata
For unknown reasons, genital warts frequently increase in number and size during pregnancy. Acceleration of viral replication by the physiological changes of pregnancy might explain perineal lesion growth and progression of some to cervical neoplasm (Fife, 1999; Rando, 1989). These lesions may sometimes grow to fill the vagina or cover the perineum, thus making vaginal delivery or episiotomy difficult (Fig. 65-7). Because HPV infection may be subclinical and multifocal, most women with vulvar lesions also have cervical infection, and vice versa (Ault, 2003; Kroupis, 2011; Reichman, 2012).
FIGURE 65-7 Extensive external genital warts in a postpartum woman.
There may be an incomplete response to treatment during pregnancy, but lesions commonly improve or regress rapidly following delivery. Consequently, wart eradication during pregnancy is usually not necessary. Therapy is directed toward minimizing treatment toxicity to the mother and fetus and debulking symptomatic genital warts. There are several agents available, but pregnancy limits their use. There is no definitive evidence that any one of the subsequently discussed treatments is superior to another (Centers for Disease Control and Prevention, 2010b; Wiley, 2002).
Trichloroacetic or bichloracetic acid, 80- to 90-percent solution, applied topically once a week, is an effective regimen for external warts. Some prefer cryotherapy, laser ablation, or surgical excision (Arena, 2001; Centers for Disease Control and Prevention, 2010b). Agents not recommended in pregnancy because of concerns for maternal and fetal safety include podophyllin resin, podofilox 0.5-percent solution or gel, imiquimod 5-percent cream, interferon therapy, and sinecatechins.
Juvenile-onset recurrent respiratory papillomatosis is a rare, benign neoplasm of the larynx. It can cause hoarseness and respiratory distress in children and is often due to HPV types 6 or 11. In some cases, maternal genital HPV infection is associated with laryngeal papillomatosis, but studies differ in their findings of neonatal transmission rates. Although some have reported rates as high as 50 percent, it is likely that these findings are from maternal contamination or transient HPV infection (Campisi, 2010; Winer, 2004). A Danish population-based study indicated a neonatal transmission risk of 7 per 1000 infected women (Silverberg, 2003). Prolonged rupture of membranes was associated with a twofold increased risk, but risk was not associated with delivery mode. This low transmission risk has been confirmed in subsequent studies (Heim, 2007; Smith, 2004). Finally, long-term follow-up studies are consistent with a very low vertical transmission risk (Manns, 1999; Smith, 2004). The benefit of cesarean delivery to decrease transmission risk is unknown, and thus it is currently not recommended solely to prevent HPV transmission (Centers for Disease Control and Prevention, 2010b). HPV vaccination may decrease the rate over time (Hawkes, 2008; Kim, 2008).
Two HPV inactivated vaccines are currently licensed in the United States. These are a quadrivalent vaccine (Gardasil) containing HPV types 6, 11, 16, and 18 and a bivalent vaccine (Cervarix) containing HPV types 16 and 18. The vaccines are both a three-dose series and are licensed for females and males aged ≤ 26 years. They are effective for males (Giuliano, 2011). The vaccines are not recommended for pregnant women, however, inadvertent exposures do occur. Garland and coworkers (2009) analyzed data on these exposures from five Phase III clinical trials of Gardasil. They found no adverse pregnancy outcomes associated with the vaccine. Wacholder and associates (2010) pooled data from two multicenter Phase III trials and found no association between HPV vaccination and miscarriage risk. Postlicensure surveillance is ongoing using a manufacturer pregnancy registry (American College of Obstetricians and Gynecologists, 2010a). Women who are breast feeding may receive the vaccine. If a woman is found to be pregnant after starting the vaccination series, the remaining doses should be delayed until after delivery.
Pregnant women commonly develop increased vaginal discharge, which in many instances is not pathological (Chap. 4, p. 50). The vaginal microbial flora provides protection against vaginal infection. Elucidation of the composition and function of the normal vaginal microflora is currently underway with the human microbiome project (Lamont, 2011).
