Sexually Transmitted Diseases and Adverse Outcomes of Pregnancy

The vaginal ecology of pregnant women does not differ substantially from that of women who are not pregnant. However, studies conducted over the last decade have established that most of the organisms that infect amniotic fluid or cause chorioamnionitis are derived from the lower genital tract. In addition, recent studies have established that some organisms that are considered part of the normal vaginal microflora are associated with an increased risk of preterm or low-birth-weight delivery or both when they are present at high density in the vagina. The chapter discusses the frequency of genital microorganisms in women of different ethnic groups. Bacterial vaginosis is a condition in which high concentrations of vaginal lactobacilli are replaced by a mixed population of Gardnerella vaginalis, anaerobic gram-negative rods and cocci, and genital mycoplasmas. A number of studies have evaluated the association between genital or urinary tract colonization with group B streptococci and adverse outcomes of pregnancy. Urogenital colonization by group B streptococci has been associated with premature rupture of membranes in several studies. To date, there are no longitudinal studies demonstrating that vaginal Escherichia coli colonization earlier in pregnancy is a risk factor for preterm birth, nor are there studies demonstrating that treatment of vaginal E. coli can prevent preterm birth. There are a number of areas suitable for further research in the area of vaginal ecology and pregnancy.

Sexually transmitted diseases (STDs) pose a significant problem to maternal, fetal, and perinatal health. While many cases of adverse pregnancy outcome may have an infectious etiology, the precise organisms responsible are often not identifiable. Furthermore, not all infections are associated with adverse pregnancy outcome. Systemic immunity within the peripheral circulation may be affected by pregnancy. Immunosuppression, as indirectly measured by loss of systemic responsiveness to previously seen antigens, appears necessary for maintenance of early pregnancy. The normal human decidua is replete with many immune and inflammatory cell populations. The majority of the cells are natural killer (NK) cells (large granulated lymphocytes expressing the CD56, NK-cell phenotype). Perhaps human leukocyte antigen (HLA)-G antigens protect the placenta from NK-cell-mediated lysis and thus play a significant role in placental immunology and in the maintenance of normal pregnancy. Pregnant women also have a high prevalence of STDs and may be at increased risk of acquiring and transmitting STD pathogens due to systemic and local attenuation of immunity. Maternally acquired infections during pregnancy can lead to multiple adverse outcomes. The immunologic consequences of STDs and their potential contribution to adverse pregnancy outcome are not well characterized. Understanding host defense mechanisms including cytokine regulation in response to infectious organisms acquired or reactivated during pregnancy enable the development of cost-effective intervention strategies to prevent adverse outcomes of pregnancy. Multidisciplinary collaborative approaches combining both basic biomedical and clinical research are required to formulate and implement effective investigative strategies to answer the fundamentally important questions.

Premature birth and low birth weight are the leading perinatal problems in the Western world. This chapter reviews the evidence supporting a linkage of subclinical infection and inflammation with preterm birth. Histologic chorioamnionitis is consistently associated with preterm birth. Examination of tissue reveals that for newborns greater than 2,500 g, approximately 20% of placentas had histologic lesions of chorioamnionitis, but for newborns less than 1,000 g, over 70% of placentas had chorioamnionitis. For births of premature infants, clinically evident infection in infants and mothers is increased. Associations have been made between some organisms or infections and subsequent preterm birth. More recent reports, summarized by Gibbs, have shown that the biochemical consequences of infection or inflammation can lead to preterm birth. Of greatest clinical interest are the antibiotic trials designed to prevent prematurity. These trials are of three different types, including trials conducted during prenatal care of women at high risk (generally greater than 10%) for preterm birth, trials involving women in preterm labor with intact membranes when the antibiotics are used concurrently with tocolytic drugs, and trials involving women with premature rupture of the membranes. Examples of such trials include prenatal treatment of Trichomonas vaginalis or treatment of low-risk patients with bacterial vaginosis.

