Association of Bacteriuria with Hypertension Risk in Pregnant Women

Introduction

The global incidence of hypertensive disorders of pregnancy has increased from 16.30 million to 18.08 million, reflecting a 10.92% rise from 1990 to 2019 [1]. Interestingly, Southeast Asia experienced a decrease from 1.6 million to 1.4 million during the same period. Despite this global trend, Indonesia, as a developing nation, grapples with a significant challenge of high maternal mortality rates [2,3]. Data from a multicenter trial conducted in 11 tertiary hospitals across Indonesia revealed an average incidence of hypertension in pregnancy at 22.1%, affecting 3219 cases out of 17 771 total deliveries [4]. An extensive study covering all provinces in Indonesia, including 9024 pregnant women from national health data, reported a prevalence of hypertension in pregnancy at 6.18%, with the highest incidence found in West Java at 10.57% [2].

Pregnancy often leads to changes in the urinary tract, both in terms of physiology and structure. These changes can increase the risk of pathogens ascending into the urinary bladder and causing urinary tract infections (UTIs) [5]. Interestingly, the incidence of UTIs is higher among pregnant women compared to other healthy women in the general population [6]. UTIs, whether symptomatic or asymptomatic, are common during pregnancy and can have adverse effects on both the mother and the newborn, such as pyelonephritis, urosepsis, premature labor, and even stillbirths [5,7].

Hypertension in pregnancy refers to elevated blood pressure, with systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg during pregnancy. Eclampsia is a severe complication of preeclampsia, characterized by generalized seizures during pregnancy or postpartum in women with signs of preeclampsia. Impending eclampsia indicates the presence of warning signs or symptoms suggesting the development of eclampsia, such as severe headache or neurological complications. Gestational hypertension is the development of persistent high blood pressure (≥140/90 mmHg) after 20 weeks of gestation without proteinuria or other signs of preeclampsia. Chronic hypertension refers to pre-existing hypertension occurring before pregnancy or first diagnosed before 20 weeks of gestation. Superimposed preeclampsia occurs when a pregnant woman with chronic hypertension develops preeclampsia. Preeclampsia is a pregnancy-specific condition characterized by high blood pressure (≥140/90 mmHg) and the presence of at least 1 of the following: proteinuria, acute kidney injury, neurological complications, hematological complications, or uteroplacental dysfunction. Severe preeclampsia is a more severe form characterized by high blood pressure (≥160/110 mmHg) and may include complications such as eclampsia or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) [8].

The diagnosis of UTIs in pregnancy is less well-studied and more challenging. Pregnant women may experience symptoms that mimic UTIs, such as frequency, abdominal pain, or contractions. Thus, sometimes it is difficult to distinguish between asymptomatic bacteriuria (ASB) and UTIs. ASB, characterized by bacteriuria without UTI signs or symptoms, can be present in pregnant women. The diagnostic workup involves various methods: 1) urine dipstick, 2) urine sediment, and 3) bacterial cultures, each of which has several limitations [7]. The parameters of the urine dipstick include nitrite and leukocyte esterase, as many gram-negative bacteria produce the enzyme nitrate reductase [9]. The sensitivity and specificity of nitrite for ASB in pregnant women are 0.55 and 0.99, respectively, while for leukocyte esterase they are 0.72 and 0.82, respectively [10]. The parameters of urine sediment include leukocyte and bacteriuria counting, with sensitivity and specificity ranging from 57.1% to 97% and 27% to 97%, respectively [11]. Urine culture parameters involve determining bacterial growth, although the exact bacterial numbers are not well defined. The most common cutoffs used in clinical practice range from >103 to 105 colony-forming units (CFU)/mL [12].

Urinary tract infections (UTIs) are associated with an increased risk of developing hypertensive disorders of pregnancy, including eclampsia, impending eclampsia, gestational hypertension, chronic hypertension, superimposed preeclampsia, preeclampsia, and severe preeclampsia. UTIs can contribute to development of these conditions through various mechanisms [13]. Infection-induced inflammation and immune response can lead to endothelial dysfunction and impaired placental development, which are key factors in the pathogenesis of hypertensive disorders of pregnancy [14]. Additionally, UTIs can cause systemic inflammatory responses, oxidative stress, and activation of the renin-angiotensin-aldosterone system, all of which contribute to elevated blood pressure and the development of hypertension in pregnancy [15]. Furthermore, UTIs can directly affect renal function and increase the risk of renal dysfunction, which is often seen in severe forms of hypertensive disorders of pregnancy. Overall, the presence of a UTI during pregnancy can significantly increase the risk and severity of hypertensive disorders, highlighting the importance of early detection and appropriate management of UTIs in pregnant women to prevent adverse outcomes [13,16].

The present study examined the correlation between bacteriuria in pregnancy as an indicator of UTIs and hypertension during pregnancy, emphasizing the importance of early identification and appropriate therapy of UTIs in pregnant women to avoid negative consequences. An observational study is necessary to investigate the relationship between urinary tract infections (UTIs) during pregnancy and hypertension in pregnancy. This multicenter study aimed to compare 226 women with hypertension in pregnancy and 517 normotensive pregnant women to evaluate the association between hypertension and bacteriuria in pregnancy. This study is particularly important in the specific district being studied, as no targeted research has been carried out in this area.

