Key Abbreviations
By mouth (per os) PO
Centers for Disease Control and Prevention CDC
Central nervous system CNS
Cerebrospinal fluid CSF
Direct fluorescence assay DFA
Elementary body EB
Enzyme immunoassay EIA
Human immunodeficiency virus HIV
Human papillomavirus HPV
Institute of Medicine IOM
Intramuscularly IM
Intravenously IV
Lipopolysaccharide LPS
Major outer membrane protein MOMP
Morbidity and Mortality Weekly Report MMWR
Nucleic acid amplification test NAAT
Polymerase chain reaction PCR
Rapid plasma reagin RPR
Reticulate body RB
Ribonucleic acid RNA
Sexually transmitted disease STD
Venereal disease research laboratory VDRL
World Health Organization WHO
Maternal and perinatal infections represent common complications of the peripartum interval. In many industrialized nations, the role of sexually transmitted pathogens is declining in its relative contribution to infections in women; however, in the United States and developing nations, the epidemic persists. Many of these pathogens are either proved or presumed to play an integral role in infectious morbidities of pregnancy and the neonatal period, and thus understanding the social, economic, and pathophysiologic burden is essential. Indeed, as our ability to readily screen the population as a whole has improved for the most prevalent or serious of these infectious agents— Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum —epidemiologic statistics have provided evidence for their implied role in preterm labor, preterm premature rupture of the membranes, intrauterine growth restriction, neonatal conjunctivitis, neonatal pneumonia, and congenital syphilis. Thus a greater understanding of the role of these prevalent pathogens in mediating disease pathogenesis has mandated that the obstetrician be well versed in the identification and management of these organisms. In this chapter, we review current trends in epidemiology, diagnosis, treatment, and prevention of common sexually transmitted infections.
Chlamydia
Epidemiology
The two most valuable sources of incidence and prevalence data on sexually transmitted pathogens are provided by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). The CDC reports sexually transmitted disease (STD) estimates for the United States using reported cases and estimates after accounting for underreporting. The Institute of Medicine (IOM) provides WHO estimates on worldwide incidences and prevalence of the four curable sexually transmitted infections: Chlamydia, gonorrhea, syphilis, and Trichomonas . Overall, the WHO 2008 global estimate places the incidence at 105.7 million new cases of chlamydia infection, 106.1 million new cases of gonorrhea, and 10.6 million new cases of syphilis among people aged 15 to 49 years. In addition, epidemiologic studies have revealed a number of basic principles regarding STDs: (1) sexually active adolescents have the highest rates of STDs of any age group ; (2) sex differences are observed in the transmission of the most prevalent STDs, with more efficient transmission from men to women; (3) curable STDs (i.e., not human immunodeficiency virus [HIV], human papillomavirus [HPV], or chronic recurrent herpes simplex virus [HSV]) are associated with more serious long-term consequences in women than in men; (4) having one or more STDs predisposes an individual to acquisition and transmission of other STDs; (5) STDs in developing nations are often constantly prevalent at a high rate and affect all age groups; and (6) marked racial disparity is apparent.
Genital tract chlamydial infections are generally ascribed to C. trachomatis and account for the most prevalent reported infectious disease in the United States. In 2013, more than 1.4 million cases were reported to the CDC. However, the actual presumed number of new cases in the United States, accounting for estimates of underreporting, is estimated at 3 million annually. These infections present unique problems for public health control programs because 50% to 70% of these infections are clinically silent in women. Unrecognized and untreated, the bacteria may remain infectious in the host for months and is readily transmitted to sex partners. Furthermore, most reported infections occur in the 15- to 24-year-old age group, individuals who often do not participate in preventive health care programs. Estimates on worldwide exposure approximate that 90 million new cases of C. trachomatis infection occur on an annual basis, which accounts for a rising majority of perinatal and neonatal complications. Of note, a primary goal of the Healthy People 2010 U.S. health promotion initiative is the elimination of racial disparities among multiple sexually transmitted pathogens. An assessment of the racial disparities of nationally notifiable disease for the year 2002 revealed a nearly tenfold increased rate for Chlamydia in blacks compared with whites (805.9 vs. 90.2 per 100,000). In 2013, the rate of Chlamydia remained 6.4 times higher among blacks compared with whites, although the rate in whites doubled in that same span of time (1147.2 vs. 180.3 per 100,000).
