Association of inflammatory biomarkers with subsequent clinical course in suspected late onset sepsis in preterm neonates

Abstract Background Sepsis is a major health issue in preterm infants. Biomarkers are used to diagnose and monitor patients with sepsis, but C-reactive protein (CRP) is proven not predictive at onset of late onset neonatal sepsis (LONS) diagnosis. The aim of this study was to evaluate the association of interleukin-6(IL-6), procalcitonin (PCT) and CRP with subsequent sepsis severity and mortality in preterm infants suspected of late onset neonatal sepsis. Methods The study was conducted at the Erasmus University Medical Center–Sophia Children’s Hospital Rotterdam. Patient data from January 2018 until October 2019 were reviewed for all preterm neonates born with a gestational age below 32 weeks with signs and symptoms suggestive of systemic infection, in whom blood was taken for blood culture and for inflammatory biomarkers determinations. Plasma IL-6 and PCT were assessed next to CRP at the moment of suspicion. We assessed the association with 7-day mortality and sepsis severity (neonatal sequential organ failure assessment (nSOFA) score, need for inotropic support, invasive ventilation and thrombocytopenia). Results A total of 480 suspected late onset neonatal sepsis episodes in 208 preterm neonates (gestational age < 32 weeks) were retrospectively analyzed, of which 143 episodes were classified as sepsis (29.8%), with 56 (11.7%) cases of culture negative, 63 (13.1%) cases of gram-positive and 24(5.0%) cases of gram-negative sepsis. A total of 24 (5.0%) sepsis episodes resulted in death within 7 days after suspicion of LONS. Both IL-6 (adjusted hazard ratio (aHR): 2.28; 95% CI 1.64–3.16; p < 0.001) and PCT (aHR: 2.91; 95% CI 1.70–5.00; p < 0.001) levels were associated with 7-day mortality; however, CRP levels were not significantly correlated with 7-day mortality (aHR: 1.16; 95% CI (0.68–2.00; p = 0.56). Log IL-6, log PCT and log CRP levels were all significantly correlated with the need for inotropic support. Conclusions Our findings show that serum IL-6 and PCT levels at moment of suspected late onset neonatal sepsis offer valuable information about sepsis severity and mortality risk in infants born below 32 weeks of gestation. The discriminative value was superior to that of CRP. Determining these biomarkers in suspected sepsis may help identify patients with imminent severe sepsis, who may require more intensive monitoring and therapy.

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cfDNA and DNases: New Biomarkers of Sepsis in Preterm Neonates—A Pilot Study

Cells ◽

10.3390/cells11020192 ◽

2022 ◽

Vol 11 (2) ◽

pp. 192

Author(s):

Moritz Lenz ◽

Thomas Maiberger ◽

Lina Armbrust ◽

Antonia Kiwit ◽

Axel Von der Wense ◽

...

Keyword(s):

Preterm Infants ◽

Neonatal Sepsis ◽

Early Onset ◽

Late Onset ◽

Dnase I ◽

Sepsis Group ◽

Preterm Neonates ◽

Control Group ◽

Suspected Sepsis ◽

Epidemiological Characteristics

Introduction: An early and accurate diagnosis of early onset neonatal sepsis (EONS) and late onset neonatal sepsis (LONS) is essential to improve the outcome of this devastating conditions. Especially, preterm infants are at risk. Reliable biomarkers are rare, clinical decision-making depends on clinical appearance and multiple laboratory findings. Markers of NET formation and NET turnover might improve diagnostic precision. Aim of this study was to evaluate the diagnostic value of NETs in sepsis diagnosis in neonatal preterm infants. Methods: Plasma samples of neonatal preterm infants with suspected sepsis were collected. Blood samples were assayed for markers of NET formation and NET turnover: cfDNA, DNase1, nucleosome, NE, and H3Cit. All clinical findings, values of laboratory markers, and epidemiological characteristics were collected retrospectively. Two subpopulations were created to divide EONS from LONS. EMA sepsis criteria for neonatal sepsis were used to generate a sepsis group (EMA positive) and a control group (EMA negative). Results: A total of 31 preterm neonates with suspected sepsis were included. Out of these, nine patients met the criteria for sepsis according to EMA. Regarding early onset neonatal sepsis (3 EONS vs. 10 controls), cfDNA, DNase I, nucleosome, and CRP were elevated significantly. H3Cit and NE did not show any significant elevations. In the late onset sepsis collective (6 LONS vs. 12 controls), cfDNA, DNase I, and CRP differed significantly compared to control group.

