Article Published in the Author Account of

Sarah E Howie

Chlamydia trachomatis Infection During Pregnancy — Known Unknowns

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.



Introduction

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.

Figure 1. Anatomy of the female reproductive tract.

Figure 1. Anatomy of the female reproductive tract.

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.

Acknowledgments

A.W.H. is supported by an MRC Clinician Scientist Fellowship.

Disclosure

The authors report no conflicts of interest.

Corresponding Author

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.

References

Adams EJ, Charlett A, Edmunds WJ, Hughes G. Chlamydia trachomatis in the United Kingdom: a systematic review and analysis of prevalence studies. Sex Transm Infect 80:354-362, 2004.

Akande V, Turner C, Horner P, Horne A, Pacey A. Impact of Chlamydia trachomatis in the reproductive setting: British Fertility Society Guidelines for practice. Hum Fertil (Camb) 13:115-125, 2010.

Batteiger BE, Xu F, Johnson RE, Rekart ML. Protective immunity to Chlamydia trachomatis genital infection: evidence from human studies. J Infect Dis 201(Suppl 2):S178-S189, 2010.

Beatty WL, Byrne GI, Morrison RP. Repeated persistent infection with chlamydia and the development of chronic inflammation and disease. Trends Microbiol 2:94-98, 1994.

Becher N, Waldorf KA, Hein M, Uldbjerg N. The cervical mucus plug: structured review of the literature. Acta Obstet Gynecol Scand 88:502-513, 2009.

Blas MM, Canchihuaman FA, Alva IE, Hawes SE. Pregnancy outcomes in women infected with Chlamydia trachomatis: a population-based cohort study in Washington state. Sex Transm Infect 83:314-318, 2007.

Brocklehurst P, Rooney G. Interventions for treating genital chlamydia trachomatis infection in pregnancy. Cochrane Database Syst Rev, CD000054, 2000.

Bulmer JN, Williams PJ, Lash GE. Immune cells in the placental bed. Int J Dev Biol 54:281-294, 2010.

Burton MJ. Trachoma: an overview. Br Med Bull 84:99-116, 2007.

Carey AJ, Beagley KW. Chlamydia trachomatis, a hidden epidemic: effects on female reproduction and options for treatment. Am J Reprod Immunol 63:576-586, 2010.

CDC Guidelines, 2010. http://www.cdc.gov/std/treatment/2010/STD-Treatment-2010-RR5912.pdf. Accessed Jul. 4, 2011.

Chen MY, Fairley CK, De GD, Hocking J, Tabrizi S, Wallace EM, Grover S, Gurrin L, Carter R, Pirotta M, Garland S. Screening pregnant women for chlamydia: what are the predictors of infection? Sex Transm Infect 85:31-35, 2009.

Cheney K, Wray L. Chlamydia and associated factors in an under 20s antenatal population. Aust N Z J Obstet Gynaecol 48:40-43, 2008.

Dalgetty DM, Sallenave JM, Critchley HO, Williams AR, Tham WY, King AE, Horne AW. Altered secretory leukocyte protease inhibitor expression in the uterine decidua of tubal compared with intrauterine pregnancy. Hum Reprod 23:1485-1490, 2008.

de la TE, Mulla MJ, Yu AG, Lee SJ, Kavathas PB, Abrahams VM. Chlamydia trachomatis infection modulates trophoblast cytokine/chemokine production. J Immunol 182:3735-3745, 2009.

Dixon RE, Ramsey KH, Schripsema JH, Sanders KM, Ward SM. Time-dependent disruption of oviduct pacemaker cells by chlamydia infection in mice. Biol Reprod 83:244-253, 2010.

ECDC Guidelines, 2009. http://www.ecdc.europa.eu/en/publications/Publications/0906_GUI_Chlamydia_Control_in_Europe.pdf. Accessed Jul. 4, 2011.

El-Shourbagy MA, El-Refaie TA, Sayed KK, Wahba KA, El-Din AS, Fathy MM. Impact of seroconversion and antichlamydial treatment on the rate of pre-eclampsia among Egyptian primigravidae. Int J Gynaecol Obstet 113:137-140, 2011.

