Risk factors associated with intraventricular hemorrhage in very-low-birth-weight premature infants

Risk factors associated with intraventricular hemorrhage in very-low-birth-weight premature infants | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Risk factors associated with intraventricular hemorrhage in very-low-birth-weight premature infants Alejandra Guadalupe Puerta-Martínez, Esteban López-Garrido, José Miguel Guerrero-Nava, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3818565/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Feb, 2024 Read the published version in Child's Nervous System → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose To analyze the association between risk factors and severe intraventricular hemorrhage (Grade II-IV) in PNB under 1500 grams. Methods Multicenter, retrospective, analytical, case-control, study in PNB under 34 weeks and under 1500 grams admitted to the NICU Case: PNB with severe intraventricular hemorrhage (grade II-IV). Logistic regression analysis was used to adjust for IVH-associated variables and odds ratios (OR). Results A total of 90 PNB files were analyzed, 45 cases and 45 controls. The highest risk factors for severe IVH were lower gestational age (OR:1.3, p < 0.001), perinatal asphyxia (OR:12, p < 0.001), Apgar < 6 at minute 1 and 5 (OR:6.3, p < 0.001). Conclusion Lower gestational age, birth asphyxia, Apgar score lower of 6, and respiratory-type factors are associated with increased risk for severe IVH. Intraventricular hemorrhage premature newborn risk factors preterm babies Introduction Intraventricular hemorrhage (IVH) is the most common type of intracranial hemorrhage in premature neonates weighing less than 1500 grams; it is a worldwide health problem whose incidence is inversely associated with weeks of gestation and birth weight; the overall incidence ranges from 20–25%, and up to 40% in those younger than 25 weeks [ 1 ]. Germinal matrix hemorrhage-intraventricular hemorrhage (GMH/IVH), originates in this anatomical area, which has an immature capillary bed, with high vascularization and active cell proliferation, it is directly connected vein of Galen, which makes it prone to arterial ischemic reperfusion insults and venous congestion, it gradually involute between 28 to 34 weeks of gestation until it becomes cerebral parenchyma by 36 weeks of gestation. The IVH pathogenesis is multifactorial, involving a combination of vascular anatomical immaturity and hemodynamic factors, in addition to possible genetic and inflammatory factors, as well as intrinsic and extrinsic hemodynamic factors. In the preterm newborn (PNB) the cerebral pressure autoregulation system is not effective, putting at risk hypoperfusion and ischemia in the area and risk of rupture of the GM vessels of the PNB. Extrinsic hemodynamic factors causing IVH include low cerebral blood flow (hypotension, low APGAR, asphyxia), high cerebral blood flow (hypertension, rapid fluid loads, hypercarbia, low hematocrit), fluctuating cerebral blood flow, factors causing increased central venous pressure (respiratory distress syndrome, positive pressure ventilation, pneumothorax, pulmonary hemorrhage), and alterations in coagulation and platelet levels. The immature cerebral venous system in the premature infant is prone to congestion and stasis, which is another factor responsible for the development of hemorrhage [ 1 – 4 ]. In this regard, in a case-control study made in Peru by Valdivieso and Ramírez (2015) it was found that birth weight less than or equal to 1.5 kg, gestational age (GA) less than 32 weeks and male sex were risk factors associated with IVH development. Also, Szecht et al (2016) analyzed 267 preterm newborns (PNB) with a GA less than 32 weeks with grade III and IV IVH where the risk factors were identified to be lack of prenatal steroid use, birth outside a tertiary level hospital, asphyxia, metabolic acidosis treated with bicarbonate and treatment of neonatal hypotension in the first days of life [ 5 , 6 ]. Moreover, in a similar study realized in extreme PNB (GA 23–26 weeks) the principal risk factor was found to be the gestational age, on the other hand, the use of prenatal steroids and reduced use of catecholamines for arterial hypotension were associated as protection factors [ 7 ]. Additionally, in a cohort study realized in 135 PNB with weight lower of 1.5 kg it was determined that 33.3% of the population developed IVH and the weight and gestational age were identified as risk factors to develop IVH [ 8 ]. Also, in a systematic review and meta-analysis, it was concluded that chorioamnionitis was an independent risk factor to develop IVH [ 9 ]. In 2019, in a meta-analysis where 13,605 PNB were analyzed, it was found that prenatal infection increases the risk of IVH for all severities [ 10 ]. On the other hand, in a transversal study in a private hospital in Mexico it was found that the use of mechanical ventilation for more than three days and low gestational age were risk factor to develop IVH [ 11 ]. In 2019 in a retrospective cohort of 495 newborns, it was found that 9.7% had a serious case of IVH also, a high frequency of the hemodynamically permeable ductus arteriosus, nevertheless, this finding was not statistically significant. On the other hand, on the same study, early treatment with indomethacin diminishes the severity of IVH [ 12 ]. In an study performed by Mountasser Mohammad in 2021 in Saudi Arabia in newborns with very low weight at birth is reported that the risk factors to develop IVH are lack of administration of prenatal steroids, pulmonary hemorrhage, hydrocortisone and inotropic use and permeable ductus arteriosus (PDA) [ 13 ]. In a retrospective review conducted in China by Tian Wu et al. (2020), it was found that both lower genital tract infection and younger gestational age can be considered as risk factors associated with progression of mild to severe IVH [ 14 ]. Also, in a retrospective cross-sectional study conducted in Iran in 2021 of 178 neonates under 32 weeks of gestation, where they compared the group with IVH and the group without IVH, they found a significant difference in risk factors such as mechanical ventilation, pneumothorax, low APGAR at 5 minutes, as well as gestational age and birth weight [ 15 ]. On the other hand, in a Ugandan cohort studied by MacLeod in neonates under 2000 grams, 15% had severe IVH, finding vaginal birth, resuscitation in the neonatal unit and gestational age < 32 weeks of gestation as associated risk factors [ 16 ]. IVH is usually developed 72 hours after birth. Among these, 50% of the cases are presented during the first day, 80–90% of the cases in the first 72 hours and practically 100% within the first 10 days after birth. Clinical manifestations depend on the severity of the bleeding, 25–50% of cases are asymptomatic (mild grades) and routine-detected by ultrasonography (silent). Some children manifest with subtle abnormalities in the level of consciousness, movements, tone, breathing and eye movements, these signs evolve over hours to days. Also, it can be observed a decrease in the hematocrit and increased serum bilirubin level. Additionally, with fewer frequencies the catastrophic presentation of the IVH which evolves in minutes to hours can be presented. The