Sexually Transmitted Diseases

Pathogenesis

As mentioned previously, the process by which C. albicans evolves from a commensal microorganism to the pathogenic microbe involved in vulvovaginal vaginitis, invasive Candida infections, and disseminated Candida sepsis is poorly understood. Kalo-Klein and Witkin suggested that hormonal status may modulate the immune system, and, as a result, influence the pathogenicity of Candida species. They observed that host responses to C. albicans were decreased in the luteal phase of the menstrual cycle. Giraldo and colleagues reported that a polymorphism in the gene coding for mannose-binding lectin (MBL2), a critical component of the mucosal innate immune system, was more frequently found in women with recurrent VVC than in those with acute VVC or controls.

The pathogenesis of invasive candidiasis is similar to that associated with bacterial microorganisms. Initially, there must be colonization resulting from adhesion of C. albicans to the skin or vaginal mucosa. Colonization is then followed by penetration of epithelial barriers, resulting in locally invasive or widely disseminated disease.

Congenital candidiasis characteristically presents at birth or within the first 24 hours after birth. It usually results from an intrauterine infection or heavy maternal vaginal colonization at the time of labor and delivery. The potential mechanisms for intrauterine Candida infection are similar to those of bacterial intraamniotic infection, including hematogenous spread from mother to fetus, invasion of intact membranes, and ascending infection after rupture of the membranes. ^, The presence of an intrauterine foreign body, most commonly a cerclage suture, is also a recognized risk factor for congenital candidiasis. VVC has not been associated with preterm birth, preterm labor, low birth weight, or prelabor rupture of the membranes (PROM). ^,

Recurrent VVC, defined as four or more episodes of symptomatic VVC within 1 year, occurs in a small percentage of women (<5%). The pathogenesis of recurrent VVC is poorly understood, and the majority of those affected do not have any apparent predisposing or underlying conditions. C. glabrata and other non- albicans Candida species are recovered from 10% to 20% of women with recurrent VVC.

Clinical Presentation And Diagnosis

The clinical manifestations of VVC in pregnancy are similar to those in the nonpregnant state: pruritus, burning, dysuria, dyspareunia, fissures, excoriations with secondary infection, and pruritus ani. The vaginal discharge is usually thick, white, and curdlike (similar to cottage cheese).

The diagnosis of VVC can be made when either (1) a 10% potassium hydroxide (KOH) wet preparation or Gram stain of a vaginal discharge sample demonstrates yeasts or pseudohyphae or (2) a culture is positive for yeast ( Fig. 50.1 ). The vaginal pH in women with VVC is normal (<4.5). Women with a positive KOH wet mount should be treated for VVC. Women who have a negative KOH smear despite clinical signs and symptoms suggestive of VVC should have vaginal cultures for yeast. For patients with recurrent VVC, the laboratory should be requested to identify the species of Candida recovered.

The clinical manifestations of congenital candidiasis range from superficial skin infection and oral infection to severe systemic disease with hemorrhage and necrosis of the heart, lungs, kidneys, and other organs. These severe manifestations are extremely uncommon and would be unlikely to occur in the absence of compromised maternal immunity or extreme neonatal prematurity. The most common route of infection is by direct contact during delivery through an infected vagina. Oropharyngeal candidiasis of the neonate (thrush) is the most frequent manifestation of congenital infection.

Treatment

The regimens recommended by the Centers for Disease Control and Prevention (CDC) for the treatment of VVC are listed in Table 50.1 . Short-course topical formulations (i.e., single-dose and 1- to 3-day regimens) effectively treat uncomplicated VVC, resulting in relief of symptoms and negative cultures in 80% to 90% of patients who complete therapy. Intravaginal preparations of butoconazole, clotrimazole, miconazole, and tioconazole are available over the counter. According to the CDC, women who previously were diagnosed with VVC are not necessarily more likely to accurately diagnose themselves. Therefore women whose symptoms persist after use of an over-the-counter preparation or who have a recurrence of symptoms within 2 months should be assessed with office-based testing.

VVC is not usually acquired through sexual intercourse, so treatment of sex partners is not recommended. Treatment of partners should be considered for women who have recurrent VVC and for male sex partners with balanitis.

