Abstract: Genital Chlamydia trachomatis infection is the commonest bacterial sexually transmitted infection worldwide. Infection prevalence peaks in young women aged between 18-25 years. Infection in women has been associated with reproductive tract pathology, infertility, and adverse pregnancy outcomes including miscarriage, early membrane rupture, pre-term labor, and postpartum endometritis. However, the evidence base varies with the population studied and the methods used to detect infection. There may be differential consequences for pathology associated with primary or recurrent infection during pregnancy. These differences may be potentiated by physiological differences in the host response to infection in the pregnant state. Such changes have particular relevance for infections of the reproductive tract. Cost effectiveness estimates for screening during pregnancy require basic knowledge of the natural history of infection and the host response to calculate associated risks. Our level of knowledge is hampered by the lack of good experimental models for human pregnancy. To make rational decisions about screening of pregnant women there is a need for case control studies that compare detection of infection by nucleic acid amplification tests with evaluation of immunity to the infection.
The information available on the consequences of sexually transmitted Chlamydia trachomatis (Ct) infection during pregnancy does not give a clear picture, but it ranges from the trivial to the alarming. Part of the gap in understanding arises from the lack of good experimental models. Although murine genital infection is widely studied, the pathology induced by the mouse pathogen Chlamydia muridarum differs from Ct infection in women. Additionally, due to the species specific anatomy and physiology of the human female reproductive tract and pregnancy placentation differences, there are no really representative experimental systems (Bulmer et al., 2010) to model the interactions between Ct, the host immune response, and the human pregnant reproductive tract. Here we will look at Ct infection in the context of reproductive tract immunity in women and examine what is known, and, what it would be good to know, about potential sequelae of genital Ct infection during human pregnancy.
Genital Chlamydia trachomatis Infection in Women
Ct is a very successful human pathogen. Genital infection with Ct serovars D-K is the most common bacterial sexually transmitted infection worldwide, with most women being unaware that they are infected (ECDC Guidelines, 2009; Carey and Beagley, 2010). In Europe, Ct prevalence is highest among 16-25 year olds, with between 5-8% testing positive using a nucleic acid amplification test (NAAT) (ECDC Guidelines, 2009). Ct is a significant public health problem because infection may lead to pelvic inflammatory disease, subfertility, and poor reproductive outcomes in some women; it is estimated to cost the UK health service £100 million a year (ECDC Guidelines, 2009; UK National Chlamydia Screening Programme, 2011).
The organism is an obligate intracellular bacterium with a complex lifecycle in human epithelial cells. Most episodes are asymptomatic and untreated which maintain the reservoir of infection. There is no available vaccine. Infection is currently detected by highly sensitive NAATs and treated effectively with antibiotics (Horner, 2008). The natural history of the genital infection in humans is poorly understood and it remains unclear whether asymptomatic or symptomatic infections, Ct or host genotype, and the host immune response influence the risk of developing disease (Howie et al., 2011; Horner, 2011).
Host Response and Limitations of Chlamydia trachomatis Detection
As with any infection, Ct induces host immune responses which can promote clearance of infection and/or contribute to subsequent pathology (Howie et al., 2011). Serum antibody levels have been the most commonly used marker of immunity following Ct infection. Serum antibodies measure both past and current infection whereas NAATs only measure current infection. As the organism is closely related to other chlamydial species there is some controversy over the best method for measuring specific antibodies and whether antibody subclass is related to pathology (Persson, 2002; Wills et al., 2009; Howie et al., 2011). There is evidence of a degree of protective immunity after experimental infection (Yu et al., 2011) and attenuated organisms can induce some protection in the murine model (Olivares-Zavaleta et al., 2010) of infection. There is also evidence of some protection in natural human infection but in most cases this is insufficient to rapidly clear the organism and fails to prevent re-infection (Batteiger et al., 2010).
Until the 1990s, infection was detected by culturing organisms with some studies also using the detection of serum antibodies. Seroprevalence was found to decrease in Japanese (Yamamoto et al., 1998) and Swedish (Persson et al., 1995) populations in the 1990s, which was interpreted as decreased infection rate. Since then, NAATs have superseded these technologies and revolutionized clinical care as they have enabled the use of non-invasive sampling techniques which do not require a genital examination. The somewhat unfortunate spin-off of this has been a decline in our knowledge of the host response to infection and a loss of scientific expertise in the laboratory culturing of Ct. Both of these are necessary to truly understand the natural history of infection in individuals and populations. This is well illustrated by recent studies in Finland comparing seroprevalence and current infection detected by NAATs which show that seroprevalence has declined but current infection prevalence increased (Lyytikainen et al., 2008a; Lyytikainen et al., 2008b). The reason for this is unclear (Johnson and Horner, 2008).