Not an infection in the ordinary sense, bacterial vaginosis (BV) is a maldistribution of normal vaginal flora. Numbers of lactobacilli are decreased, and overrepresented species are anaerobic bacteria that include Gardnerella vaginalis, Mobiluncus, and some Bacteroides species. As many as 30 percent of childbearing-aged women have bacterial vaginosis (Allsworth, 2007; Koumans, 2007; Simhan, 2008). Vitamin D deficiency has been identified as a risk factor for vaginosis in pregnancy. Moreover, douching, multiple partners, young age, smoking, and black race are associated with vaginosis in both pregnant and nonpregnant women (Bodnar, 2009; Desseauve, 2012; Hensel, 2011). In pregnancy, it is associated with preterm birth, early and late miscarriage, low birthweight, and increased neonatal morbidity (Goldenberg, 2008; Laxmi, 2012). Treatment is reserved for symptomatic women, who usually complain of a fishy-smelling discharge. Preferred treatment is metronidazole, 500 mg twice daily orally for 7 days; 250 mg three times daily orally for 7 days; or clindamycin 300 mg orally twice daily for 7 days (Centers for Disease Control and Prevention, 2010b). Unfortunately, although eradication is possible, treatment does not reduce preterm birth rates, and routine screening is not recommended (McDonald, 2007).
Trichomonas vaginalis can be identified during prenatal examination in up to 20 percent of women. Symptomatic vaginitis is much less prevalent, and it is characterized by foamy leukorrhea, pruritus, and irritation. Trichomonads are seen readily in fresh vaginal secretions as flagellated, pear-shaped, motile organisms that are somewhat larger than leukocytes.
Metronidazole, administered orally in a single 2-g dose, is effective in eradicating T vaginalis (Centers for Disease Control and Prevention, 2010b). It may be used at any gestational age—multiple studies have not shown an association between metronidazole use in any trimester of pregnancy and neonatal effects, including malformations (Briggs, 2011). Some studies have linked trichomonal infection with preterm birth, however, treatment has not decreased this risk (Gulmezoglu, 2011; Wendel, 2007). Thus, screening and treatment of asymptomatic women is not recommended during pregnancy.
Candida albicans or other Candida species can be identified by culture from the vagina during pregnancy in approximately 25 percent of women. Asymptomatic colonization requires no treatment. However, the organism may sometimes cause an extremely profuse, irritating discharge associated with a pruritic, tender, edematous vulva. Effective treatment is given with a number of azole creams that include 2-percent butoconazole, 1-percent clotrimazole, 2-percent miconazole, and 0.4- or 0.8-percent terconazole applied for 7 days (Centers for Disease Control and Prevention, 2010b). Topical treatment is recommended, but as described in Chapter 12 (p. 247), oral azoles are generally considered safe (Pitsouni, 2008). In some women, infection is likely to recur and require repeated treatment during pregnancy. In these cases, symptomatic infection usually subsides after pregnancy (Sobel, 2007).
HUMAN IMMUNODEFICIENCY VIRUS
Acquired immunodeficiency syndrome (AIDS) was first described in 1981, and it is currently one of the worst global health pandemics in recorded history. Worldwide, it was estimated in 2012 that there were 35.3 million infected persons with HIV/AIDS; 2.3 million new cases of HIV infection; and 1.6 million HIV-related deaths (UNAIDS, 2013). In the United States through 2011, the Centers for Disease Control and Prevention (2013a) estimated that there were more than 1.1 million infected individuals and more than 636,000 deaths (Centers for Disease Control and Prevention, 2013a). In 2010, women accounted for 20 percent of all HIV/AIDS cases among adults and adolescents, most of which resulted from heterosexual contact. Comparing 2008 with 2011, HIV incidence decreased in women, primarily black/African American women and women acquiring HIV through heterosexual contact.