The cost of treatment, prevention, and management of complications of chlamydial infections is estimated at $2.4 billion annually. Taken together, these factors have resulted in the endorsement of a nationwide broad-based screening program by both the CDC and IOM.
Pathogenesis
Chlamydia is a sexually transmitted pathogen generally associated with endocervical infection. Species of Chlamydia were initially serotyped according to their biologic and biochemical properties, and a greater than 95% homology in their 16s ribosomal ribonucleic acid (RNA) sequences was observed. Subsequent molecular analyses led to the reclassification of some C. psittaci strains as C. pneumoniae, a human pathogen, and C. pecorum, a pathogen of ruminants. Nevertheless, of the four species mentioned here, only C. trachomatis and C. pneumoniae claim primates as their endogenous hosts. Each of the species bears multiple strains based on serotype, which in turn are associated with distinct clinical entities. These are summarized in Table 52-1 .
| SPECIES SEROTYPE | ACUTE DISEASES | CLINICAL SEQUELAE |
|---|---|---|
| Chlamydia trachomatis | Conjunctivitis, acute urethral syndrome, cervicitis, endometritis, salpingitis, inclusion conjunctivitis, neonatal pneumonia | Trachoma, proctitis, epididymitis, Reiter syndrome, pelvic inflammatory disease, ectopic pregnancy, tubal infertility, Fitz-Hugh–Curtis syndrome |
| A, B, Ba, C D-K | ||
| L1, L2, L3 | Lymphogranuloma venereum | Reactive airway disease |
| Chlamydia pneumoniae | Pharyngitis, sinusitis, bronchitis, community-acquired pneumonia | Infection is often asymptomatic or mild with only rare life-threatening infection |
| Chlamydia psittaci | Atypical pneumonia, conjunctivitis | Spontaneous abortion |
| Parrots, cats, ewes |
Chlamydiae are obligate intracellular bacteria that grow in eukaryotic epithelial cells, and they have a unique growth cycle, distinct from all other pathogens. During the 1970s, the infectivity and growth cycle of chlamydiae was initially characterized. Known to specifically infect the cuboidal or nonciliated columnar epithelial cells common to the endocervix, urethra, and conjunctiva, this growth cycle involves infection of a susceptible host cell through a receptor-specific phagocytic process. This phagocytic process involves chlamydiae elementary bodies (EBs) that bind to the host cell through a heparin sulfate–like molecule to glycosaminoglycan receptors, and these subsequently are phagocytosed into cytoplasmic vacuoles termed phagosomes . In this fashion, chlamydiae may be considered to have a unique biphasic life cycle with dimorphic forms that are functionally and morphologically distinct. Once endocytosed, the EB differentiates into a larger pleomorphic form called the reticulate body (RB), which replicates by binary fission. The chlamydiae remain in the phagosome throughout their growth cycle, presumptively as an acquired means of escaping host lysosomes. The endosome is transported to the distal region of the Golgi apparatus and incorporates host-derived sphingolipids into the inclusion membrane. Thus it appears that chlamydiae are able to intercept host vesicular traffic bound for the plasma membrane to sequester lipids and possibly other host substances synthesized in the Golgi. Subversion of host vesicular traffic may represent a dual advantage for chlamydiae in obtaining materials from the host for its metabolism as well as in modifying the inclusion membrane to evade lysosomal fusion and immune detection.
Because chlamydiae depend on their host cell for the generation of adenosine triphosphate (ATP), they require viable cells for survival. Chlamydiae are incapable of de novo nucleotide biosynthesis and thus are dependent on host nucleotide pools. In this manner, this unique pathogen may be considered to be viruslike. On the other hand, chlamydiae resemble a bacterial pathogen in that they contain both DNA and RNA; have a modified rigid cell wall with a lipopolysaccharide (LPS) similar to that in the outer membrane of gram-negative bacteria, albeit lacking the intervening peptidoglycan layer; and multiply by binary fission.