The CDC recommends topical azole therapies as the first line of treatment for VVC during pregnancy. These topical medications should be applied for 7 days. For complicated cases of VVC, a longer duration of initial therapy (e.g., 7 to 14 days of topical therapy) is required. Although recurrent VVC can be treated with fluconazole 150-mg oral dose every third day for a total of three doses outside of pregnancy, it should not be used in the first trimester of pregnancy because of potential concern about possible teratogenic effects such as congenital heart defect and cleft lip/palate. ^, Oral fluconazole can be used later in pregnancy as it has not been associated with an increased risk of birth defects after first trimester use. ^,

Clinical Presentation And Diagnosis

Trichomonas vaginalis is a common cause of vaginitis, and the infection is usually characterized by intense pruritus, dysuria, and a malodorous, yellow-green, frothy discharge. However, variations of the gross appearance occur in approximately 50% of cases, and many women show minimal or no symptoms. The diagnosis may be confirmed by saline microscopy demonstrating many leukocytes and trichomonads, which are recognized by their size (slightly larger than leukocytes) and active flagellae ( Fig. 50.2 ). The sensitivity of saline microscopy is only 60% to 70%. Cultures for Trichomonas are more sensitive than saline microscopy, and commercial systems are available to facilitate culture. Several point-of-care diagnostic tests are available—the OSOM Trichomonas Rapid Test (Genzyme Diagnostics, Cambridge, MA) and the Affirm VPIII (Becton Dickinson, San Jose, CA), the Isothermal Helicase-Dependent AmpliVue Assay (Quidel, San Diego, California, USA), the Solana TV-Assay (Quidel), and the GeneXpert TV test (Cepheid, Sunnyvale, CA, USA). The sensitivities and specificities of these tests compared to culture or laboratory PCR testing are provided in Table 50.2 .

Although the Affirm assay has a somewhat lower specificity, the AmpliVue, Solana, and GeneXpert compare favorably with traditional laboratory testing for Trichomonas via wet prep, culture, or laboratory PCR. The OSOM test has the advantage of being cheaper, faster, and easier to perform than other available tests.

The prevalence of T. vaginalis vaginitis in pregnancy ranges from less than 10% to 50%, depending on the population. Consequently, it has been difficult to establish whether the incidence of this vaginal infection truly is increased in pregnant women.

Adverse Effects In Pregnancy

An increased rate of PROM at term has been linked to positive genital tract cultures for T. vaginalis. In the large National Institutes of Health (NIH) infection and prematurity study, T. vaginalis infection at midpregnancy was significantly associated with low birth weight (odds ratio [OR] = 1.3; 95% confidence interval [CI], 1.1 to 1.5), preterm delivery (OR = 1.3; 95% CI, 1.1 to 1.4), and PROM (OR = 1.4, 95% CI, 1.1 to 1.6), even after adjustment for confounding factors and colonization with other microbes. In addition, trichomoniasis has been associated with increased rates of HIV transmission. ^,

Treatment

The recommended treatment for trichomoniasis is oral metronidazole, 2 g in a single dose. An alternative regimen is metronidazole, 500 mg PO twice a day for 7 days. A recent meta-analysis by Howe and Kissinger demonstrated that a multidose regimen was superior to single-dose therapy. The pooled risk ratio for treatment failure was 1.87 (95% CI, 1.23 to 2.82; P < .01) for patients in the single-dose treatment group. No consistent association has been demonstrated between use of metronidazole in pregnancy and teratogenesis or mutagenesis in infants. Tinidazole, another nitroimidazole drug, has been approved by the US Food and Drug Administration for treatment of trichomoniasis (2 g PO in a single dose). However, metronidazole should be favored in pregnant women because of its superior safety profile and decreased cost. Topical agents often are unsuccessful in relieving symptoms or in eradicating this protozoon. As a study of 565 pregnant women found persistent infections after treatments in 44% of patents, a test of cure should be considered.

Among women with asymptomatic trichomoniasis in pregnancy, treatment with metronidazole during the second trimester (two 2.0-g doses 48 hours apart at 16 to 23 weeks, repeated at 24 to 29 weeks) did not result in better pregnancy outcomes than placebo. In fact, patients given metronidazole had a significantly higher frequency of preterm birth. Thus, whereas symptomatic pregnant women with trichomoniasis should be treated to relieve symptoms, routine screening and treatment of asymptomatic patients are not recommended.

