Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 3 (2013) 28–33

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Original Article

Chlamydia trachomatis infection may increase the risk of preeclampsia Catherine L. Haggerty a,b,⇑, Inge Panum c, Soren A. Uldum c, Debra C. Bass a, Jorn Olsen d, Toni Darville e,f, Jamie M. Eastman a, Hyagriv N. Simhan b,g,h, James M. Roberts a,b,g,h, Roberta B. Ness i a

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States Magee-Womens Research Institute, Pittsburgh, PA, United States c Statens Serum Institut, Copenhagen, Denmark d University of Aarhus, Denmark School of Public Health and the Danish Epidemiology Science Centre, Aarhus, Denmark e Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States f Pediatric Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States g Magee-Womens Hospital of UPMC, Pittsburgh, PA, United States h Department of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, United States i University of Texas School of Public Health, Houston, TX, United States b

a r t i c l e

i n f o

Article history: Received 18 July 2012 Accepted 4 September 2012 Available online 28 September 2012 Keywords: Chlamydia trachomatis Chlamydophila pneumoniae Cytomegalovirus Herpes simplex virus Preeclampsia

a b s t r a c t Background: Although the etiology of preeclampsia is not well understood, it has been suggested that excessive systemic inflammation may lead to oxidative stress, promoting the endothelial dysfunction characteristic of preeclampsia. Few prospective studies have examined the role of infection, an immune system stimulator, as a risk factor for preeclampsia. Methods: We conducted a longitudinal study of the relationships between Chlamydia trachomatis (CT), Chlamydophila pneumoniae (CP), cytomegalovirus (CMV), herpes simplex virus (HSV) and preeclampsia among 509 preeclamptic cases and 336 normotensive controls nested within the Danish National Birth Cohort study. Antibodies were analyzed at a first prenatal visit (mean 17.0 weeks) and at a late second/third trimester study visit. Prenatal infections were identified as IgG/IgM seroconversion or a fourfold rise in IgG antibody titers. Multiple regression models were adjusted for maternal age, BMI, smoking status, and time between blood draws. Results: CT infection was associated with preeclampsia (ORadj 1.6, 95% CI 0.7, 3.6), severe preeclampsia (ORadj 1.8, 95% CI 0.6, 5.3), and preeclampsia resulting in preterm birth (ORadj 1.7, 95% CI 0.6–4.9) or birth of a small for gestational age infant (ORadj 2.1, 95% CI 0.6, 7.5), although CT infection was uncommon (n = 33, 4.0%) and associations were not statistically significant. CP, CMV, and HSV infection were not associated with preeclampsia. Conclusions: Women with serological evidence of prenatal CT infection were more likely to develop preeclampsia, although infection was infrequent and confidence intervals were wide. Studies in populations at higher risk for STIs are needed to corroborate this association. Ó 2012 Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in Pregnancy.

⇑ Corresponding author. Address: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 516B Parran Hall, Pittsburgh, PA 15261, United States. E-mail address: [email protected] (C.L. Haggerty). 2210-7789/$ - see front matter Ó 2012 Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in Pregnancy. http://dx.doi.org/10.1016/j.preghy.2012.09.002

C.L. Haggerty et al. / Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 3 (2013) 28–33