This chapter focuses on postpartum endometritis, especially the role of sexually transmitted organisms or syndromes and the adverse effects of these infections on the reproductive health of young women. Bacteremia is complicated by septic shock in 20 to 50% of medical and surgical patients compared to 0 to 12% of obstetric patients. The mortality rate among endometritis patients with bacteremia ranges from 0 to 4.3%; if septic shock occurs, mortality ranges from 0 to 67%. A large number of risk factors for postpartum endometritis, including labor, rupture of membranes, number of vaginal examinations, use of an internal fetal monitor, low parity, general anesthesia, skill of the surgeons, duration of surgery (>60 min), estimated blood loss (>500 ml), postoperative anemia, positive amniotic fluid culture, vaginal or cervical colonization with a variety of microorganisms including sexually transmitted organisms, absence of amniotic fluid-inhibiting factor(s), failure for labor to progress, and delivery by cesarean section, are evaluated. The use of internal fetal monitoring has been accompanied by concerns about increased intrauterine infection both pre- and postdelivery. The presence of virulent bacteria, including genital mycoplasmas, in the amniotic fluid is a significant risk factor for the development of postpartum endometritis, especially post-cesarean section. The use of antibiotic prophylaxis immediately after cord clamping has been demonstrated to dramatically reduce the incidence of postpartum endometritis following cesarean section. Bacterial vaginosis is a vaginal condition associated with increased concentrations of anaerobic bacteria and G. vaginalis.

This chapter presents an overview of the methods and study designs used to assess the possible association between sexually transmitted diseases (STDs) and adverse pregnancy outcomes. The chapter defines what is meant by random and systematic error, explains how they relate to specific types of epidemiologic study designs, and suggests how errors can be minimized at both the design and analysis phases of investigation. The types of epidemiologic research designs and the quantitative estimates of effect that derive from the study designs is reviewed. The various sources of systematic error (bias), with particular emphasis on how they relate to specific types of epidemiologic studies and how they can be reduced by appropriate design and analytic strategies, is delineated. The two broad types of error can be characterized as random error and systematic error. Perinatal epidemiologic studies should focus on outcomes of major importance to the fetus, infant, or mother, including stillbirth, neonatal death, neonatal infant morbidity, major congenital malformations, and maternal mortality and morbidity. Reverse causality bias is particularly likely to occur in cross-sectional studies. Reverse causality is eliminated by ensuring that exposure occurs prior to the development of the outcome. Finally, differential information bias can be minimized by ensuring adequate blinding of subjects, investigators, and care givers. It is also often useful to blind care givers to avoid the occurrence of co-interventions, i.e., additional interventions in one of the treatment arms capable of influencing the outcome and thereby confounding the effect of the study treatment.

Bacterial vaginosis (BV) is the name of a syndrome formerly called nonspecific vaginitis, Haemophilus vaginalis vaginitis, and Gardnerella vaginalis vaginitis, among others. In the healthy vagina, the normal vaginal flora consists predominantly of Lactobacillus species, which make up about 95% or more of the total bacterial count. The cytokine concentration in the amniotic fluid of infected patients is equal to or higher than the concentration of cytokines in the cerebrospinal fluid of children with meningitis or in the abdominal fluid of adults with peritonitis. The most important aspect of BV in causing vaginitis is the tremendous increase in the concentration of the bacteria in the vagina. The increased concentration of bacteria explains, in part, the relationship between BV and preterm delivery/low birth weight and infection of the amniotic fluid and chorioamnion. The time when BV-related bacteria move from the lower to the upper genital tract is not known. This phenomenon could occur at a constant rate throughout pregnancy, but indirect information suggests otherwise. A current working hypothesis for acute or chronic chlamydia infection is that a component(s) of the immune response to chlamydia heat shock protein cross-reacts with the analogous human heat shock protein and somehow results in infertility or first-trimester spontaneous abortion and even preterm delivery. The natural history of BV in the nonpregnant patient must be elucidated. Natural history studies of women with and without BV who will attempt pregnancy are needed.

