Background
Despite decades of research, and much progress in discernment of biomarkers in the maternal circulation, the pathogenesis of preeclampsia (PE) remains elusive. The pathophysiology of PE is believed to involve aberrant placentation and an associated increase in systemic inflammation. In this conceptualization, PE becomes more likely when the level of systemic inflammatory burden inherent in pregnancy itself exceeds the maternal capacity to compensate for this additional stress. If this is the case, then it is possible to hypothesize that conditions, such as infectious disease, that increase systemic inflammatory burden should also increase the risk of PE. As urinary tract infection (UTI) represents a common source of inflammation during pregnancy, we tested whether presence of UTI during pregnancy increased the odds of developing PE. Prior work has documented this association. However many of these studies were limited by small cohort sizes and insufficient control for covariates.
Objective
The present study is a secondary analysis of a robust contemporary obstetrical cohort recruited to examine the ability of longitudinally sampled maternal angiogenic concentrations to predict PE. We hypothesize that the occurrence of UTI during a pregnancy is associated with the later occurrence of PE in that pregnancy. As PE is believed to be associated with aberrations in systemic angiogenic levels (placental growth factor and soluble isoform of VEGF receptor), we further hypothesize that there will be significant interactions between maternal angiogenic protein levels and the occurrence of UTI.
Study Design
Women aged ≥18 years (n = 2607) were recruited and followed up prospectively from the initiation of prenatal care through delivery at 3 regional academic centers. PE was defined by American Congress of Obstetricians and Gynecologists criteria and was independently validated by a panel of physicians. UTI was defined by the presence of clinical symptoms necessitating treatment in addition to supportive laboratory evidence. Multivariate logistic regression models were used and controlled for maternal age, race, parity, body mass index, hypertension, diabetes, in vitro fertilization, and smoking status.
Results
There were 129 women with diagnosed UTIs and 235 with PE. Patients with UTI in pregnancy had higher rates of PE (31.1% vs 7.8%, P < .001) compared to those without reported UTI. The mean gestational age (SD) for UTI diagnosis in PE cases and controls was 25.6 (10.4) and 21.9 (10.9) weeks, respectively ( P = .08). The unadjusted odds ratio for PE in the setting of UTI was 5.29 (95% confidence interval, 3.54–7.89). After controlling for confounders, UTI was associated with an odds ratio for PE of 3.2 (95% confidence interval, 2.0–5.1).
Conclusion
Presence of UTI in pregnancy, particularly in the third trimester, is strongly associated with PE. This association supports the hypothesis that the risk of PE is enhanced by an increased maternal inflammatory burden. Prophylaxis against UTI represents a potentially low-cost global intervention to slow or halt the development of PE.
Introduction
Preeclampsia (PE) is characterized by new-onset or worsening hypertension combined with proteinuria and associated signs and symptoms >20 weeks’ gestational age. Although overall mortality from PE has decreased in recent years, it represents a major cause of maternal morbidity and mortality, particularly in developing countries. In a large cohort of patients from low- and middle-income countries, PE conferred a 4-fold increase of maternal death and nearly a 2-fold increase in perinatal death, preterm birth, and low birthweight. Despite decades of research, and much progress in discernment of biomarkers in the maternal circulation, the pathogenesis of PE remains elusive.
Redman and Sargent suggest that pregnancy itself is a state of excess systemic inflammation. In their conceptualization, PE becomes more likely when the level of systemic inflammatory burden inherent in pregnancy itself exceeds the maternal capacity to compensate for this additional stress. If this is the case, then it is possible to hypothesize that conditions, such as infectious disease, that increase systemic inflammatory burden should also increase the risk of PE. This suggestion is not without precedent as there are multiple examples of the association between maternal infection and an increased risk of PE in the medical literature. A variety of systemic maternal infections including HIV, malaria, Chlamydia trachomatis , and periodontal disease have been suggested to increase the risk of PE. Since urinary tract infection (UTI) represents one of the most common maternal infections during pregnancy, one would expect an association with PE. Prior work has documented this association. However many of these studies were limited by small cohort sizes and insufficient control for covariates.
The present study is a secondary analysis of a robust contemporary obstetrical cohort recruited to examine the ability of longitudinally sampled maternal angiogenic concentrations to predict PE. We hypothesize that the occurrence of UTI during a pregnancy is associated with the later occurrence of PE in that pregnancy. As PE is believed to be associated with aberrations in systemic angiogenic levels (placental growth factor [PlGF] and soluble isoform of VEGF receptor [sFLT]), we further hypothesize that there will be significant interactions between maternal angiogenic protein levels and the occurrence of UTI.
