urinalysis case study

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• URINALYSIS CASES AND CRITICAL THINKING

Gerald D. Redwine, PhD, MT(ASCP)

The physical and chemical examination of urine samples plays an essential role in the diagnosis of patients’ pathological conditions. However, the sheer number of routine urinalysis can minimize their significance, especially considering that most analyses are automated, which can foster complacency for less than apparent problems. As a result of seemingly more critical concerns, one may defer the interpretation for the clinician to assess. Nevertheless, detecting abnormal results and possible causes is required, regardless of whether the analysis was manual or automated. Knowing the effects of pigmentation, drugs, pH, and ascorbic acid, for example, are samples that always need attention.

Manual analysis is further complicated, with several idiosyncrasies innate to manufacturers. For example, differences in popular brands, such as, Multistix, that requires reading each chemical pad at the specific time indicated. But the Chemstrip and vChem strips readings are stable between one and two minutes, except leukocytes read at two minutes, all necessitating the need for special attention to the manufacturers’ instructions. Concerning ascorbic acid, knowing that Chemstrip eliminates ascorbic acid interference with blood by overlaying the pad with iodate, and the vChem strips have a detection pad for the substance; in contrast, knowing that the Multistix has neither, is essential. Finally, knowing to ignore the different coloration on the perimeter of the pad on all strips and asking for a recollect on extremely high pH is also vital.

How are the critical thinking skills needed for a urinalysis assessment best developed? In academia, it seemed best, following initial training, to have students complete weeks of daily intensive practice of the entire urinalysis (physical, chemical, and microscopic) in an open lab setting on multiple patient samples. In combination with these analyses, they were given case studies like the ones administered later in a practical examination. The following is a composite of the answer stating what they thought was the most probable cause to three of the 17 cases given on their exam, using Multistix, with further comments in parenthesis. Assessments constrained the students to answer the question under the given condition, knowing they would ask for a recollect in some instances.

• What would explain the apparent disagreement between the nitrite and leukocyte reaction?
• What accounts for the clarity of the sample in the chemical examination?
• What does the Acetest suggest about the chemical reactions, based on literature?
• Non-nitrate reducing organism. (i.e., bacteria, yeast, trichomonads, and chlamydia) Or Trauma. (Other less likely possibilities.)
• Large blood. (Also slightly enhanced the protein.)
• More sensitive because of the added glycine. (Glycine detects acetone. vChem strips have the same.)

• What could explain the single most unexpected finding within the chemical reactions?
• What could account for the protein and SSA discrepancy?
• What should the adjusted strip value read?
• What is the definitive source(s) for reporting the final specific gravity (SG) reading (manual/analyzer/and or name another source) on this specimen?
• With an SG = 1.040, what value is the final specific gravity?
• Negative leukocytes could result from any or all three of the following. 1) Alkalinity 2) >3g/dL glucose 3) High specific gravity.
• Alkaline pH can cause a false positive protein; also, the blood that is missing in the supernatant for the SSA could account for the 2+ SSA.
• Because pH is ≥ 6.5, then add .005 to the dip strip value. Strip SG = 1.035 . (Multistix only)
• Because of the ≥ 100 protein, then run on the refractometer. (Total Solid (TS) meter/Refractometer.)
• Subtract 0.003 for every 1 g/dl protein; subtract 0.004 for every 1 g/dl glucose. Report SG: 1.026 .

• What could explain the disagreement that exists within the chemical reactions?
• Explain the correlation between chemical reactions and the SSA?
• What are the two specific adjustments needed for the specific gravity?
• What is the final strip specific gravity?
• A non-nitrite reducing microbe such as Trichomonas or Chlamydia . Or postrenal trauma. (Other nitrite negative possibilities. Also, if not for the trace protein, ascorbic acid is suspect.) Best observation: Yellow-Green ~ Biliverdin. False-negative bilirubin. Hence, the need for a recollection and run on a fresh sample to ascertain the true values.
• Expected the SSA to be greater. Alkaline pH can cause a false positive protein, or in this case, falsely increase the value.
• Because pH is ≥ 6.5, then add .005 to the dip strip value. Because of the ≥ 100 protein, then run on the refractometer. TS (Total Solid) meter/Refractometer. (Multistix only)
• Strip SG = 1.015.

Responses to the open lab concept, despite significantly more than usual time commitment on behalf of all involved, and reagents, the sacrifices were met with positive feedback from the students on superseding their learning outcomes. The learning outcomes summarized is critical thinking applied to urinalysis case studies.

Reference: Brunzel, N. A., MS, MLS(ASCP) CM . Fundamentals of Urine and Body Fluid Analysis , 4th Edition

Gerald D. Redwine is an associate professor at Texas State University Clinical Laboratory Science Program in San Marcos, Texas.

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Article Contents

Introduction, case report, conflicts of interest statement, ethical approval.

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Educational case: a patient with proteinuria

• Article contents
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• Supplementary Data

Christopher N Kassam, Vivian W M Yiu, Meryl H Griffiths, William G Petchey, Educational case: a patient with proteinuria, Oxford Medical Case Reports , Volume 2020, Issue 6, June 2020, omz148, https://doi.org/10.1093/omcr/omz148

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This is an educational case suitable for all readers, but aimed particularly at trainees preparing for MRCP. Using the example of a patient presenting to clinic with proteinuria, aspects of differential diagnosis, pathology and management are explored.

A 37-year-old male Caucasian administrator presented to general nephrology clinic after his GP noted 3+ proteinuria on urinalysis.

His symptoms included tiredness and frothy urine for 6 months. He had not experienced any haematuria, lower urinary tract symptoms, flank pain, ankle swelling, breathlessness or recent weight change. He had a past medical history of obstructive sleep apnoea and was not diabetic. He took no regular medications and had no known allergies. He had a family history of cardiovascular disease on his father’s side and lung cancer on his mother’s side. There was no family history of renal disease. He had never smoked. A recent HbA1c performed by his GP was 41 mmol/mol (5.9%).

On examination, the patient’s BMI was 38 kg/m 2 , and his blood pressure was 133/76 mmHg. There was no detectable peri-orbital or pedal oedema. His JVP was not raised. His chest was clear on auscultation and his kidneys were not palpable. There was no rash. Urinalysis confirmed 3+ proteinuria and no haematuria.

Diabetic nephropathy

Membranous nephropathy

Granulomatosis with polyangiitis

Lupus nephritis (class V)

Alport syndrome

Explanation: Membranous nephropathy is an immune-mediated glomerulopathy which is the commonest primary cause of nephrotic syndrome in Caucasian adults [ 1 ]. Diabetic nephropathy is a common cause of proteinuria, but HbA1c is not elevated and it is unusual for previously undiagnosed diabetes to present with proteinuria in the absence of other symptoms. Granulomatosis with polyangiitis is rare and tends to present with systemic malaise and multi-organ involvement; urinalysis typically shows both protein and blood. Class V lupus nephritis is a possibility in this case, but is less common than membranous nephropathy, and would often cause haematuria in addition. Alport syndrome is a genetic disorder (usually X-linked) caused by defects in type IV collagen synthesis; it is unlikely in the absence of a family history or deafness, and usually presents with progressive renal impairment rather than proteinuria. There is some evidence that primary focal segmental glomerulosclerosis may be overtaking membranous nephropathy as the leading primary cause of nephrotic syndrome, particularly in black patients; however, FSGS was not an option in this question [ 2 ].

Investigations were performed (Table 1). Additionally, screening tests for HIV, hepatitis B and hepatitis C were negative. Renal ultrasound demonstrated that both kidneys were of normal size, with no cysts or masses (bipolar length LEFT 11.3 cm, RIGHT 11.7 cm).

> 3.5 mg/mmol

> 30 mg/mmol

> 150 mg/mmol

> 250 mg/mmol

> 300 mg/mmol

Explanation: 24-hour urinary protein excretion is no longer routinely measured due to impracticality and inaccuracies in timing urine collection; it has largely been replaced by the spot measurement of albumin:creatinine or protein:creatinine ratio (PCR). An ACR of > 250 mg/mmol corresponds to a 24-hour urinary protein excretion of > 3.5 g, the threshold for nephrotic-range proteinuria. If urinary PCR is used, the threshold is 300 mg/mmol. An ACR of < 2.5 mg/mmol (males) or < 3.5 mg/mmol (females) is considered normal, while an ACR of 2.5–30 mg/mmol (males) or 3.5–30 mg/mmol (females) indicates microalbuminuria. Note that microalbuminuria is not usually detected by urine dipsticks.

A renal biopsy was performed to establish the underlying cause of the patient’s proteinuria. A biopsy of his left kidney was successfully taken. Representative sections are shown in Fig. 1 .

Representative sections from the biopsy of the patient’s left kidney, H&E stain.

Investigation results

Congo red staining was negative. Immunofluorescence showed some staining for IgM and complement C3 in sclerotic glomerular lesions, but was otherwise unremarkable.

Amyloidosis

Obesity-related glomerulopathy

Primary focal segmental glomerulosclerosis

Explanation: Obesity-related glomerulopathy (ORG) typically presents with sub-nephrotic proteinuria in patients with BMIs > 30 kg/m 2 . Nephrotic syndrome is not usually seen, even when the proteinuria reaches nephrotic range [ 3 , 4 ]. In case series, the prevalence of renal impairment at diagnosis has ranged from 33 to 44%, with 10–33% of patients eventually progressing to end-stage kidney disease [ 5–7 ]. However, in early stages of the disease, creatinine may be normal or low due to glomerular hyperfiltration. Pathologically, renal biopsy histology demonstrates glomerulomegaly and focal segmental glomerulosclerosis (predominantly perihilar in distribution), with non-specific immunofluorescence findings. In this case, the biopsy findings are not typical of either amyloidosis or membranous nephropathy. In addition, negative Congo red staining and myeloma screen make amyloidosis unlikely, while anti-phospholipase A2 receptor antibody is positive in 70% of patients with primary membranous nephropathy [ 1 ]. While the histological appearance of ORG has some similarities to that of diabetic nephropathy (so-called ‘diabetoid’ changes), this patient’s HbA1c indicates normal glycaemic control. Primary FSGS remains a possibility; however, patients commonly present with nephrotic syndrome, glomerulomegaly is not usually seen and a perihilar distribution of sclerotic lesions is typically associated with secondary (adaptive) causes of FSGS such as ORG. It is essential to distinguish between primary and secondary FSGS so as to avoid treating obese patients with high-dose corticosteroids for prolonged periods. Electron microscopy may further assist in making this distinction: typically in primary FSGS podocyte foot processes are diffusely effaced from early in the disease course, whereas in secondary FSGS, foot process effacement is segmental and develops more slowly [ 8 ].

Bariatric surgery

Spironolactone

Structured weight-loss programme

Watchful waiting

Explanation: There is no definitive evidence available as yet on the management of ORG. However, Renin-Angiotensin-Aldosterone blockade with an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) is the most evidence-based intervention for reducing proteinuria and preventing progression to end-stage renal disease [ 3 ]. Indeed, NICE recommends that all patients with ACR > 70 mg/mmoL due to any cause should be offered an ACE inhibitor or ARB [ 9 ]. There is also some evidence that weight-loss interventions (particularly bariatric surgery) may induce rapid improvements in glomerular hyperfiltration and proteinuria, both in patients with ORG and more broadly in obese patients with CKD [ 3 ]. However, the literature on weight-loss interventions suffers from flaws in study design and limited follow-up, and provides little evidence regarding long-term progression to end-stage renal disease.

The patient was started on ramipril 5 mg OD and advised to return for 6-monthly review in nephrology clinic. After 12 years, his BMI had increased to 41 kg/m 2 , his serum creatinine had progressively risen to 622 μmol/L and his eGFR had fallen to 8 mL/min/1.73 m 2 . He was referred to the low-clearance clinic to discuss renal replacement therapy (RRT).