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Exploring the Role of Gut Bacteria in Health and Disease in Preterm Neonates

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17196963 ◽

2020 ◽

Vol 17 (19) ◽

pp. 6963 ◽

Cited By ~ 1

Author(s):

Jimmy Kok-Foo Lee ◽

Loh Teng Hern Tan ◽

Amutha Ramadas ◽

Nurul-Syakima Ab Mutalib ◽

Learn-Han Lee

Keyword(s):

Preterm Infants ◽

Gestational Age ◽

Neonatal Sepsis ◽

Late Onset ◽

Bacterial Colonization ◽

Gut Bacteria ◽

Preterm Neonates ◽

Very Preterm Infants ◽

Very Preterm ◽

Microbial Invasion

The mortality rate of very preterm infants with birth weight <1500 g is as high as 15%. The survivors till discharge have a high incidence of significant morbidity, which includes necrotising enterocolitis (NEC), early-onset neonatal sepsis (EONS) and late-onset neonatal sepsis (LONS). More than 25% of preterm births are associated with microbial invasion of amniotic cavity. The preterm gut microbiome subsequently undergoes an early disruption before achieving bacterial maturation. It is postulated that bacterial gut colonisation at birth and postnatal intestinal dysbacteriosis precede the development of NEC and LONS in very preterm infants. In fact, bacterial colonization patterns in preterm infants greatly differ from term infants due to maternal chorioamnionitis, gestational age, delivery method, feeding type, antibiotic exposure and the environment factor in neonatal intensive care unit (NICU). In this regard, this review provides an overview on the gut bacteria in preterm neonates’ meconium and stool. More than 50% of preterm meconium contains bacteria and the proportion increases with lower gestational age. Researchers revealed that the gut bacterial diversity is reduced in preterm infants at risk for LONS and NEC. Nevertheless, the association between gut dysbacteriosis and NEC is inconclusive with regards to relative bacteria abundance and between-sample beta diversity indices. With most studies show a disruption of the Proteobacteria and Firmicutes preceding the NEC. Hence, this review sheds light on whether gut bacteria at birth either alone or in combination with postnatal gut dysbacteriosis are associated with mortality and the morbidity of LONS and NEC in very preterm infants.

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Diagnostic value of urine soluble triggering receptor expressed on myeloid cells (sTREM-1) for late-onset neonatal sepsis in infected preterm neonates

Journal of International Medical Research ◽

10.1177/0300060517749131 ◽

2018 ◽

Vol 46 (4) ◽

pp. 1606-1616 ◽

Cited By ~ 1

Author(s):

Senem Alkan Ozdemir ◽

Esra Arun Ozer ◽

Ozkan Ilhan ◽

Sumer Sutcuoglu ◽

Mansur Tatlı

Keyword(s):

Preterm Infants ◽

Predictive Value ◽

Late Onset ◽

Fatal Outcome ◽

Myeloid Cells ◽

Diagnostic Value ◽

Sepsis Group ◽

Preterm Neonates ◽

Delivery Mode ◽

Suspected Sepsis

Objective Sepsis is a complex clinical condition caused by a dysregulated immune response to an infection resulting in a fatal outcome. This study aimed to investigate the value of urine soluble triggering receptor expressed on myeloid cells (sTREM-1) for diagnosing culture-proven sepsis in preterm infants. Methods Preterm neonates were evaluated for late-onset sepsis (LOS). Laboratory investigations were performed. Urine sTREM-1 samples and blood cultures were synchronously collected. Using blood culture results, preterm neonates were divided into the culture-proven group and suspected sepsis group. Results A total of preterm 62 infants were included in the study; 31 had culture-proven sepsis and 31 were suspected as having sepsis. There were no significant differences in gestational age, sex, birth weight, and delivery mode between the groups. Neonates in the culture-proven group had significantly higher urine sTREM-1 levels than did those in the suspected sepsis group. Using a cut-off point for a urine sTREM-1 level of 78.5 pg/mL, the sensitivity was 0.90, specificity was 0.78, positive predictive value was 0.68, and negative predictive value was 0.94. Conclusions The present study highlights the role of urine sTREM-1 levels in LOS. Urine sTREM-1 may be a reliable and sensitive marker in detecting sepsis in preterm infants.