Epidemiology And Pathogenesis

This infection was formerly called nonspecific vaginitis, Gardnerella vaginalis vaginitis, or Haemophilus vaginalis vaginitis; “bacterial vaginosis” is now the preferred term. The condition is marked by a major shift in vaginal flora from the normal predominance of lactobacilli to polymicrobial flora. Specific pathogens that have been associated with this condition include G. vaginalis, Mycoplasma, Prevotella, Atopobium, Mobiluncus, Sneathea, Leptotrichia, and BV-associated bacterium 1 (BVAB1) to BVAB3 . There is no consistent pathogen or combination of pathogens that define BV, but rather it is a clinical syndrome characterized by a combination of bacteria with a proinflammatory profile and an altered local immune response.

BV is the most common type of vaginitis. Between 10% and 30% of pregnant women fulfill the criteria for BV, but half of them are asymptomatic.

Diagnosis

Clinically, the principal manifestation of BV is a malodorous, thin, gray discharge. Itching is usually not prominent. The diagnosis of BV is usually established by documenting three of the four Amsel criteria: (1) an amine-like or fishy odor that may be accentuated after addition of KOH or after coitus (owing to the alkaline pH of semen); (2) a thin, homogeneous, gray or white discharge; (3) an elevated pH (>4.5); and (4) clue cells (squamous epithelial cells so heavily stippled with bacteria that their borders are obscured) observed on saline microscopy ( Fig. 50.3 ). Typically, in cases of BV, clue cells account for more than 20% of epithelial cells, and there are few leukocytes. Microscopy and Gram stain also demonstrate a decrease in the number of lactobacilli and an increase in the presence of other bacteria. The AffirmVPIII point-of-care test includes molecular assays for Gardnerella as well as Trichomonas and Candida . The sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 87%, 81%, 4.6, and 0.16, respectively, which provides a slightly worse sensitivity and slightly better specificity than standard Ansel criteria.

Adverse Effects In Pregnancy

Evidence consistently has associated BV with an increased likelihood of preterm delivery, clinical chorioamnionitis, histologic chorioamnionitis, and endometritis. The published OR for preterm delivery in patients with BV has varied from 1.4 to 8.0.

Treatment

Among nonpregnant women, the most consistent cure rates (90%) have been achieved with metronidazole, 500 mg twice a day for 7 days. Lower cure rates (60% to 80%) are observed with a single 2.0-g dose of metronidazole. As such, the single dose regimen is no longer recommended for the treatment of BV. Oral clindamycin, 300 mg twice a day for 7 days, is an effective alternative for patients who are unable to tolerate metronidazole. Vaginal clindamycin cream (2%) and metronidazole vaginal gel (0.75%), used once daily for 5 days, also are effective in nonpregnant women. However, topical therapy is not effective in preventing some of the systematic complications of BV in pregnancy, such as preterm birth, chorioamnionitis, and endometritis. The preferred regimens in pregnancy are shown in Box 50.1 . ^{, , ,}

In view of the consistent association of BV with adverse pregnancy outcomes, clinical treatment trials have been undertaken. Five trials have been conducted in patients who were considered to be at high risk for preterm delivery (i.e., a previous preterm birth or other high-risk demographic features). Three of those studies demonstrated improvement in outcome with prenatal treatment of BV. Morales and colleagues showed that in a group of women who experienced a spontaneous preterm birth due to preterm labor or preterm PROM during a previous pregnancy, treatment of BV with oral metronidazole led to a significant reduction in preterm births, low birth weight, and PROM ( P < .05 for each).

In a prospective, two-phase trial involving 1260 women, McGregor and coworkers demonstrated that treatment of BV significantly decreased the rate of preterm births ( P < .05). Finally, among women at risk because of a previous preterm birth or low maternal weight, Hauth and associates showed that treatment with a combination of metronidazole and erythromycin significantly improved pregnancy outcome compared with placebo in those patients who had BV ( P < .006); in patients without BV, pregnancy outcome was not improved.