Increased rapid non-invasive testing in young people has resulted in earlier treatment of infected individuals. There is little evidence that this has affected the infectious reservoir as prevalence is increasing (World Health Organization, 2011). There is some concern that rapid antibiotic treatment may reduce the level of natural immunity to Ct as has been shown experimentally (Su et al., 1999). Even though infection-induced immunity is only partially protective, reduced, or absent, immunity may affect subsequent disease by promoting persistence of infection. On the other hand, strong inflammatory immune responses may themselves cause pathology. Most of the disease associated with ocular trachoma caused by Ct serovars A-C is caused by the inflammatory immune response to the organism (Burton, 2007). There is experimental evidence in primary infection with the related chlamydial species C. pneumoniae that inflammation and tissue damage persist after clearance of the organism (Fitch et al., 2010). It may be that similar inflammatory responses underlie the pathology associated with genital Ct infection (Beatty et al., 1994; Vickers et al., 2009). The implications of this for pregnant women who become infected with Ct with or without prior immunity are not clear.
Reproductive Tract Changes in Pregnancy
As well as the outer vaginal epithelium, within the internal female reproductive tract there are three distinct epithelial surfaces to be protected against infection: the cervix, the uterine lining or endometrium, and the Fallopian tubes. There are a number of immune system cells and lymphatic draining vessels in the female reproductive system but there is no associated organized lymphoid tissue. The general structure of the female reproductive tract is shown in Figure 1.
The cervix has a squamous epithelium which is continuously replaced by cells in the basal layer and secretes mucus containing a variety of anti-microbials which protect against infection (Ming et al., 2007).
During pregnancy the cervix undergoes hormone mediated remodeling resulting in cervical “ripening” and dilatation at term to allow delivery. The pregnant cervix is sealed with a complex mucus plug. This mucus plug contains elements of the innate (neutrophils, macrophages, cytokines, anti-microbial peptides, proteases, and protease inhibitors) and adaptive (immunoglobulins, cytokines) immune systems to protect the uterus and embryo against infection ascending from the lower reproductive tract (Becher et al., 2009; Lee et al., 2011).
The endometrium is maintained by progesterone released by the corpus luteum during oogenesis. In the non-pregnant uterus the upper two thirds of the endometrium is shed monthly as the progesterone supply drops when the egg is released. If a fertilized ovum implants successfully the endometrium is maintained by progesterone produced by the embryo and undergoes decidualization to form the highly vascularized maternal part of the placenta where it becomes intimately connected with the trophoblast produced by the embryo. During pregnancy the decidualized endometrium is referred to as the decidua. The decidua expresses anti-microbials (Dalgetty et al., 2008) and anti-inflammatory mediators (Macdonald et al., 2011), and contains cells involved in innate immunity (Nagamatsu and Schust, 2010) including NK cells (King et al., 2000; Vacca et al., 2011).
The epithelial surface of the Fallopian tubes has evolved to facilitate transport of the fertilized ovum to the uterine cavity and is composed of a mixture of ciliated and secretory epithelial cells. The Fallopian tube is not known to have a role in maintaining normal pregnancy. Ectopic pregnancy most commonly occurs where the fertilized ovum implants in the epithelium of the Fallopian tubes rather than the in the uterine cavity. Changes in immune cell populations have been reported in Fallopian tubes from women with ectopic pregnancies that may be related to host defence and/or to control of implantation (Shaw et al., 2011a). Previous Ct infection is a risk factor for ectopic pregnancy but most studies fail to detect bacterial DNA in Fallopian tubes from ectopic pregnancy. Experimental studies have shown that Ct infection alters the transport of fertilized ovum in the Fallopian tube by changing the behavior of the ciliated pacemaker cells (Dixon et al., 2010). In women, it has been proposed that Ct infection causes damage to Fallopian tube epithelial cells that does not repair completely once the organism is cleared and that this predisposes towards ectopic embryo implantation (King et al., 2009; Shaw et al., 2011b). This topic has been reviewed recently (Shaw et al., 2010) and will not be covered further here.