signs and symptoms range from stupor, coma, apnea, brainless posture, quadriparesis, generalized tonic convulsions, dilated pupils, bulging fontanel, irregular respiration, increased ventilatory requirement, hypotension, bradycardia and metabolic acidosis. From the later, the most common are seizures, sudden apnea, with altered sensorium, bulging fontanel and drop in the hematocrit [ 17 – 19 ] The diagnosis of IVH is established based on two essential steps, the recognition of clinical manifestations and through ultrasonography. The ideal imaging diagnosis is by Magnetic Resonance Imaging (MRI), which is a difficult study to access in the acute stage, so transfontanelar ultrasound is the preferred procedure since it is available at the patient's bedside. The American Academy of Neurology suggests performing the first screening between the first 5–7 days and the second between 36–40 weeks of corrected gestation to assess the sequelae, it is also suggested to individualize and perform the screening according to the degree of prematurity, performing the first transfontanelar ultrasound (TFUS) between 1–5 days, 10–14 days, 28 days and at term with corrected weeks of gestation. Regarding prognosis, mortality for grade III hemorrhage is 10%, for grade IV mortality is 50–60%, additionally, if hydrocephalia is presented the mortality increases in a 20 and 65–100%, respectively (Fernández-Carrocera, et al. 2004). Also, Cerebral palsy (CP) occurs more frequently in grade 2 or higher (24%), mainly in the extreme low weight preterm (< 1000gr), in grade 1 in 6–7%, grade 2 in 17%, grade 3 in 23–50% [ 20 ]. Parenchymal injury less than 1 cm of extension is not associated with CP, mainly if present in the frontoparietal region. When extensive cerebral infarction involves frontal, parietal and occipital areas, severe motor deficits (spastic hemiplegia, asymmetric quadriplegia) may be present in more than 80% of cases. The cognitive outcome is more variable, some cases with unilateral lesion maintain cognitive function in normal range. Bilateral parenchymal lesions are associated in 100% with severe motor and cognitive impairment [ 20 – 22 ]. Therefore, the aim of the present study was to evaluate the risk factors associated with the development of severe IVH in neonates admitted to the neonatal intensive care unit (NICU) with less than 34 weeks of gestation and less than 1500 g of weight at birth. Materials and methods Type of study A Multicenter, retrospective, analytical case-control study was conducted. All procedures have been authorized by the Ethics committee in Research of the Hospital Regional de Alta Especialidad de Ciudad Victoria (HRAEV, Regional Hospital of High Specialty of Victoria City, Tamaulipas, Mexico) with the authorization number: POST-22-048-PED Data collection To identify the risk factors in PNB, the physical and electronic clinical records discharged from the NICU of the HRAEV and the Hospital General of Ciudad Victoria (General Hospital of Victoria City) between January 2015 and October 2021 that met the inclusion criteria were requested to obtain the information required for the project. The NICU admission and discharge chart was reviewed and patients with less than 34 weeks of gestation and weight less than 1500 g at birth were identified. Inclusion criteria Preterm newborn with a gestational age lower than 34 weeks of gestation and body weight lower than 1500 g with a diagnosis of severe IVH were determined as cases. Preterm newborn with a gestational age lower than 34 weeks of gestation and body weight lower than 1500 g without a diagnosis of IVH were determined as control. Diagnosis of IVH The diagnosis of IVH was performed through transfontanelar ultrasound using an Acuson 300X ultrasound equipment with 8 MHz sector transducer using coronal, occipital and parasagittal. Also, the grade of IVH was classified according to severity according to the Papile scale in Grade I, II, III and IV. Data analysis The data were collected on a detailed collection sheet and then entered into a database in Microsoft Excel program Descriptive statistics was used to determine mean and standard deviation for numerical variables and frequencies and percentages for categorical variables. The statistical analysis was carried out in the SPSS software. In order to compare numerical variables, the distribution of the variables was first evaluated. The Mann-Withney U test was used when there was a normal distribution and the T test when there was not a normal distribution, and chi-square for nonparametric variables. To evaluate the association between risk factors and the presence of intraventricular hemorrhage, the logistic regression model was used to obtain the OR with its 95% CI, and a value of p < 0.05 was considered statistically significant. Results A total of 230 clinical records of PNB met the inclusion criteria. The sample size was constituted of 90 clinical records, 45 were cases and 45 were control. Among the cases, 20 had IVH grade IV (44.4%), 15 cases had grade III (33.3%) and 10 cases had grade II IVH (22.2%) with a p value of < 0.001. On the other hand, within the clinical manifestation 27 cases were catastrophic (60%), 11 cases were saltatory (24.4%), and 7 cases were silent (15.5%) with a p value < 0.001. Regarding gestational age, the mean age of the cases group was statistically significantly lower than the control group 28.1 and 30.1 weeks, respectively (p < 0.001, OR 1.3, CI 95% 0.1–0.4); the mode in both groups was 27 weeks of gestation. Similarly, weight had a statistically significant difference between cases and control groups; the mean of weight was 968.27 g and 1076.98 g, respectively (p 0.037, OR 1, CI 95% 0.04–1.05). Also, low APGAR score at minute 1 and minute 5 (OR 6.34, 95% CI 2.5–16.1, p < 0.001 and OR 3.38, 95% CI 1.29–8.88, p 0.006, respectively) had statistically significant differences. On the other hand, regarding the sex of the PNB, male sex had a higher frequency in both cases and control groups, 51 and 55%, respectively without a significant difference (p 0.067, OR 0.83, CI 95% 0.36–1.92). In contrast, there was not a significative difference when comparing primigravida and multigravida pregnancies (p = 0.34, OR 1.58, CI95% 0.61–1.6), in-vitro fecundation pregnancy (p = 0.26, OR 0.3, CI 95% 0.05–1.59), prenatal use of steroids (p = 0.34, OR 0.6, CI 95% 0.2–1.6), premature membrane rupture (> 18 h), maternal chorioamnionitis, and cervicovaginitis (p = 0.62, 0.48, and 0.19, respectively). Also, it was found that the cesarean had a higher frequency than vaginal delivery (88 and 12%, respectively) but it did not have a statistically significant difference (p = 0.059). Also, hemodynamic variables such as: hypotension (p < 0.001, OR 22.7, 95% CI 6.8–75.7), amine use (p < 0.001, OR 5.78, 95% CI 2.2–15.1) and metabolic acidosis (p < 0.001, OR 5.2, 95% CI 2-13.2) also had statistically significant differences when compared. The variable hypertension (p = 0.79, OR 0.87, 95% CI 0.31–2.4), expander use (p < 0.001, OR 9.84, 95% CI 3.71-26), patent ductus arteriosus (p = 0.2, OR 1.67, CI 0.68–4.08) were not significant. Additionally, when evaluating respiratory type variables: asphyxia (OR 12.3, 95% CI 2.62- 57, p < 0.001), hypercapnia (p < 0.001, OR 29.4, 95% CI 6.33–137), RDS (p 0.002, OR 23.7, 95% CI1. 