The estimated number of perinatally acquired AIDS cases has decreased dramatically during the past two decades (Fig. 65-8). This is predominantly due to the implementation of prenatal HIV testing and antiviral therapy given to the pregnant woman and then to her neonate (De Cock, 2012). In addition, highly active antiretroviral therapy (HAART) has led to an increasing number of people living with chronic HIV infection and thus the associated comorbidities also affecting pregnancy (Fenton, 2007).
FIGURE 65-8 Estimated number of perinatally acquired AIDS cases by year of diagnosis, 1985 to 2010, in the United States and dependent areas. (Data from the Centers for Disease Control and Prevention, 2011a.)
Causative agents of AIDS are RNA retroviruses termed human immunodeficiency viruses, HIV-1 and HIV-2. Most cases worldwide are caused by HIV-1 infection. Transmission is similar to hepatitis B virus, and sexual intercourse is the major mode. The virus also is transmitted by blood or blood-contaminated products, and infected mothers may infect their fetuses perinatally or by their breast milk. The primary determinant of HIV-1 transmission is the plasma HIV-1 viral load.
The common denominator of clinical illness with AIDS is profound immunodeficiency that gives rise to various opportunistic infections and neoplasms. Sexual transmission occurs when mucosal dendritic cells bind to the HIV envelope glycoprotein gp120. These dendritic cells then present the viral particle to thymus-derived lymphocytes, that is, T lymphocytes. These lymphocytes are defined phenotypically by the cluster of differentiation 4 (CD4) glycoprotein surface antigens. The CD4 site serves as a receptor for the virus. Coreceptors are necessary for viral entry into the cell, and two chemokine receptors—CCR5 and CXCR4—are the most frequently identified (Fauci, 2012; Sheffield, 2007). The CCR5 coreceptor is found on the cell surface of CD4 positive (CD4+) cells in high progesterone states such as pregnancy, possibly aiding viral entry (Sheffield, 2009).
After initial infection, the level of viremia usually decreases to a set point, and patients with the highest viral burden at this time progress more rapidly to AIDS and death (Fauci, 2007, 2012). And as shown in Figure 65-9, viral burden and neonatal infection incidence are directly related. Over time, the number of T cells drops insidiously and progressively, resulting eventually in profound immunosuppression. Although it is thought that pregnancy has minimal effects on CD4+ T-cell counts and HIV RNA levels, the latter are often higher 6 months postpartum than during pregnancy. Higher levels of inflammatory cytokines and a decrease in regulatory T cells in late pregnancy may contribute to maternal and fetal morbidity (Richardson, 2011).
FIGURE 65-9 Incidence of perinatal human immunodeficiency virus (HIV) infection plotted against plasma HIV-1 RNA levels in 1542 neonates born to mothers in the Women and Infants Transmission Study. (Data from Cooper, 2002.)
The incubation period from exposure to clinical disease is days to weeks, and the average is 3 to 6 weeks. Acute HIV infection is similar to many other viral syndromes and usually lasts less than 10 days. Common symptoms include fever and night sweats, fatigue, rash, headache, lymphadenopathy, pharyngitis, myalgias, arthralgias, nausea, vomiting, and diarrhea. After symptoms abate, the set point of chronic viremia is established. The progression from asymptomatic viremia to AIDS has a median time of approximately 10 years (Fauci, 2008). Route of infection, the pathogenicity of the infecting viral strain, the initial viral inoculum, and the immunological status of the host all affect the rapidity of progression.
Several clinical and laboratory manifestations will herald disease progression. Generalized lymphadenopathy, oral hairy leukoplakia, aphthous ulcers, and thrombocytopenia are common. A number of opportunistic infections associated with AIDS include esophageal or pulmonary candidiasis; persistent herpes simplex or zoster lesions; condyloma acuminata; pulmonary tuberculosis; cytomegaloviral pneumonia, retinitis, or gastrointestinal disease; molluscum contagiosum; Pneumocystis jiroveci pneumonia; toxoplasmosis; and others. Neurological disease is common, and approximately half of patients have central nervous system symptoms. A CD4+ count < 200/mm3 is also considered definitive for the diagnosis of AIDS.
