Sexually Transmitted Diseases in Pregnancy

The sexually transmitted diseases (STDs) represent interesting and frustrating challenges. The range of their clinical manifestations extends from being totally asymptomatic to being fatal. Between these two extremes, the STDs can be responsible for minor discomforts as well as considerable physical and emotional pain. Some can affect every organ system, producing irreversible damage. For some there is no cure; for most there is a lack of adequate epidemiologic control.  As pointed out by the Institute of Medicine, STDs are "public health problems that lack easy solutions because they are rooted in human behavior and fundamental societal problems."¹

As their classification indicates, all of the STDs can be transmitted through sexual contact. However, the significance of the role of direct sexual contact and the long-term medical and psychological consequences vary considerably among the diseases. Based on incidence and relative importance during pregnancy, four STDs are discussed in this chapter: syphilis, gonorrhea, herpes, and chlamydia.

Although the incidence of syphilis decreased markedly with the discovery of antibiotics, it nevertheless remains a formidable foe. On the one hand, there are several reasons why one would expect the incidence to continue to decrease: (1) the clinical manifestations of primary and secondary syphilis have remained unchanged since their original description, (2) a better-informed, health-conscious public is more likely to seek early treatment for suspicious lesions, (3) the stigma of syphilis is considerably less in today's society, and (4) recommended screening programs can identify patients at earlier, treatable stages of disease. On the other hand, the disease persists, which some claim is due to changing sexual attitudes and the increased use of antibiotics, corticosteroids, and immunosuppressants, resulting in atypical presentations of the disease.²

Syphilis remains one of medicine's challenges. The causative agent, the spirochete Treponema pallidum, has failed to develop any significant resistance to penicillin. Under such circumstances one would expect the incidence of the disease to fall to progressively lower levels until reaching an irreducible minimum or being eradicated. Such has not been the case.

Since reporting began in 1941, incidence rates for syphilis have demonstrated interesting trends with significant variations based upon gender, geography, age, and race/ethnicity.  Following record-breaking single-year increases in incidence in the late 80s, the rate of primary and secondary (P & S) syphilis decreased 89.7% in the 90s, reaching its lowest reported incidence in 2000.  Between 2001 and 2006 the rate of P & S syphilis again increased, primarily due to increases in males, specifically men who have sex with men (MSM). In 2006 the rate of syphilis in males was 5.7 times that in females and MSM accounted for 64% of cases reported that year.³

Incidence rates for congenital syphilis generally mirror those of rates for women, with a 1- to 2-year lag. Thus, after 14 years of decline, the rate of congenital syphilis increased 3.7% between 2005 and 2006. Overall, however, there has been a 74% reduction in the rate of congenital syphilis since 1996, likely due to improved prenatal screening.³

Clinical Manifestations

Primary syphilis is characterized by the classic hunterian chancre, a painless ulcer that can develop 10–90 days after exposure (average 21 days). Treponema pallidum has a propensity for moist areas and so is likely to be found wherever mucous membranes are a frequent site of sexual contact, principally the genital canal, the anorectal area, and the oropharynx. If untreated, the chancre will usually heal in 3–6 weeks and occasionally will leave a scar.

Secondary syphilis appears 3 weeks to 6 months after the primary lesion. The systemic nature of the disease is much more obvious in the secondary stage. In addition to constitutional symptoms, such as malaise and low-grade fever, patients may demonstrate one of several varieties of nonpruritic rashes, lymphadenitis, mucous patches, condylomata lata, neurologic involvement, alopecia, or (less frequently) involvement of bone, liver, spleen, or kidneys.

Latent syphilis – the hidden stage – is sometimes broken down into early latent (the first year after infection) and late latent (>1 year after infection). During this stage the symptoms of P & S disease disappear although serologic tests remain positive and pregnant women may infect their developing fetuses.

Late syphilis – also known as tertiary syphilis or neurosyphilis – can appear 3–20 years after the primary infection in 15–20% of untreated patients.⁴  With the widespread use of antibiotics, this late stage of syphilis has become very uncommon and is not discussed in this chapter.

Implications for Pregnancy

The clinical manifestations of primary and secondary syphilis are the same in the pregnant patient as in the nonpregnant. The principles of management have to do with early diagnosis and treatment in an effort to prevent fetal infection. It was once believed that the spirochetal organism could not cross the placenta prior to 16 week's gestation. Harter and Benirschke reviewed the studies on which this theory was based, posed some possible explanations for the inability of earlier investigators to detect the spirochete in early abortuses, and reported finding T. pallidum in abortion specimens as early as 9 and 10 weeks' gestation.⁵ Spence states that T. pallidum can cross the placenta as early as 6 weeks.⁶

The fetus may escape infection. This is more likely to happen if the mother has been infected for a long time or if she contracts the disease very late in pregnancy. This information is of academic interest only, because once the diagnosis of syphilis in pregnancy is confirmed, the patient should be treated regardless of the time since infection.

