A review of placental histology for infants with hypoxic ischemic encephalopathy compared with healthy controls: A retrospective case-control study

A review of placental histology for infants with hypoxic ischemic encephalopathy compared with healthy controls: A retrospective case-control study | 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 Article A review of placental histology for infants with hypoxic ischemic encephalopathy compared with healthy controls: A retrospective case-control study Aine Fox, Emma Doyle, Adam Reynolds, Michael Geary, Rocco Cuzzilla, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4570410/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective The role of the placenta in the development of hypoxic ischaemic encephalopathy (HIE) remains undefined. There is limited research comparing placental histology for infants with HIE and healthy controls. This is limiting our ability to understand its role in HIE. This study aimed to report the differences in placental histology between infants with HIE and healthy controls. Study Design A case-control study of (near-) term infants with moderate/severe HIE and healthy controls at a single tertiary NICU. Placental histology was reviewed by one perinatal histopathologist using consensus guidelines. Results Seventy-four cases and 98 controls were included. Cases had a higher incidence of pathology, including fetal vascular malperfusion, histological chorioamnionitis and delayed villous maturation. Conclusion This study demonstrates a higher incidence of placental pathology for infants born with HIE suggesting that the placenta is an important factor in the pathogenesis of HIE. Further research is required to delineate this relationship. Health sciences/Diseases/Neurological disorders/Brain injuries Health sciences/Medical research/Biomarkers/Predictive markers placental pathology placental histology neonatal encephalopathy hypoxic ischaemic encephalopathy Figures Figure 1 Introduction Neonatal encephalopathy (NE) remains a significant cause of neonatal morbidity and mortality and childhood disability across the world [ 1 , 2 ]. NE has many different aetiologies, including genetic, metabolic, infection, stroke and hypoxia ischaemia (HI). HI, known as hypoxic ischaemia encephalopathy (HIE), is the most common cause of NE. Within the classification of HI, it is well understood that HI can be acute, subacute, chronic or mixed pattern. Acute HI is recognised as an intrapartum sentinel event and accounts for 30–40% of cases of HIE. Subacute, chronic and mixed pattern HI is assumed to be the cause for the remaining cases however the mechanisms leading to these patterns of HI remain uncertain [ 3 ]. There is an increased appreciation for the role that maternal and placental factors have in the development of the fetus, including fetal brain health and development. Improving our understanding of the maternal-placental-fetal (MPF) triad provides an opportunity for enhanced antenatal and intrapartum care to positively influence the outcomes of at-risk fetuses. Placental factors are recognised as a confounding factor for the development of HIE. Placental lesions associated with inflammation and fetal malperfusion likely affect the capacity of the fetus to maintain adequate oxygenation and organ perfusion in the hypoxic-ischemic environment of labour. This likely increases a fetus’s vulnerability to peripartum hypoxic-ischemic injury and plays a role in the mechanisms and timing of brain injury [ 4 , 5 ]. There remains controversy over the influence that placental pathology has on outcomes in infants with HIE [ 6 – 8 ]. Some research suggests that placental pathology in HIE does not impact their outcome [ 6 ]. To conclude that placental pathology has no impact on outcomes in HIE, one must compare to placental histology of infants without HIE. There is limited research comparing placentae of infants with HIE and healthy infants [ 3 , 7 , 8 ]. Determining the differences between the placentae of infants with healthy brains and those with injured brains may provide insights to the role of the placenta in HIE. Aims To determine if placental pathology is more common in newborn infants with HIE compared with healthy controls. Materials and Methods This was a retrospective case-control study performed in a single tertiary Neonatal Intensive Care Unit. This case-control study of placental histology was part of a larger study investigating the relationships between placental pathology, cardiotocography (CTG) and neuroimaging for newborn infants with moderate or severe HIE. Cases Cases were near-term and term infants with moderate or severe HIE born between 2006 and 2021. In all cases, history and investigations including neuroimaging were consistent with a diagnosis of HIE. Cases were included if placental slides were available for analysis. Infants were excluded if (1) gestation < 36 weeks; (2) abnormal anatomy on brain MRI; (3) an alternative diagnosis was found to explain their encephalopathy other than HI. Controls Controls were recruited over a period of 12 months from January 2022 to January 2023. Contemporaneous control data was not possible as healthy infants do not have placental histology performed and it was felt that infants having placental histology for other reasons did not represent a group of healthy control infants. Inclusion criteria: (1) placenta available for analysis; (2) intrapartum cardiotocography (CTG) available for a minimum duration of 40 minutes; (3) born at \(\ge\) 36 weeks’ gestation and considered to be healthy with a normal neurological status and an Apgar score \(\ge\) 8 at 5 minutes; (4) no resuscitation after 5 minutes from birth; and (5) no admission to the neonatal intensive care unit. CTG was a requirement for controls as this study was part of a larger study exploring the associations of placental pathology and CTG. Exclusion criteria: (1) maternal history of recurrent miscarriage (≥ 3) or coagulopathy; or (2) clinical indication for placental analysis. Maternal and infant charts were reviewed for clinical details. Placental Analysis Case placentae were archived placental slides and control placentae were freshly prepared slides. Placental slides were reviewed by one perinatal histopathologist (ED) using the 2016 Amsterdam consensus guidelines for reporting placental histology [ 4 ] [ 5 ]. Macroscopic details (including coiling index (CI) and placental weight) were collected. For cases, this information was collected from archived clinical histology report after placental slides were reviewed. Coiling index (CI) is a measure of the number of complete coils per centimetre length of cord (normal reference range 0.1–0.3 coils/cm) [ 9 ]. The reviewer had birth weight and gestation available for interpretation of placental weight centiles and birth weight-to-placenta weight ratio (BW:PW) calculations. Statistical Analysis Statistical analysis was performed using Stata SE Version 17 (StatCorp, College Station, Texas). For summary statistics, continuous normally distributed variables were reported as means and standard deviation (SD) and continuous non-normally distributed variables were reported as medians and interquartile range. T test was used for binary and normally distributed continuous variables. Wilcoxon rank sum test was used for binary and non-normal continuous variable. Chi squared test was used for categorical variable with a cell count greater than 20. Fischer’s exact test was used for two binary variables where the cell counts were less than 20. Statistical significance was set at a p-value < 0.05. Placental pathology (Fig. 1 ) was classified into grades and stages of histological chorioamnionitis (HCA) and pattern and/or severity of fetal vascular malperfusion (FVM), maternal vascular malperfusion (MVM), villitis of unknown etiology (VUE) and delayed villous maturation (DVM). For the purpose of analysis, categories of pathology were classified as present or absent as the sub-category classifications for each pathology were too small for meaningful analysis. Results This study included 74 cases of moderate or severe HIE and 98 healthy controls. Demographics for the cases and controls are shown in Table 1. Placental histology for cases and controls are shown in Table 2 . Fetal Vascular Malperfusion FVM was present in 18 (24%) cases. Fifteen cases with FVM had CI recorded, of which 5 (33%) had hyper-coiling of the umbilical cord. Five (28%) cases with FVM had an intrapartum sentinel event (ISE), a lower proportion than the rate of ISE for all cases (43%). Eight cases with FVM had HCA and 6 cases had DVM, of which 3 cases had both HCA and DVM. Coiling Index Table 3 and Table 4 show the association between