Material and Methods

ETHICS STATEMENT:

This study was conducted in accordance with the ethics standards of the institutions involved. Approval was granted by the Ethics Committee of Margono Hospital (Approval Number: 420/03289) and the Ethics Committee of Hasan Sadikin Hospital (Approval Number: DP.04.03/D.XIV.6.5/134/2024). All procedures performed in this study involving human participants were in accordance with the ethics standards of these committees and the 1964 Helsinki Declaration and its later amendments or comparable ethics standards.

STUDY DESIGN AND SETTINGS:

This was an observational study. The study design was a cross-sectional study. The study conducted from October 2022 to September 2023 (1 year) at Hasan Sadikin General Hospital (RSHS) in West Java and Prof. Dr. Margono Soekardjo (RSMS) in Central Java, Indonesia.

STUDY POPULATION:

Pregnant women at any gestational age were enrolled in the study. Figure 1 shows a flowchart of patient selection and grouping. Inclusion criteria in this study were pregnant women with hypertension. Clinical data for the patient regarding hypertension status and bacteriuria status were obtained at the same time. Hypertension in pregnancy was defined as systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg. Eclampsia involved seizures in women with signs of preeclampsia, while impending eclampsia was indicated by symptoms like severe headache, visual disturbances, and epigastric pain. Gestational hypertension is defined as a new-onset or persistent hypertension after 20 weeks, without proteinuria. Chronic hypertension was pre-existing or diagnosed at 20 weeks. Superimposed preeclampsia occurs when chronic hypertension women develop new-onset proteinuria or preeclampsia features during pregnancy. Preeclampsia involves gestational hypertension with accompanying features. Severe preeclampsia includes more severe forms and may involve eclampsia or HELLP syndrome. Blood pressure was measured 2 times with a sphygmomanometer [8].

Inclusion criteria of this study were women with any gestational age who were admitted for obstetric care for delivery. Participants were categorized into 2 groups: those diagnosed with hypertension in pregnancy (defined as systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg) and those who remained normotensive throughout pregnancy. All women underwent routine urinalysis upon admission to screen for the presence of bacteriuria.

The patients included in the study were diagnosed with hypertension at the time of admission, excluding those with chronic hypertension diagnosed prior to admission or delivery. Classification of hypertension in pregnancy was based on the International Society for the Study of Hypertension in Pregnancy (ISSHP) guidelines [8]. Patients were admitted for pregnancy termination either from a polyclinic or an emergency delivery room.

Once diagnosed with hypertension in pregnancy, patients underwent complete blood testing and urinalysis to monitor their condition.

This research also excluded pregnant women who were younger than age 20 years and older than 35 years, had obesity, nulliparity, multiple gestations, history of chronic disease (renal disease, diabetes, chronic hypertension), or history of other infections (premature rupture of membranes, dental infections, respiratory infection such as tuberculosis, pneumonia, and other forms of infection).

As described before, a “true UTI” is present when these 3 criteria are meet:

A positive culture is defined as:

Bacteriuria denotes the existence of bacteria in the urine, which may be either symptomatic or asymptomatic [17]. In this study, bacteriuria was identified exclusively through routine urinalysis. The detection of bacteria, often quantified as the number of microorganisms per high-power field (HPF), served as the primary indicator of infection. For symptomatic individuals, any bacterial presence could suggest a urinary tract infection (UTI), while the standard threshold for significant bacteriuria is ≥100 000 colony-forming units (CFU)/mL, represented as 5+ on urinalysis. For specific patient populations, such as catheterized or symptomatic patients, bacteriuria may be considered significant at a lower threshold, such as 2+ (approximately 100 CFU/mL) [18].

In this study, a qualitative approach was used to classify bacteriuria as either ‘positive’ or ‘negative’. Positive bacteriuria was defined by the presence of bacteria on urinalysis, while negative bacteriuria referred to samples with no bacterial presence. Because urine culture is not a routine procedure in Indonesia and is only performed based on clinical indications, this qualitative bacteriuria criteria was applied as an initial screening method, particularly for pregnant women, upon admission. This approach serves as an effective first-line screening to identify potential urinary tract infections (UTIs) or asymptomatic bacteriuria, facilitating timely clinical management in this population.

SAMPLING METHOD:

This study used total sampling of all pregnant women based on inclusion criteria in the year 2022–2023 at Hasan Sadikin and Margono Hospital. These data were analyzed using the chi-square comparison method. Prevalence ratio (PR) was used to determine the association between the bacterial urinalysis tests from patients with hypertension in their pregnancy and patients with non-hypertension in their pregnancy.

DATA ANALYSIS:

To evaluate the association between the presence of bacteriuria during routine urinalysis and the occurrence of hypertension in pregnancy, crude odds ratios (OR) were calculated along with 95% confidence intervals (CI). The odds ratios were derived by comparing the frequency of hypertension and non-hypertension in patients with and without bacteriuria. A chi-squared test was performed to assess statistical significance, and a P value of <0.05 was considered statistically significant.

