Predictors of antepartum maternal sepsis and effects on neonatal outcomes: a population-based cohort study

Predictors of antepartum maternal sepsis and effects on neonatal outcomes: a population-based cohort 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Article Predictors of antepartum maternal sepsis and effects on neonatal outcomes: a population-based cohort study Nida Ozarslan, Stephanie Gaw, Arianna Cassidy, Aaron Caughey This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2203832/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 May, 2023 Read the published version in Journal of Perinatology → Version 1 posted 7 You are reading this latest preprint version Abstract Objective To examine the relationship between maternal sepsis, type of infection, and short-term neonatal outcomes. Study Design We conducted a retrospective cohort study investigating pregnancies between 2005 and 2008 in California with antepartum maternal sepsis diagnosis. Comparisons were made between sepsis cases and all other births without sepsis, using chi-squared or Fisher’s exact test. Multivariable logistic regression (MLR) was performed, adjusting for maternal characteristics. Results MLR analyses indicated that specific maternal characteristics increased the odds of maternal sepsis. Chorioamnionitis, pneumonia, pyelonephritis, listeriosis, and fungal infection were all significantly associated with maternal sepsis (p < 0.001). Neonates born to patients with maternal sepsis had a higher risk of developing certain neonatal complications. Conclusion Maternal sepsis was associated with neonatal complications. Efforts to reduce maternal sepsis may improve neonatal outcomes. Further studies are required for a better understanding of these associations and whether prevention or more rapid diagnosis and treatment can lower these risks. Health sciences/Medical research/Outcomes research Health sciences/Risk factors Health sciences/Diseases/Infectious diseases infection pregnancy neonate antenatal infection neonatal complication antenatal sepsis maternal infection Figures Figure 1 Figure 2 Figure 3 Introduction Maternal sepsis in pregnancy, which is defined as organ dysfunction resulting from infection during pregnancy, intrapartum, post-abortion, or during the postpartum period, is a significant cause of severe maternal morbidity and mortality. According to the latest CDC data, infection is the second leading cause of pregnancy-related deaths in the United States. at 12.7%, surpassed only by cardiovascular disease ( 1 ). Maternal sepsis affects 1–3/10 000 deliveries per year, but the proportion of maternal deaths caused by sepsis ranges between 4.1–6.2% ( 2 – 4 ). According to a 2013 study, between 1998–2008, the odds for both severe sepsis during pregnancy and sepsis related death increased 10% annually in the U.S. ( 5 ). A study from the U.S. noted that over 2002–2015, the rate of maternal sepsis increased from 1.2/10 000 to 3.7/10 000, with an annual increase of almost 7% ( 6 ). Mortality rates were as high as 20–28% ( 6 ). A 2014 study found maternal sepsis to have a case fatality rate of 4.4 per 100 deliveries ( 7 ). Maternal diseases causing prenatal inflammation have been linked to adverse neonatal outcomes. Even localized periodontitis, has been linked to adverse pregnancy outcomes like preterm birth ( 8 ). Interestingly, babies born to patients with pancreatitis had increased odds of being born small for gestational age, developing respiratory distress syndrome, and neonatal jaundice ( 9 ). Although acute pyelonephritis rates of pregnant patients are similar to non-pregnant females, acute pyelonephritis during pregnancy has been linked to adverse pregnancy outcomes including preterm birth ( 10 ). Besides unwanted maternal outcomes, maternal sepsis has been associated with poor neonatal outcomes as well. Previous studies have demonstrated an almost-3-fold risk of preterm delivery and a 6- to 8-fold risk of perinatal mortality, as well as an increased risk of neonatal hypoxia/acidosis ( 11 ). However, these data have been limited by smaller sample sizes. The impact of maternal sepsis on neonatal outcomes not been studied in