hyper-coiling (defined by CI >0.3) and presence of FVM. There was a higher incidence of FVM with hyper-coiling in cases compared with controls (50% v 17%). Of the 5 cases with FVM and hyper-coiling, 2 (40%) had high-grade FVM. In contrast, no controls with FVM and hyper-coiling had high-grade FVM. Maternal Vascular Malperfusion MVM was more common in controls than cases, but this difference was not statistically significant. Birth weight was significantly lower for cases with MVM compared with controls with MVM (t=2.51 p= 0.009). Cases with MVM had higher BW:PW than controls with MVM (z=-1.769 p=0.079) but this was not statistically significant. Histological Chorioamnionitis Thirty-six (49%) cases had HCA of which 22 (61%) had a fetal response. This was significantly different to the control group (p=0.001). Vilitis of Unknown Etiology VUE was more common in controls than cases, this difference approached statistical significance (p=0.061). Presence of VUE in cases had no association with birth weight (t=0.147 p=0.442), BW:PW (z=0.223 p=0.223) or maternal BMI (z=0.857 p=0.405). Delayed Villous Maturation DVM was more common in cases compared with controls, this was statistically significant (p=0.003). There was no association between presence of DVM in cases and birth weight (t=-0.4301 p=0.666), BW:PW (z=1.267 p=0.210) or maternal BMI (z=1.128 p=0.265). Differences in BW:PW, CI, incidence of MVM and VUE were not statistically significant between case and control groups (Table 2 ). Discussion This study provides evidence that placental pathology is more common in newborn infants with moderate or severe HIE than healthy controls. This study is in keeping with other studies that have compared placentae of infants with HIE and controls [ 7 , 8 , 10 ]. Several specific placental pathologies had an increased incidence in cases compared with controls, including HCA, FVM and DVM. This could indicate that these placental pathologies are either a direct cause of HIE or contribute to reduced placental reserve, resulting in earlier and more significant fetal decompensation in the setting of intrapartum HI. The incidence of FVM was higher in infants with moderate or severe HIE compared with controls. This finding supports the results of other studies [ 7 , 10 ]. There was also a higher incidence of FVM in cases without an ISE compared to those with an ISE (31% v 16%), although there were very small numbers and this was not statistically significant. This suggests that FVM may have a larger role in cases of unexplained HIE. Cases with FVM were more likely to demonstrate hyper-coiling compared with controls. Higher CI in cases could be a contributory factor to the development on FVM. This study demonstrates an increased incidence of HCA in infants with HIE compared to healthy controls. The incidence of HCA in cases in this study is also higher than the incidence of HCA reported in a healthy population in others studies [ 8 ]. This has been reported in studies previously, including in a cohort study by Novak et al where they found HCA was more common in infants with HIE with an unexplained cause [ 11 ]. For cases in this study, fetal inflammatory response (FR) was present for 61% of cases affected by HCA. Bingham et al also found cases with HCA had a much higher incidence of FR than controls with 100% of their cases with HCA having FR, although they did report a higher incidence of HCA in their control group compared to the current study[ 10 ]. This may be due to selection bias within their control group which included infants admitted to NICU for a reason other than HIE, and likely does not represent a control cohort of healthy term infants. McDonald et al and Mir et al conducted cohort studies for infants with HIE and found that HCA, particularly HCA with FR, was associated with encephalopathy and an increased severity of encephalopathy [ 12 , 13 ]. The HEAL trial found 39% of their cohort had HCA [ 14 ]. Naisell et al performed a case-control study and found no association between HIE and HCA, however their study only had 41 cases with placental findings and included infants with mild, moderate and severe HIE. Details of the number of each grade of HIE and their placental pathologies were not included in their report. Placental findings in infants with mild HIE may differ from infants with moderate or severe HIE. An inflammatory response on the fetal side of the placenta implies that the fetus was affected by inflammation. This is more commonly known as Fetal Inflammatory Response Syndrome (FIRS) [ 15 ]. FIRS is associated with increased neonatal mortality and neonatal, childhood and adult morbidity [ 16 – 18 ]. HCA, particularly in the setting of FR, has likely led to a preconditioning of the fetal brain. The inflammation may have a direct effect on the developing fetal brain and/or act as a primer for fetal brain injury in the setting of intrapartum HI. FIRS can lead to impaired perfusion, oxygen delivery and/or disseminated intravascular coagulation, leading to micro-thrombi in the capillaries, culminating in hypoxic tissue [ 19 ]. This process may increase tissue vulnerability to reduced delivery of oxygen in the setting of labour and delivery, even if HI is within the limits of a typically progressing intrapartum course. This may explain the pathogenesis of HIE for some infants with a seemingly normal intrapartum course. DVM was also significantly increased in cases. Some studies have found no association between DVM and HIE [ 10 , 13 , 20 ]. However, Harteman et al looked at the relationship between brain injury on MRI and placental findings in HIE. They found placental immaturity to be associated with white matter brain injury [ 21 ]. In contrast, MVM was more common in controls than cases but this was not statistically significant. Some studies have found features of MVM to be associated with HIE [ 10 , 13 ], in contrast to the findings in this study. Unfortunately, MVM has not been routinely reported in many placental pathology studies on HIE so it if difficult to determine if this study is an outlier in this respect or not. This study did find that where MVM was present in cases, birth weight was lower than in all cases and lower than controls with MVM. This may suggest that where MVM is present in a fetus, it could be contributing to suboptimal fetal growth and potentially impair tolerance of labour. VUE was also more common in controls than cases. In studies where VUE has been reported, it was not found to be associated with HIE [ 5 , 8 , 10 , 13 ]. Controls in this study were born during a time of the COVID-19 pandemic, and pregnancies may have been exposed to either COVID-19 infection and/or COVID-19 vaccination, both of which lead to an immune response in the mother. COVID-19 infection in pregnancy has been associated with inflammation of the placenta, termed ‘COVID placentitis’ [ 22 ]. It may be that this control group developed VUE from a COVID-19-associated immunological response. The rate of VUE in healthy pregnancies is reported in the literature to be between 6 and 33% [ 23 ], therefore this control group could also be reflective of a normal population. Strengths A major strength of this study is that it reports on a good sample size of cases with moderate or severe HIE compared with other studies on placenta pathology in HIE. It also includes a control group of neurologically healthy term infants without medical illness or clinical indication for placental assessment. Limitations Recruitment of controls was limited by the capacity of the histopathology department to process the additional workload for placenta analysis and were collected over a period of one year. It was not possible to blind the reviewer to whether the placenta slides were from a case or control. Case placenta slides were archived slides that were retrieved from storage. Control placenta slides were stored on site until they were reviewed. The reviewer was blinded to the clinical details of the cases. Due to resource limitations, we were unable to have a second reviewer to analyse the placentae leading to an inability to determine the presence of any bias within the reporting. This case-control study provides evidence for differences in placental histology between infants with moderate or severe HIE and a convenience sample of healthy controls. Infants with HIE had a higher incidence of pathology overall, and specifically for HCA, FVM and DVM. This suggests that placental pathology may be a risk factor for poor tolerance of labour and/or is likely to be a contributing factor in the pathogenesis of HIE, particularly in the absence of an ISE. Further research is required to further delineate the role of the placenta in the pathogenesis of