Congenital syphilis – a potentially eradicable disease – persists due to treatment failures, lack of prenatal care, and inadequate prenatal screening. A report by McKown and Kapernick⁷ demonstrated the need for repeat screening in late pregnancy. They found that 37% of 73 women with syphilis in pregnancy failed to receive antepartum treatment because they developed the disease following an initial negative prenatal screening test. The American College of Obstetricians and Gynecologists and the American Academy of Pediatrics recommend that women at high risk for syphilis, or who live in areas of high prevalence, should be retested early in the third trimester.⁸

The clinical manifestations of congenital syphilis depend on the severity of the infection and the gestational age at the time of exposure. The organism has been shown to cross the placenta in the first trimester, and has been associated with first-trimester losses, particularly early first-trimester losses. Late pregnancy complications are well recognized, and intrauterine infection can result in premature labor, intrauterine growth restriction, still-birth, or neonatal death.

Signs and symptoms of early congenital syphilis will appear within the first 2 years of life. Although most affected children will develop syphilitic rhinitis (“snuffles”) and perhaps a rash, numerous other organ systems may be involved, not unlike the adult secondary stage of the disease. By definition, late congenital syphilis appears in children after the age of 2 years. The clinical presentation can vary from patients who are totally asymptomatic to those who exhibit any combination of the following: Hutchinson's triad (interstitial keratitis, eighth nerve deafness, Hutchinson's teeth), saddle nose, prominent frontal bones, rhagades, gumma formation, and other complications of the skeletal and central nervous systems.

Diagnosis

All pregnant patients should be screened for syphilis when they initiate prenatal care. Patients at high risk for developing syphilis should be rescreened in the third trimester, including such patients as those with multiple partners (if known), those with suspicious lesions, victims of sexual assault, and patients who have had sexual contact with persons known to have the disease. It is also recommended that the infant's cord blood be tested for syphilis whenever the mother's serologic status is unknown.

Aside from clinically suspicious signs and symptoms, three laboratory tests are commonly used to assist in the diagnosis and treatment of syphilis.

Darkfield microscopy permits direct visualization of the living spirochete and can accurately diagnose syphilis when interpreted by a qualified person; other treponemes, particularly those found in the oral cavity, can strongly resemble T. pallidum. Another limitation of the darkfield examination is that its usefulness is restricted to those stages of the disease during which an active, accessible lesion is present.  Fluorescent antibody stains can also identify the organism but their usefulness is likewise limited by the need for specialized equipment and technicians trained in the technique.

Nontreponemal serum tests (e.g., VDRL and rapid plasma reagin, or RPR) are relatively inexpensive, fairly sensitive tests that are widely used to screen general populations. These tests detect reagin, and biologic false-positive reactions can be associated with numerous acute and chronic infections, autoimmune diseases, debilitated states, and pregnancy. These tests generally will not become positive until at least 1–2 weeks after the appearance of the primary chancre (i.e., several weeks after infection) and thus may be negative in the primary stage of disease.

Interpretation of serologic tests for syphilis in the neonate requires a basic understanding of the antigen–antibody response. For example, a negative serology in a newborn does not necessarily indicate that the child has escaped infection; the fetus may have been infected too late in the prenatal period to induce an antibody response prior to the date of birth. Therefore, if maternal history or clinical findings place the infant at risk for developing congenital syphilis and the initial screening test is negative, the serologic test should be repeated monthly for 6 months.

Conversely, a positive neonatal serology does not mean that the infant has congenital syphilis. The antibody may have been passively transferred from the mother; if this is the case, the neonatal titer should not be greater than the maternal titer, and it should be completely cleared from the infant's circulation in a few weeks. Newborn infection should be seriously considered if the infant's titer is greater than the mother's, if the infant's titer continues to rise, or if the infant has IgM antibodies.

Treponemal antibody tests – fluorescent treponemal antibody absorption (FTA-ABS), Treponema pallidum immobilization (TPI), treponemal hemagglutination (TPHA), and enzyme-linked immunosorbent assay (ELISA) – while not specific for T. pallidum, can distinguish between treponemal disease and the biologic false-positives mentioned earlier. Thus, patients with a positive nontreponemal screening test should be further evaluated with one of these more specific tests to help confirm the diagnosis. The FTA-ABS is the most commonly used of these tests and is the first of all the serologic tests to turn positive. Once positive, however, the specific treponemal antibody tests remain positive indefinitely, regardless of treatment, and are therefore not good parameters on which to base a therapeutic response.