diverse, population-based cohorts. The goal of this study was to examine factors associated with maternal sepsis during the antenatal period and examine neonatal outcomes after maternal sepsis. Materials And Methods This is a retrospective cohort study including all deliveries in California between 2005–2008, recorded in the state birth certificate registry and linked with statewide hospital discharge and death certificate data. The data were derived from linked mother-infant datasets from the California Vital Statistics Birth Certificate Data, Vital Statistics Death Certificate Data, California Patient Discharge Data, and Vital Statistics Fetal Death File. Data linkage was performed by the California Office of Statewide Health Planning and Development (OSHPD) Healthcare Information Resource Center, under the California Health and Human Services Agency (CHHS) using a unique “record linkage number” specific to the mother-infant pair. We obtained human subjects’ approval from the Institutional Review Board at Oregon Health & Science University, the California Office of Statewide Health Planning and Development (OSHPD), and the Committee for the Protection of Human Subjects (IRB00009487, approved March 13, 2013). The linked dataset did not contain potential patient privacy/identification information, so informed consent was exempted. Our primary exposure of interest was a diagnosis of maternal sepsis and we identified 687 patients with antepartum sepsis using the following International Classification of Diseases, 9th Revision [ICD-9] codes ( Supplemental Table 1 ). A total of 687 cases were identified and these were compared with 2 077 965 control deliveries. To focus on antepartum sepsis, we excluded associated codes of postpartum sepsis, endometritis, wound infection, and mastitis. Pregnancies complicated by congenital anomalies and triplet, and higher order gestations were also excluded. Analyses were performed using Stata (version 12, StataCorp; College Station, TX) and R (version 2.13.1, R Foundation for Statistical Computing; Vienna, Austria). Particular maternal characteristics, type of maternal infection, and neonatal outcomes of interest were defined. Specifically, we examined age, race/ethnicity, parity, education, insurance type, number of prenatal care visits, and twin gestation. Advanced maternal age was defined as 35 years and older at time of birth. Parity was stratified into nulliparity and multiparity. The type of inciting maternal infection was delineated as pneumonia, pyelonephritis, chorioamnionitis, fungal infection, and listeriosis. Fetal/neonatal outcomes of interest encompassed preterm delivery, stillbirth, transient tachypnea of newborn (TTN), respiratory distress syndrome, jaundice, small for gestational age (SGA), hypoglycemia, meningitis, neonatal sepsis, shock, retinopathy of prematurity (ROP), neonatal seizures, and neonatal mortality. Preterm delivery was additionally stratified by gestational age; born before 37 weeks, 32 weeks and 28 weeks. Comparisons were made between cases of sepsis and all other births without a sepsis code, using chi-squared or Fisher’s exact test, as appropriate. Multivariable logistic regression was performed adjusting for maternal age, parity, race/ethnicity, education, insurance status, degree of prenatal care, gestational age, and twin gestation. Missing data were excluded from analyses. Statistical significance was determined by a P-value of < 0.05 and 95% confidence intervals (CI) that did not cross unity. Results During the study period, there were 2 078 652 deliveries in California. Among those, we identified 687 (0.03%) cases of antepartum sepsis. These cases were compared to the remaining 2 077 965 control pregnancies. The rate of developing maternal sepsis significantly differed by maternal race/ethnicity (Table 1 , p < 0.001). The highest rate of maternal sepsis was seen in Asian and Black patients with 0.04%, followed by Hispanic patients with 0.03%. Maternal sepsis also showed a significant association with parity, public insurance, and twin gestation. Table 1 Maternal Demographics Sepsis Non-Sepsis P value General 687 (0.03%) 2 077 965 Advanced