Some interesting insights into the interaction of chlamydiae and the host immune system have emerged in the past decade. These new observations include the extensive but unexpected polymorphism of the major outer membrane protein (MOMP), the evidence for genetic susceptibility to disease, and the association of antibody response to the 60-kDa heat shock protein CHSP60 with the development of adverse sequelae following ocular and genital infections. By way of summary, MOMP is a major target for protective host immune responses, such as neutralizing antibodies and possibly protective T-cell responses. The basis for MOMP antigenic variation is allelic polymorphism at the omp-1 locus, and immune selection appears to be occurring in host populations frequently exposed to C. trachomatis. Combined with the observations that clear genetic susceptibility to disease is apparent, because only a subset of infected individuals appear to have long-term complications after acute or repeated chlamydial infections, it is now believed that chronic immune activation plays a role in propagating clinical disease. Thus susceptibility to chlamydial pelvic inflammatory disease (PID) in a study of sex workers in Nairobi, Kenya has been associated with a human leukocyte antigen (HLA) class I allele, HLA-A31. Similarly, allelic variation in the class II allele (DQ) have been shown to be positively associated with C. trachomatis tubal infertility.
In addition to host genotype playing a role in determining the severity of Chlamydia -mediated disease, aberrations in humoral immunity also appear to modulate clinical disease . Antibody response to a 57-kDa chlamydial protein was initially observed more frequently in women with tubal infertility than in controls. This protein was subsequently identified as a heat shock protein (HSP) of the GroEL family of stress proteins. The association between antibody response to CHSP60 and PID, ectopic pregnancy, tubal infertility, and trachoma has been subsequently observed in a number of population-based serotype studies. Suffice it to say that although it remains unclear whether antibody to CHSP60 is causally involved in chlamydial immunopathogenesis or is merely a marker of persistent chlamydial infection, in cells that remain infected with C. trachomatis, the constitutive expression of CHSP60 may provide continued antigenic stimulation for the CHSP60 antibody response observed in persons with long-term sequelae. Moreover, observed immunopathology may also result from aberrations in self-tolerance mediated by shared and similar epitopes between CHSP60 and endogenous HSP60, which in turn results in a classic immune cascade that leads to tissue damage.
Diagnosis
Because curative antibiotic therapies for chlamydial infections are available and inexpensive, early diagnosis is an essential component of management and prevention. Historically, isolation of Chlamydia in cell culture was the traditional method for laboratory diagnosis, and it has remained the gold standard because of its specificity. However, culture requires expensive equipment, technical expertise, and stringent transport conditions to preserve specimen viability. Thus chlamydial culture has been replaced by nucleic acid amplification tests (NAATs), which are currently recommended for screening for urogenital C. trachomatis in men and women, regardless of symptoms. The common characteristic among NAATs is that they are designed to amplify nucleic acid sequences that are specific for the organism being detected and thus do not require viable organisms. The increased sensitivity of NAATs is attributable to their ability to produce a positive signal from as little as a single copy of the target DNA or RNA. NAATs can be utilized to test for C. trachomatis in endocervical swabs from women, urethral swabs from men, first-catch urine from both men and women, and vaginal swabs from women. The ability of NAATs to detect C. trachomatis without a pelvic examination is a key advantage of NAATs, and this ability facilitates screening men and women in nontraditional screening venues. Although false-positive and false-negative results can occur, the performance of NAATs for testing for C. trachomatis is superior to both culture and other nonculture tests. The sensitivity of NAATs is generally greater than 90%, and specificity is greater than 99%. Given the performance of the NAATs, supplemental testing of NAAT-positive specimens is no longer recommended by the CDC. An additional consideration when using NAATs for detection of C. trachomatis is that they are not approved by the Food and Drug Administration (FDA) for test of cure because nucleic acid may remain from noninfective bacteria following treatment for up to 3 weeks after infection with C. trachomatis .
Other antigen-detection methods—such as enzyme immunoassay (EIA), direct fluorescence assay (DFA), nucleic acid hybridization/probe tests, and nucleic acid genetic transformation tests—are also available but are generally not recommended for routine testing for genital tract specimens. Additionally, serology screening has limited or no value in testing for uncomplicated genital C. trachomatis infection and should not be used for screening because previous chlamydial infection frequently elicits long-lasting antibodies that cannot be easily distinguished from the antibodies produced in a current infection. Table 52-2 summarizes the screening recommendations for C. trachomatis in pregnancy.
| When to screen |
|
| How to screen |
|
| Diagnostic criteria |
|
* Cell culture, direct immunfluorescence, enzyme immunosorbent assay, and nucleic acid hybridization of endocervical specimens are also available.