Automated peritoneal dialysis

Conservative management

Continuous ambulatory peritoneal dialysis

Intermittent haemodialysis

Kidney transplant

Explanation: While all patients should be offered the option of conservative management, this will not usually be the first choice in a young patient. Transplantation offers a clear survival benefit over any modality of dialysis irrespective of BMI, and current NICE guidelines suggest that patients should not be excluded from transplantation on the basis of BMI alone [ 10 , 11 ]. Kidney transplant is, therefore, the most appropriate option. However, BMI >  35 is associated with an increased risk of adverse outcomes including surgical complications and graft loss, and in practice, in the context of donor scarcity, many centres exclude very obese patients from transplantation or require weight loss prior to transplant listing [ 12 ]. Clinicians will, therefore, often find themselves offering other RRT modalities for obese patients, either long-term or as a bridge to transplant. There is no high-quality evidence regarding the effect of peritoneal dialysis versus haemodialysis on mortality or quality of life in adults, and the patient should be offered the choice of haemodialysis and peritoneal dialysis modalities depending on local service availability [ 13 ]. However, from a technical perspective, insertion of a peritoneal dialysis catheter would be difficult for a patient with BMI 41 kg/m 2 , potentially requiring a pre-sternal catheter, which is not available at all centres.

The pathogenesis of ORG is complex and incompletely understood. Obesity is known to be associated with increased circulating levels of angiotensin II, due in part to angiotensinogen synthesis in adipose tissue [ 14 ]. Increased angiotensin II results in efferent arteriole constriction and afferent arteriole dilatation (both directly and via tubuloglomerular feedback), leading to glomerular hyperfiltration. Increased glomerular pressure is thought to lead first to glomerulomegaly and eventually to podocyte detachment and FSGS lesions. There is also evidence that insulin resistance and alterations in circulating adipokine concentrations may directly contribute to podocyte loss [ 3 ].

The prevalence of obesity (defined as BMI > 30) among adults in England has risen from 15% in 1993 to 26% in 2016; similar rates are found in other parts of the UK [ 15 ]. All physicians will undoubtedly be required to manage ever-increasing numbers of obese patients. The obesity epidemic has important implications for renal medicine. Obesity is a major risk factor for both malignant and non-malignant renal disease: the relative risk for end-stage renal failure in obesity is 4.07, while 26% of non-malignant renal disease in industrialised countries is attributable to being overweight [ 16 ]. While much of this excess risk is due to the complications of obesity such as diabetes and hypertension, a sub-population of obese patients develop proteinuria in the absence of other risk factors. Studies on these patients have defined ORG as an independent pathological entity. Indeed, in the absence of routine renal biopsy, some evidence suggests that up to 10% of cases of presumed diabetic nephropathy may in fact be wholly or partly due to ORG [ 17 ].

As obesity rates continue to rise globally, the incidence of ORG is likely to rise in tandem. Being alert to the clinical presentation of ORG may facilitate early intervention with ACE inhibitors, helping to slow progression to end-stage kidney disease in these patients.

No conflicts of interest.

No funding.

No ethical approval required.

No consent required.

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Urinalysis: case presentations for the primary care physician

Affiliation.

• 1 University of Iowa, Iowa City, IA, USA.
• PMID: 25369642

Urinalysis is useful in diagnosing systemic and genitourinary conditions. In patients with suspected microscopic hematuria, urine dipstick testing may suggest the presence of blood, but results should be confirmed with a microscopic examination. In the absence of obvious causes, the evaluation of microscopic hematuria should include renal function testing, urinary tract imaging, and cystoscopy. In a patient with a ureteral stent, urinalysis alone cannot establish the diagnosis of urinary tract infection. Plain radiography of the kidneys, ureters, and bladder can identify a stent and is preferred over computed tomography. Asymptomatic bacteriuria is the isolation of bacteria in an appropriately collected urine specimen obtained from a person without symptoms of a urinary tract infection. Treatment of asymptomatic bacteriuria is not recommended in nonpregnant adults, including those with prolonged urinary catheter use.

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• Published: 16 March 2021

Prediction of urine culture results by automated urinalysis with digital flow morphology analysis

• Dokyun Kim 1 , 2 ,
• Seoung Chul Oh 1 ,
• Changseung Liu 1 , 2 , 3 ,
• Yoonjung Kim 1 ,
• Yongjung Park 1 &
• Seok Hoon Jeong 1 , 2  

Scientific Reports volume  11 , Article number:  6033 ( 2021 ) Cite this article

5328 Accesses

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Metrics details

• Bacterial infection
• Diagnostic markers
• Predictive markers
• Urinary tract infection

To investigate the association between the results of urinalysis and those of concurrent urine cultures, and to construct a prediction model for the results of urine culture. A total of 42,713 patients were included in this study. Patients were divided into two independent groups including training and test datasets. A novel prediction algorithm, designated the UTOPIA value, was constructed with the training dataset, based on an association between the results of urinalysis and those of concurrent urine culture. The diagnostic performance of the UTOPIA value was validated with the test dataset. Six variables were selected for the equation of the UTOPIA value: age of higher UTI risk [odds ratio (OR), 2.069125], female (OR, 1.400648), nitrite (per 1 grade; OR, 3.765457), leukocyte esterase (per 1 grade; OR, 1.701586), the number of WBCs (per 1 × 10 6 /L; OR, 1.000121), and the number of bacteria (per 1 × 10 6 /L; OR, 1.004195). The UTOPIA value exhibited an area under the curve value of 0.837 when validated with the independent test dataset. The UTOPIA value displayed good diagnostic performance for predicting urine culture results, which would help to reduce unnecessary culture. Different cutoffs can be used according to the clinical indication.

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Identification of clinical and urine biomarkers for uncomplicated urinary tract infection using machine learning algorithms

Automated urine sediment analyzers underestimate the severity of hematuria in glomerular diseases

Rapid pathogen identification and phenotypic antimicrobial susceptibility directly from urine specimens

Introduction.

Urinary tract infection (UTI) is the most common bacterial infection acquired in the community and in healthcare facilities. The prevalence of UTI is estimated to be 11% of the overall population, and almost half of adult women suffer from UTI at least once in their lifetime 1 , 2 . Clinical manifestations of UTI are mostly mild; however, the disease could develop serious complications, especially in certain high-risk populations including infants, pregnant women, and aged population 3 . Therefore, early diagnosis and empirical antimicrobial treatment is essential to improve clinical outcomes of patients with UTI 4 .

The gold standard for definitive diagnosis of UTI is detection of the pathogen by bacterial culture of a urine specimen 5 , and an antimicrobial susceptibility profile can be obtained by testing clinical isolates. However, urine culture is a time-consuming procedure, and the microbial spectrum of causative organisms in UTIs is narrow. Therefore, routine cultures are often not necessary to manage patients with uncomplicated UTIs, and only urinalysis either by test strip analysis and/or sediment analysis are recommended for the decision of patient management 6 . Among the components of test strip analysis, leukocyte esterase (LE) and nitrite are commonly used to diagnose UTI in routine clinical practices. Urine LE positive indicates pyuria, and urine nitrite positive indicates the presence of nitrate-reducing bacteria. However, diagnostic performance of these tests is not sufficiently high to be used alone due to limitations of the test principle 7 .

Test strip analysis is traditionally done by the dipstick based on physicochemical reactions, and the results are interpreted using a reflectometer. Automated urinalysis systems including sample preparation, aliquot, and reading have been introduced to improve test throughput and efficiency and to reduce labor and time. In addition, microscopic examination of urine sediment is also widely used to diagnose urinary tract diseases by identifying various types of cells, casts, and crystals in a urine sample. However, manual microscopic examination is a time-consuming procedure and requires expertise to maintain consistency of the result interpretation. Recently, different types of automated urine sediment analysis systems have been introduced. Among them, the iQ200 (Beckman Coulter Inc., Brea, CA, US) is an automated digital imaging-based system that uses flow morphology analysis to classify particles in a urine sample based on multiple parameters including size, shape, contrast, and texture. This instrument has exhibited satisfactory analytical performance for the quantitation of red blood cells (RBCs), white blood cells (WBCs), and epithelial cells compared with other automated sediment analysis systems and manual microscopic methods 8 .

Here, we evaluated an association between the results of urinalysis obtained by the iRICELL system including the iQ200 automated urine sediment analysis instrument with results of concurrent urine cultures. We also aimed to construct a simple but practical prediction model for the positive urine culture with the results of urinalysis including automated urine sediment analysis.

Patient characteristics and urine culture results

The median (1st–3rd quartiles) age of the 42,713 patients was 56 (24–69), and 38.7% (n = 16,519) of the patients were included in the high-risk age group (Table 1 ). Almost half (50.7%, n = 21,635) of the subjects were male, and two thirds (70.3%, n = 30,036) of the subjects were hospitalized patients. The median (1st–3rd quartiles) difference in reception time between urinalysis and urine culture was 0.3 (0.1–19.1) minutes, and the median difference in report time was 39.8 (23.7–62.7) hours. The results of urine culture were positive for 17.1% (n = 7292) of the patients, and 89.2% (n = 6506) of these were positive with a single pathogen, 4.5% (n = 325) with a single pathogen and a possible pathogen below the threshold, 3.3% (n = 220) with a single pathogen and a single normal flora, and 3.0% (n = 220) with two pathogens. The most common pathogen isolated in this study was Escherichia coli (54.9%, n = 4121 among 7512) followed by Enterococcus faecalis (11.7%, n = 878), Klebsiella pneumoniae (6.5%, n = 491), and Enterococcus faecium (5.3%, n = 400) (Supplementary Table 1 ). Patients in the urine culture-positive group exhibited a significantly higher proportion of high-risk age group (53.3% vs 35.7%, P  < 0.0001) and lower proportion of males (33.8% vs 54.1%, P  < 0.0001) than the urine culture-no growth or contamination group (Table 1 and Supplementary Table 2 ).

The results of urinalysis according to the culture results

The results of test strip and sediment analyses according to the urine culture results are summarized in Table 1 . Except for urine glucose, all parameters were significantly different between the two groups. By the multivariate binary logistic regression, three patient factors including high-risk age [odds ratio (OR), 1.967], female (OR, 1.483), and hospitalization (OR, 1.174) were significantly associated with positive results of the urine culture ( P  < 0.0001 for each) (Table 2 ). Among the test strip results, pH (OR, 1.061 per 1.0 increase; P  = 0.0007), nitrite (OR, 3.952 per 1 grade increase; P  < 0.0001), and LE (OR, 1.736 per 1 grade increase; P  < 0.0001) were independent risk factors for positive urine culture. Among the parameters of automated sediment analysis, the numbers of RBCs (OR, 1.000 per 1 × 10 6 /L increase), WBCs (OR, 1.000 per 1 × 10 6 /L increase), epithelial cells (OR, 1.001 per 1 × 10 6 /L increase), and bacteria (OR, 1.006 per 1 × 10 6 /L increase) showed significant associations with positive results of the urine culture ( P  < 0.0001 for each).

Among the variables exhibiting significant associations with positive urine culture, six variables including age of higher risk (OR, 2.069125), female (OR, 1.400648), nitrite (OR, 3.765457 per 1 grade increase), LE (OR, 1.701586 per 1 grade increase), the number of WBCs (OR, 1.000121 per 1 × 10 6 /L increase), and the number of bacteria (OR, 1.004195 per 1 × 10 6 /L increase) were selected considering the effect size of each variable by multivariable binary logistic regression in the training dataset with 21,522 patients ( P  < 0.0001 for all variables; Supplementary Table 3 ). An equation to predict urine culture results was constructed with the constant and coefficients of independently significant variables as follows:

x 1  = 1, if a **patient is at high-risk age (≤ 1 or ≥ 70 years old), otherwise x 1  = 0

x 2  = 1 for female; x 2  = 0 for male

x 3  = grade of nitrite by test strip analysis (0.5 when the result is trace or weak positive)

x 4  = grade of LE by test strip analysis (0.5 when the result is trace or weak positive)

x 5  = number of WBCs by digital flow morphology analysis (1 × 10 6 /L)

x 6  = number of bacteria by digital flow morphology analysis (1 × 10 6 /L).

Diagnostic performance of the UTOPIA value

To validate the diagnostic performance of the UTOPIA value for predicting results of urine culture, ROC curves were constructed with the independent test dataset composed of 21,191 patients from different periods, and the AUC of the UTOPIA value was 0.837 (95% CI = 0.829–0.845), which is significantly higher than that of nitrite (AUC = 0.645; 95% CI = 0.637–0.653), LE (AUC = 0.758; 95% CI = 0.749–0.767), the number of bacteria (AUC = 0.753; 95% CI = 0.743–0.762), and the number of WBCs (AUC = 0.779; 95% CI = 0.769–0.789) ( P  < 0.0001 for all comparison, Fig.  1 ). In addition, the UTOPIA value also exhibited higher AUC value than the other models including the Model 1 (AUC = 0.811; 95% CI = 0.802–0.820) which consisted of WBCs and bacteria counts by automated sediment analysis, and the Model 2 (AUC = 0.817; 95% CI = 0.808–0.826) which was composed with LE, nitrite, and the variables of Model 1 (Fig.  1 ).