Two studies of the impact of treating asymptomatic BV failed to show a benefit of such treatment. ^, In a treatment trial of women at low risk for preterm birth, oral metronidazole (twice daily for 2 days at 24 weeks, with repeat treatment if needed at 29 weeks) led to no reduction in the rate of preterm birth overall but produced a significant reduction in the subgroup of women with a previous preterm birth. In the Maternal-Fetal Medicine Units Network treatment trial of women with asymptomatic BV, the treatment regimen also was short (two 2.0-g doses at 16 to 24 weeks and again at 24 to 30 weeks, with the repeat treatment given at least 14 days after the initial doses). Use of metronidazole in this regimen led to no significant improvement overall or in any subgroup (e.g., women with a previous preterm birth). In view of these disparate results, the American College of Obstetricians and Gynecologists (ACOG) concluded in 2001 that “Currently, there are insufficient data to suggest [that] screening and treating women at either low or high risk will reduce the overall rate of preterm birth.” A Cochrane review of 21 clinical trials showed no benefit to the treatment of BV, even in patients who had a prior preterm birth. In addition, in 2020 the United States Preventive Services Task Force renewed its recommendation from 2008 to not screen asymptomatic women at low risk of preterm birth. It also again determined that the evidence regarding screening asymptomatic women at high risk of preterm birth is insufficient and conflicting, and the balance of benefits and harms cannot be determined.

Recommendations for management of BV in pregnancy are presented in Box 50.2 .

Epidemiology

Gonorrhea, caused by the gram-negative diplococcus Neisseria gonorrhoeae, is probably the oldest known STD. According to the CDC, it is the second most commonly reported communicable disease in the United States. ^, Moreover, the volume of reported cases underestimates the true incidence of the disease. From 1975 through 1997, there was a dramatic decrease of 74% in reported cases of gonorrhea. In 1998, an 8.9% increase occurred, followed by plateauing of the number of reported cases. ^, In 2003, for the first time, the reported gonorrhea rate was higher among women (118.8 per 100,000 population) than among men (113 per 100,000). In 2005, both the number of reported cases and the prevalence rate of gonorrhea increased for the first time in almost a decade, and this number has continued to increase in subsequent years, with slightly more than 800,000 cases reported in 2015 and 1,568,000 in 2018 compared to just over 600,000 in 2005.

In a cross-sectional cohort study, the authors of the National Longitudinal Study of Adolescent Health reported that the overall prevalence of gonorrhea in the United States was 0.43% (CI, 0.29% to 0.63%). The prevalence of gonorrhea in pregnancy ranges from 0% to 10%, with marked variations according to risk status and geographic locale.

A number of risk factors for gonorrhea among sexually active women have been identified. Young age is the greatest risk factor, with sexually active women younger than 25 years of age being at highest risk for gonorrhea infection. Other risk factors include previous gonococcal infection, presence of other STDs, multiple sex partners, new sex partners, inconsistent condom use, drug use, and commercial sex work. Non-White race, low socioeconomic status, inner-city dwelling, and unmarried status are additional risk factors for infection.

Pathogenesis

Transmission of N. gonorrhoeae occurs almost solely by sexual contact, and the risk of transmission from an infected male to a female partner is 50% to 90% with a single exposure. The incubation period is 3 to 5 days.

Infection with N. gonorrhoeae in pregnancy is a major concern. Although gonococcal ophthalmia neonatorum has been recognized since the late 19th century as a significant consequence of maternal infection with N. gonorrhoeae, it is only in the last 50 years that associations have been recognized between maternal infection with N. gonorrhoeae and disseminated gonococcal infection (DGI), amniotic infection syndrome, preterm PROM, chorioamnionitis, preterm birth, fetal growth restriction, neonatal sepsis, and postpartum endometritis.

Adherence of N. gonorrhoeae to the mucosal epithelium of the genital tract is the initial step in the pathogenesis of gonococcal infection. Attachment of N. gonorrhoeae is mediated by pili and other surface proteins (e.g., porin protein, opacity-associated proteins, reduction-modifiable protein). Lipopolysaccharides, immunoglobulin A, and iron-repressible proteins are additional gonococcal virulence factors. Once N. gonorrhoeae attaches to mucosal cells, it enters the cell via endocytosis. Subsequently, the organism releases endotoxin, resulting in widespread cell damage.

Clinical Manifestations