CHAPTER 65: Sexually Transmitted Infections

Syphilis and gonorrhea were prominently mentioned in the first edition of this book, with special consideration for their harmful effects on fetal development. Although Williams confined his discussion to these two infections, today, sexually transmitted diseases (STDs) include chlamydial and trichomonal infections and viral STDs such as hepatitis B, human immunodeficiency virus (HIV), herpes simplex virus (HSV), and human papillomavirus (HPV) infections. In some form, all can be injurious to the mother or fetus and thus should be aggressively sought and treated. In many instances, recommended therapies are provided in guidelines from the Centers for Disease Control and Prevention (CDC) and listed throughout the chapter.

Vertical transmission refers to passage from the mother to her fetus of an infectious agent through the placenta, during labor or delivery, or by breastfeeding. Treatment of most STDs is clearly associated with improved pregnancy outcome and prevention of perinatal morbidity. Logically, education, screening, treatment, and prevention are essential components of prenatal care.

Despite the availability of adequate therapy for decades, syphilis remains a major issue for both mother and fetus. From 2001 through 2015, the primary and secondary syphilis rates have risen almost yearly (Centers for Disease Control and Prevention, 2016c). In the United States in 2015, the combined rate for both of these among women was 1.8 cases per 100,000 persons (de Voux, 2017). For congenital syphilis, after a nadir in 2012, rates have also risen yearly to reach 12.4 cases per 100,000 live births in 2015. Of risks, higher congenital syphilis rates are linked to inadequate prenatal care, black or Hispanic race, and lack of treatment (Su, 2016). Similarly, syphilis remains a significant global health problem, with many countries reporting high numbers of new infections (Newman, 2015; World Health Organization, 2012).

Pathogenesis and Transmission

Syphilis is caused by the spirochetal bacterium Treponema pallidum. Minute abrasions on the vaginal mucosa provide an entry portal, and cervical eversion, hyperemia, and friability raise transmission risk. Spirochetes replicate and then disseminate through lymphatic channels within hours to days. The incubation period is 3 to 4 weeks depending on host factors and inoculum size.

The early stages of syphilis include primary, secondary, and early latent syphilis. These are associated with high spirochete loads, and partner transmission rates approximate 30 to 60 percent (Garnett, 1997; Singh, 1999). In late-stage disease, transmission rates decline because of smaller inoculum sizes.

Maternal syphilis can cause fetal infection by several routes. Spirochetes readily cross the placenta to cause congenital infection. 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. Fetal infection develops in >50 percent of untreated early syphilis cases and in 10 percent of late latent disease (Fiumara, 1975; Hollier, 2001).

Clinical Manifestations

Maternal Syphilis

This is staged according to clinical features and disease duration.

1. Primary syphilis is diagnosed by its characteristic chancre, which develops at the inoculation site. This solitary, painless lesion typically has a raised, firm border and a red, smooth ulcerated base without significant pus (Fig. 65-1). Nonsuppurative lymphadenopathy may develop. A chancre will usually resolve spontaneously in 2 to 8 weeks, even if untreated. Multiple lesions, if found, are predominantly in HIV-1 co-infected women.

2. Secondary syphilis stems from dissemination of spirochetes to affect 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 (Fig. 65-2). Condylomata lata are flesh-colored papules and nodules found on the perineum and perianal area (Fig. 65-3). These papules are teeming with spirochetes and are highly infectious. Most women with secondary syphilis also express constitutional symptoms such as fever, malaise, headache, and myalgias. Hepatitis, nephropathy, ocular changes, anterior uveitis, and periostitis can also develop.

3. Latent syphilis develops when primary or secondary syphilis is not treated but clinical manifestations still resolve. It is identified instead by serological testing. Early latent syphilis is subclinical 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 syphilis is a slowly progressive disease affecting any organ system but is rarely seen in reproductive-aged women.

Congenital Syphilis

Without screening and treatment, approximately 70 percent of infected women will have an adverse pregnancy outcome (Hawkes, 2011). Maternal infection can lead to preterm labor, fetal death, fetal-growth restriction, or fetal infection (Gomez, 2013). 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). Once fetal syphilis develops, however, it manifests as a continuum. Fetal hepatic abnormalities are followed by anemia and thrombocytopenia, then ascites and hydrops (Hollier, 2001). Stillbirth remains a major complication (Lawn, 2016; Su, 2016). The newborn may have jaundice with petechiae or purpuric skin lesions, lymphadenopathy, rhinitis, pneumonia, myocarditis, nephrosis, or long-bone involvement (Fig. 65-4).

With syphilitic infection, the placenta becomes large and pale (see Fig. 65-4). Microscopically, villi lose their characteristic arborization and become thicker and clubbed. Sheffield and colleagues (2002c) described these 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. The cord may also show evidence of infection. In a study of 25 untreated women, Schwartz and associates (1995) reported that necrotizing funisitis was present in a third.

Diagnosis

The United States Preventative Services Task Force recommends that clinicians screen all pregnant women for syphilis to prevent congenital infection (Wolff, 2009). Testing is ideally performed at the first prenatal visit. In populations with a high prevalence of syphilis, serological testing is repeated in the third trimester and again at delivery (Workowski, 2015).

Treponema pallidum cannot be cultured from clinical specimens. However, direct diagnosis of early-stage disease from lesion exudate, tissue, or body fluid can be completed by dark-field microscopic examination, by polymerase chain reaction (PCR), or by direct fluorescent antibody tests for T pallidum (DFA-TP) (Tsang, 2015). These methods are not widely available and are less sensitive for blood specimens (Grange, 2012; Henao-Martínez, 2014). Thus, in practice, diagnoses are mainly derived from clinical findings coupled with serological blood testing.