Receiver operating characteristics (ROC) curve analysis of the urinalysis in the prediction of urine culture positive results in the test dataset. The area under the curve (AUC) of the model 2 (combination of nitrite, leukocyte esterase, and WBC and bacteria counts) was higher than that of the model 1 (combination of WBC and bacteria counts) ( P  = 0.0002), and the UTOPIA value showed the highest AUC value among those of other tests ( P  < 0.0001).

When using > 15.11 as a cutoff for the UTOPIA value, which showed the highest Youden’s index, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 0.661, 0.862, 0.473, and 0.931, respectively (Table 3 ). A cutoff value of > 6.54 exhibited sensitivity of 0.950 and specificity of 0.330, while a cutoff value of > 34.21 showed specificity of 0.950 and sensitivity of 0.498.

Microscopic examination of urine particle is a useful tool for diagnosing UTI, although the gold standard for diagnosis is urine culture. To date, three different types of automated urine sediment analyzers have been introduced. Sysmex UF-1000i (Sysmex Corporation, Kobe, Japan) utilizes the flow cytometric method. This analyzer measures numbers of cells, bacteria, and casts by electrical impedance per flow sample volume, sizes the components by forward light-scatter, and nuclear and cytoplasmic characteristics using fluorescent dye 9 . Another instrument the cobas u701 (Roche Diagnostics International, Rotkreuz, Switzerland), which was first introduced as UriSed (77 Elektronika, Budapest, Hungary) 10 , takes 15 microscopic images per urine sample prepared in cuvettes that mimic glass slides used in manual microscopic examination, and the result images are analyzed by particle recognition software 11 . The iQ200 investigated in this study is an automated digital imaging-based system that uses flow morphology analysis. In previous studies, the iQ200 system showed reliable performance in counting RBCs, WBCs, and epithelial cells in terms of imprecision and linearity and showed good correlation with manual microscopic sediment analysis and other automated analyzers 8 , 12 , 13 .

There have been several studies to evaluate possible associations between the results of microscopic urine sediment examinations and those of urine culture. A meta-analysis for predicting positive urine culture by the results from the Sysmex UF-1000i or UF-100 systems showed good sensitivity, using the number of WBCs (pooled sensitivity, 0.87) and bacteria (pooled sensitivity, 0.92) counted by flow cytometry as indicators 14 . The number of bacteria in urine specimens obtained by Accuri C6 (BD Biosciences, San Jose, CA, US) showed good correlation with the results of urine culture when a cutoff value for urine culture positive was ≥ 10 5  CFU/mL 15 . A recent interlaboratory study exhibited that the absence of microorganisms in the iQ200 screen was the strongest solitary predictor for a negative culture result with a sensitivity of 90.5%, and higher sensitivity (95.2%) could be obtained by the algorithm based on the presence of microorganisms and the number of WBCs 16 . Another study with the iQ200 system exhibited an acceptable NPV of 97.7% and approximately 50% reduction of urine culture when using WBC ≥ 4/HPF as a cutoff in predicting urine culture results, but the PPV was only 24.5% in the same study 17 . The scoring system suggested by Foudraine et al., which was composed of clinical symptoms including dysuria and urgency and the number of WBCs obtained by the iQ200 analyzer, gave good diagnostic performance with a high AUC value of 0.950 for predicting positive blood cultures 18 . However, the diagnostic performance of a test could vary according to the characteristics and composition of cases and controls included in each study, thus it would be difficult to directly compare diagnostic performance among the studies. In addition, the definition of significant growth in urine culture in each study was different, thus it is also difficult to generalize the diagnostic performance of a test in the literature.

The UTOPIA value was designed to predict the positive urine culture with the variables including demographic conditions including age of higher risk for UTI and sex, results of urinalysis including nitrite, LE, and the numbers of WBCs and bacteria, and was validated with an independent dataset consisting of 21,191 patients in a different time period from the subjects in the training dataset. The distribution of the prevalence of UTI along with age was a J-shape with a higher frequency among the very young and a gradual increase with age, and the prevalence was significantly higher for women than men, as previously described 19 . By simply adding these two risk factors as variables of the prediction algorithm, the UTOPIA value exhibited better diagnostic performance than the other models those are consisted of only the variables from urinalysis (Fig.  1 ). This work provides a novel approach to predict the result of urine culture with the patients’ risk factors and the results of urinalysis. In addition, the UTOPIA value was designed with easy-to use data in order to incorporate into a laboratory information system easily, and thus can be automatically calculated immediately after urinalysis.

When validated with the independent test dataset, the UTOPIA value provided a good AUC value of 0.837 in the prediction of positive urine culture with high NPVs regardless of applied cutoffs. With the prevalence of our dataset (15.8%), the NPV was 0.978 (95% CI = 0.973–0.982) when applying a cutoff for the UTOPIA value of > 5.72, and 20.0% of total culture cases was estimated to be reduced at the expense of 2.2% of false negative results, i.e. 1—NPV based on the UTOPIA value (Table 3 ). Since the prevalence of the urine culture positive results can vary depending on factors such as the country, region, and patient age, appropriate cutoffs for the UTOPIA value would need to be applied for each clinical laboratory. The cost of urine culture according to the countries would be also considered. Using different cutoffs according to the allowable false negatives in each laboratory, the UTOPIA value would be utilized to reduce unnecessary urine cultures. Meanwhile, the utility of the UTOPIA value would be low if it is used for determining whether to start early empirical antibiotic treatment before the culture results are reported. In this instance, PPV of the UTOPIA value was 0.900 even when applying a high cutoff of > 92.61. Consequently, it can be applied to only 2.1% of the total patients because there would be only small number of patients showing positive results by the UTOPIA value with that high cutoff, and there would be false positive cases of 10.0%, i.e. 1—PPV, among the 2.1% of total patients as well.

In our data, the proportion of urine culture contamination cases was 28.0%, and they included in the control group to make a practical and accurate model for predicting the results of urine culture in actual clinical microbiology laboratories. In addition, the contamination group exhibited intermediate characteristics when comparing with urine culture negative and positive groups (Supplementary Table 2 ). If contamination cases were excluded from the regression model, the 1 diagnostic performance of UTOPIA value would be over-estimated.

One limitation of our study is that it was performed with the retrospective design, and 19.1% of total cases were excluded due to inaccurate quantitative results obtained by iQ200. Therefore, possible selection bias would be considered when interpreting our results. However, a large number of patients was included to minimize unpredictable bias and to enhance the statistical power with narrow CIs for the results in this study, and the study population was divided into two independent datasets including training and test datasets to improve the reliability and external validity of our results. Despite this effort, the validation of diagnostic performance of the UTOPIA value in a single hospital would be another limitation of this study, even though the independent dataset from a different time period was used in the validation. Multicenter evaluation for the diagnostic performance of the UTOPIA value calculated by the equation in this study would be helpful in the generalized application of the UTOPIA value. Additionally, we investigated the results from a single type of test strip analyzer and flow morphology analyzer among several automated urinalysis systems each utilizing different test principles and showing different semi-quantitative results for chemical parameters including LE. Separate prediction algorithms according to the type of urinalysis systems could also be developed by applying a similar approach to our study.

In conclusion, we designed a novel prediction algorithm for urine culture results based on the results of urine test strip analysis and digital flow morphology analysis, namely the UTOPIA value. The UTOPIA value showed good diagnostic performance with possibility of reducing unnecessary urine culture and flexibility to apply different cutoff values. This prediction algorithm can be used to predict urine culture results 1 to 3 days before the culture results are reported, and also has the advantage of being easily incorporated electronically into a laboratory information system. Further evaluation on the usefulness of the UTOPIA value in various clinical settings should be considered.

Materials and methods

Study design and patients.

From July 2015 to April 2020, a total of 62,656 patients were subjected to urine cultures for suspected UTIs in a tertiary hospital in South Korea. Among them, 52,772 patients were subjected to urinalyses within 6 h before or after urine culture, and 10,059 patients were excluded due to incomplete or inaccurate automated urine sediment analysis results. Finally, 42,713 patients were enrolled in this study (Fig.  2 ). Patients included in this study were divided into two datasets by the time of receipt: (1) a training dataset with 21,522 patients: cases requested between July 2015 and December 2017, and (2) a test dataset with 21,191 patients: cases requested between January 2018 and April 2020. This retrospective cross-sectional case–control study, designated the UTOPIA study (Urinalysis-based Timely and On-the-spot Prediction of Infection Algorithm), was designed to develop a simple and useful algorithm to predict urine culture results using results of urinalysis. Patient characteristics including demographic information and type of admission were investigated by reviewing electronic medical records. The protocol of this study was approved by the Institutional Review Board of Gangnam Severance Hospital (Approval No. 3-2020-0169), and the requirement of an informed consent of the participants was waived by the IRB. All methods used in this study were also performed in accordance with the relevant guidelines and regulations.

Study design and classification of cases. Solid lines indicate cases included in the analysis, while dotted lines represent excluded subjects.

Urine culture

The results of urine culture were retrieved from the electronic medical records. Urine culture was performed according to the standard protocol of the local microbiology laboratory. Briefly, one microliter of urine sample was inoculated on MacConkey agar and Blood agar, and the number of colonies was counted after an 18-h incubation to calculate bacterial load. Bacterial identification was performed using a Matrix-Assisted Laser Desorption Ionization Time-of-Flight Mass Spectrometer (MALDI-TOF MS). To make an accurate prediction model for positive urine culture, the results of urine cultures were categorized into “Positive” and “No growth or contamination”.

Automated urinalysis with digital flow morphology analysis

The results of test strip analysis and sediment analysis by digital flow morphology analysis were retrieved from the electronic medical records. Automated urinalysis were performed using the iRICELL system (Beckman Coulter Inc., Brea, CA), which consisted of the iChem VELOCITY urine chemistry analyzer and the iQ200 SPRINT urine microscopy analyzer, following the manufacturer’s instructions. For the iQ200 instrument, approximately 1.3 mL of urine passes through a flow cell, and a digital camera captures 500 images of magnified sample. Then, the Auto-particle Recognition (APR) software (current version 7.1.4) interprets the captured images. The flow morphology interpretation with flags for suspicious errors or abnormal results by the APR software were reviewed with on-screen images by operators. Based on comprehensive consideration with on-screen images, previous urinalysis results of the same patient, and the test strip results concurrently obtained by iChem, cases with discrepant interpretations between operators and the analyzing software were subjected to manual microscopic sediment examination. If needed, the results for these cases were corrected as the number of cells per high-power field by manual microscopic examination, and were excluded from our study due to inaccurate quantitative values for RBCs, WBCs, and epithelial cells by the iQ200 analyzer in those cases. During the study period, three quality control materials for the iChem VELOCITY including IRISpec CA, CB, and CC (Beckman Coulter Inc.) and two materials for the iQ200 including iQ positive and negative controls (Beckman Coulter Inc.) were run every eight hours.

The high-risk age group for UTI was defined as patients younger than 2 years or older than 69 years considering high positive rates of urine culture according to national surveillance study 20 and positive rates of urine culture according to age in our data. A positive urine culture was determined when a single uropathogen (bacterial load ≥ 10,000 CFU/mL) or two uropathogens (bacterial load of each species ≥ 100,000 CFU/mL) were recovered. Uropathogens include Gram-negative bacilli, Staphylococcus aureus , Candida species, Enterococcus species, and Aerococcus urinae , as previously described 21 . Cases with more than three species recovered from urine culture were considered as contamination regardless of the quantity of bacterial growth 21 .