Introduction Preeclampsia is a systemic maternal disease, characterized by hypertension and proteinuria [1,2], and is a leading cause of considerable maternal morbidity and perinatal morbidity and mortality worldwide. Although the need for prevention is great, the understanding of the etiology and the availability of screening are underdeveloped. A central pathophysiologic feature of preeclampsia is endothelial dysfunction, which Redman and colleagues have suggested is activated by the generalized inflammatory response to pregnancy, exaggerated in cases of preeclampsia [3]. Cross-sectional third trimester studies have shown that normal pregnancy is associated with leukocyte activation, increased neutrophil production of reactive oxygen species, and increased cytokine production [4,5] and these differences are even more striking among preeclamptic women [4–7]. A two-stage model has been proposed in which poor placentation in the first half of pregnancy leads to a hypoxic and dysfunctional placenta in later pregnancy, triggering a dysfunctional maternal endothelium and systemic inflammatory response, and finally the clinical features of preeclampsia [8]. The cause of the systemic inflammation is unknown, but it has been proposed that increased trophoblast debris released by a dysfunctional placenta may cause a maternal inflammatory burden [8]. Additionally, placental ischemia results in chronic inflammation and thus the production of cytokines and reactive oxygen species and the activation of neutrophils [9]. Other maternal factors may compound the normal inflammatory response to pregnancy, predisposing women to preeclampsia. Hayashi et al. have shown that although serum TNF-a is elevated among preeclamptic women compared to controls, placental TNF-a/total protein levels do not differ [10]. This suggests that elevated circulating maternal TNF-a may contribute to endothelial cell dysfunction and preeclampsia, but that elevated serum TNF-a may not originate from placental tissue. Bacterial and viral infections, known to elicit an overall upregulation of immune mediators, also lead to oxidative stress and endothelial dysfunction [3,4,11,12]. A handful of small epidemiologic studies have linked both bacterial and viral infections, including Chlamydia trachomatis (CT), Chlamydophila pneumonia (CP, formerly Chlamydia pneumoniae), herpes simplex virus (HSV), and cytomegalovirus (CMV) [13–24] to preeclampsia, although most investigations have been cross-sectional. As the causes of inflammation seen in preeclampsia are not clear, and as few longitudinal studies have examined the role of infection in the genesis of preeclampsia, we sought to examine the relationships between primary infection with C. trachomatis, C. pneumoniae, CMV, HSV, and preeclampsia, nested within the large Danish National Birth Cohort study of 101,046 pregnant women.

Methods Study population We performed a nested case-control study examining the serological relationships between C. trachomatis, C.

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pneumoniae, HSV 1/2, CMV and preeclampsia among the Danish National Birth Cohort (DNBC), a longitudinal population-based study of 101,033 pregnancies and offspring. The DNBC was approved by the Danish Ethics Central Committee, and details regarding recruitment, retention, and data collection have been previously published (www.DNBC.dk).{Olsen 2001} Briefly, from 1996 to 2003, general practitioners recruited women at their first prenatal visit. The first prenatal examination consisted of pregnancy confirmation and blood sampling, and women were interviewed twice during pregnancy and twice after delivery. In our study, data from cohort members were merged with National Birth Register and National Hospital Discharge Register data by means of a unique personal code given to each citizen in Denmark. Multiparous women and women with multiple gestations were excluded from our current substudy, because the available epidemiologic evidence suggests fundamental differences in risk patterns associated with preeclampsia in these women. In particular, multiparous women who develop preeclampsia often have a history of prior preeclampsia and may be more likely to be at subclinical cardiovascular risk [25]. Women with multiple gestations are also excluded because of their predictably higher risk for developing preeclampsia. We analyzed antibodies to C. trachomatis, C. pneumoniae, HSV 1/2, and CMV among a subset of 845 single gestation primiparous preeclamptic and normotensive pregnancies enrolled from 9 to 1.10 and was presumptive for the presence of IgG antibodies to HSV 1/2. A negative result entailed an index value of 0.200. CMV total antibodies were detected by an inhibition

immunoassay, where the micro titer plate was coated with crude hyperimmune CMV-reactive monkey IgG (capture antibody) [28]. 50 ll of diluted serum samples (1:5 tested in duplicate, one well with control antigen (uninfected fibroblasts) and 1:100) and CMV antigen (crude CMV full antigen diluted 1:400) was added to the coated wells. After overnight incubation in the refrigerator, the plate was washed. If present, CMV antibodies in the serum sample bound the CMV antigen in competition with CMV antigen binding to capture IgG. Unblocked antigen binding to capture layer was after wash detected by adding biotinylated CMV-reactive monkey IgG to the wells, and after incubation for 1 h at room temperature and a wash, peroxidaseconjugated avidin was added to the wells. After another incubation for 30 min at room temperature, the plate was washed and TMB was added as substrate. After incubation for 10 min at room temperature, the addition of 0.2 M H2SO4 stopped the process. The absorbance was measured using a spectrophotometer with wavelength set at 450/ 650 nm. According to the calculated cut-off the results were categorized as positive, high positive (or reactivated), negative, or non-specific. A non-specific result was reported when the OD value with control antigen and serum diluted 1:5 was

Chlamydia trachomatis infection may increase the risk of preeclampsia.

Although the etiology of preeclampsia is not well understood, it has been suggested that excessive systemic inflammation may lead to oxidative stress,...
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