Serological testing is used for diagnostic and for screening purposes. There are two types. If the first of these is positive, then the second type is also performed. This combination identifies infection and clarifies disease stage. Traditionally, the first type is nontreponemal testing, and either the Venereal Disease Research Laboratory (VDRL) or the rapid plasma reagin (RPR) is selected. Both tests measure patient immunoglobulin M and G (IgM and IgG) antibodies formed against cardiolipin that is released from damaged host cells and possibly also from treponemes. Notably, these same antibodies can also be produced in response to other acute events that include recent vaccination, febrile illness, and pregnancy itself or in response to chronic conditions such as intravenous drug abuse, systemic lupus erythematosus, aging, leprosy, or cancer. As such, these all serve as potential sources of false-positive results (Larsen, 1995). Conversely, seroconversion occurs at around 3 weeks, but can take up to 6 weeks (Peeling, 2004). Thus, women with very early primary syphilis can have initially false-negative serological test results.

With positive nontreponemal test results, findings 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). Because VDRL titers do not correspond directly to RPR titers, consistent use of the same test for surveillance is recommended. Those with treatment failure or reinfection may lack this expected decline. Importantly, some successfully treated patients may still exhibit persistently low-level positive titers, which are referred to as “serofast.” This state is more likely in older individuals, those with lower initial nontreponemal antibody titers, and those with later stages of syphilis (Seña, 2015).

The second type of serological testing is treponemal-specific. It seeks patient antibodies formed specifically against T pallidum. The antibodies detected by treponemal assays appear up to a few weeks earlier than those detected by nontreponemal tests (Levett, 2015). Tests includes the fluorescent treponemal-antibody absorption tests (FTA-ABS), the T pallidum passive particle agglutination (TP-PA) test, and various immunoassays (Association of Public Health Laboratories, 2015). Of note, these treponemal-specific tests generally remain positive throughout life.

Each of the serological tests has limitations including false-positive and -negative results. Traditionally, nontreponemal tests have been used for screening in the United States, and results are then confirmed by a specific treponemal test. Within the past several years, some laboratories have implemented a reverse screening algorithm, namely, screening first with a treponemal-specific test (Binnicker, 2012; Centers for Disease Control and Prevention, 2011). Both approaches are effective if there is a program for appropriate screening, follow-up, and treatment.

In contrast to these tests, rapid “point-of-care” (POC) syphilis screening of blood or serum samples is being developed (Singh, 2015; Tucker, 2010). These may be best used for women with limited prenatal care. Most tests are treponemal-specific, and positive POC results can then be confirmed by a laboratory nontreponemal test. In hard-to-reach populations, some countries immediately treat women with positive POC results. This practice, however, risks overtreating previously cured women who still have residual persistent treponemal antibodies. This limitation may be overcome by newer POC dual tests, which simultaneously assess nontreponemal and treponemal antibodies (Causer, 2015).

Following maternal diagnosis, sonographic evaluation is performed for fetuses >20 weeks’ gestation to search for signs of congenital syphilis. Rac and associates (2014b) noted that 31 percent of infected women diagnosed at ≥18 weeks’ gestation had abnormal fetal sonographic findings. Hepatomegaly, placental thickening, hydramnios, ascites, hydrops fetalis, and elevated middle cerebral artery Doppler velocimetry measurements are indicative of fetal infection. Before 20 weeks, treatment is highly successful, and sonographic findings are rare (Nathan, 1997).

For fetuses of viable age with sonographic findings, antepartum fetal heart rate monitoring prior to treatment is recommended. Spontaneous late decelerations or a nonreactive tracing likely reflects an extremely ill fetus that may poorly tolerate a Jarisch-Herxheimer reaction, described next. In this extreme case, consultation with a neonatologist regarding a plan of delaying treatment, pursuing delivery, and then treating in the nursery is a consideration (Wendel, 2002).

Treatment

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 (Table 65-1). During pregnancy, authorities recommend that a second dose of benzathine penicillin G be given 1 week after the initial dose. Such treatment is also given for women with concomitant HIV infection (Workowski, 2015).

Benzathine penicillin G is 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; Wendel, 1988; Zhou, 2007). Moreover, in several countries, macrolide-resistant strains of T pallidum are now prevalent (Stamm, 2015). Cephalosporins may prove useful, but data are limited (Liang, 2016). Tetracyclines, including doxycycline, are effective but generally not recommended during pregnancy, because of the risk for fetal deciduous-teeth discoloration.

All women with syphilis are offered counseling and testing for HIV and other STDs. Following syphilis treatment, serological testing to detect treatment failures is done at 3 to 6 months and usually confirms a fourfold drop in VDRL or RPR titers. During pregnancy, serological titers can be checked monthly in women at high risk for reinfection (Workowski, 2015).

In some instances, a woman may present without symptoms but describes recent sexual contact with a person who has been diagnosed with syphilis. She should be evaluated clinically and serologically. If her partner is diagnosed and their sexual contact occurred within the preceding 90 days, the gravida is treated presumptively for early syphilis, even if serological test results are negative. This accounts for early infection but before seroconversion. If contact was earlier than 90 days ago, treatment is based on serological results (Workwoski, 2015).

Penicillin Reactions

Women with a history of penicillin allergy should have either an oral stepwise penicillin-dose challenge or skin testing performed to confirm the risk of immunoglobulin E (IgE)-mediated anaphylaxis. If confirmed, penicillin desensitization, shown in Table 65-2, is recommended and then followed by benzathine penicillin G treatment (Wendel, 1985).

Distinct from allergy, a Jarisch-Herxheimer reaction develops following penicillin treatment in most women with primary syphilis and approximately half with secondary infection. Uterine contractions, mild maternal temperature elevation, decreased fetal movement, and fetal heart rate decelerations are findings. Reaction treatment is supportive with antipyretics as needed, hydration, and oxygen supplementation (Klein, 1990). In a study of 50 gravidas who received benzathine penicillin for syphilis, Myles and associates (1998) reported a 40-percent incidence of Jarisch-Herxheimer reactions. Of the 31 women monitored electronically, 42 percent developed regular uterine contractions, and 39 percent developed variable decelerations. All contractions resolved within 24 hours of therapy. Accordingly, for fetuses of viable age, some recommend administering the first dose of antibiotic in labor and delivery and with continuous fetal monitoring for at least 24 hours (Rac, 2017). Others recommend this only if sonographic signs of fetal syphilis, described earlier, are found (Duff, 2014; Wendel, 2002). If this second plan is elected, patients are counseled on reaction signs and encouraged to seek evaluation if they develop.