HIE. Abbreviations BE base excess DVM delayed villous maturation FIRS fetal inflammatory response syndrome FR fetal inflammatory response FVM fetal vascular malperfusion HI hypoxia ischaemia HCA histological chorioamnionitis HIE hypoxic ischemic encephalopathy MPF maternal-placental-fetal MVM maternal vascular malperfusion NE neonatal encephalopathy VUE vilitis of unknown etiology Declarations Authorship Statement Fox, A contributed to the design of the study, collected data, statistical analysis, interpretation of results and wrote and edited the manuscript Reynolds, A contributed to the design of the study, collected data, interpretation of results, reviewed intellectual content and edited the manuscript Doyle, E reviewed all the placental slides, provided expert knowledge and contributed to the interpretation of results, reviewed intellectual content and edited the manuscript Geary, M contributed to the design of the study and edited the manuscript Cuzzilla, R contributed to the design of the study, scoring MRI images, interpretation of results, reviewed intellectual content and edited the manuscript Hayes, B contributed to the design of the study, interpretation of data, reviewed intellectual content and edited the manuscript, supervisor of study Funding Funding for this research was provided by The Rotunda Foundation and The National Women and Infants Health Programme Ireland. Funders had no involvement in the research study design, collection of data or analysis of data. Declarations of interest None Ethics The study received ethical approval from the Rotunda Hospital Research and Ethics Committee (REC-2015-009). Approval was given to waiver consent for patients who died or have significant disability. All other families, including controls gave informed consent for their data to be included. Specifically, control gave consent of placental analysis. The study was performed in accordance with the Declaration of Helsinki. Acknowledgements We would like to thank the infants and families whose information contributed to this research study. We would like to express our appreciation to Bill and Francoise in the Rotunda Hospital pathology department for the processing of the placentae. Source of funding for the research Funding for this research was provided by The Rotunda Foundation and The National Women and Infants Health Programme Ireland. Funders had no involvement in the research study design, collection of data or analysis of data. Conflict of Interest Disclosure Statement Authors have no conflict of interest. References Hellwig, L., et al., Association of perinatal sentinel events, placental pathology and cerebral MRI in neonates with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia . Journal of Perinatology, 2022. 42(7): p. 885–891. Victor, S., et al., New possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy . Eur J Pediatr, 2022. 181(3): p. 875–887. Alongi, S., et al., Placental pathology in perinatal asphyxia: a case-control study . Front Clin Diabetes Healthc, 2023. 4: p. 1186362. Volpe, J.J., Placental assessment provides insight into mechanisms and timing of neonatal hypoxic-ischemic encephalopathy . J Neonatal Perinatal Med, 2019. 12(2): p. 113–116. Fox, A., et al., Placental pathology and neonatal encephalopathy . Int J Gynaecol Obstet, 2022. Stone, A.C., et al., The association of placental pathology and neurodevelopmental outcomes in patients with neonatal encephalopathy . Pediatric Research, 2023. Vik, T., et al., The Placenta in Neonatal Encephalopathy: A Case-Control Study . J Pediatr, 2018. 202: p. 77–85.e3. Hayes, B.C., et al., The placenta in infants > 36 weeks gestation with neonatal encephalopathy: a case control study . Arch Dis Child Fetal Neonatal Ed, 2013. 98(3): p. F233-9. Strong, T.H., Jr., et al., The umbilical coiling index . American Journal of Obstetrics & Gynecology, 1994. 170(1): p. 29–32. Bingham, A., et al., Placental findings among newborns with hypoxic ischemic encephalopathy . Journal of Perinatology, 2019. 39(4): p. 563–570. Novak, C.M., et al., Risk Factors for Neonatal Hypoxic-Ischemic Encephalopathy in the Absence of Sentinel Events . Am J Perinatol, 2019. 36(1): p. 27–33. Mir, I.N., et al., Placental pathology is associated with severity of neonatal encephalopathy and adverse developmental outcomes following hypothermia . Am J Obstet Gynecol, 2015. 213(6): p. 849.e1-7. McDonald, D.G., et al., Placental fetal thrombotic vasculopathy is associated with neonatal encephalopathy . Hum Pathol, 2004. 35(7): p. 875–80. Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic–Ischemic Encephalopathy. The Journal of Pediatrics, 2021. 237: p. 190–196. Jung, E., et al., The fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications . Semin Fetal Neonatal Med, 2020. 25(4): p. 101146. Scher, M.S., Neurologic outcome after fetal inflammatory response syndrome: Trimester-specific considerations . Semin Fetal Neonatal Med, 2020. 25(4): p. 101137. Salas, A.A., et al., Histological characteristics of the fetal inflammatory response associated with neurodevelopmental impairment and death in extremely preterm infants. J Pediatr, 2013. 163(3): p. 652-7.e1-2. Goncalves, L.F., P. Cornejo, and R. Towbin, Neuroimaging findings associated with the fetal inflammatory response syndrome . Semin Fetal Neonatal Med, 2020. 25(4): p. 101143. Granger, D. and E. Senchenkova, Chap. 5, Capillary Perfusion , in Inflammation and the Microcirculation . 2010, Morgan & Claypool Life Sciences: San Rafael (CA). Nasiell, J., et al., Hypoxic ischemic encephalopathy in newborns linked to placental and umbilical cord abnormalities . J Matern Fetal Neonatal Med, 2016. 29(5): p. 721–6. Harteman, J.C., et al., Placental pathology in full-term infants with hypoxic-ischemic neonatal encephalopathy and association with magnetic resonance imaging pattern of brain injury . J Pediatr, 2013. 163(4): p. 968 – 95.e2. Schwartz, D.A., S.B. Mulkey, and D.J. Roberts, SARS-CoV-2 placentitis, stillbirth, and maternal COVID-19 vaccination: clinical-pathologic correlations . Am J Obstet Gynecol, 2023. 228(3): p. 261–269. Shahi, M., et al., Expression of Immune Checkpoint Receptors in Placentae With Infectious and Non-Infectious Chronic Villitis . Front Immunol, 2021. 12: p. 705219. Sathasivam, R., et al., Placental weight and its relationship with the birth weight of term infants and body mass index of the mothers . J Int Med Res, 2023. 51(5): p. 3000605231172895. Tables Table 1. Participant characteristics. Data presented as mean (SD), median (IQR) and number (%). *More cases were delivered by emergency Caesarean section compared with controls (p<0.001). ^More cases had lower Apgar scores at 1 and 5 minutes compared with controls (p<0.001), ‘cases had a higher maternal BMI (p=0.039). CS=Caesarean section. Demographics Cases (n=74) Controls (n=98) Gestational age, weeks 39.5 (1.7) 39.6 (1.1) Birth weight, gram 3514 (539) 3548 (409) Female 31 (42%) 45 (46%) Maternal BMI (kg/m 2 ) (n=58, 93)’ 27.28 (4.78) 25.95 (4.28) Mode of delivery * Vaginal Assisted Vaginal Emergency CS Elective CS 23 (31%) 15 (20%) 35 (48%) 1 (1%) 68 (70%) 17 (17%) 13 (13%) 0 (0%) Apgars^ 1-minute 5-minute 1.5 (1,4) 4 (1,7) 9 (9,9) 10 (10,10) Grade of Encephalopathy Moderate Severe 40 (54%) 34 (46%) Intrapartum Sentinel Event 32 (43%) Therapeutic Hypothermia (TH) Pre TH era Did not meet criteria of TH 53 (72%) 19 2 Cord UV blood gas pH (n=61) BE (n=49) 7.2 (7.08, 7.29) -9 (-11.69, -5.0) Cord UA blood gas pH (n=64) BE (n=51) 7.05 (6.88, 7.16) -11.6 (-16.1, -7.7) Postnatal blood gas pH (n=57) BE (n=55) 7.08 (6.92, 7.19) -13.5 (-20.9, 10.9) Lactate (n=52) 12.3 (4.9) Table 2 Case and Control Placental Histology . Data presented as mean (SD), median (IQR) and number (%). Placenta Histology Cases (n=74) Controls (n=98) Statistical Analysis Placental Weight, grams 519 (127) 501 (85) t=-1.105 p=0.135 Birth Weight: Placental Weight Ratio (range 5-7 [24]) 7.0 (5.8, 8.1) 7.19 (6.5, 7.7) z=0.987 p=0.325 Coiling Index (CI) * (range 0.1-0.3) (n=46, n=98) 0.21 (0.10) 0.20 (0.08) t=-0.738 p=0.230 Fetal Vascular Malperfusion Low-Grade High-Grade 18 (24%) 9 (12%) 9 (12%) 11 (11%) 7 (7%) 5 (5%) p=0.038 Maternal Vascular Malperfusion Mild Severe 11 (15%) 10 (14%) 1 (1.4%) 25 (26%) 25 (26%) 0 (0%) p=0.129 Chorioamnionitis If yes ,fetal response 36 (49%) 22 (61%) 28 (29%) 5 (18%) X 2 =7.27 p=0.007 p=0.001 Villitis of Unknown Etiology Low-Grade High-Grade 9 (12.2%) 6 (8.1%) 3 (4%) 22 (22%) 13 (13%) 9 (9%) p=0.061 Delayed Villous Maturation 24 (30%) 10 (10%) p=0.003 Any Placental pathology 58 (78%) 68 (69%) X 2 =1.739 p=0.187 Table 3 Cases coiling index greater than 0.3 association with presence of FVM. Data presented as number (%). Coiling Index >0.3 (n=10) No FVM Any FVM 0.31 1 1 