Immune Response Changes in Pregnancy
Ct infection during pregnancy has consequences for mother, baby, and any sexual partners. During pregnancy the mother’s immune system has a dual responsibility to prevent rejection of a semi-allogeneic fetus and to maintain immune defences against pathogens to protect both mother and developing baby from infection. The species specific mechanisms by which the anatomy and physiology of the female reproductive tract and associated immune system cells and their molecules interact in pregnancy (Plaks et al., 2008; Kane et al., 2009; Negishi et al., 2011) and achieve tolerance to paternal antigens expressed by the baby have been extensively reviewed (Seavey and Mosmann, 2008; Erlebacher, 2010) but will not be further covered here.
Host defence against pathogen invasion involves integrated responses of both the innate and acquired immune systems. Both arms of immunity are altered during pregnancy and whilst there is no overall increase in infection during normal pregnancy, the way in which pathogens are handled is altered by changes in the maternal immune system (Horne et al., 2008; Koga and Mor, 2010; Witkin et al., 2011). This is particularly important for immunity to pathogens of the reproductive tract.
Innate Immunity in Pregnancy
Protection of the embryo from maternal immunity and maintaining the ability to deal with infection when the maternal decidual epithelium and the embryo-derived trophoblast are intimately associated largely depend upon cells and molecules of the innate immune system (reviewed in Horne et al., 2008). This involves complex interactions between multiple molecules (King et al., 2001; 2009; Zhao et al., 2009) and cell types including uterine NK cells and macrophages which also maintain the vascularization of the decidua (King et al., 2007; Smith et al., 2009; Nagamatsu and Schust, 2010; Vacca et al., 2011). Gene profiling studies of first trimester decidual macrophages have revealed unique populations with expression profiles consistent with abilities to remodel tissue, suppress maternal immunity, and present antigens (Gustafsson et al., 2008; Houser et al., 2011). This emphasizes the uniqueness and complexity of the decidual epithelial environment.
Acquired Immunity in Pregnancy
It is often stated that pregnancy alters maternal immunity towards a T helper 2 (Th2) phenotype although the reality appears more complex (reviewed in Witkin et al., 2011). There is a decrease in circulating levels of pro-inflammatory cytokines but also in IL-10 (Szarka et al., 2010). T lymphocytes are present in reproductive epithelium and in pregnancy decidua, and it has been reported that regulatory T cells (Treg) are present, Th2 cells outnumber Th1 cells, and Th17 cells are absent (Mjosberg et al., 2010). In the blood, levels of Treg cells are increased (Santner-Nanan et al., 2009) and alterations in dendritic cell populations have been reported (Shin et al., 2009).
Chlamydia trachomatis Infection in Pregnancy
Infection with Ct in pregnancy has been associated with a number of adverse outcomes for both mother and baby. Antibiotic treatment during pregnancy is safe and clears infection (Brocklehurst and Rooney, 2000). However, there is ongoing debate as to whether or not screening of all pregnant women and treatment of those found to be infected is desirable and/or cost effective (Akande et al., 2010; CDC Guidelines, 2010; SIGN Guidelines, 2010; UK National Chlamydia Screening Programme, 2011). There are a number of reports looking at prevalence of Ct infection in pregnant women and estimates range from 3% overall to 14% in the under 20 age group (Adams et al., 2004; Cheney and Wray, 2008; Chen et al., 2009; Silveira et al., 2010; Pereira et al., 2010; Roberts et al., 2011). The adverse outcomes associated with Ct infection in pregnancy include premature rupture of membranes (Pararas et al., 2006; Blas et al., 2007; Yu et al., 2009), miscarriage (Wilkowska-Trojniel et al., 2009; Nigro et al., 2011), and postpartum endometrial inflammation (Ismail et al., 1987). Ct infection has been associated with low birth weight in one study (Johnson et al., 2011) but not in another (Blas et al., 2007). Some studies have shown associations with preterm labor (Hollegaard et al., 2007; Blas et al., 2007) whereas others have failed to find any association (Silveira et al., 2009; Johnson et al., 2011). As these studies are based on detection of current infection and there is no information on whether infections are primary, repeated, or persistent, studies based on serology may in fact be more informative.