Equils O, Lu D, Gatter M, Witkin SS, Bertolotto C, Arditi M, McGregor JA, Simmons CF, Hobel CJ. Chlamydia heat shock protein 60 induces trophoblast apoptosis through TLR4. J Immunol 177:1257-1263, 2006.

Erlebacher A. Immune surveillance of the maternal/fetal interface: controversies, implications. Trends Endocrinol Metab 21:428-434, 2010.

Fejgin MD, Cohen I, Horvat-Kohlmann M, Charles AG, Luzon A, Samra Z. Chlamydia trachomatis infection during pregnancy: can it cause an intrauterine infection? Isr J Med Sci 33:98-102, 1997.

Fitch PM, Wheelhouse NM, Bowles P, Paterson M, Longbottom D, Entrican G, Howie SE. Ectopic lymphoid tissue formation in the lungs of mice infected with Chlamydia pneumoniae is associated with epithelial macrophage inflammatory protein-2/CXCL2 expression. Clin Exp Immunol 162:372-378, 2010.

Gencay M, Koskiniemi M, Ammala P, Fellman V, Narvanen A, Wahlstrom T, Vaheri A, Puolakkainen M. Chlamydia trachomatis seropositivity is associated both with stillbirth and preterm delivery. APMIS 108:584-588, 2000.

Gencay M, Koskiniemi M, Fellman V, Ammala P, Vaheri A, Puolakkainen M. Chlamydia trachomatis infection in mothers with preterm delivery and in their newborn infants. APMIS 109:636-640, 2001.

Gencay M, Koskiniemi M, Saikku P, Puolakkainen M, Raivio K, Koskela P, Vaheri A. Chlamydia trachomatis seropositivity during pregnancy is associated with perinatal complications. Clin Infect Dis 21:424-426, 1995.

Goulis DG, Chappell L, Gibbs RG, Williams D, Dave JR, Taylor P, de SM, Poston L, Williamson C. Association of raised titres of antibodies to Chlamydia pneumoniae with a history of pre-eclampsia. BJOG 112:299-305, 2005.

Gustafsson C, Mjosberg J, Matussek A, Geffers R, Matthiesen L, Berg G, Sharma S, Buer J, Ernerudh J. Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype. PLoS One 3:e2078, 2008.

Hollegaard S, Vogel I, Thorsen P, Jensen IP, Mordhorst CH, Jeune B. Chlamydia trachomatis C-complex serovars are a risk factor for preterm birth. In Vivo 21:107-112, 2007.

Horne AW, Stock SJ, King AE. Innate immunity and disorders of the female reproductive tract. Reproduction 135:739-749, 2008.

Horner P. Chlamydia (uncomplicated, genital). Clin Evid (Online) pii:1607, 2008.

Horner P. The etiology of acute nongonococcal urethritis — the enigma of idiopathic urethritis? Sex Transm Dis 38:187-189, 2011.

Houser BL, Tilburgs T, Hill J, Nicotra ML, Strominger JL. Two unique human decidual macrophage populations. J Immunol 186:2633-2642, 2011.

Howie SE, Horner PJ, Horne AW, Entrican G. Immunity and vaccines against sexually transmitted Chlamydia trachomatis infection. Curr Opin Infect Dis 24:56-61, 2011.

Ismail MA, Moawad AH, Poon E, Henderson C. Role of Chlamydia trachomatis in postpartum endometritis. J Reprod Med 32:280-284, 1987.

Jain A, Nag VL, Goel MM, Chandrawati, Chaturvedi UC. Adverse foetal outcome in specific IgM positive Chlamydia trachomatis infection in pregnancy. Indian J Med Res 94:420-423, 1991.

Johnson AM, Horner P. A new role for Chlamydia trachomatis serology? Sex Transm Infect 84:79-80, 2008.

Johnson HL, Ghanem KG, Zenilman JM, Erbelding EJ. Sexually transmitted infections and adverse pregnancy outcomes among women attending inner city public sexually transmitted diseases clinics. Sex Transm Dis 38:167-171, 2011.

Kakar S, Bhalla P, Maria A, Rana M, Chawla R, Mathur NB. Chlamydia trachomatis causing neonatal conjunctivitis in a tertiary care center. Indian J Med Microbiol 28:45-47, 2010.