0.32 2 0 0.33 1 0 0.34 1 0 0.36 0 1 0.38 0 1 0.4 0 1 0.48 0 1 Total 5 (50%) 5 (50%) Table 4 Controls coiling index greater than 0.3 association with presence of FVM . Data presented as number (%). Coiling Index (n=12) No FVM Any FVM 0.32 1 0 0.33 4 0 0.34 1 1 0.35 1 0 0.38 1 0 0.4 1 0 0.44 1 0 0.52 0 1 Total 10 (83%) 2 (17%) Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4570410","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":317417710,"identity":"01153422-5c63-43dc-9be2-14dda87e9c42","order_by":0,"name":"Aine Fox","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYDACZhBhw8DAz958AMiSkCFSSxoDg2TPsQSQFh4irQJqMbiRYwBiEtbC38578AFDgk1iw4Gcz69u1FjwMLAfProBnxaJw3zJBgwJacaMDWe3WeccAzqMJy3tBl5rDvOYSTD+OCzHzNi7zTiHDahFgscMrxb5wzzmPxgSDvOwMfM8M875R4QWA6AtDEAtcjxsPMyPc9uI0GJ4mMdYIgHoFwkeNjPm3D4gRcgvcufPGH74AAyx/fcfP/6c861Ojp/98DH83geBBAjFJgEmCSpHAswfSFE9CkbBKBgFIwcAADVmQLJfphAfAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-0851-5378","institution":"Royal College of Surgeons","correspondingAuthor":true,"prefix":"","firstName":"Aine","middleName":"","lastName":"Fox","suffix":""},{"id":317417711,"identity":"47cc2bf4-f10d-462b-8e69-19ec7871f2d3","order_by":1,"name":"Emma Doyle","email":"","orcid":"","institution":"Rotunda Hospital","correspondingAuthor":false,"prefix":"","firstName":"Emma","middleName":"","lastName":"Doyle","suffix":""},{"id":317417712,"identity":"0d5864a7-b9e6-4880-bbbe-39c896da555a","order_by":2,"name":"Adam Reynolds","email":"","orcid":"","institution":"Rotunda Hospital","correspondingAuthor":false,"prefix":"","firstName":"Adam","middleName":"","lastName":"Reynolds","suffix":""},{"id":317417713,"identity":"7982a213-03c2-409b-b420-6c255857d821","order_by":3,"name":"Michael Geary","email":"","orcid":"","institution":"Rotunda Hospital","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Geary","suffix":""},{"id":317417714,"identity":"2511e809-214e-405c-95ce-19608aac52a6","order_by":4,"name":"Rocco Cuzzilla","email":"","orcid":"","institution":"The Royal Women’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rocco","middleName":"","lastName":"Cuzzilla","suffix":""},{"id":317417715,"identity":"48fbfa20-1d02-4956-87e0-a3e1c9907730","order_by":5,"name":"Breda Hayes","email":"","orcid":"","institution":"The Rotunda Hospital","correspondingAuthor":false,"prefix":"","firstName":"Breda","middleName":"","lastName":"Hayes","suffix":""}],"badges":[],"createdAt":"2024-06-12 13:04:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4570410/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4570410/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60617347,"identity":"e3bda479-4f1f-4e8c-a0c8-753cbfe9da3c","added_by":"auto","created_at":"2024-07-18 20:30:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":587873,"visible":true,"origin":"","legend":"\u003cp\u003eExamples of placental pathology. \u003cem\u003ea) normal third trimester chorionic villi – 20x, b) fetal vascular malperfusion (FVM): high grade – 20x, c) maternal vascular malperfusion (MVM): accelerated villous maturation – 20x, d) acute suppurative chorioamnionitis (HCA) – 20x, e) villitis of unknown etiology (VUE) – 40x, f) delayed villous maturation (DVM) – 20 x\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4570410/v1/6a594575efd1c32228784043.png"},{"id":61156234,"identity":"d7d4396f-332a-4b1d-9da0-dbd934cdd463","added_by":"auto","created_at":"2024-07-26 10:34:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1038955,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4570410/v1/bbac408b-e692-4ed0-8e03-be090b447760.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"A review of placental histology for infants with hypoxic ischemic encephalopathy compared with healthy controls: A retrospective case-control study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeonatal encephalopathy (NE) remains a significant cause of neonatal morbidity and mortality and childhood disability across the world [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. NE has many different aetiologies, including genetic, metabolic, infection, stroke and hypoxia ischaemia (HI). HI, known as hypoxic ischaemia encephalopathy (HIE), is the most common cause of NE. Within the classification of HI, it is well understood that HI can be acute, subacute, chronic or mixed pattern. Acute HI is recognised as an intrapartum sentinel event and accounts for 30\u0026ndash;40% of cases of HIE. Subacute, chronic and mixed pattern HI is assumed to be the cause for the remaining cases however the mechanisms leading to these patterns of HI remain uncertain [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere is an increased appreciation for the role that maternal and placental factors have in the development of the fetus, including fetal brain health and development. Improving our understanding of the maternal-placental-fetal (MPF) triad provides an opportunity for enhanced antenatal and intrapartum care to positively influence the outcomes of at-risk fetuses.\u003c/p\u003e \u003cp\u003ePlacental factors are recognised as a confounding factor for the development of HIE. Placental lesions associated with inflammation and fetal malperfusion likely affect the capacity of the fetus to maintain adequate oxygenation and organ perfusion in the hypoxic-ischemic environment of labour. This likely increases a fetus\u0026rsquo;s vulnerability to peripartum hypoxic-ischemic injury and plays a role in the mechanisms and timing of brain injury [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere remains controversy over the influence that placental pathology has on outcomes in infants with HIE [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Some research suggests that placental pathology in HIE does not impact their outcome [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. To conclude that placental pathology has no impact on outcomes in HIE, one must compare to placental histology of infants without HIE. There is limited research comparing placentae of infants with HIE and healthy infants [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Determining the differences between the placentae of infants with healthy brains and those with injured brains may provide insights to the role of the placenta in HIE.\u003c/p\u003e \u003cp\u003eAims\u003c/p\u003e \u003cp\u003eTo determine if placental pathology is more common in newborn infants with HIE compared with healthy controls.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e This was a retrospective case-control study performed in a single tertiary Neonatal Intensive Care Unit. This case-control study of placental histology was part of a larger study investigating the relationships between placental pathology, cardiotocography (CTG) and neuroimaging for newborn infants with moderate or severe HIE.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCases\u003c/strong\u003e \u003cp\u003eCases were near-term and term infants with moderate or severe HIE born between 2006 and 2021. In all cases, history and investigations including neuroimaging were consistent with a diagnosis of HIE. Cases were included if placental slides were available for analysis. Infants were excluded if (1) gestation\u0026thinsp;\u0026lt;\u0026thinsp;36 weeks; (2) abnormal anatomy on brain MRI; (3) an alternative diagnosis was found to explain their encephalopathy other than HI.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eControls\u003c/p\u003e \u003cp\u003eControls were recruited over a period of 12 months from January 2022 to January 2023. Contemporaneous control data was not possible as healthy infants do not have placental histology performed and it was felt that infants having placental histology for other reasons did not represent a group of healthy control infants. Inclusion criteria: (1) placenta available for analysis; (2) intrapartum cardiotocography (CTG) available for a minimum duration of 40 minutes; (3) born at \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\ge\\)\u003c/span\u003e\u003c/span\u003e36 weeks\u0026rsquo; gestation and considered to be healthy with a normal neurological status and an Apgar score \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\ge\\)\u003c/span\u003e\u003c/span\u003e8 at 5 minutes; (4) no resuscitation after 5 minutes from birth; and (5) no admission to the neonatal intensive care unit. CTG was a requirement for controls as this study was part of a larger study exploring the associations of placental pathology and CTG.\u003c/p\u003e \u003cp\u003eExclusion criteria: (1) maternal history of recurrent miscarriage (\u0026ge;\u0026thinsp;3) or coagulopathy; or (2) clinical indication for placental analysis. Maternal and infant charts were reviewed for clinical details.