Treatment

Once the diagnosis of syphilis in pregnancy is confirmed (or if the diagnosis cannot be excluded), the patient should be treated according to the stage of the disease. A summary of treatment guidelines currently recommended by the Centers for Disease Control (CDC) are as follows (complete guidelines can be found at www.cdc.gov/std/treatment): ⁹

Primary, secondary, or early latent syphilis (less than 1 year's duration) should receive a single intramuscular injection of 2.4 million units of benzathine penicillin G. If allergic to penicillin, patients should receive erythromycin (base or stearate), 500 mg orally four times a day for 15 days (except pregnant patients – see below).

Syphilis of more than 1 year's duration (except neurosyphilis) should be treated with 2.4 million units of benzathine penicillin G intramuscularly once a week for three successive weeks (7.2 million units total).

Pregnant patients who are allergic to penicillin deserve special attention. Although doxycycline and tetracycline are acceptable alternatives for the nonpregnant patient, they should not be used in pregnancy.  Likewise erythromycin is not an acceptable alternative since it is not as effective as penicillin and does not cross the placenta in sufficient concentrations. The 2006 CDC Guidelines state that "pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin."⁹

The CDC guidelines should be followed for treatment of congenital syphilis and neurosyphilis, including recommendations for spinal fluid examinations.

Patients who can provide documentation of adequate prior treatment do not need to be retreated unless clinically or serologically they appear to have been reinfected.

All patients who have been treated for syphilis should have a VDRL test repeated at 3, 6, and 12 months following therapy and should demonstrate at least a fourfold decrease in titer during the first year. If adequately treated, most patients will eventually become serologically negative or will maintain a very low titer.

Unusual serologic responses have been noted in persons co-infected with both syphilis and HIV.  In addition, HIV-positive patients who have early syphilis might be at increased risk for neurologic complications and higher rates of treatment failures.  Thus, HIV-positive patients who are being treated for syphilis should be closely monitored for therapeutic response.

Gonorrhea is the second most commonly reported notifiable disease in the United States. Following a dramatic 74% decline in the national rate between 1975 and 1997, the rate of gonorrhea plateaued for several years before increasing again in 2005.  The rate increased for the second consecutive year in 2006 with over 358,000 reported cases, a 5.5% increase over the previous year.  Although rates of gonorrhea are essentially similar for men and women, rates for women have been slightly higher than men for the past 6 years. Rates have increased in all regions of the country except the Northeast, and only four states and Puerto Rico had 2006 rates below the HP 2010 target of 19/100,000 population.  Rates continue to be highest among adolescents and young adults, and the disparity reported in African Americans is a particular concern (2006 rates were 18 times greater in African Americans than in whites).³  The continued increase in quinolone-resistant Neisseria gonorrhoeae (QRNG) resulted in a major change in national treatment guidelines (see below under treatment).

With respect to the female genital tract, gonorrhea is perhaps the most destructive of the venereal diseases. It may be totally asymptomatic, allowing its victim to unknowingly infect others; it may also produce severe, debilitating pelvic inflammatory disease (PID), tubo-ovarian abscesses, and tubal occlusion, resulting in sterility. Thus, untreated disease can cause significant long-term psychological sequelae, as well as chronic pelvic pain.

Contrary to the syphilis spirochete, which has remained susceptible to penicillin, N. gonorrhoeae has a long history of developing resistant strains. The first case of penicillinase-producing Neisseria gonorrhoeae (PPNG) in the United States was reported in 1976 and by 1980 the annual incidence had risen to approximately 1000. By 1987 over 25,000 cases of resistant strains were reported, representing 3.2% of the total cases. In addition to PPNG, other resistant strains have surfaced – chromosomally mediated resistant strains (CMRNG) first identified in 1983, followed by tetracycline resistant forms in 1985.¹⁰  The QRNG, first identified as a problem in Asia and Hawaii in 1991, started to be more prevalent in 1999, spreading first to California and other western states, then to MSM, and more recently to other populations and regions, prompting the CDC in 2007 to remove the fluoroquinolones as a treatment option for gonococcal disease.¹¹

Clinical Manifestations

As mentioned earlier, in women the disease may be completely asymptomatic or minimally symptomatic by producing dysuria or a vaginal discharge. The clinical picture depends on the site and severity of the infection. The causative organism, N. gonorrhoeae, primarily infects columnar and pseudostratified epithelium. Because its mode of transmission is by sexual contact, it is therefore not surprising that the major sites of infection are the urogenital, anorectal, and oropharyngeal areas.