Untreated syphilis during pregnancy is associated with spontaneous abortion, stillbirth, nonimmune hydrops, premature delivery, and perinatal death. Syphilis in the United States is currently found among racial and ethnic minorities who live in poverty. A major contributor to the increased incidence of syphilis in the late 1980s and early 1990s was the use of crack cocaine and the exchange of illegal drugs for sex. Gestational syphilis primarily affects women who are young and unmarried and who receive inadequate or no prenatal care. A pregnant woman with syphilis can transmit the infection to her unborn infant in utero, presumably by a transplacental route or possibly during delivery by contact with a genital lesion. The effect of concurrent maternal infection with Treponema pallidum and HIV on the risk of fetal infection with T. pallidum and HIV remains to be elucidated. The risk of prematurity, perinatal death, and congenital infection is directly related to the stage of maternal syphilis during pregnancy. An early clue to the diagnosis of congenital syphilis is provided by examination of the placenta. The infected placenta is often large, thick, and pale; the histologic findings consist of focal villitis, endovascular and perivascular proliferation in villous vessels, and relative immaturity of the villi. Penicillin remains the drug of choice for treatment of both acquired and congenital syphilis. Prevention of syphilis among pregnant women has remained an elusive public health goal.

The purpose of this chapter is (i) to review the pathophysiology of gonorrhea during pregnancy, (ii) to summarize epidemiologic data regarding gonorrhea among pregnant women, and (iii) to discuss the manifestations of maternal and infant infections, with special emphasis on principles of prevention and management. Neisseria gonorrhoeae is a sexually transmitted bacterium which infects columnar and transitional epithelium of the genitourinary tract, including the urethra, endocervix, and anal canal, and the conjunctivae and pharynx. The majority of pregnant women with gonorrhea are asymptomatic; the proportion of symptomatic patients among pregnant women with gonorrhea has been reported to be as low as 1.2%. Pregnant women who are diagnosed with uncomplicated gonococcal infections or who are the sexual partners of men with gonorrhea should be treated with ceftriaxone (125 mg intramuscularly) in a single dose or with cefixime (400 mg orally) in a single dose. Due to the higher risk of pharyngeal gonorrhea in pregnant women, it may be preferable to treat them with ceftriaxone, since the efficacy of cefixime for treating pharyngeal gonorrhea has not been established. The problem of low utilization of prenatal care in populations with a high prevalence of gonorrhea must be promptly addressed, and strategies to reach high-risk women for diagnosis and treatment outside the context of prenatal care require exploration. Urine screening for sexually transmitted pathogens in facilities attended by underserved high-risk pregnant women is a promising alternative.

The most controversial area in mycoplasmology today continues to be the potential role of Ureaplasma urealyticum in adverse pregnancy outcome in humans. U. urealyticum can be isolated from the cervix and vagina in 52 to 76% of postpubertal girls in the absence of symptoms. Since 1970, 13 studies involving approximately 12,000 patients have been conducted to evaluate the role of cervical ureaplasmal infection in premature birth. Analysis of amniocentesis samples taken for prenatal diagnosis in the first or second trimester revealed U. urealyticum in the amniotic fluid, in the presence of intact membranes and in the absence of other microorganisms. Two prospective studies were conducted to evaluate the presence of ureaplasmas at the time of genetic amniocentesis at 12 to 20 weeks gestation when membranes were intact and there was no labor. Histologic evidence of chorioamnionitis was present in all 10 placentas and histologic evidence of pneumonia was present in all 9 fetuses. The isolation of organisms from the chorioamnion and/or amniotic fluid was associated with microscopic chorioamnionitis but not with clinical amnionitis. Risk factors for U. urealyticum colonization of the female lower genital tract include younger age, lower socioeconomic status, sexual activity with multiple partners, black ethnicity, and oral contraceptive use. Until there is widespread awareness of and acceptance of how common mycoplasmal infections of the central nervous system can be, knowledge of what group is at risk for infection, and development of improved diagnostic capabilities, it is likely that the majority of cases will not be identified.