\u003c/p\u003e \u003cp\u003ePlacental Analysis\u003c/p\u003e \u003cp\u003eCase placentae were archived placental slides and control placentae were freshly prepared slides. Placental slides were reviewed by one perinatal histopathologist (ED) using the 2016 Amsterdam consensus guidelines for reporting placental histology [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Macroscopic details (including coiling index (CI) and placental weight) were collected. For cases, this information was collected from archived clinical histology report after placental slides were reviewed. Coiling index (CI) is a measure of the number of complete coils per centimetre length of cord (normal reference range 0.1\u0026ndash;0.3 coils/cm) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The reviewer had birth weight and gestation available for interpretation of placental weight centiles and birth weight-to-placenta weight ratio (BW:PW) calculations.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using Stata SE Version 17 (StatCorp, College Station, Texas). For summary statistics, continuous normally distributed variables were reported as means and standard deviation (SD) and continuous non-normally distributed variables were reported as medians and interquartile range. T test was used for binary and normally distributed continuous variables. Wilcoxon rank sum test was used for binary and non-normal continuous variable. Chi squared test was used for categorical variable with a cell count greater than 20. Fischer\u0026rsquo;s exact test was used for two binary variables where the cell counts were less than 20. Statistical significance was set at a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003ePlacental pathology (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) was classified into grades and stages of histological chorioamnionitis (HCA) and pattern and/or severity of fetal vascular malperfusion (FVM), maternal vascular malperfusion (MVM), villitis of unknown etiology (VUE) and delayed villous maturation (DVM). For the purpose of analysis, categories of pathology were classified as present or absent as the sub-category classifications for each pathology were too small for meaningful analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThis study included 74 cases of moderate or severe HIE and 98 healthy controls. Demographics for the cases and controls are shown in Table 1. Placental histology for cases and controls are shown in Table \u003cem\u003e2\u003c/em\u003e. \u003cbr\u003e \u003c/p\u003e\n\u003ch2\u003eFetal Vascular Malperfusion\u003c/h2\u003e\n\u003cp\u003eFVM was present in 18 (24%) cases. Fifteen cases with FVM had CI recorded, of which 5 (33%) had hyper-coiling of the umbilical cord. Five (28%) cases with FVM had an intrapartum sentinel event (ISE), a lower proportion than the rate of ISE for all cases (43%). Eight cases with FVM had HCA and 6 cases had DVM, of which 3 cases had both HCA and DVM.\u003c/p\u003e\n\u003ch2\u003eCoiling Index\u003c/h2\u003e\n\u003cp\u003eTable 3 and Table \u003cem\u003e4\u003c/em\u003e show the association between hyper-coiling (defined by CI \u0026gt;0.3) and presence of FVM. There was a higher incidence of FVM with hyper-coiling in cases compared with controls (50% v 17%). Of the 5 cases with FVM and hyper-coiling, 2 (40%) had high-grade FVM. In contrast, no controls with FVM and hyper-coiling had high-grade FVM.\u003c/p\u003e\n\u003ch2\u003eMaternal Vascular Malperfusion\u003c/h2\u003e\n\u003cp\u003eMVM was more common in controls than cases, but this difference was not statistically significant. Birth weight was significantly lower for cases with MVM compared with controls with MVM (t=2.51 p= 0.009). Cases with MVM had higher BW:PW than controls with MVM (z=-1.769 p=0.079) but this was not statistically significant. \u003c/p\u003e\n\u003ch2\u003eHistological Chorioamnionitis\u003c/h2\u003e\n\u003cp\u003eThirty-six (49%) cases had HCA of which 22 (61%) had a fetal response. This was significantly different to the control group (p=0.001).\u003c/p\u003e\n\u003ch2\u003eVilitis of Unknown Etiology\u003c/h2\u003e\n\u003cp\u003eVUE was more common in controls than cases, this difference approached statistical significance (p=0.061). Presence of VUE in cases had no association with birth weight (t=0.147 p=0.442), BW:PW (z=0.223 p=0.223) or maternal BMI (z=0.857 p=0.405).\u003c/p\u003e\n\u003ch2\u003eDelayed Villous Maturation\u003c/h2\u003e\n\u003cp\u003eDVM was more common in cases compared with controls, this was statistically significant (p=0.003). There was no association between presence of DVM in cases and birth weight (t=-0.4301 p=0.666), BW:PW (z=1.267 p=0.210) or maternal BMI (z=1.128 p=0.265).\u003c/p\u003e\n\u003cp\u003eDifferences in BW:PW, CI, incidence of MVM and VUE were not statistically significant between case and control groups (Table \u003cem\u003e2\u003c/em\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides evidence that placental pathology is more common in newborn infants with moderate or severe HIE than healthy controls. This study is in keeping with other studies that have compared placentae of infants with HIE and controls [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Several specific placental pathologies had an increased incidence in cases compared with controls, including HCA, FVM and DVM. This could indicate that these placental pathologies are either a direct cause of HIE or contribute to reduced placental reserve, resulting in earlier and more significant fetal decompensation in the setting of intrapartum HI.\u003c/p\u003e \u003cp\u003eThe incidence of FVM was higher in infants with moderate or severe HIE compared with controls. This finding supports the results of other studies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. There was also a higher incidence of FVM in cases without an ISE compared to those with an ISE (31% v 16%), although there were very small numbers and this was not statistically significant. This suggests that FVM may have a larger role in cases of unexplained HIE. Cases with FVM were more likely to demonstrate hyper-coiling compared with controls. Higher CI in cases could be a contributory factor to the development on FVM.\u003c/p\u003e \u003cp\u003eThis study demonstrates an increased incidence of HCA in infants with HIE compared to healthy controls. The incidence of HCA in cases in this study is also higher than the incidence of HCA reported in a healthy population in others studies [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. This has been reported in studies previously, including in a cohort study by Novak et al where they found HCA was more common in infants with HIE with an unexplained cause [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor cases in this study, fetal inflammatory response (FR) was present for 61% of cases affected by HCA. Bingham et al also found cases with HCA had a much higher incidence of FR than controls with 100% of their cases with HCA having FR, although they did report a higher incidence of HCA in their control group compared to the current study[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This may be due to selection bias within their control group which included infants admitted to NICU for a reason other than HIE, and likely does not represent a control cohort of healthy term infants. McDonald et al and Mir et al conducted cohort studies for infants with HIE and found that HCA, particularly HCA with FR, was associated with encephalopathy and an increased severity of encephalopathy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The HEAL trial found 39% of their cohort had HCA [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Naisell et al performed a case-control study and found no association between HIE and HCA, however their study only had 41 cases with placental findings and included infants with mild, moderate and severe HIE. Details of the number of each grade of HIE and their placental pathologies were not included in their report. Placental findings in infants with mild HIE may differ from infants with moderate or severe HIE. An inflammatory response on the fetal side of the placenta implies that the fetus was affected by inflammation. This is more commonly known as Fetal Inflammatory Response Syndrome (FIRS) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. FIRS is associated with increased neonatal mortality and neonatal, childhood and adult morbidity [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. HCA, particularly in the setting of FR, has likely led to a preconditioning of the fetal brain. The inflammation may have a direct effect on the developing fetal brain and/or act as a primer for fetal brain injury in the setting of intrapartum HI. FIRS can lead to impaired perfusion, oxygen delivery and/or disseminated intravascular coagulation, leading to micro-thrombi in the capillaries, culminating in hypoxic tissue [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This process may increase tissue vulnerability to reduced delivery of oxygen in the setting of labour and delivery, even if HI is within the limits of a typically progressing intrapartum course. This may explain the pathogenesis of HIE for some infants with a seemingly normal intrapartum course.