Rectal infections may be asymptomatic or may produce symptoms of proctitis with a mucopurulent discharge. Although transmitted through sexual activity, patients do not have to participate in actual anal intercourse to develop anorectal infection. It can be transmitted by penile contact in the perineal region, by hand, or by toilet paper. Rectal infections are usually associated with genital infections.

Gonococcal pharyngitis is usually asymptomatic but may present as mild sore throat. In some cases the pharynx may be the only site of infection, depending on the person's sexual practice.

The genitourinary tract is the site of most infections. In the nonpregnant female, the organism can produce inflammation of the lower genital tract glands (Bartholin's, Skene's) or ascend by way of the cervix to produce salpingitis, peritonitis, and adnexal abscesses. Pregnant patients rarely have symptomatic intraperitoneal disease; manifestations of acute gonococcal infection in pregnancy usually are limited to the vulvovaginal area.

Cases that are inadequately treated can progress to gonococcal septicemia characterized by low-grade fever, migratory polyarthritis, and dermatitis. The skin lesions can appear anywhere on the body, although the face seems to be spared. They are frequently found on the extremities, sometimes near joints, and progress from a maculopapular rash through a pustular stage to finally become a hemorrhagic-necrotic lesion that eventually disappears altogether. If untreated, the affected joints can proceed to radiologically evident articular destruction. Other less common consequences of gonococcal septicemia include endocarditis, myocarditis, pericarditis, and meningitis.

Implications for Pregnancy

All prenatal patients should be cultured for gonorrhea during their initial visit; in addition, it is highly desirable to reculture prenatal patients in the third trimester, particularly those who are at high risk for STDs. Solola and colleagues studied patients who had been attending an inner city prenatal clinic by reculturing them at the time of admission for delivery.¹² They found 9.4% had gonorrhea; one-third of these patients had negative antenatal cultures, while two-thirds had positive cultures that were treated. While tests of cure are not routinely recommended for patients with uncomplicated gonorrhea and resolution of symptoms, pregnant patients who receive treatment may benefit from a reculture to verify cure and minimize potential infection of the neonate.

The two major concerns during pregnancy are maternal septicemia and neonatal infection. For whatever reasons, patients in the second and third trimesters of pregnancy seem to be particularly susceptible to developing disseminated gonococcal infection. Therefore, pregnant patients with positive cervical cultures, highly suspicious skin lesions, or acute arthritic complaints should be evaluated closely to rule out disseminated disease.

Ophthalmia neonatorum is the most common manifestation of neonatal infection. This is a purulent conjunctivitis that can result in blindness if left untreated. The usual method of infection is by direct contact with the bacteria during a vaginal delivery through an infected cervix. The conjunctival infection can be prevented by applying one of several prophylactic agents to the newborn's eyes (e.g., tetracycline or erythromycin); such a procedure should be routine in any hospital that provides maternity care.

Infants can also be infected in utero. If a patient should be unfortunate enough to have premature rupture of the membranes while harboring an active cervical infection, she could develop gonococcal amnionitis and her infant could suffer significant morbidity from widespread disease. These infants and infants born to women with active gonorrhea should receive appropriate antibiotic therapy.

Diagnosis

GRAM STAIN

For many years the Gram stain was a valuable aid in the diagnosis of gonorrhea. Due to its low cost, technical simplicity, and instantaneous results, it was particularly useful for situations in which patient follow-up was likely to be suboptimal (e.g., emergency rooms). Its limitations included its lack of specificity for the gonococcus and possible errors in staining technique – a technique which fewer and fewer providers are familiar with. The CDC considers the Gram stain to be insufficient to detect infection in endocervical, pharyngeal, and rectal specimens. Given the CDC's opinion and the advances in diagnostic testing outlined below, the utility of the Gram stain is likely limited to clinical facilities that are geographically isolated or with limited resources.