Statistical analysis

All statistical analyses were performed by Analyse-it for Microsoft Excel Method Evaluation Edition version 5.65.3 (Analyse-it Software, Ltd., Leeds, UK) and IBM SPSS Statistics 25 (IBM Corp., Armonk, NY, US). Patient characteristics and the results of urinalysis according to the groups classified by the urine culture results were compared with chi-square tests for categorical variables and Mann–Whitney U tests for continuous variables. Binary logistic regression with the results of urine culture as the dependent variable and those of urinalysis and patients’ characteristics as the multivariate independent variables was performed to determine the coefficient for each independent variable in the regression model. With the regression model equation, the UTOPIA value for each case in the test dataset was calculated to predict the probability for positive urine culture, and diagnostic performance of the UTOPIA value for the prediction of urine culture results was evaluated by calculating the area under the curve (AUC) value. All statistical analyses in this study were considered significant when the P value was < 0.05.

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Dokyun Kim, Seoung Chul Oh, Changseung Liu, Yoonjung Kim, Yongjung Park & Seok Hoon Jeong

Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, South Korea

Dokyun Kim, Changseung Liu & Seok Hoon Jeong

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D.K.: writing-original draft and data analysis; S.C.O.: data collect and analysis; C.L.: data analysis; Y.K.: writing-review and editing; Y.P.: conceptualization, supervision, data analysis, and writing-review and editing; S.H.J.: conceptualization and supervision.

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Kim, D., Oh, S.C., Liu, C. et al. Prediction of urine culture results by automated urinalysis with digital flow morphology analysis. Sci Rep 11 , 6033 (2021). https://doi.org/10.1038/s41598-021-85404-1

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• Introduction

Around 6,000 years ago, laboratory medicine began with the analysis of human urine as uroscopy, which later became termed urinalysis . The word "uroscopy" derives from two Greek words: " ouron," which means urine and " skopeoa," which means to 'behold, contemplate, examine, inspect'. Ancient physicians spoke of urine as a window to the body's inner workings and reflected different diseases. For instance, Hindu civilizations recognized a "sweetness" in certain people's urine, which attracted black ants. [1]  Hippocrates (460–355 BC) hypothesized that urine was a filtrate of the humors in the body, originating from the blood filtered through the kidneys. In Aphorisms, he described bubbles on the surface of fresh urine as a sign of long-term kidney disease and associated urinary sediment with fever. [2]  Galen used the phrase " diarrhea of the urine" to describe excessive urination. [3]  Theophilus Protospatharius, a seventh-century physician who wrote the first manuscript focused exclusively on urine called " De Urinis" , determined heating urine would precipitate proteins, documenting proteinuria as a disease state. [4]  Ismail of Jurjani, an eleventh-century physician, acknowledged food and aging altered urine composition and was the first to propose 24 hours urine collection.

By the late 12th-century, a French scholar named Gilles de Corbeil taught and classified 20 different types of urine, recording differences in urine sediment and color. De Corbeil also introduced the " matula," a glass vessel in which a physician could assess color, consistency, and clarity. [5] In 1630, Nicolas Fabricius de Peiresc, a French astronomer and naturalist, did the first microscopic description of urine crystals as "a heap of rhomboidal bricks." [6]  Posteriorly, in the early-mid 1800s, Richard Bright, an English physician, pioneered the field of kidney research leading him to be ultimately recognized as the "father of nephrology." These few examples illustrate how urinalysis was the first laboratory test developed in the history of medicine, how it has been persistently used for several thousand years, and how it continues to be a formidable and cost-effective tool to obtain crucial information for diagnostic purposes. [7]

• Specimen Requirements and Procedure

Urine is an unstable fluid; it changes composition as soon as it is eliminated through micturition. [7] Accurate collection, storage, and handling are crucial to maintaining the sample’s integrity. 

Urine samples collected from the first void or “morning urine” are considered the best representative for testing. The urine accumulated overnight in the bladder is more concentrated, thus provides an insight into the kidneys’ concentrating capacities and allows for the detection of trace amounts of substances that may not be present in more diluted samples. [7] [8]  However, other types of urine specimens may be ordered according to specific purposes (randomly, 2-hours postprandial, 24-hour collection). Furthermore, urine should be ideally examined within the first hour after the collection due to the instability of some urinary components (cells, casts, and crystals). If not possible, the sample should be refrigerated at 4 degrees C for up to 24 hours, which will slow down the decomposition process. Any specimen older than 24 hours cannot be used for urinalysis. [7] [8]

There are two methods to obtain a urine specimen: non-invasive and invasive techniques . Spontaneous voiding is the main non-invasive technique, although other strategies may be used in children who cannot yet control their voiding (i.e., bag urine). In contrast, urethral catheterization and suprapubic bladder puncture are the two invasive procedures described to date. The fundamental principle of either technique is to obtain a specimen without external contamination. 

Non-invasive Techniques 

Spontaneous voiding is the simplest and most commonly used method in clinical practice. Before collecting the sample, health personnel should be provided clear instructions to patients in order to minimize the chance of contamination from penile/vaginal microbiota (“clean-catch” method). Most urine collection kits include a sterile container with a lid and sterile moist towels to wipe the urethral area before collection; if not, cotton wool or toilet tissue and/or tap water with soap may be used. Traditionally, male patients are instructed to retract the foreskin and clean the glans of the penis before urinating. Consequently, females should clean the labia and urethral meatus as well before collection. Currently, it is under debate the need for these standard precautions, and even many areas no longer perform them. [7] [8] [9]

Subsequently, the patient should first void a small amount of urine into the toilet and afterward position the container mid-stream in the flow of urine. Approximately, only 15 mL to 30 mL of urine is sufficient for accurate analysis, so, in most cases, patients should be advised not to fill the containers to their full capacity. Finally, the container is closed with careful precautions not to contaminate its lid or rim, and the patient may finish urinating in the toilet, bedpan, etc. The sample must be labeled before or immediately following collection, and it should not be on the lid. [7] [8]   

Invasive Techniques

Invasive urine collection is warranted when patients cannot cooperate, have urinary incontinence or external urethral ulceration that increases contamination risk. Both of these techniques pose a risk for the inoculation of pathogens, thus causing urinary tract infections. 

Urethral catheterization involves a small French urinary catheter passed through the urethral meatus after the previous cleansing with proper equipment. Depending on the catheter, personnel may or may not need a sterile syringe. In cases where patients already have a urinary catheter placed, the specimen should never be taken from the catheter bag as it is considered contaminated. 

Suprapubic needle aspiration of the bladder is both the most invasive and uncomfortable procedure of all previously mentioned and may generate false-positive results (protein, red and white cells) as a consequence of blood contamination. They are generally reserved for situations where samples may not be obtained or are persistently contaminated through previous methods, which usually occurs in small children. The main advantage is that, by bypassing the urethra, it minimizes the risk of obtaining a contaminated sample. 

Before the procedure, trained personnel must identify the bladder by examination. If not distinguished, it is recommended to hydrate the patient and wait until correct identification or use ultrasound guidance if available. After proper cleaning with an antiseptic solution and anesthetizing the skin located approximately 5 cm above the pubic symphysis, a small needle (i.e., 22-gauge spinal needle x 10 cm in adults) is inserted approximately at 60 degrees at the point identified previously. The needle is directed slightly caudal or cephalic in adults or children, respectively, according to the anatomic location. Usually, the needle will enter the abdominal bladder after advancing it approximately 5 cm in adults. Finally, attempt to aspirate using a sterile syringe. If a sample is not obtained, advance the needle applying continuous suction on the syringe. If unsuccessful after an additional 5 cm in adults, withdraw the needle and repeat the procedure. If unsuccessful, personnel should seek help from a specialist or use ultrasound guidance if not previously done. [7] [8] [10]

• Diagnostic Tests

A complete urinalysis consists of three components or examinations: physical , chemical , and microscopical . 

• Physical examination describes the volume, color, clarity, odor, and specific gravity.
• Chemical examination identifies pH, red blood cells, white blood cells, proteins, glucose, urobilinogen, bilirubin, ketone bodies, leukocyte esterase, and nitrites.
• Microscopic examination encompasses the detection of casts, cells, crystals, and microorganisms.
• Interfering Factors

The following factors may alter the results of a urine sample analysis:

• Light and Temperature: If exposed for a considerable period of time, bilirubin and urobilinogen may decompose due to their instability under these conditions. Additionally, room temperature favors the growth of microorganisms, such as bacteria.
• Bacterial Growth: Contamination of the sample or pathogenic bacteria may produce a variety of inaccurate results. For example, they may produce a false-positive blood reaction and affect the specimen's pH towards acidity or alkaline. 
• Alkaline pH: This concentration may show false-positive results regarding the presence of protein.
• Glucose: If present in the sample, it may be metabolized by microorganisms and cause a decrease in the sample's pH.
• Contrast Agents: May produce false-positive results of specific gravity.
• Exercise: May alter the specific gravity and electrolyte concentration of the sample.
• Foods and Drugs: May alter the urine's color, odor, or pH value. Examples include, but are not limited to, red beets, blackberries, rhubarb, food coloring (e.g., aniline), ibuprofen, chloroquine, metronidazole, deferoxamine, nitrofurantoin, phenytoin, rifampicin, phenolphthalein, phenothiazines, and imipenem/cilastatin.
• Thymol: May generate false-positive reactions for albumin.
• Formaldehyde: May cause false-positive results for leukocyte esterase, peroxidase reaction, urobilinogen, and glucose if strips are used.
• Hydrochloric Acid: Although used to preserve cell structures and determine steroid concentrations, it affects the sample's pH. 
• Mercury Salts: May produce false-negative results for leukocyte esterase reaction. 
• Boric Acid: While commonly used to preserve bacteria present in urine, this substance may reduce the sensitivity of the leukocyte reagent on dipsticks and alter initial pH values. Moreover, excessive concentrations may prevent bacterial growth in samples reserved for culture. [11] [12] [13]
• Results, Reporting, and Critical Findings

Physical Examination

Only in a few instances, the color, odor, and/or appearance are of clinical significance; nonetheless, any abnormal finding should be noted.

• Normal: Yellow (light/pale to dark/deep amber)
• Amber: Bile pigments
• Brown/Black (Tea-colored): Bile pigments, cascara, chloroquine, fava beans, homogentisic acid (alkaptonuria), levodopa, melanin or oxidized melanogen, methemoglobin, methyldopa, metronidazole, myoglobin, nitrofurantoin, primaquine, rhubarb, riboflavin, senna
• Dark Yellow: Concentrated specimen (dehydration, exercise)
• Green/Blue: Amitriptyline, asparagus, biliverdin, cimetidine, clorets (breath mint), indicans, indigo carmine, indomethacin, methocarbamol, methylene blue, promethazine, propofol, pseudomonal UTI, triamterene
• Orange: Bile pigments, carrots, coumadin, nitrofurantoin, phenothiazines, phenazopyridine, rifampin, vitamin C
• Pink/Red: Beets, blackberries, chlorpromazine, food dyes, hematuria, hemoglobinuria, menstrual contamination, myoglobinuria, phenolphthalein, porphyrins, rifampin, rhubarb, senna, thioridazine, uric acid crystals. [7] [14]  A urine sample that turns red on standing suggests the presence of porphobilinogen, which is increased in acute porphyrias.
• Normal: Clear or translucent
• Associations: Bacteria, blood clots, contrast media, a diet high in purine-rich foods, fecal contamination or material (i.e., gastrointestinal-bladder fistula), lipids such as chyluria (chylomicrons in the urine), lymph fluid, mucus, precipitation of cells (red blood cells (RBC), white blood cells (WBC), squamous and non-squamous epithelial cells), casts or crystals (calcium phosphate, calcium oxalate, uric acid), pyuria, semen, small calculi, talcum powder, vaginal creams or secretions, yeast or non-specific/normal. [7] [14]  
• Not routinely reported
• Normal: "Urinoid"
• Cystine Decomposition: Sulfuric smell
• Dehydration/Prolonged Room Temperature: Strong smell
• Diabetes Mellitus: Honey
• Diabetic Ketoacidosis: Fruity/sweet
• Gastrointestinal-bladder Fistula: Fecal smell
• Maple-syrup Urine Disease: "Burnt sugar."
• Prolonged Bladder Retention: Ammoniacal
• Urinary Tract Infection: Pungent or fetid
• Medications and Diet: Onions, garlic, asparagus [7] [14]

Specific Gravity (USG)/Osmolality (O)