Materials and Methods
Study subjects
Participants were initially enrolled at 3 tertiary care academic centers: Brigham and Women’s Hospital and Beth Israel Deaconess Medical Center in Boston, MA, and the Hospital of the University of Pennsylvania in Philadelphia, PA. Women >18 years of age presenting for prenatal care <15 weeks’ gestation were eligible for enrollment. The only initial cohort exclusion criterion was higher-order multiple gestations (triplets or greater). The protocol was approved by institutional review boards at each institution, and written informed consent was obtained from all participating women.
A total of 2607 gestations with delivery at ≥24 weeks’ gestation were enrolled at the 3 study sites from October 2007 through June 2009. All subjects were prospectively enrolled in the first trimester. Among the 3 sites, Brigham and Women’s Hospital contributed 48% of the participants with Beth Israel Deaconess Medical Center and Hospital of the University of Pennsylvania contributing 29% and 23%, respectively. This analysis further excluded women with a history of renal disorders (N = 18; 0.7%). Study visits occurred at the following median (interquartile range) weeks of gestation for all participants: 10.0 (4.4-16.7), 17.8 (12.6-22.7), 26.0 (19.6-30.9), and 35.3 (31.3-39.4).
Specimen collection and laboratory assays
Maternal blood and urine samples were obtained at the 4 visits during the pregnancy. Approximately 10 mL of blood was drawn in EDTA plasma tubes at each study visit, and the samples were kept at 4°C until processing for storage within 4 hours of venipuncture. The specimens were centrifuged for 20 minutes, aliquoted, and stored at –80°C. Samples were shipped in batches on dry ice to Abbott Diagnostics where they were stored at –80°C until analysis. PlGF and sFlt-1 were measured using prototype ARCHITECT immunoassays (Abbott Laboratories, Abbott Park, IL) as previously described.
Clinical data and definitions
Information on the index pregnancy and neonate were abstracted from the medical record and supplemented with data collected specifically for the study. Maternal blood pressure and urinary protein dip were recorded at each study visit. Participants completed a brief questionnaire for background clinical and demographic information.
Gestational hypertension (was defined as blood pressures ≥140 mm Hg systolic or ≥90 mm Hg diastolic at study visits 2-4 with negative urinary protein testing. PE was defined as gestational hypertension with positive urinary protein testing (>300 mg/24 h or protein/creatinine >0.20).
We abstracted information about UTIs and other complications of pregnancy and pregnancy outcomes based on a comprehensive review of the patient’s medical records. UTI was diagnosed by the patient’s providers at each institution. For purposes of this study, a patient was consider to have UTI if she had symptoms such as dysuria and frequency along with a positive urinalysis or urine culture prompting antibiotic treatment by the patient’s provider. Therefore culture data were not universally obtained. Urinalysis was considered positive if bacteria, leukocyte esterase, or blood was present, but not if the only positive finding was proteinuria. The diagnosis of UTI was made prior to the diagnosis of PE. Women with diagnosis of UTI after diagnosis of PE were considered as having no UTI for purposes of this analysis.
The specific management of disorders varied by institution, but all cases of hypertensive disease were deidentified and reviewed by a panel of the study principle investigators. A final diagnosis was only assigned with the approval of this panel. Based on these criteria, 229 (8.8%) pregnancies were identified as PE and 138 (5.3%) as having gestational hypertension. Among PE patients 37 (16.2%) were identified with early PE ≤34 weeks.
Statistical methods
We first examined the sociodemographic and clinical characteristics of the study population based on UTI diagnosis. Differences by UTI status were tested by using Wilcoxon rank sum or χ 2 tests for quantitative and categorical variables, respectively. Logistic regression models were used to describe the relationship between UTI and either gestational hypertension or PE diagnosis. In adjusted models, covariates were included on the basis of biological plausibility or those previously shown to be associated with PE and UTI. The included covariates were maternal body mass index, race/ethnicity, parity, history of PE or diabetes, current diagnosis of chronic hypertension or gestational diabetes, use of assisted reproductive technology, and twin pregnancy. Additional sensitivity analyses were performed examining the relationship between PE and UTI in both nulliparous women and women with no history of PE. Women were then stratified by trimester of UTI diagnosis to further examine the relationship between timing of UTI diagnosis and PE.
Levels of sFlt-1 and PlGF were compared to examine the role of angiogenic factors upon the relationship between PE and UTI. Maternal plasma concentrations of angiogenic factors at a given gestational age range for a given hypertensive diagnosis were compared between women with or without UTI using Wilcoxon rank sum. To take into account the longitudinal nature of the relationship we used linear mixed effect models to generate random slopes and intercepts for either PlGF or s-FLT over time. These random intercepts and slopes were then used as predictors in the adjusted logistic regression models. Analysis was performed using SAS, Version 9.4 (SAS Institute Inc, Cary, NC) and R, Version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria).