The prevalence ratio (PR) was used to determine the likelihood of hypertension in pregnant patients with bacteriuria compared to those without bacteriuria. The statistical analysis was conducted with IBM SPSS Statistics version 29.0.1.0 (IBM Corp. Released 2023. IBM SPSS Statistics for Windows, Version 29.0. Armonk, NY: IBM Corp.).

DATA COLLECTION:

Samples were collected from the registered pregnant women who come from polyclinic or maternal emergency rooms who were hospitalized for giving birth. Samples obtained from registered pregnant women were sourced from polyclinics or maternal emergency departments where they were admitted for childbirth. All participants in our study had simultaneous blood pressure measurement and standard urinalysis. In our setting, urinalysis is a standard procedure, which is why bacteriuria and hypertension in pregnancy were detected concurrently. The observer reached a definitive diagnosis following the completion of all examinations.

Pregnant women underwent laboratory tests, including urinalysis. Urinalysis was initiated by clarifying its objective, securing informed consent, and confirming the availability of requisite equipment. The patients were directed to obtain a midstream urine specimen in a sterile container, highlighting the need of cleanliness and contamination avoidance. A complete urinalysis, including microscopic examination, was employed to obtain detailed and reliable results. Qualitative bacterial assessment was performed.

Results

This study included 743 subjects – 226 subjects with hypertension in pregnancy and 517 subjects without. Table 1 shows obstetric and clinical characteristics based on urinary tract infection (UTI) presence. Notably, pregnant women with UTIs were most commonly aged 26–35, as were those without UTIs. BMI was almost the same in the UTI group and the non-UTI group, as were parity status, gestational age, type of hypertension. There was no significant difference in patient characteristics between groups.

Prevalence ratio is a measure used in epidemiological studies to compare the likelihood of an outcome between 2 groups. It represents the ratio of the probability of an event occurring in the exposed group to the probability of the event in the unexposed group. According to the prevalence ratio, women who had bacteriuria were 1.62 times more likely to have hypertension during pregnancy compared to those without bacteriuria. The prevalence ratio (PR) for this research and its calculation used the following formula:

Notes:

Table 2 summarizes the association of bacteriuria and hypertension in pregnancy, comparing 226 women with hypertension to 517 normotensive pregnant women. Among the hypertensive group, 125 women (55.3%) had UTIs, while 101 (44.7%) did not. In contrast, in the normotensive group, 197 women (38.1%) had UTIs, and 320 (61.9%) did not.

The odds ratio (OR) for the association between UTIs and hypertension was 2.01, indicating that women with bacteriuria were approximately twice as likely to have hypertension (OR=2.01, 95% CI: 1.47–2.76, P<0.001). This association was statistically significant. Conversely, the odds ratio for non-bacteriuria was 0.5, suggesting that women without bacteriuria were less likely to have a non-hypertensive condition compared to women with bacteriuria (OR=0.5, 95% CI: 0.38–1.02, P<0.001).

Discussion

CONFOUNDING FACTORS:

The present study considered potential confounding factors in the association between urinary tract infections (UTIs) observed from bacteriuria and preeclampsia. Maternal age <20 and >35 years old, obesity, nulliparity, history of other infections, and history of chronic disease are confounders due to being linked to both UTIs and hypertension, necessitating statistical adjustment. Those confounders were excluded from the samples.

LIMITATIONS OF THE STUDY:

The investigation carried out in this multicenter research is constrained by its cross-sectional design, which hinders the ability to establish a causal link between the occurrence of bacteriuria during pregnancy and the onset of hypertension. Cross-sectional designs provide a limited view at a particular moment and are unable to determine causal relationships. To achieve a deeper understanding, additional prospective studies with larger sample sizes and the inclusion of confounders are essential.

The investigation did not evaluate additional urinalysis parameters that may signify UTIs, including nitrite, leukocyte esterase, and proteinuria. While urine culture is recognized as the criterion standard for diagnosing UTIs, it has not yet become a standard procedure for all pregnant women at Margono Soekarjo Hospital.

Another limitation of this study is the application of broad exclusion criteria, which were established to reduce potential confounders, including maternal age, obesity, nulliparity, multiple gestations, chronic diseases, and a history of other infections. This method contributed to a more uniform study group and minimized the impact of independent risk factors; however, it could restrict the applicability of the results to the wider population of pregnant women. Future studies may benefit from integrating these potential confounders into statistical models instead of omitting them from the study population.

Conclusions

We found a statistically significant association between urinary tract infections (UTIs) observed from bacteriuria during pregnancy and an increased risk of hypertension in pregnancy. Pregnant women with bacteriuria had higher odds of developing hypertension in pregnancy compared to those without. Given that bacteriuria is commonly screened during routine admissions, it could be a valuable tool for early identification of pregnant women at higher risk of developing hypertension. Close monitoring of those with bacteriuria is recommended to help manage and potentially prevent hypertensive disorders during pregnancy.