3.3 Subgroup and sensitivity analysis
Subgroup analyses were performed based on sample size, study design (cohort or cross-sectional study vs case control), economic level (developed countries vs developing countries) and whether adjustment was performed for body weight or parity. Table 2 shows the detailed results. On subgroup analysis, studies conducted in developing countries were found to be associated with a higher pooled OR (OR: 3.03, 95% CI 1.87–4.19) as compared to that of studies conducted in developed countries (OR: 1.30, 95% CI 1.21–1.39). In addition, adjustment for body weight and parity had no influence on the results (Table 2).
Sensitivity analysis of the observed association between urinary tract infection and PE was performed. The results showed that exclusion of any individual study had little influence on the pooled OR (95% CI) (Fig. 3).
4.1 Relationship between UTI during pregnancy and preeclampsia
There are lingering questions regarding the nature of association between maternal infection and PE.
Indeed the relationship between UTI during pregnancy and PE has evoked much debate in the last 40 years. In the absence of any definitive evidence, the precise nature of the association, whether casual, confounded, or spurious, is yet to be elucidated. The subject of our research is important as UTI is a common occurrence in pregnant women, and can be easily diagnosed and effectively treated. Detection of an association between UTI in pregnancy and PE could help devise interventions for early diagnosis and treatment of UTI, which would ameliorate a major cause of complication in pregnant women.
Our study suggests that UTI during pregnancy had 1.31-fold higher risk of PE. Minassian et al also found that pregnant women with UTI were more likely to develop PE in mid-pregnancy. Moreover, results from 2 nonrandomized clinical trials from Germany and Croatia suggest that antibiotic treatment for bacteriuria could significantly reduce the incidence of PE (OR: 0.22, 95% CI: 0.17–0.30 and OR: 0.36, 95% CI: 0.20–0.64, respectively), as compared to that in pregnant women with untreated bacteriuria. Furthermore, a prospective cohort study in 2013 claimed that pregnant women with asymptomatic bacteriuria (ASB) (32–34 weeks of gestation) were at a 3.79 times higher risk of developing PE as compared to pregnant women without ASB; however, no significant difference was seen in early screening and treatment of UTI (till 20 weeks of gestation) between the 2. Overall, these findings imply that early screening and treatment of UTI can reduce the incidence of PE.
In addition, our subgroup analysis revealed that pregnant women with UTI in developing countries were at an increased risk of PE as compared to their counterparts in developed countries. This appears to be due to better quality of antenatal care in the developed countries that includes regular screening for UTI.
Furthermore, obesity and primiparity are known high risk factors for PE. In our subgroup analysis, adjustment for body weight and parity had no influence on the results.
The pathogenesis of PE remains unclear so far, despite decades of research. The pathophysiology of PE is believed to involve aberrant placentation and systemic inflammation. In a study by LaMarca et al inflammatory responses in preeclamptic pregnancies was found to be excessive as compared to that in normal pregnancies. Uteroplacental atherosis is known to be directly associated with PE. Moreover, inflammatory response plays an important role in the initiation and enhancement of uteroplacental atherosis. Therefore, it is plausible that infectious disease, which increase systemic inflammatory burden would also increase the risk of PE. During pregnancy, UTI is one of the most common maternal infections, which can potentially lead to activation of systemic inflammatory response and endothelial injury; this in turn can lead to placental hypoxia and uteroplacental atherosis, and eventual development of PE.
4.3 Strengths and limitations
This study reveals the relationship between UTI during pregnancy and PE through meta-analysis, which is relatively innovative. In addition, our findings are more reliable than those of the meta-analysis by Conde-Agudelo et al, owing to the low level of heterogeneity in our study. However, our meta-analysis also has several limitations. We restricted the scope of our meta-analysis to studies published in English language and missed some articles, which may have introduced an element of publication bias. Furthermore, some studies did not adjust for potential risk factors in a consistent manner. Maternal age, prepregnancy obesity, and primiparity are known risk factors for PE. The lack of adjustment for these confounding factors may have slightly overestimated the OR. Finally, because of a lack of randomized controlled trials, we had to consider only observational studies, which inevitably led to clinical heterogeneity as compared to that associated with double-blind randomized controlled trials.
To conclude, results of our meta-analysis are consistent with those of previous studies which have implicated UTI as a risk factor for the development of PE in pregnant women. Furthermore, it lends credence to the importance of screening for, and treatment of, UTI in pregnant women, especially in developing countries. However, due to its nature, meta-analysis is vulnerable to several forms of bias which may get introduced during the stage of literature search, retrieval, review, and/or data extraction. Randomized controlled trials with robust methodology, and which take cognizance of the timeline of events, dose-response association, and the treatment effects are required to confirm the relation between UTI and PE of pregnancy.
The authors thank The First Affiliated Hospital of Xiamen University, The First Affiliated Hospital of Dalian Medical University, and No. 210 Hospital of PLA during the preparation of the manuscript. We also appreciate the Medjaden Bioscience Limited for their edit and proofreading.
Conceptualization: Ling Yan, Hongdong Hang, Bin Yan.
Data curation: Hongdong Hang, Bin Yan.
Formal analysis: Ling Yan, Yu Jin, Bin Yan.
Funding acquisition: Ling Yan, Yu Jin.
Investigation: Ling Yan, Yu Jin.
Methodology: Yu Jin.
Resources: Bin Yan.
Supervision: Ling Yan, Hongdong Hang, Bin Yan.
Validation: Hongdong Hang, Bin Yan.
Visualization: Bin Yan.
Writing – original draft: Ling Yan, Bin Yan.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
meta-analysis; preeclampsia; urinary tract infection during pregnancy