Materials and Methods
Study subjects
Participants were initially enrolled at 3 tertiary care academic centers: Brigham and Women’s Hospital and Beth Israel Deaconess Medical Center in Boston, MA, and the Hospital of the University of Pennsylvania in Philadelphia, PA. Women >18 years of age presenting for prenatal care <15 weeks’ gestation were eligible for enrollment. The only initial cohort exclusion criterion was higher-order multiple gestations (triplets or greater). The protocol was approved by institutional review boards at each institution, and written informed consent was obtained from all participating women.
A total of 2607 gestations with delivery at ≥24 weeks’ gestation were enrolled at the 3 study sites from October 2007 through June 2009. All subjects were prospectively enrolled in the first trimester. Among the 3 sites, Brigham and Women’s Hospital contributed 48% of the participants with Beth Israel Deaconess Medical Center and Hospital of the University of Pennsylvania contributing 29% and 23%, respectively. This analysis further excluded women with a history of renal disorders (N = 18; 0.7%). Study visits occurred at the following median (interquartile range) weeks of gestation for all participants: 10.0 (4.4-16.7), 17.8 (12.6-22.7), 26.0 (19.6-30.9), and 35.3 (31.3-39.4).
Specimen collection and laboratory assays
Maternal blood and urine samples were obtained at the 4 visits during the pregnancy. Approximately 10 mL of blood was drawn in EDTA plasma tubes at each study visit, and the samples were kept at 4°C until processing for storage within 4 hours of venipuncture. The specimens were centrifuged for 20 minutes, aliquoted, and stored at –80°C. Samples were shipped in batches on dry ice to Abbott Diagnostics where they were stored at –80°C until analysis. PlGF and sFlt-1 were measured using prototype ARCHITECT immunoassays (Abbott Laboratories, Abbott Park, IL) as previously described.
Clinical data and definitions
Information on the index pregnancy and neonate were abstracted from the medical record and supplemented with data collected specifically for the study. Maternal blood pressure and urinary protein dip were recorded at each study visit. Participants completed a brief questionnaire for background clinical and demographic information.
Gestational hypertension (was defined as blood pressures ≥140 mm Hg systolic or ≥90 mm Hg diastolic at study visits 2-4 with negative urinary protein testing. PE was defined as gestational hypertension with positive urinary protein testing (>300 mg/24 h or protein/creatinine >0.20).
We abstracted information about UTIs and other complications of pregnancy and pregnancy outcomes based on a comprehensive review of the patient’s medical records. UTI was diagnosed by the patient’s providers at each institution. For purposes of this study, a patient was consider to have UTI if she had symptoms such as dysuria and frequency along with a positive urinalysis or urine culture prompting antibiotic treatment by the patient’s provider. Therefore culture data were not universally obtained. Urinalysis was considered positive if bacteria, leukocyte esterase, or blood was present, but not if the only positive finding was proteinuria. The diagnosis of UTI was made prior to the diagnosis of PE. Women with diagnosis of UTI after diagnosis of PE were considered as having no UTI for purposes of this analysis.
The specific management of disorders varied by institution, but all cases of hypertensive disease were deidentified and reviewed by a panel of the study principle investigators. A final diagnosis was only assigned with the approval of this panel. Based on these criteria, 229 (8.8%) pregnancies were identified as PE and 138 (5.3%) as having gestational hypertension. Among PE patients 37 (16.2%) were identified with early PE ≤34 weeks.
Statistical methods
We first examined the sociodemographic and clinical characteristics of the study population based on UTI diagnosis. Differences by UTI status were tested by using Wilcoxon rank sum or χ 2 tests for quantitative and categorical variables, respectively. Logistic regression models were used to describe the relationship between UTI and either gestational hypertension or PE diagnosis. In adjusted models, covariates were included on the basis of biological plausibility or those previously shown to be associated with PE and UTI. The included covariates were maternal body mass index, race/ethnicity, parity, history of PE or diabetes, current diagnosis of chronic hypertension or gestational diabetes, use of assisted reproductive technology, and twin pregnancy. Additional sensitivity analyses were performed examining the relationship between PE and UTI in both nulliparous women and women with no history of PE. Women were then stratified by trimester of UTI diagnosis to further examine the relationship between timing of UTI diagnosis and PE.
Levels of sFlt-1 and PlGF were compared to examine the role of angiogenic factors upon the relationship between PE and UTI. Maternal plasma concentrations of angiogenic factors at a given gestational age range for a given hypertensive diagnosis were compared between women with or without UTI using Wilcoxon rank sum. To take into account the longitudinal nature of the relationship we used linear mixed effect models to generate random slopes and intercepts for either PlGF or s-FLT over time. These random intercepts and slopes were then used as predictors in the adjusted logistic regression models. Analysis was performed using SAS, Version 9.4 (SAS Institute Inc, Cary, NC) and R, Version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria).