Perinatal transmission of Chlamydia trachomatis is a frequent occurrence and is the most clearly defined adverse outcome of chlamydial infections during pregnancy. The objective of this communication is to assess available information on other possible adverse outcomes of chlamydial infection in pregnancy. C. trachomatis infection may cause urethritis, cervicitis, endometritis, or salpingitis, and these may be either clinically apparent or subclinical. Chlamydial endometritis has been characterized as a plasma cell endometritis because of infiltration of the endometrium with plasma cells. This association of chlamydial infection with inflammatory infiltrates in the endometrium raises the possibility that such infections are associated with failure of implantation or early pregnancy loss due to spontaneous abortion. Amoxicillin renders women culture negative and prevents transmission to their infants. The immune response appears to play a significant role in the pathogenesis of ocular trachoma and in Chlamydia-associated tubal infertility and ectopic pregnancy.

Trichomoniasis is the most common nonviral sexually transmitted disease worldwide. It has been estimated that more than 180 million people are infected with Trichomonas vaginalis. Infection with T. vaginalis can be asymptomatic or can be associated with acute vaginitis. T. vaginalis infects the squamous epithelium of the lower genital tract almost exclusively, in both women and men. In women, the vagina, exocervix, urethra, and Skene’s glands are the main sites of infection. In men, the infection is urethral and usually without symptoms. Some investigators have found an association between T. vaginalis infection and prematurity. After successful therapy, recurrent vaginal infection may occur. However, T. vaginalis almost never spreads outside the human genitourinary system. Infection with T. vaginalis may elicit an inflammation characterized by discharge. Symptoms of vaginal trichomoniasis include abnormal frothy discharge and genital irritation. Observation of live protozoa in specimens from the vagina or urethra is definitive evidence of genital trichomoniasis. Trichomonas culture is the most sensitive diagnostic procedure but will miss up to 15% of infected cases. Monoclonal antibodies to T. vaginalis have been used to identify vaginal trichomoniasis. Metronidazole can produce chromosomal alterations in bacteria and may increase the incidence of tumors in susceptible animals. In summary, T. vaginalis is likely to be an important factor in prematurity. Better diagnostic tests (amenable to screening use), better therapy, and appropriate clinical trials are needed to determine whether screening and treatment should be used to prevent prematurity.

This chapter familiarizes clinicians with the literature regarding outcomes of pregnancies of human immunodeficiency virus (HIV)-infected women, and describes strategies to minimize transmission and to reduce the frequency of adverse perinatal outcomes. Pregnant women with a high viral load, revealed by high titers of HIV or p24 antigenemia, apparently are a group at particularly high risk of transmission. Acute viremia associated with maternal seroconversion in the year prior to pregnancy or during breast-feeding appears to be associated with increased rates of vertical transmission. Intensive exposure of the infant’s thin skin or mucosal surfaces to maternal blood and secretions during the birth process could provide a significant route for virus transmission. Advanced immunologic deterioration, as demonstrated by decreased numbers of circulating CD4+ lymphocytes, has been associated with an increased risk of vertical transmission. Over the last several years, a great deal has been learned about the timing of transmission. There are no data to support antepartum, intrapartum, and neonatal (breast-feeding) transmission of HIV. Most reports from developed countries suggest that, other than transmission of HIV infection, pregnancy outcomes are not affected by serostatus, at least in asymptomatic patients. Women who choose to maintain their pregnancy should be aware that certain interventions may reduce the risk of perinatal HIV transmission and that several other approaches are under study to determine whether they will have additional benefit. The single most important step in prenatal care today is the use of zidovudine (ZDV) in the antepartum, intrapartum, and neonatal periods.

To discuss the rationale of herpes simplex virus (HSV) serologic testing in the prevention of neonatal herpes and other adverse consequences of genital herpes complicating pregnancy, it is necessary to review the classification of this infection. The appropriate classification of genital herpes during pregnancy depends upon accurate serotyping of the patient by type-specific serologic assays. A recent study demonstrated that antepartum asymptomatic shedding of HSV as determined by weekly HSV cultures does not predict whether HSV will be present in the genital tract at the onset of labor. Recent studies have demonstrated that most of the morbidity and the majority of cases of neonatal herpes in pregnancy are due not to women whose genital herpes reactivated at the onset of labor but to women acquiring genital herpes, frequently asymptomatically, in late pregnancy. Even if every patient entering pregnancy with symptomatic recurrent genital herpes underwent a cesarean section, only a minority of cases of neonatal herpes would be prevented. Cesarean section may even decrease the transplacental transmission of protective anti-HSV antibodies. Acyclovir is extremely effective in suppressing both symptomatic recurrences and asymptomatic shedding in nonimmunosuppressed, nonpregnant adults. Until the prospective studies of prophylactic acyclovir in late pregnancy which are in progress have been completed and evaluated for safety and efficacy, the prophylactic use of acyclovir in late pregnancy must be approached with caution and certainly only after complete informed consent is given by the patient.