The urinary specific gravity (USG) and osmolality are of special importance because they indicate the kidney's capacity to dilute or concentrate urine. USG is defined as the ratio between the density of urine and the density of an equal volume of pure distilled water. Normal values are lab-dependent since there are multiple methods to calculate this parameter (hydrometer, dipstick reagent pad, refractometer, and harmonic oscillation or urinometry). As it depends primarily on mass, it is not a truly reliable measure for quantifying the exact number of solute particles. Thus, USG is commonly used to rapidly estimate screen urine concentration, employing the term hyposthenuric and hypersthenuric depending on whether the USG is diminished, or elevated. Isosthenuria connotes urine with a fixed specific gravity and portends renal disease. Conversely, osmolality is a measure of the sum of all dissolved particles in urine. It is more reliable and accurate than USG for evaluating kidney function. Urine osmolality ranges from 50-1200 mOsmol/kg; the key is to always compare to serum osmolality to establish a pathological condition. Both parameters directly correlate; for example, a USG of 1.010 approximates to a urine osmolality of 300 mOsm/kg. [7] [15]

• Normal: USG = 1.002-1.035 (usually 1.016 to 1.022). O = 50-1200 mOsm/kg (usually 275-900 mOsm/kg) [Both parameters are lab dependent]
• Variations according to the patient’s diet, health, hydration status, and physical activity.
• High Values: Contrast media, dehydration, decreased renal blood flow (shock, heart failure, renal artery stenosis), diarrhea, emesis, excessive sweating, glycosuria, hepatic failure, syndrome of inappropriate antidiuretic hormone (SIADH)
• Low Values: Acute tubular necrosis, acute adrenal insufficiency, aldosteronism, diuretic use, diabetes insipidus, excessive fluid intake (psychogenic polydipsia), impaired renal function, interstitial nephritis, hypercalcemia, hypokalaemia, pyelonephritis
• False Elevation: Dextran solutions, intravenous (IV) radiopaque contrast media, proteinuria
• False Depression: Alkaline urine [7] [11] [14] [15]
• Normal: 0.5 to 1.5 cc/kg/hour or 600 and 2,000 mL daily in adults (typically 1,000– 1,600 mL/day)
• Anuria (less than 100 cc/day) and oliguria (less than 500 cc/day): Severe dehydration from vomiting, diarrhea, hemorrhage or excessive sweating; renal disease, renal obstruction, renal ischemia secondary to heart failure or hypotension
• Polyuria (greater than 2,500 - 3,000 cc/day): Alcohol or caffeine consumption, diabetes mellitus, diabetes insipidus, diuretics, increased water intake, saline or glucose intravenous therapy [7]
• Normal: Appears upon agitation and dissipates readily on standing
• Associations: Proteinuria, bile pigments, retrograde ejaculation, medications (phenazopyridine, etc.), non-specific/unexplained [7] [11] [14]

Chemical Examination

Urine pH is a vital piece of information and provides insight into tubular function. Normally, urine is slightly acidic because of metabolic activity. A urinary pH greater than 5.5 in the presence of systemic acidemia (serum pH less than 7.35) suggests renal dysfunction related to an inability to excrete hydrogen ions. On the contrary, the most common cause of alkaline urine is a stale urine sample due to the growth of bacteria and the breakdown of urea releasing ammonia. Determination of urinary pH is helpful for the diagnosis and management of urinary tract infections and crystals/calculi formation. [7] [11] [14]

• Normal: 4.5 to 8 (usually 5.5 to 6.5)
• High Values (alkaline): Stale/old urine specimens (most common), hyperventilation, presence of urease-producing bacteria, renal tubular acidosis, vegetarian diet, vomiting.
• Low Values (acid): Cranberry juice, dehydration, diabetes mellitus, diabetic ketoacidosis, diarrhea, emphysema, high protein diet, starvation, potassium depletion, medications (methionine, mandelic acid, etc.), and a possible predisposition to the formation of renal or bladder calculi. [7] [11] [14] [15]

Proteinuria is another critical finding. In normal conditions, the glomerular capillary wall is permeable to molecules of less than 20,000 Daltons. Most of the small fraction of filtered proteins are reabsorbed and metabolized by the proximal tubule cells. Thus, proteins are normally present in urine in trace amounts. From the total urinary proteins, approximately one-third of the total is albumin, another third is a protein secreted by the tubular cells called Tamm–Horsfall glycoprotein, and the rest is made up of plasma proteins such as globulins. Proteinuria can be classified into a transient or persistent, with the first one typically been a benign condition (i.e., orthostatic proteinuria due to prolonged standing). For the latter, persistent proteinuria can my categorized as a glomerular pattern, a tubular pattern, and an overflow pattern. The first occurs when proteins that are not normally filtered (i.e., albumin, transferrin) pass by a damaged glomerular capillary wall. Thus, this pattern may be seen with low serum albumin, secondary generalized edema, and high serum lipids as in nephrotic syndrome. Usually, protein excretion is greater than 3.0 g/day to 3.5 g/day. The tubular pattern results from the tubular cells' inability to reabsorb filtered proteins. Consequently, small serum proteins are typically seen in the microscopic examination, and proteinuria is not relatively high (approximately 1 g/day to 2 g/day). Finally, overflow proteinuria occurs when excessive concentrations of small proteins in plasma are filtered, and tubular cells reabsorption's capacity is surpassed, which occurs in conditions such as rhabdomyolysis (myoglobin) and multiple myeloma (Bence Jones light chains). This phenomenon harms tubular cells, and they may be seen on microscopic examination.   Qualitative assessment of minimal amounts of proteinuria serves as a marker for glomerular injury and risk of progression of renal disease. Normal albumin excretion is less than or equal to 29 mg/g creatinine. It is best to express albuminuria per gram of creatinine. According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, albuminuria can be classified into three stages: A1 (less than 30 mg/g creatinine; normal to mildly increased), A2 (30 mg/g to 300 mg/g creatinine; moderately increased, formerly termed as "microalbuminuria"), and A3 (greater than 300 mg/g creatinine; severely increased). [7] [14] [16] [17]

Normal: Proteinuria  less than or equal to 150 mg/day (typically albuminuria less than 30 mg/day) or 10 mg/dL

• Albuminuria of 30 mg/day to 300 mg/day is an indicator of early renal disease, glomerular injury, and risk of progression of renal disease
• Other Associations: Multiple myeloma, congestive heart failure, Fanconi syndrome, Wilson disease, pyelonephritis, and physiological conditions (strenuous exercise, fever, hypothermia, emotional distress, orthostatic proteinuria, and dehydration)
• False-positive: Alkaline or concentrated urine, phenazopyridine, quaternary ammonia compounds
• False-negative: Acid or dilute urine, primary protein is not albumin [7] [11] [14] [15]

Blood Cells

• Dipstick test for blood detects primarily the peroxidase activity of erythrocytes, but myoglobin and hemoglobin can also catalyze this reaction. Thus, a positive test result indicates hematuria, myoglobinuria, or hemoglobinuria.
• Normal: Negative (usually) or less than or equal to 5 RBCs per mL (lab-dependent value)
• Hematuria: Renal calculi, glomerulonephritis, pyelonephritis, tumors, trauma, anticoagulants, strenuous exercise, exposure to toxic chemicals
• Hemoglobinuria: Hemolytic anemias, RBC trauma, strenuous exercise, transfusion reactions, severe burns, infections (i.e., malaria)
• Myoglobinuria: Muscle trauma eg, rhabdomyolysis, prolonged coma, convulsions, drug abuse, extensive exertion, alcoholism/overdose, muscle wasting diseases
• False-positive: Dehydration, exercise, hemoglobinuria, menstrual blood, myoglobinuria
• False-negative: Captopril, elevated specific gravity, acid urine, proteinuria, vitamin C [7] [11] [14] [15]

Glycosuria occurs when the filtered load of glucose exceeds the tubular cells' ability to reabsorb it, which normally happens at a glucose serum concentration of around 180  mg per dL. Furthermore, nitrites are not normally found in urine, and it is highly specific for urinary tract infection. However, due to its low sensitivity, a negative result does not rule out infection. [14]

• Normal: Negative
• Associations: Diabetes mellitus, Cushing syndrome, Fanconi syndrome, glucose infusion, pregnancy.
• Glucosuria with normal plasma glucose without other features of Fanconi syndrome is due to a benign condition referred to as renal glycosuria and is due to a mutation in the sodium-glucose linked transporter 2
• False-positive: Ketones, levodopa
• False-negative: Elevated specific gravity, uric acid, vitamin C [7] [11] [14] [15]

Bilirubin (conjugated)

• Normal: There is no bilirubin in normal urine 
• Associations: Liver dysfunction, biliary obstruction, congenital hyperbilirubinemia, viral or drug-induced hepatitis, cirrhosis
• False-positive: medications such as phenazopyridine that have a similar color at the low pH of the reagent pad
• False-negative: stale/old urine specimens, chlorpromazine, selenium [7] [11] [14] [15]

Urobilinogen

• The degradation product of bilirubin metabolism from bacteria in the intestine
• Normal: 0.1 mg/dL to 1 mg/dL in random samples or up to 4 mg/daily
• Elevation: Hemolysis, liver disease (cirrhosis, hepatitis), sickle cell disease, thalassemia
• Decrease: Antibiotic use, bile duct obstruction
• False-positive: Elevated nitrite levels, phenazopyridine, porphobilinogen, sulfonamides, and aminosalicylic acid
• False-negative: Prolonged exposition to daylight, formaldehyde, high levels of nitrites [7] [11] [14] [15]

Ketone Bodies

• Products of body fat metabolism
• Normal: Negative
• Associations: Uncontrolled diabetes mellitus (diabetic ketoacidosis), pregnancy, carbohydrate-free diets, starvation, febrile illness.
• False-positive: Acid urine, elevated specific gravity, mesna, phenolphthalein, some drug metabolites (e.g., levodopa, captopril)
• False-negative: Stale/old urine specimens.
• Remember : Reagent strips do not detect beta-hydroxy-butyric acid, only acetoacetic acid and acetone [7] [11] [14] [15]
• Products originating from the reduction of urinary nitrates
• Associations: Urinary tract infection (UTI) from a nitrate reductase-positive bacteria ( E. coli, Proteus, Enterobacter, Klebsiella, Streptococcus faecalis and Staphylococcus aureus )
• False-positive: Contamination, exposure of dipstick to air, pigmented materials, phenazopyridine
• False-negative: elevated specific gravity, elevated urobilinogen levels, nitrate reductase-negative bacteria, acid urine, vitamin C, urine with less than 4 hours of bladder resting, absent dietary nitrates
• Remember : A negative result does not rule out UTI [7] [11] [14] [15]

Leukocyte Esterase

• An enzyme present in certain WBCs (except lymphocytes)
• Associations: Inflammation of the urinary tract, sterile pyuria (balanitis, urethritis, tuberculosis, bladder tumors, nephrolithiasis, foreign bodies, exercise, glomerulonephritis, corticosteroids, and cyclophosphamide), fever, glomerulonephritis, pelvic inflammation
• False-positive: Contamination, highly pigmented urine, strong oxidizing agents, Trichomonas
• False-negative: Elevated specific gravity, glycosuria, ketonuria, proteinuria, some oxidizing drugs (cephalexin, nitrofurantoin, tetracycline, gentamicin), vitamin C [7] [14] [15]

Microscopic examination

Casts are a coagulum composed of the trapped contents of tubule lumen and Tamm-Horsfall mucoprotein. They originate in the lumen the distal convoluted tubule or collecting duct with pH alterations or long periods of urinary concentration or stasis. The casts preserve the cylindrical shape of the tubule in which they were formed. Only a few hyaline or finely granular casts may be seen under normal physiological conditions. Cellular casts can dissolve within 30 to 10 minutes depending on the pH of the urine sample, thus promptly testing is mandatory for appropriate testing. 