There are unique gynecological issues for women with HIV, such as menstrual abnormalities, contraceptive needs, and genital neoplasia, that are discussed in Williams Gynecology, 2nd edition (Werner, 2012). Some of these as well as other STIs may persist into pregnancy (Cejtin, 2003; Stuart, 2005). Repeated pregnancy has no significant effect on the clinical or immunological course of viral infection (Minkoff, 2003).
Prenatal HIV Screening
The Centers for Disease Control and Prevention (2006, 2010a), The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2011), and the United States Preventive Services Task Force (2012) recommend prenatal HIV screening using an opt-out approach. This means that the woman is notified that HIV testing is included in a comprehensive set of antenatal tests, but that testing may be declined. Women are given information regarding HIV but are not required to sign a specific consent. Through the use of such opt-out strategies, HIV testing rates have increased. Each provider should be aware of specific state laws concerning screening.
In areas in which the incidence of HIV or AIDS is 1 per 1000 person-years or greater, or in women at high risk for acquiring HIV during pregnancy, repeat testing in the third trimester is recommended (American College of Obstetricians and Gynecologists, 2011). High-risk factors include injection drug use, prostitution, a suspected or known HIV-infected sexual partner, multiple sexual partners, or a diagnosis of another sexually transmitted disease. Several states also recommend or require HIV testing at delivery.
Screening is performed using an enzyme-linked immunoassay with a sensitivity > 99.5 percent. A positive test is confirmed with either a Western blot or immunofluorescence assay (IFA), both of which have high specificity. According to the Centers for Disease Control and Prevention (2001), antibody can be detected in most patients within 1 month of infection, and thus, antibody serotesting may not exclude early infection. For acute primary HIV infection, identification of viral p24 core antigen or viral RNA or DNA is possible. False-positive confirmatory results are rare (Centers for Disease Control and Prevention, 2010b).
Women with limited prenatal care or with undocumented HIV status at delivery should have a “rapid” HIV test performed. These tests can detect HIV antibody in 60 minutes or less and have sensitivities and specificities comparable with those of conventional ELISAs (Chetty, 2012). A negative rapid test result does not need to be confirmed. However, in a woman exposed to HIV within the last 3 months, repeat testing is recommended. A positive rapid test result should be confirmed with a Western blot or IFA test. As shown in Table 65-6, peripartum and neonatal interventions to reduce perinatal transmission are based on the initial rapid testing results, and this can be discontinued if the confirmatory test is negative (American College of Obstetricians and Gynecologists, 2011; Centers for Disease Control and Prevention, 2010b). A detailed list of the rapid HIV tests currently available in the United States can be found at http://www.cdc.gov/hiv/topics/testing/resources/factsheets/rt-lab.htm (Centers for Disease Control and Prevention, 2007). The Mother-Infant Rapid Intervention at Delivery (MIRIAD) multicenter study indicated that rapid HIV testing can be used to identify infected women so that peripartum antiretroviral prophylaxis can be administered to mother and infant (Bulterys, 2004).
TABLE 65-6. Strategy for Rapid Human Immunodeficiency Virus (HIV) Testing of Pregnant Women in Labor
If the rapid HIV test result in labor and delivery is positive, the obstetrical provider should take the following steps:
1. Tell the woman she may have HIV infection and that her neonate also may be exposed
2. Explain that the rapid test result is preliminary and that false-positive results are possible
3. Assure the woman that a second test is being performed to confirm the positive rapid test result
4. To reduce the risk of transmission to the infant, immediate initiation of antiretroviral prophylaxis should be recommended without waiting for the results of the confirmatory test
5. Once the woman gives birth, discontinue maternal antiretroviral therapy pending receipt of confirmatory test results
6. Tell the women that she should postpone breast feeding until the confirmatory result is available because she should not breast feed if she is infected with HIV
7. Inform pediatric care providers (depending on state requirements) of positive maternal test results so that they may institute the appropriate neonatal prophylaxis
Summarized from American College of Obstetricians and Gynecologists, 2011.