Treatment
The recommended treatment regimen for uncomplicated genital Chlamydia infection has remained largely unchanged since 1998, with the exception of amoxicillin now being considered an alternative regimen due to treatment failures in response to penicillin-class antibiotics in vitro and in animal studies. In pregnancy, the CDC recommends azithromycin in a single 1-g oral dose ( Box 52-1 ). Amoxicillin 500 mg orally three times daily for 7 days and various erythromycin formulations are also available with dosing that can be utilized as an alternative regimen (see Box 52-1 ). Doxycycline, ofloxacin, and levofloxacin are part of the treatment options in a nonpregnant patient; however, they are contraindicated in pregnancy and should not be used in this population. To minimize transmission and reinfection, patients should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen and should also be instructed to abstain from sexual intercourse until all of their sex partners have been treated for the same duration. A repeat chlamydial test should be performed 3 to 4 weeks after treatment is completed. Longitudinal studies of Chlamydia -infected adolescent female patients have demonstrated a high risk for Chlamydia reinfection and for other STD infections within a few months of initial diagnosis. Because of the high incidence of Chlamydia infection that can occur in the months following a treated infection, CDC guidelines recommend that health care providers repeat testing 3 months after infection. Additionally, women under the age of 25 and patients at high risk for Chlamydia infection should be retested in the third trimester of pregnancy. In addition to treating the pregnant woman, any sex partners within the preceding 60 days of diagnosis—or the most recent sex partner, if that has been longer than 60 days—should be evaluated and treated to help reduce the rate of reinfection as well as infection of others.
* The Centers for Disease Control and Prevention recommends treating individuals with a positive Chlamydia -sensitive nucleic acid amplification test (NAAT). Although tetracycline and doxycycline have the greatest activity against C. trachomatis, these drugs should not be used in pregnancy because of their effects on bone and on dental enamel of the developing fetus (see Chapter 8 ). Owing to gastrointestinal side effects with erythromycin, azithromycin is the drug of choice in pregnancy.
for Chlamydia trachomatis Infections in Pregnancy †† Sex partners within the preceding 60 days of diagnosis or the most recent sex partner, if that has been longer than 60 days, should be evaluated and treated also.
Recommended Regimen †
Azithromycin, 1 g orally in a single dose
Alternative Regimens
Amoxicillin 500 mg orally three times a day for 7 days or
Erythromycin base, 500 mg orally four times a day for 7 days or
Erythromycin base, 250 mg orally four times a day for 14 days or
Erythromycin ethylsuccinate, 800 mg orally four times a day for 7 days or
Erythromycin ethylsuccinate, 400 mg orally four times a day for 14 days
Gonorrhea
Epidemiology
The reported incidence of Neisseria gonorrhoeae infection was 333,004 cases in the United States in 2013 (106.1 cases per 100,000). However, the actual number of reported cases may be underrepresented by as much as 40%, yielding a U.S. estimate of 700,000 cases annually. In contrast to Chlamydia, the worldwide prevalence of gonorrhea may be significantly less than that observed in the United States, as supported by epidemiologic data from Canada and Western Europe.
Historically, a review of trends in the incidence of reported gonorrhea in the United States from 1941 to 1997 reveals peak increases among both men and women in the interval around World War II and again in 1975, peaking at 473 cases per 100,000. The steady decline since 1975 has been accompanied by three interesting observations. First, the male-to-female ratio of reported cases not only declined from a high of 3 : 1, it changed to a female prevalence in 2013, by a ratio of 1 : 2. Second, racial disparity is noted, with a 12.4-fold higher rate among blacks compared with whites (426.6 vs. 34.5 per 100,000). Third, the single greatest determinant of gonorrhea incidence since 1975 has so far been age: annual reported cases are highest in adolescents aged 15 to 19 years (459.2 per 100,000) and in young adults aged 20 to 24 years (541.6 per 100,000).