Results
The clinical and demographic characteristics of the cohort are presented in Table 1 . Among the 2589 patients in the cohort, 126 (4.9%) patients were diagnosed with UTI and 229 (8.8%) developed PE. There were no statistically significant differences in age, parity, pregestational diabetes, and smoking status between women with and without UTI during pregnancy. Patients with UTI were more likely to be African American (21.4% vs 29.5%, P < .03) with a higher body mass index (26.1 vs 30.0, P < .0001). Women who underwent assisted reproductive technology (9.2% vs 17.8%, P = .001) or a twin pregnancy (4.3% vs 18.6%, P < .0001) or those with the diagnosis of chronic hypertension (5.6% vs 19.4%, P < .0001) were more likely to be affected with UTI.
| Total, n = 2589 | UTI, n = 126 | No UTI, n = 2464 | P value a | |
|---|---|---|---|---|
| Maternal age, y | 31.2 ± 5.7 (18–50) | 30.6 ± 5.9 (18–46) | 31.2 ± 5.7 (18–50) | .26 |
| Maternal BMI at recruitment, kg/m 2 | 26.3 ± 6.3 (16.4–67.8) | 30.0 ± 7.8 (18.8–52.8) | 26.1 ± 6.2 (16.4–67.8) | <.0001 |
| Race | ||||
| Caucasian | 1520 (58.7%) | 59 (46.8%) | 1461 (59.3%) | .02 |
| African American | 564 (21.8%) | 37 (29.4%) | 527 (21.4%) | |
| Hispanic | 248 (9.6%) | 21 (16.7%) | 227 (9.2%) | |
| Asian or other | 257 (9.9%) | 9 (7.1%) | 248 (10.1%) | |
| Nulliparous | 738 (28.5%) | 42 (33.3%) | 696 (28.3%) | .22 |
| Personal history of preeclampsia | 99 (3.8%) | 7 (5.6%) | 92 (3.7%) | .30 |
| Current diagnosis of preeclampsia | 229 (8.8%) | 37 (29.4%) | 192 (7.8%) | <.0001 |
| Current diagnosis of chronic hypertension | 157 (6.1%) | 24 (19.1%) | 133 (5.4%) | <.0001 |
| Pregestational diabetes | 56 (2.2%) | 4 (3.2%) | 52 (2.1%) | .42 |
| Current diagnosis of gestational diabetes | 127 (4.9%) | 14 (11.1%) | 113 (4.6%) | .0009 |
| Underwent assisted reproductive technology | 250 (9.7%) | 22 (17.5%) | 228 (9.3%) | .002 |
| Smoked during pregnancy | 91 (3.5%) | 3 (2.4%) | 88 (3.6%) | .62 |
| Twin gestation | 131 (5.1%) | 24 (19.1%) | 107 (4.3%) | <.0001 |
a Refers to χ 2 , Fisher exact, or Wilcoxon rank sum tests as appropriate between UTI categories.
Women with UTI in pregnancy had higher rates of PE compared to those without UTI (31.0% vs 7.8%, P < .0001). As presented in Table 2 , developing UTI during pregnancy significantly increased the odds of developing PE by nearly 3-fold (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.8–4.6) after adjustment for confounders. Furthermore, women with UTI in pregnancy were at an increased risk of early PE necessitating delivery <34 weeks’ gestation (OR, 5.5; 95% CI, 2.3–12.7). The increased odds of developing PE after diagnosis of UTI during pregnancy persisted in nulliparous women (OR, 5.1; 95% CI, 2.4–10.6) and women who had no history of PE (OR, 3.0; 95% CI, 1.9–4.8).
| Unadjusted OR (95% CI) | P value | Adjusted OR (95% CI) | P value | |
|---|---|---|---|---|
| All participants a | ||||
| All preeclampsia, N = 229 | 4.9 (3.3–7.4) | <.0001 | 2.9 (1.8–4.6) | <.0001 |
| Preeclampsia ≤ 34 wk, N = 37 | 10.8 (5.2–22.5) | <.0001 | 5.5 (2.3–12.7) | <.0001 |
| Preeclampsia >34 wk, N = 197 | 4.0 (2.5–6.4) | <.0001 | 2.5 (1.5–4.1) | .0006 |
| Nulliparous participants b | ||||
| All preeclampsia, N = 72 | 7.2 (3.6–14.2) | <.0001 | 5.1 (2.4–10.6) | <.0001 |
| No history of preeclampsia c | ||||
| All preeclampsia, N = 199 | 5.2 (3.4–8.1) | <.0001 | 3.0 (1.9–4.8) | .0001 |
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