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Can Endocan Predict Late-Onset Neonatal Sepsis?

Journal of Pediatric Infectious Diseases ◽

10.1055/s-0038-1675239 ◽

2018 ◽

Vol 14 (03) ◽

pp. 096-102 ◽

Cited By ~ 1

Author(s):

Cuneyt Tayman ◽

Nilufer Okur ◽

Utku Serkant ◽

Ufuk Cakir ◽

Halit Halil ◽

...

Keyword(s):

Preterm Infants ◽

Neonatal Sepsis ◽

Late Onset ◽

Leukocyte Count ◽

Clinical Findings ◽

Sepsis Group ◽

Suspected Sepsis ◽

Sepsis Diagnosis ◽

Reactive Protein ◽

Significant Difference

Objective Endocan, a proteoglycan secreted by endothelial cells, plays a role in the pathogenesis of sepsis. Endocan is an effective diagnostic and prognostic biomarker of sepsis in adult patients. We evaluate the utility of endocan as a new biomarker in the recognition of late-onset neonatal sepsis (LOS) in preterm infants. Methods This study included preterm infants at gestational age ≤ 32 weeks diagnosed with LOS. Sepsis was diagnosed in the presence of three or more clinical findings plus significant elevation of C-reactive protein (CRP) or interleukin 6 (IL-6) levels. Blood samples were obtained to determine leukocyte count, CRP, IL-6, and endocan levels immediately after the sepsis diagnosis and on the 3rd and 7th day after diagnosis. Results A total of 102 preterm infants, 52 with LOS (21 proven, 31 suspected sepsis) and 50 controls, were included in the study. Mean leukocyte count, serum CRP, IL-6, and endocan levels were significantly higher in the LOS group compared with healthy controls (p < 0.001) at enrolment. Serial measurements showed no significant difference in CRP and IL-6 levels between the proven and suspected sepsis groups, while endocan levels were significantly higher at enrolment and on day 7 in the proven sepsis group (p = 0.003 and p = 0.01, respectively). The endocan levels of preterm infants who died were significantly higher at all time points (p < 0.001, p = 0.001, and p = 0.004, respectively). Conclusion Endocan is an effective, reliable, and promising new biomarker for detecting LOS in preterm infants.

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Procalcitonin is a Prognosis Biomarker in Late Onset Neonatal Sepsis: A Pilot Study

10.21203/rs.3.rs-822579/v1 ◽

2021 ◽

Author(s):

Valerie Ruetsch ◽

Simon Barreault ◽

Nolwenn Le Sache ◽

Pierre Tissieres

Keyword(s):

Preterm Infants ◽

Gestational Age ◽

Neonatal Sepsis ◽

Neonatal Intensive Care ◽

Late Onset ◽

Area Under The Curve ◽

Neonatal Morbidity ◽

Good Prognosis ◽

Operating Characteristics ◽

Sepsis Diagnosis

Abstract Background. Neonatal sepsis contributes substantially to neonatal morbidity and mortality. Procalcitonin (PCT) is a recognized biomarker for the diagnosis of late-onset neonatal sepsis (LONS), however, little is known about the prognosis value of PCT in LONS. This study aims at assessing PCT value as a prognosis biomarker in preterm infants with LONS. Methods. Retrospective single center observational cohort. All premature infants (less than 32 weeks of gestational age) with LONS admitted in a tertiary neonatal intensive care unit.Discussion. Among the 59 preterm infants included in the analysis, 48 survived (81.4%, 48/59). Deceased patients had a significantly lower gestational age (p=0,025) and weight (p= 0,016) at the time of LONS diagnosis. Although PCT values were not different between both groups at the time of LONS diagnosis, it was more elevated during the first 24 hours in deceased patients (p=0,041). Accuracy of PCT for LONS prognosis ranged from 0.70 to 0.82 of area under the curve on reciever operating characteristics curves. Optimal PCT cut-off values at LONS diagnosis was 8,92 µg/L (Youden’s J index 0.53), 15.75 µg/L for PCT values during the first 24 hours (J index 0.56), and 6.74 µg/L between 24 and 48 hours after diagnosis (J index 0.54). The estimated survival probability at day 60 was above 95% for patient with a PCT value at sepsis diagnosis under 8,9 µg/L and less than 45% if higher (p<0.0001). Conclusion. A PCT value > 8.92 µg/L obtained at LONS diagnosis suspicion seems to be a good prognosis biomarker.