\u003c/p\u003e \u003cp\u003eDVM was also significantly increased in cases. Some studies have found no association between DVM and HIE [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. However, Harteman et al looked at the relationship between brain injury on MRI and placental findings in HIE. They found placental immaturity to be associated with white matter brain injury [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast, MVM was more common in controls than cases but this was not statistically significant. Some studies have found features of MVM to be associated with HIE [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], in contrast to the findings in this study. Unfortunately, MVM has not been routinely reported in many placental pathology studies on HIE so it if difficult to determine if this study is an outlier in this respect or not. This study did find that where MVM was present in cases, birth weight was lower than in all cases and lower than controls with MVM. This may suggest that where MVM is present in a fetus, it could be contributing to suboptimal fetal growth and potentially impair tolerance of labour.\u003c/p\u003e \u003cp\u003eVUE was also more common in controls than cases. In studies where VUE has been reported, it was not found to be associated with HIE [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Controls in this study were born during a time of the COVID-19 pandemic, and pregnancies may have been exposed to either COVID-19 infection and/or COVID-19 vaccination, both of which lead to an immune response in the mother. COVID-19 infection in pregnancy has been associated with inflammation of the placenta, termed \u0026lsquo;COVID placentitis\u0026rsquo; [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. It may be that this control group developed VUE from a COVID-19-associated immunological response. The rate of VUE in healthy pregnancies is reported in the literature to be between 6 and 33% [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], therefore this control group could also be reflective of a normal population.\u003c/p\u003e \u003cp\u003eStrengths\u003c/p\u003e \u003cp\u003eA major strength of this study is that it reports on a good sample size of cases with moderate or severe HIE compared with other studies on placenta pathology in HIE. It also includes a control group of neurologically healthy term infants without medical illness or clinical indication for placental assessment.\u003c/p\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003cp\u003eRecruitment of controls was limited by the capacity of the histopathology department to process the additional workload for placenta analysis and were collected over a period of one year. It was not possible to blind the reviewer to whether the placenta slides were from a case or control. Case placenta slides were archived slides that were retrieved from storage. Control placenta slides were stored on site until they were reviewed. The reviewer was blinded to the clinical details of the cases. Due to resource limitations, we were unable to have a second reviewer to analyse the placentae leading to an inability to determine the presence of any bias within the reporting.\u003c/p\u003e \u003cp\u003eThis case-control study provides evidence for differences in placental histology between infants with moderate or severe HIE and a convenience sample of healthy controls. Infants with HIE had a higher incidence of pathology overall, and specifically for HCA, FVM and DVM. This suggests that placental pathology may be a risk factor for poor tolerance of labour and/or is likely to be a contributing factor in the pathogenesis of HIE, particularly in the absence of an ISE. Further research is required to further delineate the role of the placenta in the pathogenesis of HIE.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eBE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;base excess\u003c/p\u003e\n\u003cp\u003eDVM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;delayed villous maturation\u003c/p\u003e\n\u003cp\u003eFIRS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;fetal inflammatory response syndrome\u003c/p\u003e\n\u003cp\u003eFR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;fetal inflammatory response\u003c/p\u003e\n\u003cp\u003eFVM \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;fetal vascular malperfusion\u003c/p\u003e\n\u003cp\u003eHI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;hypoxia ischaemia\u003c/p\u003e\n\u003cp\u003eHCA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;histological chorioamnionitis\u003c/p\u003e\n\u003cp\u003eHIE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;hypoxic ischemic encephalopathy\u003c/p\u003e\n\u003cp\u003eMPF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;maternal-placental-fetal\u003c/p\u003e\n\u003cp\u003eMVM \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;maternal vascular malperfusion\u003c/p\u003e\n\u003cp\u003eNE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;neonatal encephalopathy\u003c/p\u003e\n\u003cp\u003eVUE \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;vilitis of unknown etiology\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthorship Statement\u003c/h2\u003e\n\u003cp\u003eFox, A contributed to the design of the study, collected data, statistical analysis, interpretation of results and wrote and edited the manuscript\u003c/p\u003e\n\u003cp\u003eReynolds, A contributed to the design of the study, collected data, interpretation of results, reviewed intellectual content and edited the manuscript\u003c/p\u003e\n\u003cp\u003eDoyle, E reviewed all the placental slides, provided expert knowledge and contributed to the interpretation of results, reviewed intellectual content and edited the manuscript\u003c/p\u003e\n\u003cp\u003eGeary, M contributed to the design of the study and edited the manuscript\u003c/p\u003e\n\u003cp\u003eCuzzilla, R contributed to the design of the study, scoring MRI images, interpretation of results, reviewed intellectual content and edited the manuscript\u003c/p\u003e\n\u003cp\u003eHayes, B contributed to the design of the study, interpretation of data, reviewed intellectual content and edited the manuscript, supervisor of study\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eFunding for this research was provided by The Rotunda Foundation and The National Women and Infants Health Programme Ireland. Funders had no involvement in the research study design, collection of data or analysis of data.\u003c/p\u003e\n\u003ch2\u003eDeclarations of interest\u003c/h2\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003ch2\u003eEthics\u003c/h2\u003e\n\u003cp\u003eThe study received ethical approval from the Rotunda Hospital Research and Ethics Committee (REC-2015-009). Approval was given to waiver consent for patients who died or have significant disability. All other families, including controls gave informed consent for their data to be included. Specifically, control gave consent of placental analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was performed in accordance with the Declaration of Helsinki. \u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAcknowledgements\u003c/h2\u003e\n\u003cp\u003eWe would like to thank the infants and families whose information contributed to this research study. We would like to express our appreciation to Bill and Francoise in the Rotunda Hospital pathology department for the processing of the placentae.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eSource of funding for the research\u003c/h2\u003e\n\u003cp\u003eFunding for this research was provided by The Rotunda Foundation and The National Women and Infants Health Programme Ireland. \u0026nbsp;Funders had no involvement in the research study design, collection of data or analysis of data.\u003c/p\u003e\n\u003ch1\u003eConflict of Interest Disclosure Statement\u003c/h1\u003e\n\u003cp\u003eAuthors have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHellwig, L., et al., \u003cem\u003eAssociation of perinatal sentinel events, placental pathology and cerebral MRI in neonates with hypoxic-ischemic encephalopathy receiving therapeutic hypothermia\u003c/em\u003e. Journal of Perinatology, 2022. 