33–421), pulmonary hemorrhage (p-value 0.02, OR 5.38, 95% CI 1-26.5), invasive mechanical ventilation (p < 0.001, OR 19.9, 95% CI 2.48–159), and surfactant administration (p-value = 0.003, OR 3.69, 95% CI 1.5–8.8) had statistically significant differences when compared. In contrast, the variable severe apnea and pneumothorax were not significant (p = 0.5, OR 0.6, 95% CI 0.1–2.4 and p = 0.04, OR 0.2, 95% CI 0.04-1 respectively). Likewise, hematological variables such as thrombocytopenia (p = 0.003, OR 3.69, 95% CI 1.53–8.89), leukocytosis > 25,000 (p = 0.005, OR 3.44, 95% CI 1.42–8.3), and CRP > 10 (p = 0.007, OR 3.5, 95% CI 1.37–8.9) had statistically significant differences when compared. On the other hand, anemia (p = 0.2, OR 1.76, 95% CI 0.6- 5), transfusion (p = 0.79, OR 1.14, 95% CI 0.4–3.15), > 6 transfusions (p = 0.74), coagulopathy (p = 0.2, OR 0.6, 95% CI 0.2–1.4), immunoglobulin administration (p = 1.0, OR 1.0, 95% CI 0.35–2.81), and leukopenia < 5000 (p = 1, OR 1, 95% CI 0.3–2.6) were not significative. Lastly, 40% of the cases developed a complication, of which 11 were hydrocephalus (24.4%), 7 porencephaly (15.5%). Mortality was higher in cases compared to controls (42% vs 11%) with a statistically significant difference when compared (p < 0.001, OR 5.85 95% CI 1.9–17.6). There was no significant difference in days of hospital stay between cases and controls 52 ± 47 vs 55 ± 28 d(p = 0.37). Discussion The IVH continues to be a worldwide health problem, mainly in PNB under 1500 grams. Despite technological advances and knowledge in neonatal care, which has increased the survival of the most PNB, the incidence of IVH has remained without changes; there is no effective pharmacological treatment to prevent the development of IVH, additionally, there is a high risk of neurological sequelae to those who suffer from IVH. To date, the most important protocol for IVH prevention is the basic management focused on modifying risk factors. This study was performed in two institutions in the northeast of Mexico of 2nd and 3rd level, it was focused in analyzing which factors are associated with a high risk for the development of IVH grade II-IV, considered as serious due to the high risk of neurological sequelae, with the suspicion that ventilatory management plays a fundamental role in the IVH development. The results obtained in this study are similar to those reported in most of the literature being that the higher the prematurity and lower the birth weight, the higher the risk for the development of HIV. Most of the literature states that a gestational age of 28 weeks or less is the most affected, although this can be variable according to the institution or the country involved; for example in the study of MacLeod R et al. performed in Uganda in 2021, it was found that PNB with a weight lower than 2000 gr were affected, also it represented a higher risk those individuals with less than 32 weeks of gestation [ 5 , 7 , 8 , 15 – 16 , 23 – 24 ]. In contrast with other studies, the use of prenatal steroids and cesarean birth were not shown to be a protective factor, although cesarean birth predominated in the controls, it did not show significance, similar to the study by Valdivieso G et al, where it was found that vaginal birth was not a risk factor, this may be associated with the high rate of cesarean in the population studied, as well as the protocolized use of prenatal steroids, especially in the tertiary level hospital that participated in this study [ 5 , 6 , 7 , 13 , 16 , 24 ]. On the other hand, premature membrane rupture, maternal chorioamnionitis and cervicovaginitis, which are considered of high-risk given the inflammatory process that they produce at the level of the immature cerebral maculature, showed no significant difference between the two groups, unlike previously reported studies and meta-analyses, probably associated with the routine prenatal use of antibiotics in the threat of preterm delivery [ 9 , 10 , 14 , 26 – 27 ]. Additionally, the presence of asphyxia and low APGAR at birth at both minute 1 and minute 5 were significant with OR 12 and 6 respectively, most likely because these two events have a direct impact on cerebral perfusion, secondary to hemodynamic instability, especially in the reperfusion phase [ 16 , 23 – 24 ]. Few studies have focused on risk factors for the development of severe IVH. The risk factors associated with severe IVH reported in studies are younger gestational age < 28 weeks, clinical chorioamnionitis, asphyxia, acidosis, and hypotension [ 12 , 16 , 17 , 23 , 26 , 30 ]. In this study, it was found as factors associated with an elevated risk for severe IVH, hypercapnia in first place with OR 29.4, followed by acute respiratory distress syndrome OR 23.7, hypotension OR 22.7, invasive mechanical ventilation OR 19.9, asphyxia OR 12.3, APGAR < 6 per minute OR 6.3, use of amines OR 5.78, pulmonary hemorrhage OR 5.38, metabolic acidosis OR 5.25, use of surfactant OR 3. 6, also it was observed that both hemodynamic and ventilatory factors play an important role in the development of severe IVH, being the respiratory factors more severe than hemodynamic factors, the later finding was similar to the reported in the cohort of Poryo M. et al. and the cohort of Vesoulis ZA identified the risk factors and alteration in blood pressure, respectively, with their association with severe HIV; therefore the maintenance of blood gas homeostasis and timely hemodynamic management is of vital importance. 30,31 Additionally, Khanafer-Larocque et al. in a retrospective cohort in Canada found that 70% of preterm infants with severe HIV had hypercapnia, similar to the finding in the present study (96%) [ 12 , 23 ]. On the other hand, it is worth mentioning that the use of prenatal steroids was not significant, ADRS, predominated in the cases and consequently the need for surfactant and ventilatory support, which were significant for the development of severe IVH. As for PDA, similar to the study conducted by Khanafer-Larocque I et al, it was observed more frequently in cases, but was not significant for the development of severe IVH [ 12 ]. According to Mohammad Al-Mouqdad et al. neonatal hypotension and low hematocrit in the first 3 days of life were associated with severe IVH in very low birth weight infants and in our study hypotension, amine use and metabolic acidosis were also significant [ 13 ]. According to Wu et al. 8.2% of PNB (< 32 weeks) with grade II/III IVH will progress within 7 days to grade III/IV IVH, at least one-fifth to one-third of preterm infants with IVH die during hospitalization. The mortality observed in the present study was higher than reported in the literature, with a significant difference to that of the controls (44 vs 11%, p < 0.001, OR 5.85, CI:1.9–17.6), which correlates with the prevalence of catastrophic clinical manifestation in the cases; it is worth mentioning that most of the cases of death occurred in the secondary level hospital, a fact that refers to the need for the care of these PNB in a tertiary level hospital. In spite of HIV being a morbidity that frequently merits prolonged intra-hospital attention, especially if complicated by hydrocephalus, in this study we found no difference in hospital