Kane N, Kelly R, Saunders PT, Critchley HO. Proliferation of uterine natural killer cells is induced by human chorionic gonadotropin and mediated via the mannose receptor. Endocrinology 150:2882-2888, 2009.

King A, Hiby SE, Gardner L, Joseph S, Bowen JM, Verma S, Burrows TD, Loke YW. Recognition of trophoblast HLA class I molecules by decidual NK cell receptors-a review. Placenta 21(Suppl A):S81-S85, 2000.

King AE, Critchley HO, Kelly RW. The NF-kappaB pathway in human endometrium and first trimester decidua. Mol Hum Reprod 7:175-183, 2001.

King AE, Kelly RW, Sallenave JM, Bocking AD, Challis JR. Innate immune defences in the human uterus during pregnancy. Placenta 28:1099-1106, 2007.

King AE, Wheelhouse N, Cameron S, McDonald SE, Lee KF, Entrican G, Critchley HO, Horne AW. Expression of secretory leukocyte protease inhibitor and elafin in human Fallopian tube and in an in-vitro model of Chlamydia trachomatis infection. Hum Reprod 24:679-686, 2009.

Kishore J, Agarwal J, Agrawal S, Ayyagari A. Seroanalysis of Chlamydia trachomatis and S-TORCH agents in women with recurrent spontaneous abortions. Indian J Pathol Microbiol 46:684-687, 2003.

Koga K, Mor G. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy disorders. Am J Reprod Immunol 63:587-600, 2010.

Lee DC, Hassan SS, Romero R, Tarca AL, Bhatti G, Gervasi MT, Caruso JA, Stemmer PM, Kim CJ, Hansen LK, Becher N, Uldbjerg N. Protein profiling underscores immunological functions of uterine cervical mucus plug in human pregnancy. J Proteomics 74:817-828, 2011.

Lyytikainen E, Kaasila M, Hiltunen-Back E, Lehtinen M, Tasanen K, Surcel HM, Koskela P, Paavonen J. A discrepancy of Chlamydia trachomatis incidence and prevalence trends in Finland 1983-2003. BMC Infect Dis 8:169, 2008a.

Lyytikainen E, Kaasila M, Koskela P, Lehtinen M, Patama T, Pukkala E, Tasanen K, Surcel HM, Paavonen J. Chlamydia trachomatis seroprevalence atlas of Finland 1983-2003. Sex Transm Infect 84:19-22, 2008b.

Macdonald LJ, Boddy SC, Denison FC, Sales KJ, Jabbour HN. A role for Lipoxin A4 as an anti-inflammatory mediator in the human endometrium. Reproduction, epub ahead of print, May 9, 2011.

Mardh PA. Influence of infection with Chlamydia trachomatis on pregnancy outcome, infant health and life-long sequelae in infected offspring. Best Pract Res Clin Obstet Gynaecol 16:847-864, 2002.

Ming L, Xiaoling P, Yan L, Lili W, Qi W, Xiyong Y, Boyao W, Ning H. Purification of antimicrobial factors from human cervical mucus. Hum Reprod 22:1810-1815, 2007.

Mjosberg J, Berg G, Jenmalm MC, Ernerudh J. FOXP3+ regulatory T cells and T helper 1, T helper 2, and T helper 17 cells in human early pregnancy decidua. Biol Reprod 82:698-705, 2010.

Nagamatsu T, Schust DJ. The contribution of macrophages to normal and pathological pregnancies. Am J Reprod Immunol 63:460-471, 2010.

Negishi M, Izumi Y, Aleemuzzaman S, Inaba N, Hayakawa S. Lipopolysaccharide (LPS)-induced interferon (IFN)-gamma production by decidual mononuclear cells (DMNC) is interleukin (IL)-2 and IL-12 dependent. Am J Reprod Immunol 65:20-27, 2011.

Nigro G, Mazzocco M, Mattia E, Di Renzo GC, Carta G, Anceschi MM. Role of the infections in recurrent spontaneous abortion. J Matern Fetal Neonatal Med, epub ahead of print, Jan. 24, 2011.