42(7): p. 885\u0026ndash;891.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVictor, S., et al., \u003cem\u003eNew possibilities for neuroprotection in neonatal hypoxic-ischemic encephalopathy\u003c/em\u003e. Eur J Pediatr, 2022. 181(3): p. 875\u0026ndash;887.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlongi, S., et al., \u003cem\u003ePlacental pathology in perinatal asphyxia: a case-control study\u003c/em\u003e. Front Clin Diabetes Healthc, 2023. 4: p. 1186362.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVolpe, J.J., \u003cem\u003ePlacental assessment provides insight into mechanisms and timing of neonatal hypoxic-ischemic encephalopathy\u003c/em\u003e. J Neonatal Perinatal Med, 2019. 12(2): p. 113\u0026ndash;116.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFox, A., et al., \u003cem\u003ePlacental pathology and neonatal encephalopathy\u003c/em\u003e. Int J Gynaecol Obstet, 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStone, A.C., et al., \u003cem\u003eThe association of placental pathology and neurodevelopmental outcomes in patients with neonatal encephalopathy\u003c/em\u003e. Pediatric Research, 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVik, T., et al., \u003cem\u003eThe Placenta in Neonatal Encephalopathy: A Case-Control Study\u003c/em\u003e. J Pediatr, 2018. 202: p. 77\u0026ndash;85.e3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHayes, B.C., et al., \u003cem\u003eThe placenta in infants\u0026thinsp;\u0026gt;\u0026thinsp;36 weeks gestation with neonatal encephalopathy: a case control study\u003c/em\u003e. Arch Dis Child Fetal Neonatal Ed, 2013. 98(3): p. F233-9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStrong, T.H., Jr., et al., \u003cem\u003eThe umbilical coiling index\u003c/em\u003e. American Journal of Obstetrics \u0026amp; Gynecology, 1994. 170(1): p. 29\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBingham, A., et al., \u003cem\u003ePlacental findings among newborns with hypoxic ischemic encephalopathy\u003c/em\u003e. Journal of Perinatology, 2019. 39(4): p. 563\u0026ndash;570.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNovak, C.M., et al., \u003cem\u003eRisk Factors for Neonatal Hypoxic-Ischemic Encephalopathy in the Absence of Sentinel Events\u003c/em\u003e. Am J Perinatol, 2019. 36(1): p. 27\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMir, I.N., et al., \u003cem\u003ePlacental pathology is associated with severity of neonatal encephalopathy and adverse developmental outcomes following hypothermia\u003c/em\u003e. Am J Obstet Gynecol, 2015. 213(6): p. 849.e1-7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcDonald, D.G., et al., \u003cem\u003ePlacental fetal thrombotic vasculopathy is associated with neonatal encephalopathy\u003c/em\u003e. Hum Pathol, 2004. 35(7): p. 875\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003e\u003cem\u003eAcute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic\u0026ndash;Ischemic Encephalopathy.\u003c/em\u003e The Journal of Pediatrics, 2021. 237: p. 190\u0026ndash;196.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJung, E., et al., \u003cem\u003eThe fetal inflammatory response syndrome: the origins of a concept, pathophysiology, diagnosis, and obstetrical implications\u003c/em\u003e. Semin Fetal Neonatal Med, 2020. 25(4): p. 101146.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScher, M.S., \u003cem\u003eNeurologic outcome after fetal inflammatory response syndrome: Trimester-specific considerations\u003c/em\u003e. Semin Fetal Neonatal Med, 2020. 25(4): p. 101137.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSalas, A.A., et al., \u003cem\u003eHistological characteristics of the fetal inflammatory response associated with neurodevelopmental impairment and death in extremely preterm infants.\u003c/em\u003e J Pediatr, 2013. 163(3): p. 652-7.e1-2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoncalves, L.F., P. Cornejo, and R. Towbin, \u003cem\u003eNeuroimaging findings associated with the fetal inflammatory response syndrome\u003c/em\u003e. Semin Fetal Neonatal Med, 2020. 25(4): p. 101143.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGranger, D. and E. Senchenkova, Chap. 5, \u003cem\u003eCapillary Perfusion\u003c/em\u003e, in \u003cem\u003eInflammation and the Microcirculation\u003c/em\u003e. 2010, Morgan \u0026amp; Claypool Life Sciences: San Rafael (CA).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNasiell, J., et al., \u003cem\u003eHypoxic ischemic encephalopathy in newborns linked to placental and umbilical cord abnormalities\u003c/em\u003e. J Matern Fetal Neonatal Med, 2016. 29(5): p. 721\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHarteman, J.C., et al., \u003cem\u003ePlacental pathology in full-term infants with hypoxic-ischemic neonatal encephalopathy and association with magnetic resonance imaging pattern of brain injury\u003c/em\u003e. J Pediatr, 2013. 163(4): p. 968\u0026thinsp;\u0026ndash;\u0026thinsp;95.e2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchwartz, D.A., S.B. Mulkey, and D.J. Roberts, \u003cem\u003eSARS-CoV-2 placentitis, stillbirth, and maternal COVID-19 vaccination: clinical-pathologic correlations\u003c/em\u003e. Am J Obstet Gynecol, 2023. 228(3): p. 261\u0026ndash;269.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShahi, M., et al., \u003cem\u003eExpression of Immune Checkpoint Receptors in Placentae With Infectious and Non-Infectious Chronic Villitis\u003c/em\u003e. Front Immunol, 2021. 12: p. 705219.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSathasivam, R., et al., \u003cem\u003ePlacental weight and its relationship with the birth weight of term infants and body mass index of the mothers\u003c/em\u003e. J Int Med Res, 2023. 51(5): p. 3000605231172895.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. \u0026nbsp;Participant characteristics. Data presented as mean (SD), median (IQR) and number (%). \u0026nbsp;*More cases were delivered by emergency Caesarean section compared with controls (p\u0026lt;0.001). \u0026nbsp;^More cases had lower Apgar scores at 1 and 5 minutes compared with controls (p\u0026lt;0.001), \u0026lsquo;cases had a higher maternal BMI (p=0.039). \u0026nbsp;CS=Caesarean section.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"595\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCases\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=74)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=98)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eGestational age, weeks\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e39.5 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e39.6 (1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eBirth weight, gram\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e3514 (539)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e3548 (409)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e31 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e45 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eMaternal BMI (kg/m\u003csup\u003e2\u003c/sup\u003e) (n=58, 93)\u0026rsquo;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e27.28 (4.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e25.95 (4.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eMode of delivery *\u003c/p\u003e\n \u003cp\u003eVaginal\u003c/p\u003e\n \u003cp\u003eAssisted Vaginal\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eEmergency CS\u003c/p\u003e\n \u003cp\u003eElective CS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e23 (31%)\u003c/p\u003e\n \u003cp\u003e15 (20%)\u003c/p\u003e\n \u003cp\u003e35 (48%)\u003c/p\u003e\n \u003cp\u003e1 (1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e68 (70%)\u003c/p\u003e\n \u003cp\u003e17 (17%)\u003c/p\u003e\n \u003cp\u003e13 (13%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eApgars^\u003c/p\u003e\n \u003cp\u003e1-minute\u003c/p\u003e\n \u003cp\u003e5-minute\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e1.5 (1,4)\u003c/p\u003e\n \u003cp\u003e4 (1,7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;9 (9,9)\u003c/p\u003e\n \u003cp\u003e10 (10,10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eGrade of Encephalopathy\u003c/p\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e40 (54%)\u003c/p\u003e\n \u003cp\u003e34 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eIntrapartum Sentinel Event\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e32 (43%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eTherapeutic Hypothermia (TH)\u003c/p\u003e\n \u003cp\u003ePre TH era\u003c/p\u003e\n \u003cp\u003eDid not meet criteria of TH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e53 (72%)\u003c/p\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eCord UV blood gas\u003c/p\u003e\n \u003cp\u003epH (n=61)\u003c/p\u003e\n \u003cp\u003eBE (n=49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7.2 (7.08, 7.29)\u003c/p\u003e\n \u003cp\u003e-9 (-11.69, -5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eCord UA blood gas\u003c/p\u003e\n \u003cp\u003epH (n=64)\u003c/p\u003e\n \u003cp\u003eBE (n=51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7.05 (6.88, 7.16)\u003c/p\u003e\n \u003cp\u003e-11.6 (-16.1, -7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003ePostnatal blood gas\u003c/p\u003e\n \u003cp\u003epH (n=57)\u003c/p\u003e\n \u003cp\u003eBE (n=55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e7.08 (6.92, 7.19)\u003c/p\u003e\n \u003cp\u003e-13.5 (-20.9, 10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.59731543624161%\" valign=\"top\"\u003e\n \u003cp\u003eLactate (n=52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e12.3 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.201342281879196%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;2\u0026nbsp;Case and Control Placental Histology\u003cem\u003e.