stay between cases and controls, probably due to the high mortality in cases in the first weeks. Post-hemorrhagic hydrocephalus has been described to be more frequent the higher the degree of severity of IVH, in this study we found a higher frequency of hydrocephalus than reported by Christian et al (24.4% vs 9.0%) [ 22 – 29 ]. Conclusions The etiology of IVH is multifactorial, lower gestational age (28 vs 30 weeks), lower birth weight (987 vs 1121gr), APGAR < 6 at both minute 1 and minute 5 and birth asphyxia in PNB with weight less than 1500 gr, play a key role in the perinatal phase in the development of IVH. Hypercapnia, ARDS, hypotension, invasive mechanical ventilation, inotropic use, pulmonary hemorrhage, and metabolic acidosis, followed by surfactant use, thrombocytopenia 10mg/dl and leukocytosis > 25 000 are associated with a high risk for the development of severe IVH, being the respiratory variables predominating factors. Declarations Declaration of interest statement: The authors declare that they have no competing conflicts of interest or known personal relationships that could have influenced the work reported in this paper. Ethics approval: The use and care of laboratory rodents was performed according to the Animal Laboratory Center of Pediatrics, Children’s Hospital of Fudan University and approved by the Committee of Animal Laboratory Management and Ethics, Shanghai Children’s Hospital. Authors’ contributions AGPM, ELG, HYMP made substantial contributions to conception and design. AGPM, ELG, HYMP collected the data. ELG, HYMP made analysis and interpretation of data. AGPM, ELG, JMGN, RVR, HYMP drafted the manuscript. HYMP revised the manuscript and gave final approval of the version to be published. Agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. 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Med Univer 7(28):116–122 Lizama O, Hernández H, Rivera F, Tori A (2014) Incidencia de la hemorragia intraventricular en prematuros de muy bajo peso y sus factores asociados en un hospital nacional de Lima, Perú. Rev Med Herediana 25(2):60–67 ISSN 1729-214X Gracia SR, de la Cuesta Martín CR, Moisés VR, Pérez DR, Pisón RP, Montejo AR (2011) Corioamnionitis clínica y riesgo de hemorragia intraventricular grave en recién nacidos ⩽28 semanas de gestación. Acta Pediátr Esp 69(11):490–494 Parodi A, De Angelis LC, Re M, Raffa S, Malova M, Rossi A, Severino M, Tortora D, Morana G, Calevo MG, Brisigotti MP, Buffelli F, Fulcheri E, Ramenghi LA (2020) Placental Pathology Findings and the Risk of Intraventricular and Cerebellar Hemorrhage in Preterm Neonates. Front Neurol 11:761. 10.3389/fneur.2020.00761 Shahid G, Jamal M, Nisar YB (2017) Risk Factors of Subependymal Hemorrhage-Intraventricular Haemorrhage in Preterm Infants. Jour Rawalpindi Medl College 21(1):23–28 Inder TE, Pearlman JL, Volpe JJ (2018) Preterm Intraventricular Hemorrhage/Posthemorrhagic hydrocephalus. In: Volpe’s Neurology of the Newborn, 6th, Volpe JJ (Ed), Philadelphia, Elsevier 637 Additional Declarations No competing interests reported. Supplementary Files Appendices.docx Cite Share Download PDF Status: Published Journal Publication published 13 Feb, 2024 Read the published version in Child's Nervous System → Version 1 posted Editorial decision: Revision requested 17 Jan, 2024 Reviews received at journal 14 Jan, 2024 Reviewers agreed at journal 07 Jan, 2024 Reviewers invited by journal 05 Jan, 2024 Submission checks completed at journal 29 Dec, 2023 Editor assigned by journal 29 Dec, 2023 First submitted to journal 28 Dec, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3818565","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":264246166,"identity":"87631aa7-1668-4579-a151-673a13437b49","order_by":0,"name":"Alejandra Guadalupe Puerta-Martínez","email":"","orcid":"","institution":"Hospital Regional de Alta Especialidad de Cd. Victoria \"Bicentenario 2010\"","correspondingAuthor":false,"prefix":"","firstName":"Alejandra","middleName":"Guadalupe","lastName":"Puerta-Martínez","suffix":""},{"id":264246167,"identity":"e2a33a2d-50df-4bf4-93d4-c55bea4c4642","order_by":1,"name":"Esteban López-Garrido","email":"","orcid":"","institution":"Hospital Regional de Alta Especialidad de Cd. Victoria \"Bicentenario 2010\"","correspondingAuthor":false,"prefix":"","firstName":"Esteban","middleName":"","lastName":"López-Garrido","suffix":""},{"id":264246168,"identity":"f42eb4af-8141-4e26-a5fc-5f19ce539b45","order_by":2,"name":"José Miguel Guerrero-Nava","email":"","orcid":"","institution":"Universidad del Valle de México","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"Miguel","lastName":"Guerrero-Nava","suffix":""},{"id":264246169,"identity":"481cf2ef-ef90-4049-a0f8-30120b2d95dd","order_by":3,"name":"Rodrigo Vargas-Ruiz","email":"","orcid":"","institution":"Universidad Autónoma de Tamaulipas","correspondingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"","lastName":"Vargas-Ruiz","suffix":""},{"id":264246170,"identity":"05309642-521b-41a9-b348-83a99e39f3d5","order_by":4,"name":"Hadassa Yuef Martinez-Padron","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYBACAzACAeYDjA+AFA8f8VrYEphBLB42UrSwSYBpQlrM2Q9v/Pjjj13ihmPMxyq/5tjJsDEwP3x0A48Wy560YmnetmSgFra027LbkoEOYzM2zsHnsAM5BtKMDcyJG+73mN2W3MYM1MLDJo1Xy/k3xj9//KkH2sJjViy5rZ4ILTdyzCR42A6DtTB+3HaYGC3Pyqx5244bzzzGlizNuO04DxszIb+cT95888efatm+Y8wHP/7cVm3Pz9788DE+LTDg2AAkmHlATGYilIOAPYhg/EGk6lEwCkbBKBhZAABEg0mSzAG7GwAAAABJRU5ErkJggg==","orcid":"","institution":"Hospital Regional de Alta Especialidad de Cd. Victoria \"Bicentenario 2010\"","correspondingAuthor":true,"prefix":"","firstName":"Hadassa","middleName":"Yuef","lastName":"Martinez-Padron","suffix":""}],"badges":[],"createdAt":"2023-12-28 22:29:39","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3818565/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3818565/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00381-024-06310-1","type":"published","date":"2024-02-13T15:01:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51322918,"identity":"656a175a-2287-4fe4-a19d-81d0cc32309a","added_by":"auto","created_at":"2024-02-19 15:13:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":240239,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3818565/v1/c560ae1a-72ee-4db8-8197-f0d8abf42546.pdf"},{"id":49043824,"identity":"6c64c05c-ece9-43a2-b227-78e4ec956adb","added_by":"auto","created_at":"2024-01-02 06:28:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20300,"visible":true,"origin":"","legend":"","description":"","filename":"Appendices.docx","url":"https://assets-eu.researchsquare.com/files/rs-3818565/v1/55882e6acaf1f990f1957526.