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Protocol: Pentoxifylline optimal dose finding trial in preterm neonates with suspected late onset sepsis (PTX-trial)

BMC Pediatrics ◽

10.1186/s12887-021-02975-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Serife Kurul ◽

H. Rob Taal ◽

Robert B. Flint ◽

Jan Mazela ◽

Irwin K. M. Reiss ◽

...

Keyword(s):

Preterm Infants ◽

Late Onset ◽

Medical Center ◽

Optimal Dose ◽

Dose Finding ◽

Preterm Neonates ◽

Optimal Dosage ◽

Open Label ◽

Main Trial ◽

Late Onset Sepsis

Abstract Background Late onset sepsis is a leading cause of death and morbidity in preterm infants. Despite optimal antibiotic treatment, sepsis related mortality and morbidity is still high. Pentoxifylline (PTX) is a methylxanthine with promising immunomodulatory properties, which can be used as an additional therapy next to antibiotics in preterm infants. PTX is increasingly used off-label in neonatal intensive care units, however up till now no dose finding study has been done for PTX in this specific population. The aim of this study (PTX-trial) is to determine the optimal dose of PTX in preterm infants (gestational age < 30 weeks) with (suspected) late onset sepsis. Dose finding in this particular population is unique, since for most drugs used in neonates the optimal dosage has not been investigated in phase II dose-seeking studies. Methods The PTX-trial is a prospective open label sequential dose-optimization study with an adapted continual reassessment method. An up-and-down dose-response design will be used, with dose step-up and step-down titration after every 3 patients. The PTX starting dosage will be 30 mg/kg/day in 6 hours as described in most previous neonatal studies. Efficacy is defined by means of biochemical and clinical parameters. Toxicity in these vulnerable patients is unwarranted. The optimal dose is defined as the ED75 (i.e., clinically and chemically effective dose for 75% of patients) in preterm neonates with late onset sepsis. We plan to include 30 neonates to determine the optimal dose using this study design. Subsequently, the optimal dose will be validated in 10 additional preterm neonates. In parallel, pharmacokinetics of PTX and its metabolites will be described as well as longitudinal evaluation of metabolomics and proteomics. Discussion The study has been approved by the Regional Medical Ethics Board of Erasmus Medical Center University Rotterdam (MEC 2019-0477) and registered at Clinicaltrials.gov (NCT04152980). Results of the main trial and each of the secondary endpoints will be submitted for publications in peer-reviewed journals. Trial registration Clinicaltrials.gov, NCT04152980, Registered November 6th, 2019

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The serum level of C-reactive protein in neonatal sepsis

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh0806253v ◽

2008 ◽

Vol 136 (5-6) ◽

pp. 253-257 ◽

Cited By ~ 3

Author(s):

Brankica Vasiljevic ◽

Olga Antonovic ◽

Svjetlana Maglajlic-Djukic ◽

Miroslava Gojnic

Keyword(s):