Pathogenesis
In contrast to chlamydiae species, the pathogenesis of N. gonorrhoeae and human disease is more straightforward and reflects classic bacterial pathogenesis. N. gonorrhoeae is a gram-negative diplococcus for which humans are the only natural host. Like the other endocervical infectious pathogens, gonorrhea also bears a predilection for the columnar epithelium, which lines the mucous membranes of the anogenital tract. Gonococcal pathogens adhere to these mucosal cells through attachment of pili and other surface proteins, which results in the release of lipopolysaccharide and likely instigates mucosal damage. Following adherence, N. gonorrhoeae is pinocytosed and is thereby transported into epithelial cells. Unlike chlamydiae, the gonococcus does not replicate in the phagosome, and hence it evades lysosomal degradation. Rather gonococci persist in the host by virtue of their ability to alter the host environment. In sum, multiple structures of N. gonorrhoeae enable pathogenesis by a variety of immune-evasive mechanisms that include immunoglobulin A (IgA) protease, iron repression, and cell-adherence mechanisms.
Diagnosis
The gold standard for diagnosis of gonorrhea infection was previously isolation of the organism by culture. Traditionally, specimens are streaked on a selective (Thayer-Martin or Martin-Lewis) or nonselective (chocolate agar) medium. Inoculated media are incubated at 35° to 36.5° C in an atmosphere supplemented with 5% CO 2 and are evaluated at 24 and 48 hours. Subsequent diagnosis is made by identification of the organism with growth on the medium, with a Gram stain and oxidase test on colonies identifying Gram-negative, oxidase-positive diplococci morphology. A confirmed laboratory diagnosis of N. gonorrhoeae cannot be made on the basis of these tests alone. However, antimicrobial therapy should be initiated following an initial presumptive test result, but additional tests must be performed to confirm the identity of an isolate as N. gonorrhoeae. Whereas culture isolation is also suitable for non–genital tract specimens, using selective media is necessary if the anatomic source of the specimen normally contains other bacterial species.
The advantages of gonorrheal culture are high sensitivity and specificity, low cost, suitability for use with different types of specimens, and the ability to retain the isolate for additional testing. The major disadvantage of culture for N. gonorrhoeae is that specimens must be transported under conditions adequate to maintain the viability of organisms. Another disadvantage is that a minimum of 24 to 48 hours is required from specimen collection to the report of a presumptive culture result. Due to the technical difficulties with culture, other nonculture tests were developed. However, the importance of maintaining the option of culture remains important for N. gonorrhoeae . Indications for culture for N. gonorrhoeae include testing in suspected cases of treatment failure, monitoring antibiotic resistance, and testing in cases of suspected extragenital infection and exposure due to sexual abuse.
As with C. trachomatis , the current recommended test for routine screening for N. gonorrhoeae is NAATs regardless of symptoms. NAATs can be utilized to test for N. gonorrhoeae in endocervical swabs from women, urethral swabs from men, first-catch urine from both men and women, and vaginal swabs from women. The ability of NAATs to detect N. gonorrhoeae without a pelvic examination is a key advantage of NAATs, and this ability facilitates screening men and women in nontraditional screening venues. Whereas false-positive and false-negative results can occur, the performance of NAATs for testing for N. gonorrhoeae is superior to both culture and other nonculture tests. The sensitivity of NAATs is generally greater than 90%, and specificity is greater than 99%. Given the performance of NAATs, supplemental testing of NAAT-positive specimens is no longer recommended by the CDC. An additional consideration when using NAATs for detection of N. gonorrhoeae is that they are not FDA approved for test of cure because nucleic acid may remain from noninfective bacteria following treatment for up to 2 weeks.
Additional tests have been studied for N. gonorrhoeae testing. Nucleic acid hybridization assays are available to detect N. gonorrhoeae , although they are not recommended for routine use and are no longer routinely available. A large number of EIA tests for detecting N. gonorrhoeae infection have been studied, but their performance and cost characteristics for N. gonorrhoeae infection have not made them competitive with other available tests. Similar to EIAs, DFA is also not appropriate as a diagnostic test for the direct detection of N. gonorrhoeae in clinical specimens. A serologic screening or diagnostic assay is not available for N. gonorrhoeae. Table 52-3 reviews the recommended screening for N. gonorrhoeae in infections in pregnancy.