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk factors associated with intraventricular hemorrhage in very-low-birth-weight premature infants","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIntraventricular hemorrhage (IVH) is the most common type of intracranial hemorrhage in premature neonates weighing less than 1500 grams; it is a worldwide health problem whose incidence is inversely associated with weeks of gestation and birth weight; the overall incidence ranges from 20\u0026ndash;25%, and up to 40% in those younger than 25 weeks [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGerminal matrix hemorrhage-intraventricular hemorrhage (GMH/IVH), originates in this anatomical area, which has an immature capillary bed, with high vascularization and active cell proliferation, it is directly connected vein of Galen, which makes it prone to arterial ischemic reperfusion insults and venous congestion, it gradually involute between 28 to 34 weeks of gestation until it becomes cerebral parenchyma by 36 weeks of gestation. The IVH pathogenesis is multifactorial, involving a combination of vascular anatomical immaturity and hemodynamic factors, in addition to possible genetic and inflammatory factors, as well as intrinsic and extrinsic hemodynamic factors. In the preterm newborn (PNB) the cerebral pressure autoregulation system is not effective, putting at risk hypoperfusion and ischemia in the area and risk of rupture of the GM vessels of the PNB. Extrinsic hemodynamic factors causing IVH include low cerebral blood flow (hypotension, low APGAR, asphyxia), high cerebral blood flow (hypertension, rapid fluid loads, hypercarbia, low hematocrit), fluctuating cerebral blood flow, factors causing increased central venous pressure (respiratory distress syndrome, positive pressure ventilation, pneumothorax, pulmonary hemorrhage), and alterations in coagulation and platelet levels. The immature cerebral venous system in the premature infant is prone to congestion and stasis, which is another factor responsible for the development of hemorrhage [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this regard, in a case-control study made in Peru by Valdivieso and Ram\u0026iacute;rez (2015) it was found that birth weight less than or equal to 1.5 kg, gestational age (GA) less than 32 weeks and male sex were risk factors associated with IVH development. Also, Szecht et al (2016) analyzed 267 preterm newborns (PNB) with a GA less than 32 weeks with grade III and IV IVH where the risk factors were identified to be lack of prenatal steroid use, birth outside a tertiary level hospital, asphyxia, metabolic acidosis treated with bicarbonate and treatment of neonatal hypotension in the first days of life [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMoreover, in a similar study realized in extreme PNB (GA 23\u0026ndash;26 weeks) the principal risk factor was found to be the gestational age, on the other hand, the use of prenatal steroids and reduced use of catecholamines for arterial hypotension were associated as protection factors [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Additionally, in a cohort study realized in 135 PNB with weight lower of 1.5 kg it was determined that 33.3% of the population developed IVH and the weight and gestational age were identified as risk factors to develop IVH [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Also, in a systematic review and meta-analysis, it was concluded that chorioamnionitis was an independent risk factor to develop IVH [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In 2019, in a meta-analysis where 13,605 PNB were analyzed, it was found that prenatal infection increases the risk of IVH for all severities [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. On the other hand, in a transversal study in a private hospital in Mexico it was found that the use of mechanical ventilation for more than three days and low gestational age were risk factor to develop IVH [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 2019 in a retrospective cohort of 495 newborns, it was found that 9.7% had a serious case of IVH also, a high frequency of the hemodynamically permeable ductus arteriosus, nevertheless, this finding was not statistically significant. On the other hand, on the same study, early treatment with indomethacin diminishes the severity of IVH [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In an study performed by Mountasser Mohammad in 2021 in Saudi Arabia in newborns with very low weight at birth is reported that the risk factors to develop IVH are lack of administration of prenatal steroids, pulmonary hemorrhage, hydrocortisone and inotropic use and permeable ductus arteriosus (PDA) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e In a retrospective review conducted in China by Tian Wu et al. (2020), it was found that both lower genital tract infection and younger gestational age can be considered as risk factors associated with progression of mild to severe IVH [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Also, in a retrospective cross-sectional study conducted in Iran in 2021 of 178 neonates under 32 weeks of gestation, where they compared the group with IVH and the group without IVH, they found a significant difference in risk factors such as mechanical ventilation, pneumothorax, low APGAR at 5 minutes, as well as gestational age and birth weight [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. On the other hand, in a Ugandan cohort studied by MacLeod in neonates under 2000 grams, 15% had severe IVH, finding vaginal birth, resuscitation in the neonatal unit and gestational age\u0026thinsp;\u0026lt;\u0026thinsp;32 weeks of gestation as associated risk factors [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIVH is usually developed 72 hours after birth. Among these, 50% of the cases are presented during the first day, 80\u0026ndash;90% of the cases in the first 72 hours and practically 100% within the first 10 days after birth. Clinical manifestations depend on the severity of the bleeding, 25\u0026ndash;50% of cases are asymptomatic (mild grades) and routine-detected by ultrasonography (silent). Some children manifest with subtle abnormalities in the level of consciousness, movements, tone, breathing and eye movements, these signs evolve over hours to days. Also, it can be observed a decrease in the hematocrit and increased serum bilirubin level. Additionally, with fewer frequencies the catastrophic presentation of the IVH which evolves in minutes to hours can be presented. The signs and symptoms range from stupor, coma, apnea, brainless posture, quadriparesis, generalized tonic convulsions, dilated pupils, bulging fontanel, irregular respiration, increased ventilatory requirement, hypotension, bradycardia and metabolic acidosis. From the later, the most common are seizures, sudden apnea, with altered sensorium, bulging fontanel and drop in the hematocrit [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe diagnosis of IVH is established based on two essential steps, the recognition of clinical manifestations and through ultrasonography. The ideal imaging diagnosis is by Magnetic Resonance Imaging (MRI), which is a difficult study to access in the acute stage, so transfontanelar ultrasound is the preferred procedure since it is available at the patient's bedside. The American Academy of Neurology suggests performing the first screening between the first 5\u0026ndash;7 days and the second between 36\u0026ndash;40 weeks of corrected gestation to assess the sequelae, it is also suggested to individualize and perform the screening according to the degree of prematurity, performing the first transfontanelar ultrasound (TFUS) between 1\u0026ndash;5 days, 10\u0026ndash;14 days, 28 days and at term with corrected weeks of gestation. Regarding prognosis, mortality for grade III hemorrhage is 10%, for grade IV mortality is 