Maternal and Perinatal Transmission
Transplacental HIV transmission can occur early, and the virus has even been identified in specimens from elective abortion (Lewis, 1990). In most cases, however, mother-to-child transmission at the time of delivery is the most common cause of pediatric HIV infections. Between 15 and 40 percent of neonates born to non–breast-feeding, untreated, HIV-infected mothers are infected. Kourtis and colleagues (2001) have proposed a model for estimation of the temporal distribution of vertical transmission. They estimate that 20 percent of transmission occurs before 36 weeks’ gestation, 50 percent in the days before delivery, and 30 percent intrapartum. Transmission rates for breast feeding may be as high as 30 to 40 percent and are associated with systemic HIV viral burden (Kourtis, 2006, 2007a; Slyker, 2012). Vertical transmission is more common with preterm births, especially with prolonged membrane rupture. Analyzing data from the Perinatal AIDS Collaborative Transmission Study, Kuhn and coworkers (1999) reported a nearly fourfold increased risk with preterm delivery. Although an increased risk of perinatal transmission has been associated with membrane rupture in the past, recent analyses in the setting of combination antiviral therapy have not found this to be a risk factor with an HIV viral load < 1000 copies/mL (Cotter, 2012).
In nonpregnant individuals, there is an association between concomitant STIs and horizontal HIV transmission. There is also evidence that vertical perinatal transmission may be increased with STIs (Schulte, 2001; Watts, 2012). Women with maternal HSV-2 antibody have a significant 50-percent increased risk of intrapartum HIV-1 maternal-to-child transmission (Cowan, 2008). They attributed up to 25 percent of vertical transmission to maternal HSV-2 co-infection. Elevated cytokine and chemokine levels in the placenta, reflecting inflammation, are associated with in utero transmission (Kumar, 2012). A recent Cochrane analysis, however, has failed to show that sexually transmitted infection control is an effective HIV prevention strategy (Ng, 2011).
Perinatal HIV transmission is most accurately correlated with maternal plasma HIV RNA burden (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012; Watts, 2002). As shown in Figure 65-9, cohort neonatal infection was 1 percent with < 400 copies/mL, and it was > 30 percent when maternal viral RNA levels were > 100,000 copies/mL. Transmission of HIV infection, however, has been observed at all HIV RNA levels, including those that were nondetectable by current assays. This may be attributed to discordance between the viral load in plasma and that in the genital secretions. Because of these findings, the viral load should not be used to determine whether to initiate antiretroviral therapy in pregnancy.
Effective contraception should be discussed if pregnancy is undesired. Certain antiviral medications decrease hormonal contraception efficacy and are discussed in Chapter 38 (p. 708). Recommendations are also available at http://AIDSinfo.nih.gov and are updated frequently as new data become available. Counseling also includes education for decreasing high-risk sexual behaviors to prevent transmission and to decrease the acquisition of other sexually transmitted diseases. Currently used antiretroviral medications are reviewed to avoid those with high teratogenic potential should the woman become pregnant. A specific example is efavirenz, which has significant teratogenic effects on primate fetuses (Panel on Antiretroviral Guidelines for Adults and Adolescents, 2013). Preference should also include those that decrease HIV RNA viral load effectively before pregnancy.