CULTURE

Culture was the diagnostic test of choice until the development of polymerase chain reaction tests became available.  Although the culture was reportedly 100% specific, its sensitivity was less than ideal, particularly in asymptomatic women.  Additional disadvantages of culture included storage, transport, and 48 hour wait for results. Culture remains, however, the only way to determine antibiotic resistance which assumes increased importance in cases of treatment failures.  Culture remains the best option for the diagnosis of N. gonorrhoeae in non-genital sites (pharynx and rectum) since the non-culture tests are not FDA-cleared for testing in those sites

NAAT

Nucleic acid amplification techniques (NAATs) use polymerase chain reaction technology to detect fewer organisms.  Although more expensive than other methods, NAATs have high sensitivity and specificity, can provide results in hours, and do not require special handling. They are FDA-cleared for the widest range of specimen types, including endocervical, vaginal, and male urethral swabs, plus female and male urine.  Newer assays have the additional advantage of being able to detect gonorrhea and chlamydia from a single specimen. NAATs cannot provide information on antibiotic resistance; therefore in cases of treatment failures, testing needs to be augmented by use of culture.

Treatment

Since this section is devoted to the effects of gonorrhea in pregnancy, the following regimens refer to the treatment of uncomplicated gonococcal infection in pregnancy.  Recommended treatments for PID, pharyngitis, conjunctivitis, and disseminated disease can be found on the Centers for Disease Control and Prevention website, www.cdc.gov/std/treatment. Since the CDC no longer recommends the use of fluoroquinolones for the treatment of gonococcal infections, the only remaining option is Ceftriaxone, 125 mg intramuscularly.¹¹

A single dose of azithromycin 2 grams orally has been shown to be effective against uncomplicated gonococcal infections, but the CDC does not recommend its use due to concerns of the development of resistance.  Azithromycin might be considered for patients with documented severe allergic reactions to penicillins or cephalosporins.⁹

Approximately 40% of pregnant women infected with N. gonorrhoeae will also be infected with chlamydia. Therefore, it is recommended that patients who are treated for gonorrhea should also be treated for C. trachomatis infection, unless they have a negative chlamydial NAAT result (non-NAAT chlamydial tests are not sensitive enough to forego treatment).

Since case reporting data are not available, the incidence of genital herpes simplex virus infection (HSV) is only available by estimates, based upon office visit data and serologic surveys.  These estimates report that at least 50 million persons in the United States have genital HSV³ and 26% of women have antibodies to HSV-2.¹³ Many of the estimates of genital HSV infection likely are underestimates since many patients are completely asymptomatic and do not seek care; less than 10% of individuals who are seropositive for HSV-2 have a history of genital HSV.¹³  There are several other reasons for this marked underreporting: (1) the lesions may spontaneously heal before the patient seeks medical attention, (2) the patient may diagnose herself and decide to forego the expenses of an office visit, particularly if she is aware there is no cure, (3) an increasing percentage of genital HSV is caused by HSV-1, and (4) the cultures may be falsely negative. Aside from its prevalence, genital herpes is probably the most feared and potentially the most devastating of the STDs discussed in this chapter. It is the only one for which there is no cure. Once infected, a person is subjected to periodic recurrences, which can result in considerable emotional distress or sexual dysfunction. In addition its major importance during pregnancy is due to its potential to cause life-threatening neonatal infections.

Herpes simplex virus infections can be caused by either the type I (HSV-1) or the type II (HSV-2) virus. Most infections of the oral cavity and upper torso are due to HSV-1.  Historically most genital infections have been caused by HSV-2. There is considerable overlap, however, and the virus can be transmitted by masturbation, orogenital contact, or poor hygiene.  It has been reported that 30–40% of genital HSV infections – and up to 80% of new genital infections – are caused by HSV-1.¹⁴

Clinical Manifestations

Genital HSV infections can be classified as primary, nonprimary first episode, or recurrent.

Primary infections occur in patients with no antibodies to either HSV-1 or HSV-2. Primary infections are generally more severe than recurrent episodes and are frequently associated with signs and symptoms of viremia, such as fever and malaise. Patients may experience paresthesias or other unusual sensations of the infected area just prior to the appearance of vesicles. The vesicular stage is often pruritic, becoming quite painful when the vesicles rupture. Unless the vesicles become secondarily infected, they will eventually spontaneously heal without a scar.

Nonprimary first episode refers to patients with genital HSV-1 or 2 who have preexisting antibodies to the type not responsible for the current infection.

Recurrent infection refers to patients who have antibodies to the HSV type causing the current infection. Recurrent episodes can be highly variable in frequency and severity, but generally are less symptomatic than the primary infection. The virus remains dormant in the nerve ganglia until reactivated by another systemic illness, emotional stress, a debilitating disease, or an immunosuppressed condition.