50\u0026ndash;60%, additionally, if hydrocephalia is presented the mortality increases in a 20 and 65\u0026ndash;100%, respectively (Fern\u0026aacute;ndez-Carrocera, et al. 2004). Also, Cerebral palsy (CP) occurs more frequently in grade 2 or higher (24%), mainly in the extreme low weight preterm (\u0026lt;\u0026thinsp;1000gr), in grade 1 in 6\u0026ndash;7%, grade 2 in 17%, grade 3 in 23\u0026ndash;50% [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eParenchymal injury less than 1 cm of extension is not associated with CP, mainly if present in the frontoparietal region. When extensive cerebral infarction involves frontal, parietal and occipital areas, severe motor deficits (spastic hemiplegia, asymmetric quadriplegia) may be present in more than 80% of cases. The cognitive outcome is more variable, some cases with unilateral lesion maintain cognitive function in normal range. Bilateral parenchymal lesions are associated in 100% with severe motor and cognitive impairment [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, the aim of the present study was to evaluate the risk factors associated with the development of severe IVH in neonates admitted to the neonatal intensive care unit (NICU) with less than 34 weeks of gestation and less than 1500 g of weight at birth.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eType of study\u003c/p\u003e \u003cp\u003eA Multicenter, retrospective, analytical case-control study was conducted. All procedures have been authorized by the Ethics committee in Research of the Hospital Regional de Alta Especialidad de Ciudad Victoria (HRAEV, Regional Hospital of High Specialty of Victoria City, Tamaulipas, Mexico) with the authorization number: POST-22-048-PED\u003c/p\u003e \u003cp\u003eData collection\u003c/p\u003e \u003cp\u003e To identify the risk factors in PNB, the physical and electronic clinical records discharged from the NICU of the HRAEV and the Hospital General of Ciudad Victoria (General Hospital of Victoria City) between January 2015 and October 2021 that met the inclusion criteria were requested to obtain the information required for the project. The NICU admission and discharge chart was reviewed and patients with less than 34 weeks of gestation and weight less than 1500 g at birth were identified.\u003c/p\u003e \u003cp\u003eInclusion criteria\u003c/p\u003e \u003cp\u003ePreterm newborn with a gestational age lower than 34 weeks of gestation and body weight lower than 1500 g with a diagnosis of severe IVH were determined as cases.\u003c/p\u003e \u003cp\u003ePreterm newborn with a gestational age lower than 34 weeks of gestation and body weight lower than 1500 g without a diagnosis of IVH were determined as control.\u003c/p\u003e \u003cp\u003eDiagnosis of IVH\u003c/p\u003e \u003cp\u003eThe diagnosis of IVH was performed through transfontanelar ultrasound using an Acuson 300X ultrasound equipment with 8 MHz sector transducer using coronal, occipital and parasagittal. Also, the grade of IVH was classified according to severity according to the Papile scale in Grade I, II, III and IV.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eThe data were collected on a detailed collection sheet and then entered into a database in Microsoft Excel program Descriptive statistics was used to determine mean and standard deviation for numerical variables and frequencies and percentages for categorical variables. The statistical analysis was carried out in the SPSS software. In order to compare numerical variables, the distribution of the variables was first evaluated. The Mann-Withney U test was used when there was a normal distribution and the T test when there was not a normal distribution, and chi-square for nonparametric variables. To evaluate the association between risk factors and the presence of intraventricular hemorrhage, the logistic regression model was used to obtain the OR with its 95% CI, and a value of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 230 clinical records of PNB met the inclusion criteria. The sample size was constituted of 90 clinical records, 45 were cases and 45 were control. Among the cases, 20 had IVH grade IV (44.4%), 15 cases had grade III (33.3%) and 10 cases had grade II IVH (22.2%) with a p value of \u0026lt;\u0026thinsp;0.001. On the other hand, within the clinical manifestation 27 cases were catastrophic (60%), 11 cases were saltatory (24.4%), and 7 cases were silent (15.5%) with a p value\u0026thinsp;\u0026lt;\u0026thinsp;0.001.\u003c/p\u003e \u003cp\u003eRegarding gestational age, the mean age of the cases group was statistically significantly lower than the control group 28.1 and 30.1 weeks, respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 1.3, CI 95% 0.1\u0026ndash;0.4); the mode in both groups was 27 weeks of gestation. Similarly, weight had a statistically significant difference between cases and control groups; the mean of weight was 968.27 g and 1076.98 g, respectively (p 0.037, OR 1, CI 95% 0.04\u0026ndash;1.05). Also, low APGAR score at minute 1 and minute 5 (OR 6.34, 95% CI 2.5\u0026ndash;16.1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and OR 3.38, 95% CI 1.29\u0026ndash;8.88, p 0.006, respectively) had statistically significant differences. On the other hand, regarding the sex of the PNB, male sex had a higher frequency in both cases and control groups, 51 and 55%, respectively without a significant difference (p 0.067, OR 0.83, CI 95% 0.36\u0026ndash;1.92).\u003c/p\u003e \u003cp\u003eIn contrast, there was not a significative difference when comparing primigravida and multigravida pregnancies (p\u0026thinsp;=\u0026thinsp;0.34, OR 1.58, CI95% 0.61\u0026ndash;1.6), \u003cem\u003ein-vitro\u003c/em\u003e fecundation pregnancy (p\u0026thinsp;=\u0026thinsp;0.26, OR 0.3, CI 95% 0.05\u0026ndash;1.59), prenatal use of steroids (p\u0026thinsp;=\u0026thinsp;0.34, OR 0.6, CI 95% 0.2\u0026ndash;1.6), premature membrane rupture (\u0026gt;\u0026thinsp;18 h), maternal chorioamnionitis, and cervicovaginitis (p\u0026thinsp;=\u0026thinsp;0.62, 0.48, and 0.19, respectively). Also, it was found that the cesarean had a higher frequency than vaginal delivery (88 and 12%, respectively) but it did not have a statistically significant difference (p\u0026thinsp;=\u0026thinsp;0.059).\u003c/p\u003e \u003cp\u003eAlso, hemodynamic variables such as: hypotension (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 22.7, 95% CI 6.8\u0026ndash;75.7), amine use (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 5.78, 95% CI 2.2\u0026ndash;15.1) and metabolic acidosis (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 5.2, 95% CI 2-13.2) also had statistically significant differences when compared. The variable hypertension (p\u0026thinsp;=\u0026thinsp;0.79, OR 0.87, 95% CI 0.31\u0026ndash;2.4), expander use (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 9.84, 95% CI 3.71-26), patent ductus arteriosus (p\u0026thinsp;=\u0026thinsp;0.2, OR 1.67, CI 0.68\u0026ndash;4.08) were not significant.\u003c/p\u003e \u003cp\u003eAdditionally, when evaluating respiratory type variables: asphyxia (OR 12.3, 95% CI 2.62- 57, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), hypercapnia (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 29.4, 95% CI 6.33\u0026ndash;137), RDS (p 0.002, OR 23.7, 95% CI1. 