Of notifiable STDs, infections caused by Neisseria gonorrhoeae are the second most common. The incidence of gonorrhea in the United States has continued to rise since 2009, and in 2015, the rate was 124 cases per 100,000 persons (Centers for Disease Control and Prevention, 2016c). The highest rates in women of any ethnicity were in those aged 15 to 24 years. In pregnant women, its prevalence approximates 0.6 percent (Blatt, 2012). In most pregnant women, 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).

Gonococcal infection can have deleterious effects in any trimester. Untreated gonococcal cervicitis is associated with septic abortion as well as infection after voluntary abortion (Burkman, 1976). Preterm delivery, prematurely ruptured membranes, chorioamnionitis, and postpartum infection are more frequent in women with gonococcal infection (Alger, 1988; Johnson, 2011).

Vertical transmission of gonorrhea is predominantly due to fetal contact with vaginal infection during birth. The predominant sequela is gonococcal ophthalmia neonatorum, which can lead to corneal scarring, ocular perforation, and blindness. Transmission rates are high and approximate 40 percent (Laga, 1986). Accordingly, as discussed in Chapter 32 (Preventive Care), ocular prophylaxis is provided to newborns (Mabry-Hernandez, 2010).

Screening and Treatment

Pregnant women who live in high-prevalence areas or who are at risk for gonorrhea should undergo first-trimester screening. Risk factors include age ≤25 years; prior gonococcal infection; other STDs; prostitution; new or multiple sexual partners; drug abuse; black, Hispanic, or American Indian or Alaska Native ethnicity; and inconsistent condom use (American Academy of Pediatrics, 2017). For women who test positive, screening for syphilis, chlamydial infection, and HIV should precede treatment, if possible. Gonococcal infection is a marker for concomitant chlamydial infection. Thus, if chlamydial testing is unavailable, presumptive chlamydial therapy is given to women treated for gonorrhea.

Screening for gonorrhea in women is by culture or nucleic acid amplification tests (NAATs). NAATs have replaced culture in most laboratories, and kits are available for specific collection from the vagina, endocervix, or urine. Of these, vaginal or cervical samples are preferred, as urine collection may detect up to 10 percent fewer infections (Papp, 2014). If used, the initial urine stream, not midstream, is collected. NAATs are also recommended for diagnosis of rectal or pharyngeal disease, but participating laboratories must be CLIA (Clinical Laboratory Improvement Amendments) compliant with required test modifications. Culture is also available for these anatomical sites. Rapid POC tests for gonorrhea, although available, do not yet reach the sensitivity or specificity of culture or NAAT and have not been rigorously studied in pregnant women (Herbst de Cortina, 2016).

Gonorrhea treatment has evolved during the past decade due to the ability of N gonorrhoeae to rapidly develop antimicrobial resistance. The current treatment for uncomplicated gonococcal infection during pregnancy is 250 mg of ceftriaxone intramuscularly plus 1 g of azithromycin orally (Workowski, 2015). The latter provides another drug with a different mechanism of action against N gonorrhoeae and treats chlamydial co-infections. Patients are instructed to abstain from sexual intercourse for 7 days after they and their sexual partners have completed treatment. As an alternative regimen, a single, 400-mg oral dose of cefixime plus 1 g of azithromycin should be reserved for situations that preclude ceftriaxone treatment. With cephalosporin allergy, a 240-mg intramuscular dose of gentamicin can be coupled with a 2-g oral azithromycin dose. Repeat testing is recommended in the third trimester for any woman treated for gonorrhea in the first trimester and for any uninfected woman who is at high risk for gonococcal infection (American Academy of Pediatrics, 2017).

Treatment is recommended for sexual contacts. Expedited therapy, discussed in Herpes Simplex Virus, is a less-desirable option due to the now-preferred injectable regimen.

Disseminated Gonococcal Infections

Gonococcal bacteremia may cause disseminated infections that manifest as petechial or pustular skin lesions, arthralgias, or septic arthritis. For treatment of septic arthritis, the CDC recommends ceftriaxone, 1 g intramuscularly or intravenously (IV) every 24 hours plus a single 1-g oral dose of azithromycin (Workowski, 2015). Treatment is continued for 24 to 48 hours after clinical improvement, and therapy is then changed to an oral agent to complete 1 week of therapy. Prompt recognition and antimicrobial treatment will usually yield favorable outcomes in pregnancy (Bleich, 2012). Meningitis and endocarditis rarely complicate pregnancy, but they may be fatal (Bataskov, 1991; Burgis, 2006). For gonococcal endocarditis, ceftriaxone 1 to 2 g IV every 12 hours should be continued for at least 4 weeks, and for meningitis, 10 to 14 days. A single 1-g oral dose of azithromycin is also provided for chlamydial co-infection (Workowski, 2015).

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 common reportable STD in the United States, and the overall chlamydial infection rate among women was 646 cases per 100,000 females in 2015 (Centers for Disease Control and Prevention, 2016c).

Most pregnant women have asymptomatic infection, but a third have urethral syndrome, urethritis, or Bartholin gland infection (Peipert, 2003). Mucopurulent cervicitis may be due to chlamydial or gonococcal infection or both. Other chlamydial infections not usually seen in pregnancy are endometritis, salpingitis, 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). It is disputed whether untreated cervical infection increases the risk of preterm delivery, preterm ruptured membranes, low birthweight, or perinatal mortality (Andrews, 2000, 2006; Blas, 2007; Johnson, 2011; Moodley, 2017; Silva, 2011). Chlamydial infection has not been associated with a greater risk of chorioamnionitis or with peripartum pelvic infection (Berman, 1987; Gibbs, 1987). However, 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, and uterine tenderness.

Infection poses a higher risk to the newborn than to the mother. Vertical transmission leads to infection in 8 to 44 percent of neonates delivered vaginally from affected women (Rosenman, 2003). Of neonatal infections, conjunctivitis is the most common (Chap. 32, Preventive Care). Perinatal transmission to newborns can also cause pneumonia.