Studies of genital herpes in pregnancy have been a major source of new knowledge about the herpes simplex virus (HSV) infections of the genital tract and the epidemiology of HSV-1 and HSV-2 transmission by sexual contact. The transmission of HSV to infants usually results from exposure, during delivery, to maternal genital secretions that contain infectious virus. Since both HSV-1 and HSV-2 can cause genital herpes, neonatal infection can be due to either virus type, but most cases in the United States are due to HSV-2. Exposure to HSV at delivery does not lead inevitably to neonatal herpes. In fact, as is true for many other pathogens, most exposed infants escape Infection. Cervical infection is also much more likely in first-episode genital herpes as opposed to recurrent disease, permitting prolonged exposure during the birth process. Neonates infected with HSV have a very poor induction of active immunity to the virus. Cesarean delivery is recommended if lesions of genital herpes are present at the onset of labor. When a neonate is exposed to a first episode of maternal genital herpes, viral cultures of the eyes, throat, urine, stool, and cerebrospinal fluid (CSF) are recommended at 48 h or when the exposure is identified. Higher antibody titers may also diminish morbidity even if the infant becomes infected, by enhancing the likelihood that the infection will be localized rather than systemic.

This chapter describes some of the key epidemiologic characteristics of human cytomegalovirus (HCMV) maternal-fetal infection, including sources of maternal infection and maternal populations with increased rates of infection and fetal transmission, and provides a limited description of maternal immune responses associated with protection from fetal transmission and disease. The seemingly complex natural history of congenital HCMV infection can be greatly simplified by an understanding of the maternal component of the maternal-fetal infection. Primary infection during pregnancy can develop as a result of exposure to infectious virus from several sources. Epidemiologic studies have documented that exposure to infected children and sexual exposure represent the two most common modes of community acquisition of HCMV. The consequences of intrauterine HCMV infection can range from mild, clinically inapparent infection to severe, life-threatening multiorgan disease. Progressive hearing loss is limited almost exclusively to infants with congenital infections which follow primary maternal infection. The most obvious method of limiting disease caused by intrauterine HCMV infection is to develop and use an effective vaccine. This may be accomplished by active vaccination, as has been demonstrated by universal rubella immunization. Live, replicating HCMV vaccines have been proposed as a means of doing this, but to date no direct evidence has been provided to suggest that current live virus vaccine formulations can provide such immunity.

This chapter briefly summarizes maternally transmitted genital human papillomavirus (HPV) infections in children and problems associated with HPV-related diseases among pregnant women near parturition. Most of the discussion focuses on juvenile-onset laryngeal papillomatosis (recurrent respiratory papillomatosis [RRP]), the most challenging and costly of the diseases associated with mother-child HPV transmission. Laryngeal papillomatosis is the most common benign neoplasm of the larynx. The lesions are characterized by recurrent tumors, which cause hoarseness and upper airway obstruction. The incidence of both juvenile-onset and adult-onset papillomatosis is unknown, and the prevalence of disease has not been accurately assessed. The various forms of therapy have included different ablative and surgical techniques, topical and oral medical therapies, interferon, and laser therapy. Most of these treatment strategies have been evaluated by means of uncontrolled trials, although a few well-designed controlled clinical trials have evaluated the effects of intramuscular interferon as an adjunct therapy for control of RRP. Congenital condylomata acuminata is a rarely reported disease of newborns and infants. Several case reports, however, clearly indicate the occurrence of maternal-fetal transmission even in the absence of fetal exposure to the maternal genital tract through cesarean delivery. Research in the field of maternal transmission of HPV to infants has been hampered by the same limitations that have slowed progress in studies of genital HPV and cervical neoplasia—inability to culture or propagate the virus and uncertain test characteristics (sensitivity and specificity) in identification of HPV infection.