33\u0026ndash;421), pulmonary hemorrhage (p-value 0.02, OR 5.38, 95% CI 1-26.5), invasive mechanical ventilation (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 19.9, 95% CI 2.48\u0026ndash;159), and surfactant administration (p-value\u0026thinsp;=\u0026thinsp;0.003, OR 3.69, 95% CI 1.5\u0026ndash;8.8) had statistically significant differences when compared. In contrast, the variable severe apnea and pneumothorax were not significant (p\u0026thinsp;=\u0026thinsp;0.5, OR 0.6, 95% CI 0.1\u0026ndash;2.4 and p\u0026thinsp;=\u0026thinsp;0.04, OR 0.2, 95% CI 0.04-1 respectively).\u003c/p\u003e \u003cp\u003eLikewise, hematological variables such as thrombocytopenia (p\u0026thinsp;=\u0026thinsp;0.003, OR 3.69, 95% CI 1.53\u0026ndash;8.89), leukocytosis\u0026thinsp;\u0026gt;\u0026thinsp;25,000 (p\u0026thinsp;=\u0026thinsp;0.005, OR 3.44, 95% CI 1.42\u0026ndash;8.3), and CRP\u0026thinsp;\u0026gt;\u0026thinsp;10 (p\u0026thinsp;=\u0026thinsp;0.007, OR 3.5, 95% CI 1.37\u0026ndash;8.9) had statistically significant differences when compared. On the other hand, anemia (p\u0026thinsp;=\u0026thinsp;0.2, OR 1.76, 95% CI 0.6- 5), transfusion (p\u0026thinsp;=\u0026thinsp;0.79, OR 1.14, 95% CI 0.4\u0026ndash;3.15), \u0026gt; 6 transfusions (p\u0026thinsp;=\u0026thinsp;0.74), coagulopathy (p\u0026thinsp;=\u0026thinsp;0.2, OR 0.6, 95% CI 0.2\u0026ndash;1.4), immunoglobulin administration (p\u0026thinsp;=\u0026thinsp;1.0, OR 1.0, 95% CI 0.35\u0026ndash;2.81), and leukopenia\u0026thinsp;\u0026lt;\u0026thinsp;5000 (p\u0026thinsp;=\u0026thinsp;1, OR 1, 95% CI 0.3\u0026ndash;2.6) were not significative.\u003c/p\u003e \u003cp\u003eLastly, 40% of the cases developed a complication, of which 11 were hydrocephalus (24.4%), 7 porencephaly (15.5%). Mortality was higher in cases compared to controls (42% vs 11%) with a statistically significant difference when compared (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 5.85 95% CI 1.9\u0026ndash;17.6). There was no significant difference in days of hospital stay between cases and controls 52\u0026thinsp;\u0026plusmn;\u0026thinsp;47 vs 55\u0026thinsp;\u0026plusmn;\u0026thinsp;28 d(p\u0026thinsp;=\u0026thinsp;0.37).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe IVH continues to be a worldwide health problem, mainly in PNB under 1500 grams. Despite technological advances and knowledge in neonatal care, which has increased the survival of the most PNB, the incidence of IVH has remained without changes; there is no effective pharmacological treatment to prevent the development of IVH, additionally, there is a high risk of neurological sequelae to those who suffer from IVH. To date, the most important protocol for IVH prevention is the basic management focused on modifying risk factors. This study was performed in two institutions in the northeast of Mexico of 2nd and 3rd level, it was focused in analyzing which factors are associated with a high risk for the development of IVH grade II-IV, considered as serious due to the high risk of neurological sequelae, with the suspicion that ventilatory management plays a fundamental role in the IVH development. The results obtained in this study are similar to those reported in most of the literature being that the higher the prematurity and lower the birth weight, the higher the risk for the development of HIV. Most of the literature states that a gestational age of 28 weeks or less is the most affected, although this can be variable according to the institution or the country involved; for example in the study of MacLeod R et al. performed in Uganda in 2021, it was found that PNB with a weight lower than 2000 gr were affected, also it represented a higher risk those individuals with less than 32 weeks of gestation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast with other studies, the use of prenatal steroids and cesarean birth were not shown to be a protective factor, although cesarean birth predominated in the controls, it did not show significance, similar to the study by Valdivieso G et al, where it was found that vaginal birth was not a risk factor, this may be associated with the high rate of cesarean in the population studied, as well as the protocolized use of prenatal steroids, especially in the tertiary level hospital that participated in this study [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOn the other hand, premature membrane rupture, maternal chorioamnionitis and cervicovaginitis, which are considered of high-risk given the inflammatory process that they produce at the level of the immature cerebral maculature, showed no significant difference between the two groups, unlike previously reported studies and meta-analyses, probably associated with the routine prenatal use of antibiotics in the threat of preterm delivery [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdditionally, the presence of asphyxia and low APGAR at birth at both minute 1 and minute 5 were significant with OR 12 and 6 respectively, most likely because these two events have a direct impact on cerebral perfusion, secondary to hemodynamic instability, especially in the reperfusion phase [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFew studies have focused on risk factors for the development of severe IVH. The risk factors associated with severe IVH reported in studies are younger gestational age\u0026thinsp;\u0026lt;\u0026thinsp;28 weeks, clinical chorioamnionitis, asphyxia, acidosis, and hypotension [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In this study, it was found as factors associated with an elevated risk for severe IVH, hypercapnia in first place with OR 29.4, followed by acute respiratory distress syndrome OR 23.7, hypotension OR 22.7, invasive mechanical ventilation OR 19.9, asphyxia OR 12.3, APGAR\u0026thinsp;\u0026lt;\u0026thinsp;6 per minute OR 6.3, use of amines OR 5.78, pulmonary hemorrhage OR 5.38, metabolic acidosis OR 5.25, use of surfactant OR 3. 6, also it was observed that both hemodynamic and ventilatory factors play an important role in the development of severe IVH, being the respiratory factors more severe than hemodynamic factors, the later finding was similar to the reported in the cohort of Poryo M. et al. and the cohort of Vesoulis ZA identified the risk factors and alteration in blood pressure, respectively, with their association with severe HIV; therefore the maintenance of blood gas homeostasis and timely hemodynamic management is of vital importance.