Maternal Age 132 (0.04%) 357 915 0.167 Maternal Race < 0.001 White 140 (0.02%) 564 270 Black 47 (0.04%) 105 980 Hispanic 388 (0.03%) 1 126 919 Asian 101 (0.04%) 238 448 Other 11 (0.03%) 39 806 Missing data 0 2 542 Parity < 0.001 Nulliparous 313 (0.04%) 804 103 Multiparous 357 (0.03%) 1 267 331 Missing data 17 6 531 Some College Education 280 (0.03%) 899 995 0.219 Insurance Type 0.013 Public 364 (0.04%) 1 001 622 Private 323 (0.03%) 1 076 343 Fever than 5 Prenatal Care Visits 60 (0.07%) 85 429 < 0.001 Twins 37 (0.06%) 58 687 < 0.001 When controlling for potential confounders, the incidence of maternal sepsis remained associated with many of the above factors, including Hispanic ethnicity (adjusted odds ratio (aOR) 1.3, CI 1.0-1.6) Asian race (aOR 1.7, CI 1.3–2.2), nulliparity (aOR 1.5, CI 1.3–1.8), and having public insurance (aOR 1.3, CI 1.0-1.5) (Fig. 1 , Supplemental Table 2 ). The relationship between specific maternal infections and the development of maternal sepsis was investigated (Fig. 2 , Supplemental Table 3 ). Chorioamnionitis, pyelonephritis, pneumonia, listeriosis, and fungal infections were all significantly (p < 0.001) associated with maternal sepsis. Chorioamnionitis and pyelonephritis were the most common infections leading to sepsis, constituting 21.7% and 13.1% of sepsis cases, respectively. Listeriosis was rare, causing 0.44% of sepsis cases; however, it led to the highest odds of developing sepsis (aOR 83.4, CI 16.9-410.8). When examining outcomes of the pregnancy, septic patients had significantly higher rates of preterm delivery, as compared to non-septic patients, 27.1% vs. 10.1% respectively (p < 0.001, Table 2 ). The rates of deliveries prior to 32 weeks (12.8% vs. 1.4%, p < 0.001) and before 28 weeks (6.0% vs. 0.4%, p < 0.001) were also increased with maternal sepsis. Patients with maternal sepsis had higher rates of cesarean section compared to non-septic patients, 39.2% and 30.4% respectively (p < 0.001). Table 2 Distribution of Neonatal Complications Incidence among patients with sepsis (n = 687) Incidence among patients without sepsis (n = 2 078 533) P value Shock 1.75% 0.01% < 0.001 Preterm Delivery <37 weeks 27.07% 10.11% < 0.001 <32 weeks 12.81% 1.38% < 0.001 <28 weeks 5.97% 0.39% < 0.001 Neonatal Demise 3.64% 0.25% < 0.001 Stillbirth 3.49% 0.34% < 0.001 Transient Tachypnea of Newborn 4.66% 2.19% < 0.001 Respiratory Distress Syndrome 7.71% 1.03% < 0.001 Jaundice 26.20% 15.72% < 0.001 Small for Gestational Age 8.15% 5.78% 0.003 Hypoglycemia 2.33% 0.82% < 0.001 Meningitis 0.58% 0.01% < 0.001 Neonatal Sepsis 10.04% 1.57% < 0.001 Retinopathy of Prematurity 1.31% 0.08% < 0.001 Neonatal Seizure 0.73% 0.06% < 0.001 Maternal sepsis was also related to higher rates of neonatal complications. Sepsis was associated with an increased risk of both fetal (3.5% vs. 0.3%, p < 0.001) and neonatal demise (3.9% vs. 0.3%, p < 0.001). Neonatal seizures were more commonly seen in neonates born to patients with maternal sepsis (0.7% vs. 0.06%, p < 0.001). The rates of neonatal infection such as neonatal shock (1.8% vs. 0.01%, p < 0.001), sepsis (10.0% vs. 1.6%, p < 0.001), and meningitis (0.6% vs. 0.01%, p < 0.001), were higher in neonates born to patients with maternal sepsis. Other adverse neonatal outcomes such as respiratory distress syndrome (7.7% vs. 1.0%, p < 0.001), transient tachypnea of newborn (4.7% vs. 2.2%, p < 0.001), small for gestational age (9.5% vs. 6.5%, p = 0.003), hypoglycemia (2.3% vs. 0.8%, p < 0.001), jaundice (26.2% vs. 15.7%, p < 0.001), and retinopathy of prematurity (1.3% vs. 0.1%, p < 0.001) were all more commonly seen with maternal sepsis. Even after controlling for potential confounders including gestational age, the associations between maternal sepsis and adverse neonatal outcomes persisted (Fig. 3 , Supplemental Table 4 ). Maternal sepsis increased the risk of neonatal demise (aOR 4.2, CI 2.2-8.), neonatal seizure (aOR 8.9, CI 3.3–23.9), and neonatal infections such as shock (aOR 142.0, CI 73.6-274.2), sepsis (aOR 4.8, CI 3.6–6.4) and meningitis (aOR 31.2, CI 9.8–99.0). Odds were also higher for developing neonatal complications including transient tachypnea of newborn (aOR 