Assessment of adverse consequences of Ct infection during pregnancy in a U.S. cohort showed that persistent or recurrent infection posed no significant risk but that primary infection during pregnancy was associated with preterm delivery and premature membrane rupture (Sweet et al., 1987). Their definition of primary infection was based upon the presence of IgM antibodies in serum indicating that prior immunity was protective even in currently infected women. IgM antibodies have been associated with preterm delivery and IgG antibodies with stillbirth in Finnish women (Gencay et al., 2000). Differences in IgG and IgA levels have been shown in infected women with and without miscarriage (Wilkowska-Trojniel et al., 2009) and a higher incidence of IgM antibodies to Ct was reported to be associated with recurrent miscarriage (Kishore et al., 2003). Thus the interplay between the organism and host immune response may be critical. A recent study of placentas from women with premature labor found a strong association with detection of Ct and the degree of tissue inflammation found (Rours et al., 2011). Taken together one explanation of this conflicting data is that women with primary infection are at increased risk of complications during pregnancy. Due to lack of prior immunity and changes in immunity during pregnancy such women may have a greater risk of intra-uterine infection. If a reliable method can be designed, vaccination may offer a future strategy for prevention of Ct related pathology in pregnancy.
As well as adverse pregnancy outcomes, maternal Ct infection and IgM antibodies have been associated with neonatal problems including low birth weight (Jain et al., 1991) and need for intensive care (Gencay et al., 1995). The organism can be vertically transmitted in utero and at birth (Fejgin et al., 1997; Gencay et al., 2001; Mardh, 2002; Yu et al., 2009) and may adversely affect the maternal/fetal immune balance and the maintenance of pregnancy. Vertical infection can cause respiratory infection in babies (Rours et al., 2009) and neonatal conjunctivitis (Kakar et al., 2010).
Does Chlamydia trachomatis Infection in Pregnancy Predispose to Preeclampsia?
Preeclampsia is a serious complication of late pregnancy that has been associated with changes in the immune system. Changes in immune balance towards increased circulating pro-inflammatory cytokines (Szarka et al., 2010) and cells with a Th1 phenotype (Saito and Sakai, 2003) together with non-pregnant levels of circulating Treg cells (Santner-Nanan et al., 2009) have all been reported in preeclampsia. A role for natural killer (NK) cells in changing this balance has been reported and has led to the suggestion that in some cases this condition may be caused by pro-inflammatory immune responses (Saito et al., 2007).
Experimental studies have shown that Ct infection of trophoblast cells alter chemokine and cytokine secretion (de la Torre et al., 2009) and Ct heat shock protein induces apoptosis in trophoblast cells (Equils et al., 2006). Thus chlamydial infection may promote changes in the balance of maternal immunity which may be deleterious to the developing baby. There is no reported information on Ct infection and preeclampsia although it has been suggested that there may be an association (Equils et al., 2006). However, there are a number of studies in the literature reporting associations between infection with the related respiratory pathogen C. pneumoniae (Cp) and preeclampsia (Xie et al., 2010; El-Shourbagy et al., 2011). The risk of preeclampsia was increased among women with serum IgG antibodies to Cp (Xie et al., 2010); the risk of a second pregnancy with preeclampsia was increased in women with high levels of anti-Cp antibodies (Goulis et al., 2005); and the risk of preeclampsia in pregnant women who had IgG antibodies to Cp was reduced by anti-chlamydial treatment (El-Shourbagy et al., 2011). Taken together these results again suggest that it is not the presence or absence of a pathogen but rather the interplay between chlamydial pathogens and the host immune response that determines disease outcome. Future epidemiological studies are needed to establish whether Ct infection may also be associated with preeclampsia in pregnancy.
Concluding Remarks - What Information Do We Need to Determine Risk?
Ct infection during pregnancy carries a risk of vertical transmission and may adversely affect the mother’s health and pregnancy outcome. Treatment of the infection during pregnancy is safe but relies upon detection. Women with primary infection during pregnancy may be at increased risk of morbidity and pregnancy failure due to intrauterine infection. Case control studies are needed where pregnant women tested positive by NAATs for Ct infection are also tested by serology to distinguish between primary and recurrent infection and are followed up for pregnancy outcome. This would establish whether or not there is a difference in morbidity due to Ct infection associated with pregnancy stratified on the basis of exposure. This in turn would allow for better risk estimates for pregnant women and determination of whether or not Ct screening based on NAATs and serology during pregnancy is likely to be cost-effective.
A.W.H. is supported by an MRC Clinician Scientist Fellowship.
The authors report no conflicts of interest.
Dr. Sarah E.M. Howie, Professor of Immunopathology, MRC Centre for Inflammation Research, University of Edinburgh, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK.
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 12(62):57-64, July 2011. Copyright © Discovery Medicine. All rights reserved.]