• Normal: Absent
• Associations: Glomerulonephritis, vasculitis, intrinsic renal disease (tubulointerstitial nephritis, acute tubular injury/necrosis), strenuous exercise (see image attached) [7] [14] [15]
• Associations: Pyelonephritis, interstitial nephritis, glomerulonephritis, renal inflammatory processes (see image attached) [7] [14] [15]
• Normal: Absent
• Associations: Acute tubular injury/necrosis, interstitial nephritis, glomerulonephritis, eclampsia, nephritic syndrome, transplant rejection, heavy metal ingestion, renal disease [7] [14] [15]
• Associations: Glomerular or tubular disease, pyelonephritis, advanced renal disease, viral infections, stress/exercise, non-specific [7] [14] [15]
• Associations: Advanced renal failure (dilated tubules with decreased flow) [7] [14] [15]
• Normal: Up to 5 casts/low-power field
• Associations: Normal finding in concentrated urine, fever, exercise, diuretics, pyelonephritis, chronic renal disease [7] [14] [15]
• Associations: Heavy proteinuria (nephrotic syndrome), renal disease, hypothyroidism, acute tubular necrosis, diabetes mellitus, severe crush injuries [7] [14] [15]
• Normal: 0-5 cells/high-power field
• Associations: UTI, inflammation [7] [14] [15]
• Associations: Interstitial nephritis, acute tubular necrosis, UTI, kidney transplant rejection, hepatorenal syndrome [7] [14] [15]
• Squamous, transitional, or renal tubular cells 
• Type of cell encountered depends on the location of the disease process
• Normal: Less than or equal to 15-20 squamous epithelial cells/high-power field
• Squamous (most common): Contamination
• Transitional: Normal, UTI
• Renal Tubular: Heavy metal poisoning, drug-induced toxicity, viral infections, pyelonephritis, malignancy, acute tubular necrosis [7] [14] [15]
• Associations: UTI, contamination [7] [14] [15]

End products of metabolism are found highly concentrated in the urine and can precipitate in the form of crystals. The presence of crystals is not necessarily associated with pathological states, although several types of crystals are associated with certain diseases. For example, cholesterol crystals are seen in polycystic renal disease and nephrotic syndrome and polycystic renal disease; leucine and tyrosine crystals are associated with severe liver disease. [7] [14]

• Yellow to orange-brown, diamond- or barrel-shaped crystals
• Associations: Acid urine, hyperuricosuria, uric acid nephropathy, normal (see image attached) [7] [14]
• Most commonly encountered crystal in human urine
• Refractile square "envelope" shape
• Associations: Ethylene glycol poisoning, acid urine, hyperoxaluria, normal (see image attached) [7] [14]
• Associations: Alkaline urine, decreased urine volume, a diet rich in calcium, prolonged immobilization, overactive parathyroid glands, bone metastases, normal [7] [14]
• "Coffin lid" appearance crystals
• Associations: Alkaline urine, decreased urine volume, UTI from urease-producing bacteria ( Proteus, Klebsiella ) [7] [14]
• Colorless crystals with a hexagonal shape
• Associations: Cystinuria [7] [14]
• Associations: Antibiotics containing sulfa [7] [14]
• Clinical Significance

Urinalysis is an ancient diagnostic screening test that has stood the test of time and is still useful in clinical laboratories since it plays a critical role in the health assessment process. [11] [13]  For some, a urinalysis is considered as the most common, simple, and relevant screening exam that provides clinicians with valuable information about the general health status of a patient, including hydration, urinary tract infection, diabetes mellitus, and liver or renal disease. [8]

• Quality Control and Lab Safety

Multiple reagent strips and tablets are used for several semiquantitative and qualitative tests, which allow the analysis of diverse parameters such as glucose, albumin, specific gravity, hydrogen ions, electrolytes, leukocytes, leukocyte esterase, nitrite, ketones, blood, bilirubin, urobilinogen, and heme. Most reagent strips are narrow bands of plastic 4 mm to 6 mm wide and 11 cm to 12 cm long with a series of absorbent pads. Each pad contains reagents for different reactions, so various tests can be carried out simultaneously. The reagent strip method comprises multiple complex chemical reactions. A color change on the pad demonstrates a reaction which can be compared to a color chart provided by the manufacturer for result interpretation. When using this method, it is essential to test the urine promptly, understand the advantages and limitations of each test, and establish controls. [7]

Reagent strips are designed to react progressively, modifying color for positive reactions along the strip at specific periods. The fundamental principle corresponds to read the strip at the specified time from the manufacturer to obtain accurate results. These times are established on the label of the bottle containing the particular strip. Furthermore, the reagent trips should never be stored in alternative containers because they have a relatively short shelf life. Expired strips may produce inaccurate results, the expiration date is also located on the bottle. [11]

Additionally, some computerized urine analyzers are available for reading reagent strips. They show the analysis on a small screen and print them out to include in the patient’s records. These analyzers comprise greater accuracy, convenience, simplicity, and time savings. However, they may not be able at many facilities due to financial limits. [11]

• Enhancing Healthcare Team Outcomes

A urinalysis is a valuable test commonly used in clinical practice. Depending on the technique and hospital, most samples are usually collected by nurses or phlebotomists who must determine whether or not the specimen meets the minimum requirements for proper analysis. They should be familiar with each method of collection and educate patients for appropriate sampling in the outpatient setting. In addition, as many conditions may alter the sample analysis (food, drugs, exercise, intercourse, room temperature, daylight, etc.), adequate recording and communication between the interprofessional team ensure discarding possible false-positive or false-negative results. Accurate collections provide key information for screening multiple systemic diseases and monitor treatment progress.

Finally, careful consideration of current guidelines must be done at all times. For example, the American Academy of Pediatrics no longer recommends performing routine screening urinalysis for asymptomatic children and adolescents. [18]  However, in adults, it is an excellent cost-effective screening test in primary care to screen for certain diseases.

• Review Questions
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Triple Phosphate Crystals, Urine Contributed by RWTH Aachen (CC by 2.0) https://creativecommons.org/licenses/by/2.0/

Uric Acid Crystals, Rosette-Shaped. The image shows rosette-shaped uric acid crystals on light microscopy. Iqbal Osman, Public Domain, via Wikimedia Commons

Example of red cell cast. Contributed by Rian Kabir, MD

White Blood Cell Cast Contributed by Bharat Sachdeva MD

Disclosure: Daniel Queremel Milani declares no relevant financial relationships with ineligible companies.

Disclosure: Ishwarlal Jialal declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Queremel Milani DA, Jialal I. Urinalysis. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Case Study: Diagnosing and Managing BPH in a Male Patient With Urinary Symptoms

Dean Elterman, MD, discusses how a comprehensive approach to diagnosing and managing benign prostatic hyperplasia (BPH) involves a combination of symptom assessment, lifestyle modifications, pharmacotherapy, and regular follow-up to optimize patient outcomes.

EP: 1 . Comprehensive Insights into the Historical and Modern Treatment Strategies for BPH

Ep: 2 . advancements in mist for bph: options, guidelines, and patient-centered decision-making, ep: 3 . optimizing bph management: evaluating mist options and key treatment considerations, ep: 4 . real-world treatment of bph: outcomes and patient education, ep: 5 . case study: diagnosing and managing bph in a male patient with urinary symptoms, ep: 6 . closing.

Video content above is prompted by the following:

• History of straining to initiate and maintain a urinary stream, a weak and intermittent urinary stream, a sensation of incomplete bladder emptying after urination, and nocturia; absence of hematuria or dysuria.
• No history of urinary tract infections or other urological conditions
• Hypertension (well-controlled with medication)
• Hyperlipidemia
• No previous surgical history
• Digital rectal examination reveals an enlarged, nonnodular prostate (approximately 50 g); no other significant findings.
• Laboratory and Diagnostic Tests: Serum prostate-specific antigen level: 2.5 ng/mL; urinalysis: normal; uroflowmetry: peak flow rate of 8 mL/sec (borderline obstructed); post-void residual urine volume: 120 mL; transrectal ultrasound: prostate volume estimated at 55 g.
• Please describe your approach to diagnosing, treating, and managing this patient.

• Open access
• Published: 13 September 2024

Group B streptococcus colonization in pregnancy and neonatal outcomes: a three-year monocentric retrospective study during and after the COVID-19 pandemic

• Gregorio Serra   ORCID: orcid.org/0000-0002-2918-9826 1 ,
• Lucia Lo Scalzo 1 ,
• Maria Giordano 1 ,
• Mario Giuffrè 1 ,
• Pietro Trupiano 1 ,
• Renato Venezia 1 &
• Giovanni Corsello 1  

Italian Journal of Pediatrics volume  50 , Article number:  175 ( 2024 ) Cite this article

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Group B Streptococcus (GBS) is a major cause of sepsis and meningitis in newborns. The Centers for Disease Control and Prevention (CDC) recommends to pregnant women, between 35 and 37 weeks of gestation, universal vaginal-rectal screening for GBS colonization, aimed at intrapartum antibiotic prophylaxis (IAP). The latter is the only currently available and highly effective method against early onset GBS neonatal infections. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the preventive measures implemented to mitigate the effects of SARS-CoV-2 infection led to the reduction in the access to many health facilities and services, including the obstetric and perinatal ones. The purpose of the present study was to evaluate the prevalence of maternal GBS colonization, as well as use of IAP and incidence of episodes of neonatal GBS infection when antibiotic prophylaxis has not been carried out in colonized and/or at risk subjects, in a population of pregnant women during (years 2020–2021) and after (year 2022) the COVID-19 pandemic, also with the aim to establish possible epidemiological and clinical differences in the two subjects’ groups.

We retrospectively analyzed the clinical data of pregnant women admitted to, and delivering, at the Gynaecology and Obstetrics Unit, Department of Sciences for Health Promotion and Mother and Child Care, of the University Hospital of Palermo, Italy, from 01.01.2020 to 31.12.2022. For each of them, we recorded pertinent socio-demographic information, clinical data related to pregnancy, delivery and peripartum , and specifically execution and status of vaginal and rectal swab test for GBS detection, along with eventual administration and modality of IAP. The neonatal outcome was investigated in all cases at risk (positive maternal swabs status for GBS, either vaginal or rectal, with or without/incomplete IAP, preterm labor and/or delivery, premature rupture of membranes ≥ 18 h, previous pregnancy ended with neonatal early onset GBS disease [EOD], urine culture positive for GBS in any trimester of current gestation, intrapartum temperature ≥ 38 °C and/or any clinical/laboratory signs of suspected chorioamnionitis). The data concerning mothers and neonates at risk, observed during the pandemic (years 2020–2021), were compared with those of both subjects’ groups with overlapping risk factors recorded in the following period (year 2022). The chi squared test has been applied in order to find out the relationship between pregnant women with GBS colonization receiving IAP and outcome of their neonates.

The total source population of the study consisted of 2109 pregnant women, in addition to their 2144 newborns. Our analysis, however, focused on women and neonates with risk factors. The vaginal-rectal swab for GBS was performed in 1559 (73.92%) individuals. The test resulted positive in 178 cases overall (11.42% of those undergoing the screening). Amongst our whole sample of 2109 subjects, 298 women had an indication for IAP (vaginal and/or rectal GBS colonization, previous pregnancy ended with neonatal GBS EOD, urine culture positive for GBS in any trimester of current gestation, and unknown GBS status at labor onset with at least any among delivery at < 37 weeks’ gestation, amniotic membranes rupture ≥ 18 h and/or intrapartum temperature ≥ 38.0 °C), and 64 (21.48%) received adequate treatment; for 23 (7.72%) it was inadequate/incomplete, while 211 (70.8%) did not receive IAP despite maternal GBS colonization and/or the presence of any of the above mentioned risk factors. Comparing the frequency of performing vaginal-rectal swabs in the women admitted in the two time periods, the quote of those screened out of the total in the pandemic period (years 2020–2021) was higher than that of those undergoing GBS screening out of the total admitted in the year 2022 (75.65% vs. 70.38%, p  = 0.009), while a greater number (not statistically significant, p  = 0.12) of adequate and complete IAP was conducted in 2022, than in the previous biennium (26.36 vs. 18.62%). During the whole 3 years study period, as expected, none of the newborns of mothers with GBS colonization and/or risk factors receiving IAP developed EOD. Conversely, 13 neonates with EOD, out of 179 (7.3%) born to mothers with risk factors, were observed: 3 among these patients’ mothers performed incomplete IAP, while the other 10 did not receive IAP. Neither cases of neonatal meningitis, nor deaths were observed. The incidence rate in the full triennium under investigation, estimated as the ratio between the number of babies developing the disease out of the total of 2144 newborns, was 6.06‰; among those born to mothers with risk factors, if comparing the two time periods, the incidence was 8.06% in the pandemic biennium, while 5.45% in the following year, evidencing thus no statistical significance ( p  = 0.53).