Management During Pregnancy
These women need special attention and are seen in consultation by physicians with special interest in this field. At Parkland Hospital, the initial assessment of an HIV-infected pregnant woman includes:
• Standard prenatal laboratory surveys that include serum creatinine, hemogram, and bacteriuria screening (Chap. 9, p. 171)
• Plasma HIV RNA quantification—“viral load,” CD4+ T-lymphocyte count, and antiretroviral resistance testing
• Serum hepatic aminotransferase levels
• HSV-1 and -2, cytomegalovirus, toxoplasmosis, and hepatitis C serology screening
• Baseline chest radiograph
• Tuberculosis skin testing—purified protein derivative (PPD) or interferon-gamma release assay
• Evaluation of need for pneumococcal, hepatitis B, hepatitis A, Tdap, and influenza vaccines
• Sonographic evaluation to establish gestational age.
Treatment is recommended for all HIV-infected pregnant women. This may be a departure for those not receiving treatment when nonpregnant because they did not meet certain criteria. Treatment reduces the risk of perinatal transmission regardless of CD4+ T-cell count or HIV RNA level. Antiretroviral therapy is complicated, and pregnancy only adds to the complexity. In general, HAART is begun if the woman is not already receiving one of the regimens. Antiretroviral agents are grouped into several classes and used to design antiretroviral regimens (Table 65-7). The 2012 Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission classify each agent into five use categories: preferred, alternative, use in special circumstances, not recommended, and insufficient data to recommend use. The woman is counseled regarding risks and benefits of antiretroviral agents to make an informed decision as to her treatment regimen. Regardless of what regimen is begun, adherence is important because the risk of viral drug resistance is lessened.
TABLE 65-7. Classes of Antiretroviral Drugs
The Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission (2012) has issued guidelines that detail management of different scenarios during pregnancy (Table 65-8). Women already taking HAART at pregnancy onset are encouraged to continue the regimen if there is adequate viral suppression. The neural-tube defect risk associated with efavirenz is restricted to the first 6 weeks of pregnancy. Thus, efavirenz can be continued if the woman presents after this time and if adequate virological suppression is documented. Until recently, addition of zidovudine to all regimens was recommended. Currently, however, in women with adequate viremia suppression with a regimen not containing zidovudine, continuation of the current regimen is appropriate. Zidovudine is given intravenously during labor and delivery to women with an HIV RNA viral load > 400 copies/mL or who have an unknown viral load near delivery (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012). A 2 mg/kg load is infused over 1 hour followed by zidovudine 1 mg/kg/hr until delivery.
TABLE 65-8. Recommendations for Antiviral Drug Use During Pregnancy
Women who have never received antiretroviral therapy—antiretroviral naïve—fall into two categories. First, women who meet the criteria for antiretroviral therapy initiation in nonpregnant adults are given HAART regardless of trimester. Because of an increased risk of hepatotoxicity, nevirapine is reserved for women with a CD4+ cell count < 250 cells/mm3. In general, the starting HAART regimen is two nucleoside reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor(s). At Parkland Hospital as of 2014, our standard regimen in treatment-naïve women is lopinavir/ritonavir—formulated as Kaletra—plus zidovudine/lamivudine—formulated as Combivir. The lopinavir/ritonavir regimen should be increased in the late second and third trimester. Atazanavir, another protease inhibitor, is also now listed as a preferred agent and can be used in place of lopinavir/ritonavir. If used, it is combined with low-dose ritonavir boosting.
The second category contains treatment-naïve HIV-infected pregnant women who do not meet nonpregnant adult indications for antiretroviral therapy. These women are counseled regarding the benefits of initiating therapy to prevent perinatal viral transmission. Because of potential teratogenic effects, women may delay therapy until the second trimester. That said, however, earlier initiation may be more effective in reducing perinatal transmission (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012; Read, 2012).
Women who have previously received antiretroviral therapy but are currently not taking medications should undergo HIV resistance testing because antiretroviral use increases their risk of drug resistance. Regimens may then be tailored based on prior medication use and response as well as current resistance patterns. The final group includes women who present in labor and who are taking no medications. These women are given intravenous zidovudine intrapartum (see Table 65-8). The National Perinatal HIV Hotline (1–888–448–8765) is a federally funded service that provides free consultation to providers.