\u003csup\u003e30,31\u003c/sup\u003e Additionally, Khanafer-Larocque et al. in a retrospective cohort in Canada found that 70% of preterm infants with severe HIV had hypercapnia, similar to the finding in the present study (96%) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOn the other hand, it is worth mentioning that the use of prenatal steroids was not significant, ADRS, predominated in the cases and consequently the need for surfactant and ventilatory support, which were significant for the development of severe IVH. As for PDA, similar to the study conducted by Khanafer-Larocque I et al, it was observed more frequently in cases, but was not significant for the development of severe IVH [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. According to Mohammad Al-Mouqdad et al. neonatal hypotension and low hematocrit in the first 3 days of life were associated with severe IVH in very low birth weight infants and in our study hypotension, amine use and metabolic acidosis were also significant [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to Wu et al. 8.2% of PNB (\u0026lt;\u0026thinsp;32 weeks) with grade II/III IVH will progress within 7 days to grade III/IV IVH, at least one-fifth to one-third of preterm infants with IVH die during hospitalization. The mortality observed in the present study was higher than reported in the literature, with a significant difference to that of the controls (44 vs 11%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, OR 5.85, CI:1.9\u0026ndash;17.6), which correlates with the prevalence of catastrophic clinical manifestation in the cases; it is worth mentioning that most of the cases of death occurred in the secondary level hospital, a fact that refers to the need for the care of these PNB in a tertiary level hospital. In spite of HIV being a morbidity that frequently merits prolonged intra-hospital attention, especially if complicated by hydrocephalus, in this study we found no difference in hospital stay between cases and controls, probably due to the high mortality in cases in the first weeks. Post-hemorrhagic hydrocephalus has been described to be more frequent the higher the degree of severity of IVH, in this study we found a higher frequency of hydrocephalus than reported by Christian et al (24.4% vs 9.0%) [\u003cspan additionalcitationids=\"CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe etiology of IVH is multifactorial, lower gestational age (28 vs 30 weeks), lower birth weight (987 vs 1121gr), APGAR\u0026thinsp;\u0026lt;\u0026thinsp;6 at both minute 1 and minute 5 and birth asphyxia in PNB with weight less than 1500 gr, play a key role in the perinatal phase in the development of IVH. Hypercapnia, ARDS, hypotension, invasive mechanical ventilation, inotropic use, pulmonary hemorrhage, and metabolic acidosis, followed by surfactant use, thrombocytopenia\u0026thinsp;\u0026lt;\u0026thinsp;100 000, C-reactive protein\u0026thinsp;\u0026gt;\u0026thinsp;10mg/dl and leukocytosis\u0026thinsp;\u0026gt;\u0026thinsp;25 000 are associated with a high risk for the development of severe IVH, being the respiratory variables predominating factors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of interest statement: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing conflicts of interest or known personal relationships that could have influenced the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe use and care of laboratory rodents was performed according to the Animal Laboratory Center of Pediatrics, Children\u0026rsquo;s Hospital of Fudan University and approved by the Committee of Animal Laboratory Management and Ethics, Shanghai Children\u0026rsquo;s Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAGPM, ELG, HYMP made substantial contributions to conception and design. \u003cbr\u003e AGPM, ELG, HYMP collected the data. \u003c/p\u003e\n\u003cp\u003eELG, HYMP made analysis and interpretation of data. \u003c/p\u003e\n\u003cp\u003eAGPM, ELG, JMGN, RVR, HYMP drafted the manuscript. \u003c/p\u003e\n\u003cp\u003eHYMP revised the manuscript and gave final approval of the version to be published. \u003c/p\u003e\n\u003cp\u003eAgreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement: \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEgesa WI, Odoch S, Odong RJ, Nakalema G, Asiimwe D, Ekuk E, Twesigemukama S, Turyasiima M, Lokengama RK, Waibi WM, Abdirashid S, Kajoba D, Kumbakulu PK (2021) Germinal Matrix-Intraventricular Hemorrhage: A Tale of Preterm Infants. 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Front Neurol 11:761. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2020.00761\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2020.00761\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShahid G, Jamal M, Nisar YB (2017) Risk Factors of Subependymal Hemorrhage-Intraventricular Haemorrhage in Preterm Infants. Jour Rawalpindi Medl College 21(1):23\u0026ndash;28\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInder TE, Pearlman JL, Volpe JJ (2018) Preterm Intraventricular Hemorrhage/Posthemorrhagic hydrocephalus. In: Volpe\u0026rsquo;s Neurology of the Newborn, 6th, Volpe JJ (Ed), Philadelphia, Elsevier 637\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Intraventricular hemorrhage, premature newborn, risk factors, preterm babies","lastPublishedDoi":"10.21203/rs.3.rs-3818565/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3818565/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo analyze the association between risk factors and severe intraventricular hemorrhage (Grade II-IV) in PNB under 1500 grams.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eMulticenter, retrospective, analytical, case-control, study in PNB under 34 weeks and under 1500 grams admitted to the NICU Case: PNB with severe intraventricular hemorrhage (grade II-IV). Logistic regression analysis was used to adjust for IVH-associated variables and odds ratios (OR).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 90 PNB files were analyzed, 45 cases and 45 controls. The highest risk factors for severe IVH were lower gestational age (OR:1.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), perinatal asphyxia (OR:12, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), Apgar\u0026thinsp;\u0026lt;\u0026thinsp;6 at minute 1 and 5 (OR:6.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eLower gestational age, birth asphyxia, Apgar score lower of 6, and respiratory-type factors are associated with increased risk for severe IVH.\u003c/p\u003e","manuscriptTitle":"Risk factors associated with intraventricular hemorrhage in very-low-birth-weight premature infants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-02 06:28:18","doi":"10.21203/rs.3.rs-3818565/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-01-17T16:19:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-14T11:05:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7b56244a-7ae4-4853-b995-6121823e6c37","date":"2024-01-07T14:13:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-05T19:09:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-29T07:11:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-29T07:11:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Child's Nervous System","date":"2023-12-28T22:14:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d4624d65-af3c-4f8d-ad3f-cda099cf52c4","owner":[],"postedDate":"January 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-02-19T15:06:29+00:00","versionOfRecord":{"articleIdentity":"rs-3818565","link":"https://doi.org/10.1007/s00381-024-06310-1","journal":{"identity":"childs-nervous-system","isVorOnly":false,"title":"Child's Nervous System"},"publishedOn":"2024-02-13 15:01:15","publishedOnDateReadable":"February 13th, 2024"},"versionCreatedAt":"2024-01-02 06:28:18","video":"","vorDoi":"10.1007/s00381-024-06310-1","vorDoiUrl":"https://doi.org/10.1007/s00381-024-06310-1","workflowStages":[]},"version":"v1","identity":"rs-3818565","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3818565","identity":"rs-3818565","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}