Implications for Pregnancy

The importance of genital herpes in pregnancy cannot be overemphasized. There is some evidence to suggest that pregnancy is associated with an increased incidence of disseminated herpes infections, usually seen only in the otherwise medically compromised adult.^{15, 16} Although rare, such cases of disseminated infection have maternal mortality rates as high as 50%.¹⁷ Fortunately, in most cases the course of maternal herpes will not differ from that in the nonpregnant patient.

The principal concern caused by herpes in pregnancy is the potential devastation that could be caused if the infant becomes infected. Although the incidence of neonatal herpes infection is low – ranging from 1/3000 to 1/20,000 live births – infected newborns have a mortality rate ranging from 4% for those with CNS disease to 30% for those with disseminated disease. Approximately 20% of survivors of neonatal herpes will have long-term neurologic sequelae.¹⁸

The infants usually contract the virus during a vaginal delivery through an infected birth canal. If the membranes have ruptured, the possibility of an ascending, transcervical infection also exists. However, intact membranes do not guarantee the absence of infection. Transplacental infections can occur. In fact, in a nationwide surveillance, 12% of all infants diagnosed as having HSV infections had been delivered by cesarean section prior to rupture of the membranes.¹⁹

Primary and nonprimary first episode infections in pregnancy are much more likely to result in significant infant morbidity than recurrent episodes.^{20, 21} The risk of transmission to the neonate is particularly high (30-50%) in women who acquire the infection late in pregnancy. The risk is much lower (<1%) among women with histories of recurrent herpes at term or who acquire primary infections in the first trimester.³ Although controversial it is quite possible that the infants of mothers with recurrent infections may benefit from passive immunity secondary to maternal antibody production.²² HSV titers are reported to be lower and the virus is less likely to involve the cervix with recurrent infections. Following a primary first episode of HSV-2, 10.6% of weekly cultures detected asymptomatic cervical shedding, compared with only 0.5% of visits following a nonprimary first episode.²⁰  As stated earlier an increasing number of genital HSV infections appear to be caused by the HSV-1; thus, typing the virus could be beneficial in counseling patients since recurrences and subclinical shedding are much less frequent for genital HSV-1 infection than for HSV-2 infection.

While researchers continue to seek a cure, clinicians must concentrate on prevention, amelioration of symptoms, and decreased transmission.  Pregnant patients should be questioned about their – and their partners' – history of previous herpes infections. Those with positive histories should be educated and counseled about appropriate sexual practices to decrease the likelihood of neonatal infection. Although universal screening is not practical nor recommended, patients with suspicious lesions should be tested to identify the specific type of HSV.        

Admittedly, certain groups of patients are at greater risk for having herpes in pregnancy, including patients with suspicious lesions, patients with a history of herpes, and patients whose sexual partners have a history of past or present infection. Additional risk factors include duration of sexual activity, minority ethnicity, family income, and number of sex partners.²³

Current recommendations for the management of patients at risk for genital herpes infection during pregnancy are aimed at decreasing the risk of transmission to the neonate by (1) decreasing the potential for recurrences in the last weeks of gestation, and (2) decreasing the infant's exposure at the time of delivery:^{8, 9, 24}

1. For women with a history of genital herpes, suppression therapy with antivirals in late pregnancy diminishes the frequency of recurrences at term. Women with active recurrent genital herpes should be offered suppressive therapy from 36 weeks to delivery. The most widely used regimen is acyclovir 400 mg orally twice a day.  Famiciclovir and Valacyclovir have not been as extensively studied in pregnancy, but will likely prove to be equally safe.
2. For women with a history of genital herpes but without lesions at the time of delivery, a vaginal delivery should be anticipated.
3. Fetal scalp electrodes should be avoided if possible, but may be used if necessary in patients with a history of recurrent disease and no active lesions.
   
4. For women with active lesions or with prodromal symptoms (e.g., vulvar pain or burning), a Cesarean section should be offered as soon as possible, whether or not membranes have ruptured.
5. Women who present with preterm premature rupture of the membranes need to be considered on an individual basis, weighing the risk of prematurity against the risk of neonatal HSV infection. There is no consensus on a gestational age when one risk outweighs the other.

Infants of mothers with positive herpes during late pregnancy should be followed closely during the first month of life, because the average age at onset of illness is 11–16 days.

Postpartum care should be dictated by the degree of risk of infection. Aside from emphasizing good puerperal hygiene, the infected mother can be treated as a routine postpartum patient, although her contact with others should be restricted. Breast-feeding is permissible as long as the infant does not come in direct contact with any lesions, and rooming-in is probably beneficial. Infants at high risk of infection should be closely observed and managed in consultation with a specialist.