Screening and Treatment

Currently, the U.S. Preventive Services Task Force (LeFevre, 2014) as well as the American Academy of Pediatrics and American College of Obstetricians and Gynecologists (2017) recommend chlamydia screening for all women at the first prenatal visit. The College further suggests testing in the third trimester for those treated in the first trimester; all women aged ≤25 years; and those aged ≥25 years with behavioral factors, which mirror those for women at risk for gonorrhea. In one review of repeat chlamydial infections among women, the reinfection rate was 14 percent, and most recurred within the first 8 to 10 months (Hosenfeld, 2009).

Diagnosis is made predominantly by culture or NAAT. Cultures are more expensive and less accurate than newer NAATs (Greer, 2008). Of samples for NAAT, vaginal or cervical samples are preferred, as urine collection may detect up to 10 percent fewer infections (Papp, 2014; Wiesenfeld, 2017). However, Roberts and associates (2011) evaluated NAAT of urine specimens compared with cervical secretions in more than 2000 pregnant women and found them to be equivalent. As with gonorrhea, the first portion of the urine stream is collected.

Currently recommended treatment regimens for chlamydial infections are shown in Table 65-3. Azithromycin is first-line treatment and is safe and effective in pregnancy. The fluoroquinolones and doxycycline are usually avoided in pregnancy, and erythromycin estolate is contraindicated because of drug-related hepatotoxicity. Chlamydial testing is repeated 3 to 4 weeks after therapy completion and again 3 months after treatment. In high-risk individuals, third-trimester rescreening is recommended (Workowski, 2015).

Expedited Partner Therapy

To prevent STD transmission, guidelines for expedited partner therapy (EPT) have been created by the Centers for Disease Control and Prevention (2006a) and are endorsed by the American College of Obstetricians and Gynecologists (2015). With EPT, a prescription is provided to the diagnosed patient for their partner. It is delivered by the patient to their partner without medical assessment of the partner or professional counseling. EPT ideally does not replace traditional strategies, such as standard patient referral with screening for other STDs.

EPT is acceptable for treatment of sexual contacts with chlamydial infection. In light of new guidelines that recommend injectable ceftriaxone, EPT for gonorrhea is less desirable unless the partner will otherwise not seek treatment (Centers for Disease Control and Prevention, 2016a). Fewer data are available to assess this strategy for trichomoniasis (Kissinger, 2006; Schwebke, 2010). EPT is not recommended for syphilis (Workowski, 2015).

Although sanctioned by the CDC, EPT is not legal in several states. Moreover, the risk of litigation in the event of adverse outcomes may be elevated when a practice has uncertain legal status or is outside formally accepted community practice standards (Centers for Disease Control and Prevention, 2006a). The legal status of EPT in each of the 50 states can be found at: http://www.cdc.gov/std/ept/legal/default.htm.

Lymphogranuloma Venereum

L₁, L₂, and L₃ serovars of C trachomatis cause lymphogranuloma venereum (LGV). The primary genital infection is transient, is seldom recognized, and is not linked with vertical transmission to the fetus. It can be confused with chancroid. Classically, matted inguinal adenitis may develop on either side of the inguinal ligament to give rise to the “groove sign.” At times, these nodes may suppurate. 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 may also evolve.

For treatment during pregnancy, erythromycin base, 500 mg orally four times daily, is given for 21 days (Workowski, 2015). Some authorities instead use szithromycin, 1 g orally weekly for 21 days, although data regarding efficacy are scarce.

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.

Adult Disease

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).

Clinical Manifestations

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 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.

Vertical Transmission

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).

Diagnosis

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.

Management

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.

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).

Haemophilus ducreyi can cause painful, nonindurated genital ulcers termed soft chancres. At times, these are accompanied by painful suppurative inguinal lymphadenopathy. Although common in some developing countries, only 11 cases were reported in the United States in 2015 (Centers for Disease Control and Prevention, 2016c). Appropriate media are not widely accessible, and no Food and Drug Administration (FDA)-cleared PCR test is yet available. Instead, painful genital ulcer(s) and negative screening for syphilis or HSV leads to a presumptive diagnosis. 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 (Workowski, 2015).

This is a common STD, and more than 40 types infect the genital tract. In the United States from 2005 to 2006, the overall HPV prevalence was 40 percent in females aged 14 to 59 years (Liu, 2016). Prevalence is highest in younger women, and some of this seroprevalence now reflects HPV vaccination in this age group (Brouwer, 2015). Most reproductive-aged women become infected within a few years of becoming sexually active, and most infections are asymptomatic and transient. High-risk types are those with the most oncogenic potential. Of these, HPV types 16 and 18 are often associated with dysplasia (Chap. 63, Epithelial Neoplasia). Mucocutaneous external genital warts termed condyloma acuminata are usually caused by types 6 and 11.

For unknown reasons, genital warts frequently increase in number and size during pregnancy. These lesions may sometimes grow to fill the vagina or cover the perineum, thus making vaginal delivery or episiotomy difficult. Maternal HPV infection does not appear to be related to preterm labor (Subramaniam, 2016).

Condyloma Acuminata Treatment

Genital wart eradication during pregnancy is usually not necessary unless they are symptomatic. Therapy is directed toward debulking symptomatic warts yet minimizing treatment toxicity to the mother and fetus. Several agents are available, but no definitive evidence supports superiority of one over another (Workowski, 2015). Response to treatment during pregnancy may be incomplete, but lesions frequently improve or regress rapidly following delivery.

Trichloroacetic or bichloracetic acid, 80- to 90-percent solution, applied topically weekly, is an effective regimen for external warts. Some prefer cryotherapy, laser ablation, or surgical excision. Agents not recommended in pregnancy because of concerns for maternal and fetal safety include podophyllin resin, podofilox solution or gel, imiquimod cream, and sinecatechins.