CD4+ T-lymphocyte count, HIV RNA viral load measurement, complete blood count, and liver function tests are done 4 weeks after beginning or changing therapy to assess response and exclude toxicity. Thereafter, HIV RNA viral loads are measured monthly until RNA levels are undetectable. CD4 T-lymphocyte and HIV RNA levels can then be measured every trimester. If the HIV RNA viral load increases or does not decrease appropriately, then medication compliance and antiretroviral drug resistance are assessed. Poor adherence to therapy is a significant problem in pregnancy.
Although there was an association of early studies with glucose intolerance and protease inhibitor use, this has not been corroborated (Hitti, 2007; Tang, 2006). Standard serum glucose screening should be performed at 24 to 28 weeks unless indicated earlier. In addition, careful surveillance is important for interactions between antiretroviral drugs as well as therapies for opportunistic infection, hepatitis B and C, and tuberculosis (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012; Piscitelli, 2001).
Complications of HIV Infection
Management of some HIV complications may be altered by pregnancy. If the CD4+ T-cell count is < 200/mm3, primary prophylaxis for Pneumocystis jiroveci (formerly P carinii) pneumonia is recommended with sulfamethoxazole-trimethoprim or dapsone. Pneumonitis is treated with oral or IV sulfamethoxazole-trimethoprim or dapsone-trimethoprim. Other symptomatic opportunistic infections that may develop are from latent or newly acquired toxoplasmosis, herpes virus, mycobacteria, and candida. The National Institutes of Health, Centers for Disease Control and Prevention, and Infectious Diseases Society of America (2013) have published guidelines for prevention and treatment of opportunistic infections. Maternal HIV infection has also been associated with fetal-growth restriction, preeclampsia, and preterm membrane rupture (Ndirangu, 2012; Rollins, 2007; Suy, 2006).
Even with treatment, the incidence of perinatal complications in HIV-infected women is increased, although the newer drug regimens may diminish these rates. Multiple studies reviewed in the 2012 Perinatal Treatment Guidelines address the association of antiretroviral medications with preterm delivery. Most of those have shown a small but significantly increased risk. Kourtis and colleagues (2007b) performed a metaanalysis of 14 European and U.S. studies and found no overall greater risk for preterm delivery. They did find, however, that women taking regimens that included a protease inhibitor had a small increased risk—1.3-fold—that was nevertheless significant. Antiretroviral medication use in the second half of pregnancy was shown by Lopez and associates (2012) to increase iatrogenic preterm birth but did not affect spontaneous preterm birth rates. This slightly increased frequency of preterm birth clearly is outweighed by the benefits of decreasing perinatal HIV transmission.
At least two follow-up studies of children from the Pediatric AIDS Clinical Trial Group (PACTG) 076 Study found no adverse effects at 18 months and up to a mean of 5.6 years after zidovudine exposure (Culnane, 1999; Sperling, 1998). Prenatal exposure to HAART may increase the risk for neonatal neutropenia and anemia, although no long-term hematological or hepatic toxicities have been documented (Bae, 2008; Dryden-Peterson, 2011). Preliminary data also show a possible effect on infant mitochondrial DNA proliferation and/or expression with maternal antiretroviral drug treatment (Cote, 2008; Hernandez, 2012; Jitratkosol, 2012). For these reasons, long-term follow-up is recommended for all infants exposed in utero to antiviral medications.
Prenatal HIV Transmission
Maternal HAART treatment along with intrapartum zidovudine prophylaxis has dramatically reduced the perinatal HIV transmission risk from approximately 25 percent to 2 percent or less. HAART during pregnancy was reported to be associated with a decreased incidence of placental villitis, which may partially account for the lower HIV transmission rate in treated women (Stewart, 2014a). Optimal management of labor is uncertain, but if labor is progressing with intact membranes, artificial rupture and invasive fetal monitoring are avoided. Labor augmentation is used when needed to shorten the interval to delivery to further decrease the transmission risk. Operative delivery with forceps or vacuum extractor is avoided if possible. Postpartum hemorrhage is managed with oxytocin and prostaglandin analogues. Methergine and other ergot alkaloids adversely interact with reverse transcriptase and protease inhibitors to cause severe vasoconstriction.