\u003c/em\u003e Data presented as mean (SD), median (IQR) and number (%). \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"604\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePlacenta Histology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCases\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e(n=98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003ePlacental Weight, grams\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e519 (127)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e501 (85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003et=-1.105 p=0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003eBirth Weight: Placental Weight Ratio (range 5-7\u0026nbsp;[24])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e7.0 (5.8, 8.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e7.19 (6.5, 7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003ez=0.987 p=0.325\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003eCoiling Index (CI) * (range 0.1-0.3) (n=46, n=98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e0.21 (0.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e0.20 (0.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003et=-0.738 p=0.230\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003eFetal Vascular Malperfusion\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLow-Grade\u003c/p\u003e\n \u003cp\u003eHigh-Grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e18 (24%)\u003c/p\u003e\n \u003cp\u003e9 (12%)\u003c/p\u003e\n \u003cp\u003e9 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e11 (11%)\u003c/p\u003e\n \u003cp\u003e7 (7%)\u003c/p\u003e\n \u003cp\u003e5 (5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ep=0.038\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003eMaternal Vascular Malperfusion\u003c/p\u003e\n \u003cp\u003eMild\u003c/p\u003e\n \u003cp\u003eSevere\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11 (15%)\u003c/p\u003e\n \u003cp\u003e10 (14%)\u003c/p\u003e\n \u003cp\u003e1 (1.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e25 (26%)\u003c/p\u003e\n \u003cp\u003e25 (26%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep=0.129\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003eChorioamnionitis\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eIf yes ,fetal response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;36 (49%)\u003c/p\u003e\n \u003cp\u003e22 (61%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;28 (29%)\u003c/p\u003e\n \u003cp\u003e5 (18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eX\u003csup\u003e2\u003c/sup\u003e=7.27 p=0.007\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ep=0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003eVillitis of Unknown Etiology\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLow-Grade\u003c/p\u003e\n \u003cp\u003eHigh-Grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;9 (12.2%)\u003c/p\u003e\n \u003cp\u003e6 (8.1%)\u003c/p\u003e\n \u003cp\u003e3 (4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;22 (22%)\u003c/p\u003e\n \u003cp\u003e13 (13%)\u003c/p\u003e\n \u003cp\u003e9 (9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003ep=0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003eDelayed Villous Maturation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e24 (30%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e10 (10%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep=0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"37.47927031509121%\" valign=\"top\"\u003e\n \u003cp\u003eAny Placental pathology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e58 (78%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.739635157545607%\" valign=\"top\"\u003e\n \u003cp\u003e68 (69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.041459369817577%\" valign=\"top\"\u003e\n \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e=1.739 p=0.187\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 3 Cases coiling index greater than 0.3 association with presence of FVM. Data presented as number (%). \u0026nbsp;\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoiling Index \u0026gt;0.3 (n=10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo FVM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny FVM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e2\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e0\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e5 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e5 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;4\u0026nbsp;Controls coiling index greater than 0.3 association with presence of FVM\u003cem\u003e. Data presented as number (%). \u0026nbsp;\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCoiling Index (n=12)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo FVM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny FVM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e10 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e2 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"placental pathology, placental histology, neonatal encephalopathy, hypoxic ischaemic encephalopathy","lastPublishedDoi":"10.21203/rs.3.rs-4570410/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4570410/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObjective\u003c/p\u003e\n\u003cp\u003eThe role of the placenta in the development of hypoxic ischaemic encephalopathy (HIE) remains undefined. \u0026nbsp;There is limited research comparing placental histology for infants with HIE and healthy controls. \u0026nbsp;This is limiting our ability to understand its role in HIE. \u0026nbsp;This study aimed to report the differences in placental histology between infants with HIE and healthy controls.\u003c/p\u003e\n\u003cp\u003eStudy Design\u003c/p\u003e\n\u003cp\u003eA case-control study of (near-) term infants with moderate/severe HIE and healthy controls at a single tertiary NICU. \u0026nbsp;Placental histology was reviewed by one perinatal histopathologist using consensus guidelines.\u003c/p\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003cp\u003eSeventy-four cases and 98 controls were included. \u0026nbsp;Cases had a higher incidence of pathology, including fetal vascular malperfusion, histological chorioamnionitis and delayed villous maturation.\u003c/p\u003e\n\u003cp\u003eConclusion\u003c/p\u003e\n\u003cp\u003eThis study demonstrates a higher incidence of placental pathology for infants born with HIE suggesting that the placenta is an important factor in the pathogenesis of HIE. Further research is required to delineate this relationship.\u003c/p\u003e","manuscriptTitle":"A review of placental histology for infants with hypoxic ischemic encephalopathy compared with healthy controls: A retrospective case-control study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 20:30:04","doi":"10.21203/rs.3.rs-4570410/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"008bff90-cfeb-40d3-ad4e-9e3442dd2abf","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":33568124,"name":"Health sciences/Diseases/Neurological disorders/Brain injuries"},{"id":33568125,"name":"Health sciences/Medical research/Biomarkers/Predictive markers"}],"tags":[],"updatedAt":"2024-07-26T10:26:31+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-18 20:30:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4570410","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4570410","identity":"rs-4570410","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}