There are three vaccines available for long-term prevention. Gardasil (HPV4) is a quadrivalent vaccine against HPV types 6, 11, 16, and 18. This is being replaced by Gardasil 9 (HPV9), a nonavalent vaccine that protects against all the types in HPV4 plus types 31, 33, 45, 52, and 58. Cervarix (HPV2) is a bivalent vaccine against HPVs 16 and 18. One of these vaccines is selected and given as a three-dose series on a schedule of 0, 1–2, and 6 months for those aged 15 to 26 years. A two-dose regimen, given at 0 and again at 6 to 12 months, is now recommended for girls aged 9 to 14 years (Meites, 2016). Vaccines are licensed for females aged 9 to 26 years, and the target age is 11 to 12 years. The vaccines are not recommended for pregnant women, however, inadvertent exposures do occur. No adverse pregnancy outcomes are associated with the vaccines (Moreira, 2016; Panagiotou, 2015; Vichnin, 2015). If a woman is found to be pregnant after starting the vaccination series, the remaining doses are delayed and given after delivery (American College of Obstetricians and Gynecologists, 2017a). Women who are breastfeeding may receive the vaccine.

Neonatal Infection

Vertical transmission rates of HPV to the newborn are minimal. Juvenile-onset recurrent respiratory papillomatosis (JoRRP) is a rare, benign neoplasm of the larynx. It can cause hoarseness and respiratory distress in children and is most often caused by HPV 6 or 11. Risks for infection are maternal genital HPV infection and longer labors (Niyibizi, 2014). Many newborns are likely exposed to HPV, but few develop JoRRP (Silverberg, 2003; Smith, 2004; Tenti, 1999). For example, the national incidence of JoRRP in 2006 in the United States ranged from 0.5 to 1 per 100,000 children (Marsico, 2014).

The benefit of cesarean delivery to decrease transmission risk is unknown, and thus it is currently not recommended solely to prevent HPV transmission (Workowski, 2015). HPV vaccination may ultimately decrease JoRRP rates in the future (Matys, 2012).

Pregnant women frequently develop increased vaginal discharge. This may be a physiological discharge, described in Chapter 4 (Cervix), but should be differentiated from symptomatic vaginitis, which is also common in pregnancy. Fortunately, vaginitis is prevented in part by normal vaginal flora. To better understand this, studies of the composition and function of the normal vaginal microflora are currently underway with the Vaginal Human Microbiome Project (Huang, 2014).

Bacterial Vaginosis

Diagnosis

Not an infection in the ordinary sense, bacterial vaginosis (BV) is a maldistribution of normal vaginal flora. With BV, numbers of lactobacilli are decreased, and anaerobic bacteria species are overrepresented. These anaerobes include Gardnerella, Prevotella, Mobiluncus, and Bacteroides species; Atopobium vaginae; and BV-associated bacteria, provisionally named BVAB1, BVAB2, and BVAB3. These last three are newly recognized bacteria found in women with BV (Fredricks, 2005).

Molecular ribosomal RNA gene sequencing techniques have greatly aided this understanding of the vaginal flora, also called the vaginal microbiota. Five types of vaginal microbiota exist, referred to as community state types (CSTs). And, a woman can be categorized to one of these five CSTs based on her vaginal microbiota composition (Ravel, 2011). Researchers have begun to quantify the risk of BV by these CST groups. Specifically, CSTs I, II, III, and V are rich in lactobacilli. In contrast, CST IV is a heterogeneous microbiota of strict anaerobes and is associated with BV. CSTs vary racially, and CST IV is also the most common in asymptomatic, healthy black women (Fettweis, 2014). Pregnancy-related changes in vaginal microbiota are also being defined and may hold keys to adverse BV-related pregnancy outcomes, discussed subsequently (Romero, 2014).

Of childbearing-aged women in the United States, nearly 30 percent have BV. In black women, the prevalence approximates 50 percent (Allsworth, 2007). Most women are asymptomatic, but a foul, thin vaginal discharge is a typical complaint. Associated risk factors are douching, multiple partners, smoking, and altered host immunity (Desseauve, 2012; Koumans, 2007; Murphy, 2016).

For clinical diagnosis of BV, three of the four following criteria are present: (1) vaginal pH >4.5; (2) a thin, milky, noninflammatory vaginal discharge; (3) >20 percent clue cells seen microscopically; and (4) a fishy odor after addition of 10-percent potassium hydroxide to vaginal secretion samples (Amsel, 1983). The last is described as a positive “whiff test.” Likewise, alkalinity of seminal fluid and blood are responsible for foul-odor complaints after intercourse and with menses in affected women. Clue cells are vaginal epithelial cells containing many attached bacteria, which create a poorly defined stippled cellular border (Fig. 65-6). The higher vaginal pH stems from diminished acid production by lactobacilli. Similarly, Trichomonas vaginalis infection is also associated with anaerobic overgrowth and resultant elaborated amines. Thus, women diagnosed with BV should have no microscopic evidence of trichomoniasis (see Fig. 65-6).

The Nugent score, used primarily in research studies rather than clinical practice, is a system employed for diagnosing BV (Nugent, 1991). During microscopic examination of a gram-stained vaginal discharge smear, scores are calculated by assessing bacteria staining and morphology.

Treatment

Several adverse pregnancy-related health outcomes associated with BV are preterm birth, premature rupture of the membranes, and postpartum endometritis (Hillier, 1995; Leitich, 2003; Watts, 1990). It also increases susceptibility to STDs, including HIV (Atashili, 2008; Brotman, 2010). For women at low risk for preterm birth, however, treatment of BV does not reduce preterm birth rates (Brocklehurst, 2013; Carey, 2000). For high-risk women, evidence is conflicting. Currently, the American College of Obstetricians and Gynecologists (2016c), CDC, and U.S. Preventive Services Task Force do not recommend routine BV screening of asymptomatic gravidas—at either high or low risk for preterm delivery—to prevent preterm birth (Nygren, 2008; Workowski, 2015).

Treatment is reserved for symptomatic women. Preferred drugs are metronidazole, 500 mg twice daily orally for 7 days; metronidazole 0.75-percent gel, one applicator intravaginally, daily for 5 days; or clindamycin 2-percent cream, one applicator intravaginally nightly for 7 days. Alternatives are clindamycin, 300 mg orally twice daily for 7 days, or 100-mg clindamycin ovules placed intravaginally nightly for 3 days (Workowski, 2015). It is still debated whether BV is a sexually transmitted infection. But, treatment of a male partner does not appear to lower recurrence rates (Amaya-Guio, 2016).