Conclusions

The present study revealed in our Department an increased prevalence of pregnant women screened for, and colonized by GBS, in the last decade. However, an overall still low frequency of vaginal-rectal swabs performed for GBS, and low number of adequate and complete IAP despite the presence of risk factors have been found, which did not notably change during the two time periods. Moreover, significant EOD incidence rates have been reported among children of mothers carrying risk factors, although also in this case no statistically significant differences have been observed during and after the pandemic. Such data seem to be in contrast to those reported during the COVID-19, showing a decrease in the access to health facilities and increased mortality/morbidity rates also due to the restrictive measures adopted to mitigate the effects of the pandemic. These findings might be explained by the presence within the same metropolitan area of our Department of a COVID hospital and birthing center, which all the patients with SARS-CoV-2 infection referred to, and likely leading to a weaker concern of getting sick perceived by our patients. Although IAP is an easy procedure to implement, however adherence and uniformity in the management protocols are still not optimal. Therefore, the prophylactic measures adopted to date cannot be considered fully satisfactory, and should be improved. Better skills integration and obstetrical-neonatological collaboration, in addition to new effective preventive tools, like vaccines able to prevent invasive disease, may allow further reduction in morbidity and mortality rates related to GBS perinatal infection.

Group B Streptococcus (GBS), also known as Streptococcus agalactiae for its causative role in bovine mastitis, is present in the genitourinary and gastrointestinal tracts of pregnant women. Maternal GBS colonization rates vary worldwide from 10 to 40%, with mean prevalence of 18% [ 1 , 2 , 3 , 4 ]. In the newborn, GBS infection may give rise to both early (EOD) and late onset diseases (LOD). EOD is generally acquired by vertical transmission, and its most common clinical pictures include sepsis, pneumonia and meningitis. LOD, conversely, may be observed between 7 and 90 days of life, and the association with maternal colonization is not as strong as for EOD [ 5 , 6 , 7 ]. Intrapartum antibiotic prophylaxis (IAP), administrated ≥ 4 h before delivery, is the only currently available and highly effective method against early onset GBS neonatal infections. It allowed a reduction in the incidence of EOD of more than 80%, from 1.8 newborns per 1,000 live births in the 1990s to 0.23 newborns per 1,000 live births in 2015, although not being able to limit the impact of LOD [ 8 , 9 ]. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, more than 6.9 million people died worldwide due to SARS-CoV-2 infection [ 10 ]. In Italy, it has been associated with significant clinical and psychological effects, also in pregnant women. Indeed, the infection control and the preventive measures (social distancing, mask wearing, hand hygiene and quarantine) implemented to mitigate the effects of the pandemic, led to the reduction in the access to many health facilities and services, including the obstetric and perinatal ones (only 28% of maternal and perinatal healthcare facilities continued to provide outpatient routine visits and examinations as usual, while 59% of them provided visits to a limited extent) [ 11 ]. Such decrease was linked both to the difficulties encountered by people in keeping the support from other family members within the hospital, and to the fear of contracting the infection [ 12 , 13 ]. This additional negative impact of COVID-19 (besides the direct one caused by the infection) might have caused also worse health outcomes in pregnant women, especially in groups at major risk for social or economic reasons. The purpose of the present study was to retrospectively evaluate the prevalence rates of maternal vaginal-rectal GBS colonization, as well as use of IAP and incidence of episodes of neonatal GBS infection when antibiotic prophylaxis has not been carried out in colonized and/or at risk subjects, in a population of pregnant women during (years 2020–2021) and after (year 2022) the COVID-19 pandemic, also with the aim to establish possible epidemiological and clinical differences in the two subjects’ groups.

We retrospectively analyzed the clinical data of pregnant women admitted to, and delivering, at the Gynaecology and Obstetrics Unit, Department of Sciences for Health Promotion and Mother and Child Care, of the University Hospital of Palermo, Italy, from 01.01.2020 to 31.12.2022. For each of them, we recorded the pertinent socio-demographic information, and the clinical data related to pregnancy, delivery and peripartum . Such items are detailed and presented in Table  1 .

We considered the results of vaginal and rectal swabs for GBS, performed between weeks 35 + 0 and 37 + 0 of gestation. This procedure is usually performed routinely in our Hospital in such time window, according to the indications of the Centers for Disease Control and Prevention (CDC) [ 8 , 14 ]. Specifically, IAP was recommended in women with a positive GBS screening culture (excluding those undergoing cesarean delivery with intact amniotic membranes before labor onset), a previous child with early onset GBS disease, bacteriuria documenting GBS in the current pregnancy, and in those with unknown GBS status at labor onset and at least one of the following risk factors: delivery at < 37 weeks’ gestation, amniotic membranes rupture ≥ 18 h and/or intrapartum temperature ≥ 38.0 °C [ 15 , 16 , 17 ]. However, many variations of practice, based on the individual gynecologist and/or on mother’s compliance, have been observed during the study period in our sample population. Ampicillin was the first-line drug used, and it was administered intravenously (IV) at the dose of 2 g, followed by 1 g IV every 4 h until delivery. Cefazolin was the option chosen for women allergic to penicillin but not at high risk for anaphylaxis, while clindamycin or vancomycin have been used for high risk of anaphylaxis to penicillin, according to guidelines [ 18 , 19 ]. IAP was considered adequate and complete when administered ≥ 4 h before delivery [ 8 ]. We focused on the rate of patients undergoing GBS screening, and on those with positive GBS screening tests. We also evaluated the indications for IAP, as well as the modality of IAP execution (if either adequate/complete or not).

The neonatal outcome was investigated in all cases at risk (positive maternal swabs status for GBS, either vaginal or rectal, with or without/incomplete IAP, preterm labor and/or delivery, premature rupture of membranes ≥ 18 h, previous pregnancy ended with neonatal EOD, urine culture positive for GBS in any trimester of current gestation, intrapartum temperature ≥ 38 °C, and/or any clinical/laboratory signs of suspected chorioamnionitis). In-depth data analyzed for each newborn are reported in Table  2 .

The data observed during the pandemic (years 2020–2021) were compared with those recorded in the following period (year 2022).

Statistical analysis

We used R version 4.0.4 (R Foundation for Statistical Computing, Vienna, Austria) for data analysis. Simple descriptive statistics were expressed as frequency and percentage for categorical variables, mean and standard deviation for continuous variables. Paired-samples t-test was used to compare data on the vaginal-rectal GBS colonization rate, as well as use of IAP and its effects on neonatal outcomes during (years 2020–2021) and after (year 2022) the COVID-19 pandemic. The Chi-squared test has been applied for comparison between two groups, and precisely in order to find out the relationship between pregnant women with GBS colonization receiving IAP and outcome of their neonates.

A p value lower than 0.05 was considered statistically significant.

Socio-demographic information, and clinical data related to pregnancy, delivery and peripartum

The total number of deliveries observed during the study period was 2315, including 35 twin births (all bigeminal). The medical records were not available for 206 mothers, and therefore the source population of the study involved 2109 pregnant women, in addition to their 2144 newborns. Evaluated by year, the total number of delivering women was as follows: 660 in 2020, 757 in 2021, and 692 in 2022. There were 141 preterm (< 37 weeks of gestational age) deliveries, while the other 1968 were full-term ones. In the population under investigation, the average age was 30.42 ± 6 years, ranging between 15 and 52. Foreign mothers, defined as those who were not born in Italy, were the 12.94%. The most frequent countries of birth were Bangladesh (40.2%), Nigeria (15.01%), Morocco (7.69%), Romania (7.47%) and Tunisia (5.1%). The 69.41% of participants were resident in urban areas, while 30.59% came from rural ones. In regard with mothers’ occupation, 73.82% were housewives, 14.22% employees, 10.38% freelance professionals and 1.57% craftswomen/tradeswomen. In our sample, 1004 women (47.61%) had vaginal deliveries, while 650 (30.82%) and 455 (21.57%) underwent elective and emergency cesarean sections, respectively. 779 participants (36.94%) were primiparous. Sociodemographic and clinical data related to pregnancy, delivery and peripartum of the source population of women are summarized in Table  3 .

Prevalence rates of maternal GBS colonization and use of IAP

The vaginal-rectal swab for GBS was performed in 1559 (73.92%) individuals. More precisely, 512 were carried out in 2020, 560 in 2021 and 487 in 2022. The test resulted positive in 178 cases overall (11.42% of those undergoing the screening): 56 were those in 2020, 66 in 2021, and 56 in 2022.

Among GBS-positive patients, 41 (23.03%) received complete IAP, while to 20 (11.24%) an incomplete IAP was administered. 48 women (26.97%) did not receive IAP, due to cesarean sections performed before the onset of labor and with intact amniotic membranes; 69 subjects (38.76%), conversely, did not undergo IAP despite the presence of one or more clinical indications (Table  4 ).

Of the 550 (26.08%) pregnant women with unknown GBS colonization status, 120 (21.82%) had intrapartum risk factors. In this group, preterm delivery (< 37 weeks of gestation) was the only risk condition in 65 patients (11.82%), PROM ≥ 18 h in 43 (7.82%), while 12 (2.18%) of them had both risk factors (preterm delivery and PROM ≥ 18 h). No women presented with fever and/or other signs of chorioamnionitis. Considering only the individuals with intrapartum risk factors, 23 (19.17%) received complete IAP, the prophylaxis was incomplete in 3 (2.5%) cases, and for 94 (78.33%) it was not administered (Table  5 ).

Amongst our overall sample of 2109 subjects, 298 women had an indication for IAP (vaginal and/or rectal GBS colonization, previous child with EOD, bacteriuria documenting GBS in the current pregnancy, and unknown GBS status at labor onset and at least any among delivery at < 37 weeks’ gestation, amniotic membranes rupture ≥ 18 h and/or intrapartum temperature ≥ 38.0 °C), and 64 (21.48%) received adequate treatment; for 23 (7.72%) it was inadequate/incomplete, while 211 (70.8%) did not receive IAP despite maternal GBS colonization and/or the presence of any of the above mentioned risk factors. Most cases where the prophylaxis was indicated, but in which it was not performed or was inadequate/incomplete, were represented by pregnant women admitted to hospital in advanced labor or presenting with precipitous delivery. In a few subjects IAP was simply omitted, probably for misinterpreted/incorrect data on GBS swabs at the time of birth.

Comparing the Italian mothers with the foreign ones, a higher ( p  < 0.0001 ) frequency of vaginal-rectal swabs for GBS was found in the whole period under investigation among the former (75.49% vs. 63.37%), as well as a greater number (although not statistically significant, p  = 0.72) of adequate and complete IAP (21.86% vs. 19.61%). Conversely, the rate of positive GBS swabs was significantly higher among the foreign mothers (10.46% in the group of Italian women vs. 19.08% in the latter, p  = 0.0008). Comparing the frequency of performing vaginal-rectal swabs in the women admitted in the two time periods, the quote of those screened out of the total in the pandemic period (years 2020–2021) was higher than that of those undergoing GBS screening out of the total admitted in the year 2022 (75.65% vs. 70.38%, p  = 0.009), while a greater number (however not statistically significant, p  = 0.12) of adequate and complete IAP was conducted in 2022, than in the previous biennium (26.36 vs. 18.62%). Finally, the comparison between the periods during and after COVID-19 revealed a mildly lower (without statistical significance, p  = 0.94) GBS colonization rate during the pandemic than the following year (11.38% vs. 11.5%; Table  6 ).

Effects of maternal GBS colonization in the newborn

During the study period, as expected, none of the newborns of mothers with GBS colonization and/or risk factors receiving IAP developed EOD. Conversely, 13 neonates with EOD, out of 179 (7.3%) born to mothers with risk factors (including overall those showing positive, negative, and unknown GBS status, i.e. 60, 11 and 108 respectively), were observed: the incidence rate, estimated as the ratio between the number of babies developing the disease out of the total of 2144 newborns delivered in the 3 years studied, was 6.06‰. Neonatal sepsis was noted in 10 babies born to 121 mothers who did not perform IAP (8.2%), and in 3 neonates born to 19 women whose prophylaxis was incomplete (15.7%). Furthermore, EOD incidence in the COVID-19 period was 8.06% (10 cases out of 124 women with risk factors), while that of the post-pandemic year analyzed was 5.45% (3/55 born to mothers at risk), without a statistically significant difference between the two time periods ( p  = 0.53). Among the infected neonates, 9 were male and 4 female. Mean gestational age was 39 + 4 weeks. All newborns had normal Apgar scores (> 7) at 1 and 5 min. The average birth weight was 3249 ± 482 g, length 49.6 ± 2.7 cm, and occipitofrontal circumference 34.0 ± 1.5 cm. 2 of them were small for gestational age (SGA), while 11 were appropriate for gestational age (AGA).