Cesarean delivery has been recommended to decrease HIV prenatal transmission. An earlier metaanalysis of 15 prospective cohort studies by the International Perinatal HIV Group (1999) included 8533 mother-neonate pairs. Vertical HIV transmission was shown to be reduced by about half when cesarean was compared with vaginal delivery. When antiretroviral therapy was given in the prenatal, intrapartum, and neonatal periods along with cesarean delivery, the likelihood of neonatal transmission was reduced by 87 percent compared with vaginal delivery and without antiretroviral therapy. The European Mode of Delivery Collaboration (1999) has reported similar findings.
Based on these observations, the American College of Obstetricians and Gynecologists (2010b) concluded that scheduled cesarean delivery should be discussed and recommended for HIV-infected women whose HIV-1 RNA load exceeds 1000 copies/mL. Scheduled delivery is recommended at 38 weeks’ gestation in these women. Although data are insufficient to estimate such benefits for women whose HIV RNA levels are < 1000 copies/mL, it is unlikely that scheduled cesarean delivery would confer additional risk reduction if the woman has been taking antiviral therapy (Jamieson, 2007; Read, 2005). If cesarean delivery is performed for obstetrical indications, it should be performed at 39 weeks with standard perioperative antimicrobials for prophylaxis. HIV-infected women undergoing a scheduled cesarean delivery should be given IV zidovudine as a loading dose followed by 2 more hours of continuous maintenance therapy—a total of 3 hours of infused zidovudine.
Vertical transmission is increased by breast feeding, and it generally is not recommended for HIV-positive women in the United States (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2012; Read, 2003). The probability of HIV transmission per liter of breast milk ingested is estimated to be similar in magnitude to heterosexual transmission with unsafe sex in adults (Richardson, 2003). As with other exposures, risk is related to the maternal HIV RNA level, HIV disease status, breast health, and duration of breast feeding (De Cock, 2000; John-Stewart, 2004). Most transmission occurs in the first 6 months, and as many as two thirds of infections in breast-fed infants are from breast milk. In the Petra Study Team (2002) from Africa, the prophylactic benefits of short-course perinatal antiviral regimens were diminished considerably by 18 months of age due to breast feeding. The World Health Organization (2010) has recommended exclusive breast feeding the first 6 months of life for infants of women living in developing countries in which infectious diseases and malnutrition are the primary causes of infant deaths. Breast feeding can be continued for 12 months until a nutritionally adequate diet is available.
Many otherwise healthy women with normal CD4+ T-cell counts and low HIV RNA levels may discontinue treatment after delivery and be closely monitored according to adult guidelines. The exception is the woman who plans another pregnancy in the near future. Stewart and colleagues (2014b) showed that interpregnancy viral load suppression is associated with less vertical transmission in a subsequent pregnancy. Psychosocial support is essential during this time, especially while awaiting diagnostic testing for pediatric infection. Contraceptive needs are complex and also may entail condoms in discordantly infected couples. As discussed in Chapter 38 (p. 708), antiretroviral drugs may affect oral contraceptive hormone levels and possibly of injectable agents (Stuart, 2012). Intrauterine devices may be an acceptable choice in some women with normal immunocompetence and a low risk for STIs. The Centers for Disease Control and Prevention has recently revised the recommendations for the use of hormonal contraception among women at high risk for HIV infection or infected with HIV (Tepper, 2012). It reaffirmed prior recommendations that hormonal contraception use is safe for these women and that condom use should be encouraged regardless of contraceptive method.
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