Diagnosis

The physical findings are frequently so characteristic that one is often tempted to make the diagnosis clinically. However, clinical diagnosis is both insensitive and nonspecific. Due to the serious social and medical implications of the disease, laboratory confirmation is desirable whenever possible.

Cell culture is the preferred method of diagnosis, but has many disadvantages. Because the amount of live virus recoverable from any given lesion decreases following rupture of the vesicle, older lesions may yield falsely negative cultures. Strict attention must be paid to culture technique and the type of transport media used. Many laboratories are reluctant to report a culture as negative unless it has been incubated for at least 6–7 days. Lastly, herpes cultures are generally quite expensive, although newer techniques have resulted in recent cost reductions.

Cytologic examination of smears taken from suspicious lesions may demonstrate characteristic cellular changes. Routine Pap smears, however, have been reported to be positive in only three-fourths of cases with culture-proven herpes.²⁵ Improvements in cytologic diagnosis based on enzyme-linked (ELISA) or fluorescein-tagged herpes antibodies have made cytologic evaluation considerably more accurate. Some even prefer these antibody-dependent reactions to cell culture, as the former can be positive in the presence of dead virus.

Polymerase chain reaction (PCR) techniques are more sensitive than culture and can detect virus in lower concentrations. However, currently there are problems with standardization and the PCR tests are not approved by the FDA for clinical testing of genital lesions.

Type-specific serologic assays can distinguish between HSV-1 and HSV-2 and several are approved by the FDA.  Although HSV-1 can cause both oral and genital infections, detection of HSV-2 antibodies is diagnostic of genital infection (past or present).  Many adults are already seropositive due to childhood or asymptomatic adult infections. Thus, they may be of value only if one can document either seroconversion (from negative to positive) or a significant rise in titer, both of which occur following a primary infection. The antigenic stimulus in recurrent infections is generally not strong enough to elicit a significant rise in the patient's basic titer.

Treatment

Because there is no cure for herpes, therapy should be directed toward relief of discomfort, appropriate treatment of complications (e.g., secondary bacterial infection or urinary retention), and attempts at decreasing transmission. Antiviral chemotherapy is the current mainstay of management. The antivirals have been shown to decrease the severity and duration of primary genital herpes infections and decrease the frequency and duration of recurrent episodes. Three antivirals are currently available – acyclovir, famiciclovir, and valacyclovir.  Since this chapter addresses the treatment of HSV in pregnancy, only the recommended doses for Acyclovir are listed.  Famiciclovir and Valacyclovir have enhanced absorption profiles and will likely be included in future recommended regimens.

Recommended regimens for Acyclovir treatment in pregnancy:⁹

Primary infection: 400 mg orally three times a day for 7–10 days, or 200 mg orally five times a day for 7–10 days

Recurrent infection (episodic therapy): 400 mg orally three times a day for 5 days, or 800 mg orally twice a day for 5 days, or 800 mg orally three times a day for 2 days 

Recurrent infection (suppressive therapy): 400 mg orally twice a day

Painful perineal lesions can be treated with sitz baths, good hygiene, and topical anesthetics.

Chlamydia trachomatis infections are the most commonly-reported notifiable diseases in the United States. It is difficult to accurately discuss increases in actual disease incidence because a certain percentage of the increase is undoubtedly due to increased reporting. The first year in which all 50 states had regulations requiring the reporting of chlamydia was 2000.  In 2006 the number of reported cases exceeded 1 million and was almost three times the number of reported cases of gonorrhea.³  Incidence rates for women were three times those for men, another likely reflection of a screening differential; however the lower rates for men suggest that many of the male partners of infected women are not being diagnosed or reported. Incidence rates among women vary considerably among populations served.  Risk factors include young age (15–24), unmarried status, recent new sex partner or multiple sex partners, inner-city residence, and history of STDs. The rate for African Americans was eight times higher than that of whites. In 2006, the median state-specific chlamydia test positivity among 15–24-year-old women screened in family planning clinics nationwide was 6.7% (range 2.8–16.9%).³

The chlamydial organism has been particularly interesting to microbiologists because it shares certain characteristics with both viruses and bacteria and is considered a parasitic bacterium owing to its obligatory intracellular existence. So far, 15 immunotypes of Chlamydia trachomatis have been identified, eight of which are responsible for the above-mentioned STD (three others cause lymphogranuloma venereum, the remaining four produce trachoma).