Olivares-Zavaleta N, Whitmire W, Gardner D, Caldwell HD. Immunization with the attenuated plasmidless Chlamydia trachomatis L2(25667R) strain provides partial protection in a murine model of female genitourinary tract infection. Vaccine 28:1454-1462, 2010.

Pararas MV, Skevaki CL, Kafetzis DA. Preterm birth due to maternal infection: causative pathogens and modes of prevention. Eur J Clin Microbiol Infect Dis 25:562-569, 2006.

Pereira SM, Etlinger D, Aguiar LS, Peres SV, Longatto FA. Simultaneous Chlamydia trachomatis and HPV infection in pregnant women. Diagn Cytopathol 38:397-401, 2010.

Persson K. The role of serology, antibiotic susceptibility testing and serovar determination in genital chlamydial infections. Best Pract Res Clin Obstet Gynaecol 16:801-814, 2002.

Persson K, Mansson A, Jonsson E, Nordenfelt E. Decline of Herpes simplex virus type 2 and Chlamydia trachomatis infections from 1970 to 1993 indicated by a similar change in antibody pattern. Scand J Infect Dis 27:195-199, 1995.

Plaks V, Birnberg T, Berkutzki T, Sela S, BenYashar A, Kalchenko V, Mor G, Keshet E, Dekel N, Neeman M, Jung S. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest 118:3954-3965, 2008.

Roberts SW, Sheffield JS, McIntire DD, Alexander JM. Urine screening for Chlamydia trachomatis during pregnancy. Obstet Gynecol 117:883-885, 2011.

Rours GI, de Krijger RR, Ott A, Willemse HF, de Groot R, Zimmermann LJ, Kornelisse RF, Verbrugh HA, Verkooijen RP. Chlamydia trachomatis and placental inflammation in early preterm delivery. Eur J Epidemiol 26(5):421-428, 2011.

Rours GI, Hammerschlag MR, Van Doornum GJ, Hop WC, de Groot R, Willemse HF, Verbrugh HA, Verkooyen RP. Chlamydia trachomatis respiratory infection in Dutch infants. Arch Dis Child 94:705-707, 2009.

Saito S, Sakai M. Th1/Th2 balance in preeclampsia. J Reprod Immunol 59:161-173, 2003.

Saito S, Shiozaki A, Nakashima A, Sakai M, Sasaki Y. The role of the immune system in preeclampsia. Mol Aspects Med 28:192-209, 2007.

Santner-Nanan B, Peek MJ, Khanam R, Richarts L, Zhu E, Fazekas de St GB, Nanan R. Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia. J Immunol 183:7023-7030, 2009.

Seavey MM, Mosmann TR. Immunoregulation of fetal and anti-paternal immune responses. Immunol Res 40:97-113, 2008.

Shaw JL, Dey SK, Critchley HO, Horne AW. Current knowledge of the aetiology of human tubal ectopic pregnancy. Hum Reprod Update 16:432-444, 2010.

Shaw JL, Fitch P, Cartwright J, Entrican G, Schwarze J, Critchley HO, Horne AW. Lymphoid and myeloid cell populations in the non-pregnant human fallopian tube and in ectopic pregnancy. J Reprod Immunol 89:84-91, 2011a.

Shaw JL, Wills GS, Lee KF, Horner PJ, McClure MO, Abrahams VM, Wheelhouse N, Jabbour HN, Critchley HO, Entrican G, Horne AW. Chlamydia trachomatis infection increases Fallopian tube PROKR2 via TLR2 and NFkappaB activation resulting in a microenvironment predisposed to ectopic pregnancy. Am J Pathol 178:253-260, 2011b.

Shin S, Jang JY, Roh EY, Yoon JH, Kim JS, Han KS, Kim S, Yun Y, Choi YS, Choi JD, Kim SH, Kim SJ, Song EY. Differences in circulating dendritic cell subtypes in pregnant women, cord blood and healthy adult women. J Korean Med Sci 24:853-859, 2009.

SIGN Guidelines, 2010. http://sign.ac.uk/pdf/sign109.pdf. Accessed Jul. 4, 2011.

Silveira MF, Erbelding EJ, Ghanem KG, Johnson HL, Burke AE, Zenilman JM. Risk of Chlamydia trachomatis infection during pregnancy: effectiveness of guidelines-based screening in identifying cases. Int J STD AIDS 21:367-370, 2010.