Trichomoniasis

Diagnosis

Vaginitis caused by Trichomonas vaginalis is common, and its prevalence in the United States approximates 3 percent in nonpregnant and pregnant women (Allsworth, 2009; Satterwhite, 2013). The prevalence is higher in those older than 30 years compared with younger women. Risks include black race, douching, and greater number of lifetime sexual partners (Sutton, 2007). Among women, frequent sites of infection include the urethra, endocervix, and vagina. Symptomatic vaginitis is characterized by yellow purulent discharge, pruritus, vulvovaginal erythema, and colpitis macularis, which is often termed a “strawberry cervix” and reflects a patchy, maculoerythematous ectocervix (Wølner-Hanssen, 1989).

Trichomonads are flagellated, pear-shaped, motile organisms that are somewhat larger than leukocytes. These parasites can readily be seen microscopically moving briskly in a sample mixed on a slide with saline. Prompt inspection of vaginal secretions is advantageous because trichomonads slow with cooling. At times, T vaginalis may be found incidentally on a Pap test slide. Both of these microscopic slide tests have low diagnostic sensitivity that approximates only 60 percent (Krieger, 1988; Wiese, 2000). And, Pap tests can yield false-positive results. Thus, Pap test trichomonad findings warrant wet-prep microscopy or other diagnostic confirmation (American College of Obstetricians and Gynecologists, 2017c). Of other tests, culture is expensive, lengthy, and sensitivities are 75 to 95 percent (Association of Public Health Laboratories, 2016; Huppert, 2007). Laboratory NAAT analysis of a vaginal, endocervical, or urine sample is available, is completed in minutes to hours, and offers superior sensitivity of 95 to 100 percent (Schwebke, 2011; Van Der Pol, 2014). Rapid POC testing is also available but may sacrifice sensitivity for speed. The OSOM Trichomonas Rapid Test provides results in 10 minutes, is suitable for office use, and has sensitivities of 88 to 98 percent (Herbst de Cortina, 2016).

Treatment

Metronidazole, administered orally in a single 2-g dose, is effective in eradicating T vaginalis. For those with HIV infection, treatment instead with metronidazole 500 mg orally twice daily for 7 days improves efficacy. Because of the high rate of reinfection among women treated for trichomoniasis, retesting for T vaginalis is recommended for all sexually active women within 3 months following initial treatment (Workowski, 2015).

Metronidazole, an FDA category B drug, is not teratogenic or fetotoxic, but has displayed some tumorigenicity in animal studies (Briggs, 2015; Czeizel, 1998). For this reason, the manufacturer recommends against its use during the first trimester (Pfizer, 2016). Fewer data are available for tinidazole, which is a category C drug, and thus metronidazole is preferred. Metronidazole and tinidazole have similar chemical structures, and those allergic to metronidazole may also react to tinidazole. For allergic patients, metronidazole desensitization is effective, and one scheme is outlined in the study by Helms and coworkers (2008). With postpartum breastfeeding, feeds are delayed for 24 hours following the last oral metronidazole dose per manufacturer prescribing information. For tinidazole, the delay is 72 hours.

Perinatal transmission of trichomoniasis by direct contact in the birth canal is rare but may lead to neonatal respiratory or genital infection (Bruins, 2013; Trintis, 2010). Some studies have linked trichomonal infection with preterm birth. A few other studies implicate this infection with preterm premature rupture of membranes and small-for-gestational age newborns (Silver, 2014). However, treatment did not lower preterm birth rates in a randomized study by Klebanoff and colleagues (2001). Also, in this study, but not one by Mann and coworkers (2009), treatment for trichomoniasis was associated instead with a higher preterm birth rate.

In sum, treatment for symptomatic women is reasonable and outlined above. For most asymptomatic women during pregnancy, screening is not recommended. However, for pregnant women with HIV infection, screening at the first prenatal visit and prompt treatment are encouraged. This is because T vaginalis infection in pregnant women with HIV may be a risk factor for vertical HIV transmission (Gumbo, 2010; Workowski, 2015).

Candidiasis

Candida albicans or other candidal species can be identified by culture from the vagina during pregnancy in approximately 20 percent of women. A link between candidiasis and preterm birth is not robust (Cotch, 1998; Kiss, 2004; Roberts, 2015). Thus, asymptomatic colonization requires no treatment. The organism, however, can create an extremely profuse, irritating discharge.

For symptoms, effective treatment is a 100-mg miconazole vaginal suppository or a 2-percent butoconazole, 1-percent clotrimazole, 2-percent miconazole, or 0.4-percent terconazole cream, any of which is used daily for 7 days. A shorter, 3-day regimen is daily 2-percent clotrimazole, 4-percent miconazole, or 0.8-percent tioconazole cream, or daily 200-mg miconazole or 80-mg terconazole suppository (Workowski, 2015). 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). For treatment, the American College of Obstetricians and Gynecologists (2017c) and the CDC recommend topical rather than oral azoles for symptoms. As discussed further in Chapter 12 (Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blocking Drugs), oral fluconazole is generally not considered teratogenic, but in 2016, the FDA released a safety alert regarding a possible link with miscarriage (Mølgaard-Nielsen, 2016).

Etiopathogenesis and Epidemiology

Causative agents of acquired immunodeficiency syndrome (AIDS) are RNA retroviruses termed human immunodeficiency viruses, HIV-1 and HIV-2. Most cases worldwide are caused by HIV-1 infection. Sexual intercourse is the major mode of transmission. The virus also is passed by blood, and infected mothers may infect their fetuses during labor and delivery or by breast milk. The primary determinant of transmission is the plasma HIV-1 viral load.

For sexual transmission, the viral HIV envelope binds to mucosal dendritic cells. These cells then present the viral particle to specific T lymphocytes. These lymphocytes are defined phenotypically by their cluster of differentiation 4 (CD4) glycoprotein surface antigens. The CD4 site serves as a receptor for the virus. Once infected, CD4 T lymphocytes may die, and the common denominator of clinical illness with AIDS is profound immunodeficiency that gives rise to various opportunistic infections and neoplasms.