Gestational Age ◽

Neonatal Sepsis ◽

Late Onset ◽

Hematological Parameters ◽

Clinical Signs ◽

Preterm Neonates ◽

C Reactive Protein ◽

Reactive Protein ◽

Early Onset Sepsis ◽

Serum Crp

INTRODUCTION C-reactive protein (CRP) is the most common diagnostic marker of infection. OBJECTIVE Objectives of this study were to determine the serum CRP level in neonates with sepsis and establish the influence of gestational age (GA) on the CRP level in the first few weeks after birth. METHOD Diagnosis of neonatal sepsis was established by the presence of clinical signs of sepsis, isolation of the causative agent of sepsis and abnormal hematological parameters. All neonates were divided into two groups: early onset sepsis (EOS) and late onset sepsis (LOS). According to GA all neonates were divided into three groups: <32 GA, 32-36 GA and ?37 GA. Serum CRP was measured 0-72 h after the onset of signs and symptoms of infection. RESULTS This study included all neonates with sepsis at our Institute during 2003. EOS was diagnosed in 130 neonates (mean age was 33 weeks; range 27-41 weeks) and 33 infants (mean age 29 weeks; range 27-38 weeks). We defined a relevant CRP response as a concentration of >10 mg/l for term and near term neonates and >5 mg/l for preterm neonates. The maximum concentrations of CRP were reached 48 hr after the first symptoms of neonatal sepsis. CONCLUSION CRP levels are proportional with increasing GA and body weight in EOS. The effects of gestational age do not influence CRP levels in LOS. Maturation changes in the immune system are the most likely explanation for this and partly the organisms responsible for an infection may be different at different gestational ages and also in EOS and LOS. There is no correlation with serum CRP levels and with the severity of the disease and bad prognosis in EOS.

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Prolonged empiric antibiotics and time to full enteral feed in preterm infants less than 29 weeks of gestational age

Journal of Neonatal-Perinatal Medicine ◽

10.3233/npm-200555 ◽

2021 ◽

pp. 1-5

Author(s):

M.R. Alturk ◽

H. Salama ◽

H. Al Rifai ◽

M. Al Qubaisi ◽

S. Alobaidly

Keyword(s):

Parenteral Nutrition ◽

Preterm Infants ◽

Antibiotic Treatment ◽

Gestational Age ◽

Late Onset ◽

Blood Cultures ◽

Hospital Death ◽

Late Onset Sepsis ◽

Empiric Antibiotic ◽

Antibiotic Courses

BACKGROUND: Early empiric antibiotic exposure appears to negatively influence feeding tolerance in preterm infants. However, the effect of prolonged antibiotic treatment is unknown. The objective of this study was to investigate whether prolonged antibiotics impact the time to full enteral feed in infants less than 29 weeks of gestational age with negative blood cultures. METHODS: Retrospective data for infants less than 29 weeks gestation age were retrieved from the PEARL-Peristat perinatal registry in Qatar. Exclusion criteria were major congenital anomalies, conditions requiring surgery in the first 10 days of life, positive blood cultures in the first 48 hours of life, and death within the first week of life. Antibiotic courses were categorized as prolonged if continued more than 48 hours. The primary outcome was the duration of total parenteral nutrition. RESULTS: Of 199 study infants, 185 (92.9%) underwent antibiotic treatment for > 48 hours despite negative blood cultures. The median duration of parenteral nutrition was not significantly different between the prolonged and short antibiotic groups (25 and 22 days, respectively; p = 0.139). Infants with prolonged antibiotic courses experienced non-significantly higher levels of necrotizing enterocolitis (7.1% and 18.4%, respectively), bronchopulmonary dysplasia (28.6% and 45.4%, respectively), and retinopathy of prematurity (14.3% and 38.4%, respectively). There were no differences in the late-onset sepsis rate (78.6% and 82.1%, respectively) and the in-hospital death rate (7.1% and 7.6%, respectively). CONCLUSIONS: Prolonged antibiotic treatment in infants less than 29 weeks gestation with negative blood cultures has no significant impact on the time to full enteral feed.

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67 Are NICUs too busy?

Paediatrics & Child Health ◽

10.1093/pch/pxab061.052 ◽

2021 ◽

Vol 26 (Supplement_1) ◽

pp. e47-e48

Author(s):

Marc Beltempo ◽

Robert Platt ◽

Anne-Sophie Julien ◽

Regis Blais ◽

Bertelle Valerie ◽

...

Keyword(s):