Silveira MF, Ghanem KG, Erbelding EJ, Burke AE, Johnson HL, Singh RH, Zenilman JM. Chlamydia trachomatis infection during pregnancy and the risk of preterm birth: a case-control study. Int J STD AIDS 20:465-469, 2009.

Smith SD, Dunk CE, Aplin JD, Harris LK, Jones RL. Evidence for immune cell involvement in decidual spiral arteriole remodeling in early human pregnancy. Am J Pathol 174:1959-1971, 2009.

Su H, Morrison R, Messer R, Whitmire W, Hughes S, Caldwell HD. The effect of doxycycline treatment on the development of protective immunity in a murine model of chlamydial genital infection. J Infect Dis 180:1252-1258, 1999.

Sweet RL, Landers DV, Walker C, Schachter J. Chlamydia trachomatis infection and pregnancy outcome. Am J Obstet Gynecol 156:824-833, 1987.

Szarka A, Rigo J, Jr., Lazar L, Beko G, Molvarec A. Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol 11:59, 2010.

UK National Chlamydia Screening Programme, 2011. http://www.chlamydiascreening.nhs.uk/ps/. Accessed Jul. 4, 2011.

Vacca P, Vitale C, Montaldo E, Conte R, Cantoni C, Fulcheri E, Darretta V, Moretta L, Mingari MC. CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells. Proc Natl Acad Sci U S A 108:2402-2407, 2011.

Vickers DM, Zhang Q, Osgood ND. Immunobiological outcomes of repeated chlamydial infection from two models of within-host population dynamics. PLoS One 4:e6886, 2009.

World Health Organization, 2011. http://www.who.int/vaccine_research/diseases/soa_std/en/index1.html. Accessed Jul. 4, 2011.

Wilkowska-Trojniel M, Zdrodowska-Stefanow B, Ostaszewska-Puchalska I, Redzko S, Przepiesc J, Zdrodowski M. The influence of Chlamydia trachomatis infection on spontaneous abortions. Adv Med Sci 54:86-90, 2009.

Wills GS, Horner PJ, Reynolds R, Johnson AM, Muir DA, Brown DW, Winston A, Broadbent AJ, Parker D, McClure MO. Pgp3 Antibody enzyme-linked immunosorbent assay, a sensitive and specific assay for seroepidemiological analysis of Chlamydia trachomatis infection. Clin Vaccine Immunol 16:835-843, 2009.

Witkin SS, Linhares IM, Bongiovanni AM, Herway C, Skupski D. Unique alterations in infection-induced immune activation during pregnancy. BJOG 118:145-153, 2011.

Xie F, Hu Y, Magee LA, Money DM, Patrick DM, Brunham RM, Thomas E, von Dadelszen P. Chlamydia pneumoniae infection in preeclampsia. Hypertens Pregnancy 29:468-477, 2010.

Yamamoto T, Moji K, Kusano Y, Kurokawa K, Kawagoe K, Katamine S. Trend in Chlamydia trachomatis infection among pregnant women in the past ten years in Japan: significance of Chlamydia trachomatis seroprevalence. Sex Transm Dis 25:516-521, 1998.

Yu H, Karunakaran KP, Kelly I, Shen C, Jiang X, Foster LJ, Brunham RC. Immunization with live and dead Chlamydia muridarum induces different levels of protective immunity in a murine genital tract model: correlation with MHC class II peptide presentation and multifunctional Th1 cells. J Immunol 186:3615-3621, 2011.

Yu J, Wu S, Li F, Hu L. Vertical transmission of Chlamydia trachomatis in Chongqing China. Curr Microbiol 58:315-320, 2009.

Zhao J, Lei Z, Liu Y, Li B, Zhang L, Fang H, Song C, Wang X, Zhang GM, Feng ZH, Huang B. Human pregnancy up-regulates Tim-3 in innate immune cells for systemic immunity. J Immunol 182:6618-6624, 2009.

[Discovery Medicine; ISSN: 1539-6509; Discov Med 12(62):57-64, July 2011. Copyright © Discovery Medicine. All rights reserved.]

Access This PDF as a Subscriber |
Close
Close
E-mail It
Close