In the United States, the CDC (2016c) estimated that more than 1.2 million individuals were infected in 2013, and new cases numbered more than 39,000. Approximately 8500 women with HIV give birth annually in the United States. However, the estimated number of perinatally acquired HIV cases has decreased dramatically, and the perinatal transmission rate in 2013 was 1.8 percent (Centers for Disease Control and Prevention, 2016b, 2017). This is predominantly due to the implementation of prenatal HIV testing and antiretroviral therapy (ART) for the woman and then her neonate.

Clinical Manifestations

The incubation period from exposure to clinical disease averages 3 to 6 weeks. Acute HIV infection is similar to many other viral syndromes and usually lasts less than 10 days. Common symptoms, if any, include fever, fatigue, rash, headache, lymphadenopathy, pharyngitis, myalgias, nausea, and diarrhea. After symptoms abate, 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). According to the CDC, AIDS is defined by a CD4 T-cell count <200 cells/μL, by CD4 T-cells comprising <14 percent of all lymphocytes, or one of several AIDS-defining illnesses (Schneider, 2008; Selik, 2014). 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.

Prenatal HIV Screening

The CDC (2006b) and the American College of Obstetricians and Gynecologists (2016e) recommend prenatal HIV screening using an opt-out approach. This means that a 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. Specific state laws concerning screening vary and can be found at: www.cdc.gov/hiv/policies/law/states/testing.html.

Repeat testing during the third trimester, preferably before 36 weeks’ gestation, is considered for all pregnant women. Retesting is recommended for those at risk for acquiring HIV or for women in high-risk areas, namely, those with rates of HIV infection of 1 per 1000 pregnant women screened (Workowski, 2015). At-risk factors include injection drug use, prostitution, a suspected or known HIV-infected sexual partner, multiple sexual partners, or a diagnosis of another STD (American College of Obstetricians and Gynecologists, 2016e).

The initial laboratory screening test for HIV is an antigen/antibody combination immunoassay that detects antibodies against HIV-1 and HIV-2 and detects HIV-1 p24 antigen (Centers for Disease Control and Prevention, 2014). Antibody can be detected in most patients within 1 month of infection, and thus, antibody serotesting may not exclude early infection. Instead, for acute primary HIV infection, identification of viral p24 core antigen or viral RNA is possible. No further testing is required for specimens that are negative on the initial immunoassay unless a known exposure to HIV has occurred.

As shown in Figure 65-7, specimens with a “reactive” (that is, a positive) antigen/antibody combination immunoassay result should be tested with an antibody immunoassay that differentiates HIV-1 antibodies from HIV-2 antibodies. The HIV-1/HIV-2 antibody differentiation immunoassay is resulted as positive or negative for HIV-1 antibodies, for HIV-2 antibodies, or for HIV antibodies, undifferentiated. If these two serial immunoassays are discordant, an HIV-1 NAAT—qualitative or quantitative HIV RNA test—is performed (Centers for Disease Control and Prevention, 2014).

Women with undocumented HIV status at delivery should have a fourth-generation HIV antigen/antibody combination screening test performed on a blood sample. A negative screening test result does not need confirmation. However, in cases of recent HIV exposure, consideration is given to peripartum interventions to reduce perinatal transmission despite negative HIV testing. Repeat interval testing is recommended to exclude very early infection not identified with the initial screen. With a positive fourth-generation HIV testing result, peripartum and neonatal interventions to reduce perinatal transmission are initiated. This includes avoidance of breastfeeding, although breast milk may be stored until confirmatory test results are available. Interventions can be discontinued if confirmatory testing is negative. To confirm a positive result from any initial HIV test, the laboratory testing algorithm in Figure 65-7 should be used and begins with the antigen/antibody combination immunoassay.

Vertical Transmission

Viral burden and neonatal infection rates are directly related. In one cohort, neonatal infection was 1 percent with <400 copies/mL, and it was 23 percent when maternal viral RNA levels were >30,000 copies/mL (Cooper, 2002). Among 2615 infants born to mothers taking ART before conception and during pregnancy, there were no cases of vertical transmission with maternal viral loads <50 copies/mL at delivery (Mandelbrot, 2015). Transmission of HIV infection, however, has been observed at all HIV RNA levels, including those that were nondetectable by current assays. Transplacental HIV transmission can occur early, and the virus has even been identified in specimens from elective abortion (Lewis, 1990). Kourtis and colleagues (2001) estimated that 20 percent of vertical transmission occurs before 36 weeks’ gestation, 50 percent in the days before delivery, and 30 percent intrapartum. Transmission rates for breastfeeding may be as high as 30 to 40 percent and are associated with increasing HIV viral burden (Kourtis, 2006, 2007; Slyker, 2012). In nonpregnant individuals, concomitant STDs and horizontal HIV transmission are linked. Evidence also supports that vertical transmission rates may be increased by comorbid STDs (Schulte, 2001; Watts, 2012).

Antepartum Care

Pregnant women with HIV infection need special attention and are seen in consultation by physicians with special interest in this field. An additional resource is the National Perinatal HIV Hotline (1–888–448–8765), which is a federally funded service that provides free antepartum, intrapartum, or postpartum consultation to providers. At Parkland Hospital, an HIV-infected pregnant woman is initially assessed with the following:

• Standard prenatal laboratory surveys that include serum creatinine, complete blood count, and bacteriuria screening

• Plasma HIV RNA quantification—“viral load”—CD4 T-cell count, and antiretroviral resistance testing

• Serum hepatic aminotransferase levels

• HSV-1 and 2, cytomegalovirus, toxoplasmosis, and hepatitis B and C serological screening

• Baseline chest radiograph

• Tuberculosis testing with purified protein derivative (PPD) skin testing, or interferon-gamma release assay

• Evaluation of need for pneumococcal, hepatitis A, hepatitis B, Tdap, and influenza vaccines

• Sonographic evaluation to establish gestational age.

During pregnancy, the risk of HIV transmission does not appear to be increased with amniocentesis or other invasive diagnostic procedures in women receiving effective ART resulting in viral suppression (Floridia, 2017). For women not receiving ART, the risk rises approximately twofold (Mandelbrot, 1996). If amniocentesis is performed, efforts are taken to avoid passing through the placenta (Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, 2016).