Clinical Manifestations

In the female, C. trachomatis has been directly or indirectly associated with the following:

  Bartholinitis
  Cervicitis
  Dysuria
  Salpingitis
  Pelvic inflammatory disease
  Perihepatitis (Fitz-Hugh-Curtis syndrome)
  Infertility
  Postpartum endometritis

As is the case with most STDs, patients with chlamydial infection may be completely asymptomatic; as many as 50% of infected women may have no symptoms.  Untreated pregnant women can pass the infection to their neonates during delivery; vertical transmission occurs at least 50% of the time and can cause neonatal conjunctivitis and/or pneumonitis.²⁶

Implications for Pregnancy

The significance of chlamydial infection during pregnancy remains controversial. Older reports had listed Chlamydia trachomatis as a possible cause of spontaneous abortions, preterm labor, premature rupture of the membranes, low-birth-weight infants, fetal deaths, and postpartum endometritis. Studies continue to report conflicting results, however, and these claims remain to be substantiated.^{27, 28, 29} One variable that may help to explain some of the apparently contradictory reports is the severity of infection. Several authors have reported that although chlamydial infection alone did not increase the risk of an adverse pregnancy outcome, a subset of chlamydia-positive patients who also had IgM antibody against Chlamydia trachomatis did demonstrate increased incidences of premature rupture of the membranes, preterm delivery, low-birth-weight infants, and postpartum endometritis.^{27, 30, 31}  A 2000 report from the Maternal-Fetal Medicine Units Network found that chlamydial infection at 24 weeks was associated with a two- to threefold increased risk for preterm birth.³²  Clarification of the role of chlamydial infections in pregnancy outcomes awaits further studies.

There is no doubt, however, that perinatal transmission is associated with neonatal conjunctivitis and afebrile pneumonia. Pregnant women should be screened at the time of their first prenatal visit, and those at increased risk may be tested again in the third trimester.

Although not all infected infants will develop symptoms, 25–50% of infants exposed to the chlamydia organism at birth will develop acute conjunctivitis of the newborn. Neonatal ocular prophylaxis with antibiotic ointments does not prevent conjunctivitis; therefore, if diagnosed in the newborn, the disease should be treated with systemic therapy. Ten to 20% of exposed infants will develop pneumonia in the first few months of life and chlamydial organisms are very likely responsible for many cases of undiagnosed upper respiratory tract infections during this same period. C. trachomatis infection should be considered for infants who develop pneumonia in the first 3 months of life, particularly those whose mothers were treated or who were at high risk for disease. Although otitis media is not as common, it is associated with the pneumonia in about 50% of cases. Chlamydial pneumonia usually does not produce a febrile response, yet may cause apneic episodes and airway obstruction; for these reasons it has been suggested that Chlamydia may play a role in the sudden infant death syndrome, and the possibility of such a relationship deserves further study.

Diagnosis

There are several tests available for diagnosis of C. trachomatis, including culture, direct immunofluorescence, enzyme immunoassay, DNA probe, and polymerase chain reaction (PCR). Cultures are expensive, require special handling, and are less accurate than newer tests. Nucleic acid amplification tests (NAATs) are the most sensitive and are available not only for testing endocervical and male urethral swabs but are also FDA-cleared for testing urine specimens.

Treatment

Recommended treatments for nonpregnant women and partners of pregnant women include:⁹

Azithromycin 1 gram orally in a single dose, or

Doxycycline 100 mg orally twice a day for 7 days

Recommended treatments for pregnant women, for whom doxycycline is contraindicated, include:

Azithromycin 1 gram orally in a single dose, or

Amoxicillin 500 mg orally three times a day for 7 days

Several alternative treatment regimens are available on the Centers for Disease Control and Prevention website, www.cdc.gov/std/treatment.

Clearly the azithromycin regimen offers many advantages. As a single dose therapy it is much preferred to multi-day courses of antibiotics; for patients known to have poor compliance or difficult follow-up, the treatment can actually be administered and observed.

Successful treatment with any regimen requires treatment of all sex partners and abstention from intercourse for 7 days after the single dose therapy or until completion of a 7-day regimen.  With the exception of pregnant women, test-of-cure is not recommended unless symptoms persist or there is a suspicion of reinfection or therapeutic noncompliance.  When test-of-cure is performed, it should not be done within 3 weeks of therapy due to the increased chance of obtaining either a false negative or a false positive result.

Women who have been treated for chlamydia are at increased risk of a repeat infection.^{33, 34} The CDC considers women who have repeat infections to have an elevated risk for PID and other complications when compared with the initial infection.  Clinicians are encouraged to retest all women who have been treated for chlamydial infections 3 months after treatment or whenever they seek care during the following year. This recommendation for retesting is distinct from test-of-cure.