Clinical manifestations included septic shock (1), jaundice (1), respiratory distress (4), feeding difficulties/regurgitation associated with hypotonia (6), while hyperpyrexia was present in 1 case (Fig.  1 ).

Clinical manifestations of EOD neonates

Increased inflammation indices (CRP and/or PCT) were detected in all newborns. Blood cultures were carried out in all subjects before the start of antibiotic therapy, and resulted negative in all cases. 4 subjects required hospitalization in the NICU, while in 9 cases the admission to the Neonatal Pathology Unit (sub-intensive care setting) was necessary. The patients were hospitalized for an average of 11 ± 3 days. The mean duration of antibiotic therapy was 7 ± 3 days. Empiric therapy with ampicillin (100 mg/kg/dose every 12 h) and gentamicin (4 mg/kg/dose every 24 h) was promptly started in all neonates. The antimicrobial treatment was continued until clinical symptoms disappeared, as well as complete blood counts, inflammation indices, and blood culture tests gave normal/negative results. There was no evidence of meningitis in any case, and no deaths were observed (Table  7 ).

Group B Streptococcus is a major cause of invasive infections in neonates, with the colonization of the vaginal-rectal tract of pregnant women being the main transmission source. Our data provide updated insights about the prevalence of vaginal-rectal GBS colonization in pregnancy. In addition, the present study shows the rates of adhesion to GBS screening and to IAP in a cohort of pregnant women referring to a II level University Hospital in the city of Palermo, Italy. In our sample, the quote of subjects screened for GBS (in all of them a complete vaginal–rectal swab was performed) out of the total addressed to our Mother and Child Department was 73.92%. Such data were higher than those of a previous retrospective study carried out in our Hospital in 2012, and also than the rates recorded by Berardi A. et al. in 2011 in Central Italy, which were 66.03% and 67.9% respectively (Fig.  2 a) [ 20 , 21 ]. According with CDC and the Italian Obstetrics Society guidelines, the execution of vaginal–rectal cultures for GBS is recommended between 35 and 37 weeks of gestation, and such indications were those followed also in the present study [ 8 , 14 ]. In our population vaginal and rectal swabs were positive for GBS in the 10.42% of cases; this value is at the lower range of the national average, which is between 10 and 20% [ 22 ]. Comparing the current analysis with that carried out in 2012 in our Hospital [ 20 ], an increased prevalence of GBS colonization in our population has been observed in the last few years (from 7.98 to 11.42%) (Fig.  2 b) [ 19 ].

Comparison of GBS screening among the current study and those previously reported in our Hospital and in Central Italy (a) , and of maternal GBS colonization between the present analysis and that conducted by Puccio et al. in 2012 in our Department (b)

Worldwide, frequencies of maternal GBS carriers have been reported to range from 14 to 30% in high-income countries (mildly higher than the present survey), to be around 19% in the Sub-Saharan region, and 12–15% in India and Pakistan [ 23 , 24 , 25 ]. Differences in the detected rate of vaginal-rectal GBS colonization may reflect the different demographic characteristics of the populations under investigation. Actually, GBS incidence rates can vary, either according to geographical region or time period [ 26 ]. Indeed, when comparing COVID-19 with the post-pandemic scenario , we detected a mild decrease in GBS maternal colonization during the years 2020–2021 (11.38% vs. 11.5%).

Amongst our overall sample, only 21.48% women received adequate IAP in presence of clinical indications (positive GBS screening culture or intrapartum risk factors). The consequent higher rate of subjects who did not receive or performed incomplete/inadequate IAP can be due to those women admitted in advanced labor or presenting with a precipitous one, in addition to the few cases in which it was omitted for misinterpreted/incorrect data on GBS status at delivery. Such gap is a critical issue which clinicians must be focused on, aiming at reducing the preventable maternal and neonatal adverse outcomes, implementing awareness, antenatal care programs and dedicated operative Department protocols. Indeed, in Central Italy a major proportion (> 90%) of individuals showing GBS-positive cultures received adequate treatment [ 21 ]. In the USA, the prevalence of mothers with an indication for IAP who received adequate treatment increased, from 73.8% between 1998 and 1999 to 85.1% between 2003 and 2004 [ 27 , 28 ]. Comparing the pandemic period (years 2020–2021) with the following one (2022), a higher frequency in the execution of vaginal-rectal swabs for GBS and a lower (although not statistically significant) of adequate and complete IAP, were found in the first two years than in 2022. Actually, despite the infection control and preventive measures adopted to lessen the pandemic’s effects resulted in a decrease in the access to various health facilities, including obstetric and perinatal care services, however in our care setting such reduction was not observed, probably due to the presence within the same metropolitan area of our Department, of a dedicated COVID hospital and birthing center (as documented also by the decrease of the total number of deliveries evidenced during the year 2022, corresponding to the suspension of the COVID hospital activity and its reconversion to regular health care), which all patients with SARS-CoV-2 infection referred to. Therefore, it may be likely that the reduction in the health care accesses reported during the pandemic did not occur in the present experience due to a weaker concern of getting sick perceived by our patients, as well as to the availability offered in our facility to maintain the support of other family members during hospital stay and antenatal care visits [ 11 , 12 , 13 ]. Finally, we detected inequalities between the Italian women and the foreign ones due to the major number of swabs performed among the former and, although not statistically significant, higher colonization rates in the latter.

We reported an EOD incidence of 7.69% among children of mothers carrying risk factors, and of 6.06‰ out of the total number of newborns delivered during the 3-year investigation (i.e., n  = 2144). In our study the clinical picture of the early form of disease was represented by sepsis. According to literature, respiratory signs were the initial most common typical symptoms, only preceded by poor feeding/regurgitation associated with hypotonia, frequently described in literature reports as well [ 29 ]. The other less common clinical manifestations identified were fever, jaundice, and septic shock, which are not typical of GBS, and which can occur in other bacterial infections. Mortality is estimated to be 2–5% in full-term children, and increases by 25% in preterm infants; nonetheless, in our sample (in which, however, no preterm babies were present) neither deaths nor meningitis were documented [ 30 , 31 ]. It is noteworthy that, as expected, none of the mothers’ patients received adequate/complete IAP, with evidence of EOD both in the group of those born to women with non-performed (8.2%) or incomplete (15.7%) prophylaxis. These data further highlight how relevant could be to begin IAP as soon as possible, when a clinical indication is identified, due to the beneficial effects of a prompt IAP (at least four hours before birth).

Our results demonstrate that there is still a relevant number of women who do not perform appropriate IAP despite being properly identified as colonized with GBS at delivery, in addition to those who are not even recognized as GBS-positive by antenatal screening cultures. The identification and treatment of candidates for IAP are necessary, as moreover evidenced by the present study, also owing to the higher risk of developing EOD for neonates born to mothers without GBS screening and not receiving adequate and/or complete IAP. In order to stop and/or limit GBS infections, local public health organizations should support both microbiological surveillance and educational initiatives [ 32 , 33 ]. These interventions, actually, are able to reduce by 80% the risk of neonatal sepsis or meningitis, specifically early onset ones, i.e. those between birth and the completion of the 6th day of life [ 34 , 35 , 36 ]. Indeed, such strategies cannot be effective in the remaining 20% of early infections, as they are not linked to fetal contamination with the bacteria encountered during the passage through the vaginal canal at birth. They are, rather, dependent on infections contracted prior to the delivery, due to the ascending passage of germs to the fetus, especially in case of premature rupture of membranes. Although the total number of cases of neonatal GBS infection is not reported to be overly high, as highlighted also in the present analysis, however it is clear that the prophylaxis measures adopted to date cannot be considered fully satisfactory. Pregnant woman screening, indeed, is not always easy to implement, as well as the administration of intrapartum antibiotics, which often does not follow in the clinical daily practice (as evidenced in our experience), the effective modalities established by CDC guidelines for the eradication of the bacterium. Clinicians, then, need to be careful and accurate in the correct adhesion to care protocols, also in consideration of the high number of inadequate and/or missing IAP administrations, as documented by the present analysis. In addition to the implementation and improvement of antibiotic prophylaxis, however, the search for alternative preventive tools, such as the production of an effective and safe vaccine administered to the mother, appears urgent and not postponable [ 37 , 38 , 39 , 40 ].

The present study revealed in our Department an increased prevalence of pregnant women screened for, and colonized by GBS, in the last decade. However, an overall still low frequency of vaginal-rectal swabs performed for GBS, and low number of adequate and complete IAP despite the presence of risk factors have been found, which did not notably change during the two time periods. Moreover, relevant EOD incidence rates have been reported among children of mothers carrying risk factors, although no statistically significant differences have been observed during and after the COVID-19. Such data seems to be in contrast with those observed during the pandemic for other care settings (especially emergency care areas, as well as surgery and diagnostic services), where notable delays in diagnosis and treatment, and increase in mortality/morbidity rates due to the indirect effects of COVID-19 (reduction in the number of clinical checks, fear in the access to health facilities) have been described. However, in our care setting such findings were not observed, probably due to the presence, within the same metropolitan area of our Department, of a dedicated COVID hospital and birthing center, which all subjects with SARS-CoV-2 infection referred to. This likely led to a weaker concern of getting sick perceived by our patients, as well as to the availability offered in our facility to maintain the support of other family members during the hospital stay and the antenatal care visits. Furthermore, inequalities in the number of swabs performed persist, compared to the past, between Italian and foreign women, highlighting an insufficient health support provided to migrant and at risk populations [ 32 ].

Although IAP is an easy procedure to implement, and our population of women subjected to screening increased in the last years, nonetheless adherence and uniformity of its management protocols are still not optimal. Despite the total number of neonatal GBS infections is not reported to be overly high, as documented also in the present analysis, however the prophylactic measures adopted to date cannot be considered fully satisfactory, and therefore should be improved. Better skills integration and obstetric-neonatological collaboration, in addition to new effective preventive tools, like vaccines [ 41 , 42 ] able to prevent invasive disease, may allow further reduction in morbidity and mortality rates related to GBS perinatal infection.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

Centers for Disease Control and Prevention

Coronavirus disease 2019

C-reactive protein

Early onset disease

Group B Streptococcus

• Intrapartum antibiotic prophylaxis

Intravenous

Late onset disease

Neonatal intensive care unit

Procalcitonin

Premature rupture of membranes

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Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties “Giuseppe D’Alessandro”, University of Palermo, Palermo, Italy

Gregorio Serra, Lucia Lo Scalzo, Maria Giordano, Mario Giuffrè, Pietro Trupiano, Renato Venezia & Giovanni Corsello

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GS drafted the manuscript and took care of the patients. LLS performed the statistical analysis and drafted the first version of the paper. MGio gathered the data related to pregnant women. MGiu revised the manuscript. PT reviewed the literature, made the database and analyzed the data. RV supervised the study and revised the paper. GC conceived the study, revised the manuscript and gave final approval of the version to be submitted. All authors red and approved the manuscript as submitted.

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Correspondence to Gregorio Serra .

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The study was approved by the Mother and Child Department of the University of Palermo, ethics committee Palermo 1 (Palermo, Italy). All procedures performed in this report were in accordance with the ethical standards of the institutional and national research committee, and with the 1964 Helsinki declaration and its later amendments, or comparable ethical standards.

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We declare that the first and last author of the manuscript, Gregorio Serra and Giovanni Corsello, have the role, within Italian Journal of Pediatrics, as Associate Editor and Editor-in-chief respectively.

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Serra, G., Scalzo, L.L., Giordano, M. et al. Group B streptococcus colonization in pregnancy and neonatal outcomes: a three-year monocentric retrospective study during and after the COVID-19 pandemic. Ital J Pediatr 50 , 175 (2024). https://doi.org/10.1186/s13052-024-01738-2

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Received : 25 April 2024

Accepted : 31 August 2024

Published : 13 September 2024

DOI : https://doi.org/10.1186/s13052-024-01738-2

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