Antiretroviral Therapy

In overview, the ideal strategy to suppress viral load and minimize vertical HIV transmission includes: (1) preconceptional ART, (2) antepartum ART, (3) intrapartum continuation of the antepartum oral ART regimen plus IV zidovudine, and (4) newborn ART prophylaxis. ART is recommended for all HIV-infected pregnant women, and it should be initiated as early in pregnancy as possible. Treatment reduces the risk of perinatal transmission regardless of CD4 T-cell count or HIV RNA level. Adherence is essential because the risk of viral drug resistance is lessened. As for nonpregnant adults, pregnant women are treated with at least three antiviral agents.

The Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission (2016) has issued guidelines for four different scenarios during pregnancy (Table 65-5).

The following paragraphs summarize these recommendations. First, women already taking ART at pregnancy onset are encouraged to continue the regimen if viral suppression is adequate. Didanosine, stavudine, and full-dose ritonavir, which differs from ritonavir-boosted agents, are exceptions due to pregnancy toxicity but not teratogenicity.

Second, women who have never received antiretroviral therapy—antiretroviral naïve—are given ART regardless of trimester. In general, the starting regimen comprises two nucleoside reverse transcriptase inhibitors plus either a ritonavir-boosted protease inhibitor or an integrase inhibitor.

Third, women who have previously received antiretroviral therapy but are currently not taking medications should undergo HIV resistance testing because prior ART use raises their risk of drug resistance. Typically, ART is initiated prior to receiving results of these drug-resistance tests. In this case, initial ART selection should factor results of prior resistance testing, if available; prior ART regimen; and current ART pregnancy guidelines, that is, those for ART-naïve women. Drug-resistance testing may then modify the initial regimen.

For these three categories of women taking antepartum ART, therapy surveillance is outlined in Table 65-5. Most patients with adequate viral response have at least a 1-log viral load decline within 1 to 4 weeks after starting therapy. For those who fail to achieve this decline, options include review of drug resistance study results, confirmation of regimen compliance, and ART modification.

During labor and delivery, oral medications can be taken with sips of water. Additionally, IV zidovudine is given to women with an HIV RNA viral load >1000 copies/mL or who have an unknown viral load near delivery. At Parkland Hospital, we administer intrapartum IV zidovudine to all HIV-positive women, regardless of viral load. A 2 mg/kg load is infused over 1 hour followed by zidovudine 1 mg/kg/hr until delivery. In this instance, for gravidas already taking antepartum oral zidovudine, their oral dose can be held, and IV drug is instead administered. HIV-infected women undergoing a scheduled cesarean delivery are given IV zidovudine as a loading dose followed by 2 more hours of continuous maintenance therapy—a total of 3 hours of infused zidovudine.

The fourth group includes women who present in labor and who are taking no medications. These women are given IV zidovudine intrapartum as just described.

Delivery Planning

During labor, artificial membrane rupture, fetal scalp electrode placement, episiotomy, and operative vaginal delivery are reserved for clear obstetrical indications (Mandelbrot, 1996; Peters, 2016). Labor augmentation is used when needed to shorten the interval to delivery to further lower the transmission risk. Delayed cord clamping in preterm neonates is acceptable. Neuraxial analgesia is suitable. Postpartum hemorrhage is best managed with oxytocin and prostaglandin analogues. Methylergonovine (Methergine) and other ergot alkaloids adversely interact with reverse transcriptase and protease inhibitors to cause severe vasoconstriction.

In some cases, cesarean delivery lowers HIV prenatal transmission (European Mode of Delivery Collaboration, 1999; International Perinatal HIV Group, 1999). The American College of Obstetricians and Gynecologists (2017b) recommends that scheduled cesarean delivery be discussed and recommended for HIV-infected women with HIV-1 RNA loads >1000 copies/mL. Scheduled delivery is recommended at 38 weeks’ gestation in these women to avert spontaneous labor.

For women with HIV RNA levels ≤1000 copies/mL, data are insufficient to predict similar benefits, and scheduled cesarean delivery is unlikely to confer additional risk reduction for women already taking ART and achieving viral suppression (Briand, 2013; Jamieson, 2007; Read, 2005). Vaginal delivery in this group may be elected. However, if cesarean delivery is instead chosen for a well-counseled woman in this group, it should be performed at 39 weeks. Similarly, cesarean delivery performed for obstetrical indications in this lower-viral-load group should be done at 39 weeks when possible.

Postpartum Care

Vertical transmission is increased by breastfeeding, and it generally is not recommended for HIV-positive women in the United States, where formula is readily available (Read, 2003). In nutritionally deprived countries, where infectious disease and malnutrition are primary causes of infant death, the World Health Organization (2016) recommends exclusive breastfeeding during the first 6 to 12 months.

The Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission (2016) strongly recommends that ART regimens not be discontinued postpartum but continued lifelong for the advantages of viral suppression. Ideally, all those planning pregnancy should be receiving ART and have a plasma viral load below detectable levels before conception. As one benefit, interpregnancy viral load suppression is associated with less vertical transmission in a subsequent pregnancy (French, 2014; Mandelbrot, 2015; Stewart, 2014; Townsend, 2014). Reassuringly, for those seeking subsequent pregnancy, when ART is available, repeated pregnancy in a healthy woman with HIV has no significant effect on disease progression (Calvert, 2015). Linkage to general HIV care postpartum is critical to maintain viral suppression (Swain, 2016).

For women who do not have HIV infection, but whose partner is seropositive, current guidance supports the use of highly active antiretroviral therapy with viral suppression in the infected partner (treatment as prevention), and consideration of antiretroviral preexposure prophylaxis (PreP) for the HIV-negative partner. The well-counseled couple can consider periovulatory condomless intercourse, or uterine insemination or in vitro fertilization after sperm washing for assisted conception (Brooks, 2017; Kawwass, 2017).

If, instead, pregnancy is undesired, effective contraception is discussed (Chap. 38, Introduction). Counseling also includes education for decreasing high-risk sexual behaviors to prevent transmission and to decrease other STD acquisition. Similarly, women with HIV have unique gynecological issues, such as genital neoplasia, which require special attention (American College of Obstetricians and Gynecologists, 2016a; Werner, 2016).