This chapter reviews two diseases such as chlamydial abortion and chlamydial endometritis, which are likely to be of interest to workers in the field of human chlamydiosis. The causal agent of enzootic abortion of ewes (EAE) is the ovine abortifacient form of Chlamydia psittaci, previously designated biotype 1 and immunotype 1. Most studies have reported a remarkable degree of homogeneity of strains of C. psittaci in molecular terms. When EAE is experimentally reproduced in naive ewes by subcutaneous injection or by dosing via the oropharyngeal route, abortions usually occur in 40 to 50% of animals, with 75 to 90% excreting chlamydiae at lambing or at abortion. A monoclonal antibody against another surface-expressed antigen of C. psittaci, an 89-kDa protein, reduced infection by 60% in a tissue culture model, suggesting that antibodies against this protein may also be involved in acquired immunity. Three principal antigenic preparations have been used in vaccines: (i) inactivated forms of the cultured organism; (ii) a temperature-sensitive, attenuated mutant; and (iii) protein extracted from genetically engineered bacteria expressing the major outer membrane protein. Due to the relatively recent recognition of bovine chlamydial infertility, metritis, and salpingitis, the most reliable descriptions of its clinical expression are provided by experimental infection studies. Both forms of chlamydial infection of ruminants offer useful comparative features for human reproductive tract disease. The bovine disease is still in the very early stages of characterization, and so the full extent of its usefulness as a model for human disease remains to be determined.

Bovine trichomoniasis has many similarities to human trichomoniasis. Both protozoan infections are sexually transmitted and are characterized by clinical signs that vary from asymptomatic to purulent discharge after weeks to months of infection. Since bovine trichomoniasis is a naturally occurring sexually transmitted infection, it can better serve as a model for human trichomoniasis. The bovine infection causes significant economic loss due to reproductive failure and consequently has been well studied. The use of this model to help understand human infection may be quite productive for two reasons: (i) the similarities in host-pathogen relationships may imply similarities in immune mechanisms of protection; and (ii) the early loss of pregnancy in bovine trichomoniasis should stimulate research on adverse outcomes in the first and second trimester of pregnancy in women with trichomoniasis. The clinical picture and the pathogenesis of bovine trichomoniasis and campylobacteriosis are very similar in that these two extracellular pathogens are transmitted exclusively by sexual contact. Evidence suggests that vaccination with the purified adherence antigen may prevent pregnancy failure. In the future, control of bovine trichomoniasis may rely on immunoprophylaxis, but currently, accurate diagnosis and management are the basis of prevention and control efforts. Several observations on bovine trichomoniasis are of interest to researchers investigating the control of human trichomoniasis. The commercially available vaccine for bovine trichomoniasis consists of whole cells.

Preterm labor that results in premature birth is the most common cause of perinatal mortality, accounting for 80% of perinatal deaths which are not attributable to congenital malformations. There is now considerable evidence to suggest that cytokines participate in the pathogenesis of infection-associated preterm labor. To examine the temporal and quantitative relationships between intra-amniotic infection and preterm labor, the authors developed a simian model involving chronically catheterized rhesus monkeys (Macaca mulatta) with timed gestations. Bacterial vaginosis, previously associated with preterm labor and intra-amniotic infection in women, was identified by Gram stain criteria in 8 of 31 monkeys (26%), a prevalence similar to that reported in women, and was likewise associated with increased intravaginal concentrations of Gardnerella vaginalis, Mobiluncus spp., and anaerobes. Following intra-amniotic infection, increases in prostaglandin E2 (PGE2) and PGF2α concentrations in amniotic fluid occur in parallel with increases in cytokine concentrations in amniotic fluid and precede increases in uterine contractility. The presence of a single fetus, the hormonal control of parturition, and hemochorial placentation with an abundant amniotic fluid cavity all approximate the human situation. Ideally, prevention of prematurity should be directed toward identification and eradication of the offending microorganism while it is still confined to the lower genital tract, as has been demonstrated for certain lower genital tract infections.