Preterm Infants ◽

Patient Outcomes ◽

Gestational Age ◽

Late Onset ◽

Mode Of Delivery ◽

Random Effect ◽

Organizational Factors ◽

Neurological Injury ◽

Very Preterm Infants ◽

Very Preterm

Abstract Primary Subject area Neonatal-Perinatal Medicine Background In a health care system with limited resources, hospital organizational factors such as unit occupancy and nurse-to-patient ratios may contribute to patient outcomes. Objectives We aimed to assess the association of NICU occupancy and nurse staffing with outcomes of very preterm infants born < 33 weeks gestational age (GA). Design/Methods This was a multicenter retrospective cohort study of infants born 23-32 weeks GA without major congenital anomaly, admitted within 2 days after birth to one of four Level 3 NICUs in Quebec, Canada (2015-2018). For each 8 h shift, data on unit occupancy were obtained from a central provincial database (SiteNeo) and linked to the hospital nursing hours database (Logibec). Unit occupancy rates and nursing provision ratios (nursing hours/recommended nursing hours based on patient dependency categories) were pooled for the first shift, 24 h, and 7 days of admission for each infant. Patient data were obtained from the Canadian Neonatal Network database. Primary outcome was mortality and/or morbidity (severe neurological injury, bronchopulmonary dysplasia, necrotizing enterocolitis, and late-onset sepsis, severe retinopathy of prematurity). Adjusted odds ratios (AOR) for association of exposure with outcomes were estimated using generalized linear mixed models with a random effect for center, while adjusting for confounders (gestational age, small for gestational age, sex, outborn, Score for Neonatal Acute Physiology version 2, mode of delivery, and the other organizational variables). Results Among 1870 infants included in analyses, 796 (43%) had mortality/morbidity. Median occupancy was 89% (IQR 82-94) and median nursing provision was 1.13 (IQR 0.97-1.37). Overall higher NICU occupancy on shift of admission, first 24 h, and 7 days were associated with higher odds of mortality/morbidity (Figure 1) but nursing provision was not (Figure 2). Subgroup analysis by GA (< 29 and 29-32 weeks) yielded similar results (not shown). Generalized linear mixed model analyses showed that a 5% reduction in occupancy in the first 24 h of admission was associated with a 6% reduction in mortality/morbidity. Conclusion NICU occupancy is associated with mortality/morbidity among very preterm infants and may reflect lack of adequate resources in periods of high activity. Interventions aimed at reducing occupancy and maintaining adequate resources need to be considered as strategies to improve patient outcomes.

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Comparison of neonatal outcomes of small for gestational age and appropriate for gestational age preterm infants born at 28–36 weeks of gestation: a multicentre study in Ethiopia

BMJ Paediatrics Open ◽

10.1136/bmjpo-2020-000740 ◽

2020 ◽

Vol 4 (1) ◽

pp. e000740

Author(s):

Netsanet Workneh Gidi ◽

Robert L Goldenberg ◽

Assaye K Nigussie ◽

Elizabeth McClure ◽

Amha Mekasha ◽

...

Keyword(s):

Preterm Infants ◽

Gestational Age ◽

Small For Gestational Age ◽

Late Onset ◽

Early Recognition ◽

Neonatal Outcomes ◽

P Value ◽

Prolonged Hospitalisation ◽

Increased Risk ◽

Appropriate For Gestational Age

PurposeThe aim of this study was to assess morbidity and mortality pattern of small for gestational age (SGA) preterm infants in comparison to appropriate for gestational age (AGA) preterm infants of similar gestational age.MethodWe compared neonatal outcomes of 1336, 1:1 matched, singleton SGA and AGA preterm infants based on their gestational age using data from the study ‘Causes of Illness and Death of Preterm Infants in Ethiopia (SIP)’. Data were analysed using SPSS V.23. ORs and 95% CIs and χ2 tests were done, p value of <0.05 was considered statistically significant.ResultThe majority of the infants (1194, 89%) were moderate to late preterm (32–36 weeks of gestation), 763 (57%) were females. Male preterm infants had higher risk of being SGA than female infants (p<0.001). SGA infants had increased risk of hypoglycaemic (OR and 95% CI 1.6 (1.2 to 2.0), necrotising enterocolitis (NEC) 2.3 (1.2 to 4.1), polycythaemia 3.0 (1.6 to 5.4), late-onset neonatal sepsis (LOS) 3.6 (1.1 to 10.9)) and prolonged hospitalisation 2.9 (2.0 to 4.2). The rates of respiratory distress syndrome (RDS), apnoea and mortality were similar in the SGA and AGA groups.ConclusionNeonatal complications such as hypoglycaemic, NEC, LOS, polycythaemia and prolonged hospitalisation are more common in SGA infants, while rates of RDS and mortality are similar in SGA and AGA groups. Early recognition of SGA status, high index of suspicion and screening for complications associated and timely intervention to prevent complications need due consideration.

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