1.5, CI 1.0- 2.3), small for gestational age (aOR 1.1, CI 1.1–1.9), neonatal hypoglycemia (aOR 1.9, CI 1.1–3.3), jaundice (aOR 1.5, CI 1.3–1.9), and retinopathy of prematurity (aOR 5.9, CI 2.7–13.1) with maternal sepsis. Discussion In our study, we found that maternal sepsis increased the risk of fetal and neonatal mortality and morbidities such as meningitis, sepsis, and shock. Other adverse neonatal outcomes were also more commonly seen in patients with maternal sepsis such as preterm delivery and small for gestational age. Preterm delivery associated with maternal sepsis would be predicted to lead to neonatal complications. However, the association between maternal sepsis and neonatal complications persisted even when controlling for gestational age. Additionally, we have previously reported antepartum sepsis as a risk factor for placental dysfunction ( 12 ). This suggests that there may be some effect from maternal sepsis itself that impacts the neonate beyond the expected consequences of preterm birth. The distribution of various infections among pregnant patients in our sample with sepsis was investigated. The most common was chorioamnionitis, at 21.7%, and the least common was listeriosis, at 0.44%. In a multicenter case-control study, chorioamnionitis was also the most common cause of maternal sepsis, but not specified as antepartum sepsis ( 13 ). It was shown that neonates born to patients with chorioamnionitis had a higher risk for NICU admissions, asphyxia at delivery requiring resuscitation, intraventricular hemorrhage, respiratory distress syndrome, and intrauterine infection ( 14 ). A prospective cohort study investigating pregnancies complicated with clinical chorioamnionitis, maternal fever or histological chorioamnionitis revealed that prenatal inflammation reduced the protective effect of advanced gestational age and constituted a risk factor for adverse neonatal outcomes ( 15 ). Although listeriosis was rare, it was associated with the highest odds for the development of maternal sepsis. Pregnant patients were found to be 16–18 times more likely to experience listeriosis compared to non-pregnant females, and pregnant patients constituted 16–27% of all listeriosis cases ( 16 , 17 ). According to a national prospective cohort study conducted in France, maternal listeriosis led to adverse pregnancy outcomes including preterm birth, neonatal listeriosis, fetal and neonatal death in more than 80% of affected pregnancies ( 18 ). Two separate studies from China reported 57.1% and 73% fetal-neonatal mortality rates due to maternal listeriosis ( 19 , 20 ). In an observational study conducted in New Zealand, listeriosis during pregnancy resulted in the hospitalization of all infected pregnant patients and one-third of these pregnancies resulted in intrauterine death or stillbirth, proving the severity of listeriosis ( 21 ). In parallel, a study investigating seven pregnant patients with listeriosis, all pregnancies were complicated with preterm delivery ( 22 ). We show that in a large cohort of deliveries in California, certain maternal characteristics and specific infections pose an increased risk of developing sepsis prior to delivery. Maternal race/ethnicity was significantly associated with sepsis, with Asian/Pacific Islander and Hispanic patients at greatest risk. Such findings are unlikely to have a biological underpinning, but rather identify socio-cultural differences as well as inculcated systemic racism within society and the health system leading to such health inequities. Thus, it was not surprising that another group at increased risk of developing sepsis were those with public insurance who similarly may face challenges in accessing care. According to the World Health Organization, the frequency of infection-related maternal deaths around the world is much greater than previously estimated ( 23 ). Considering the adverse fetal and maternal outcomes of sepsis during pregnancy, early recognition of maternal sepsis is crucial. It has been shown that the administration of antibiotics within the first hour of diagnosis (deemed the golden hour) drastically reduces mortality rates in sepsis ( 13 , 24 – 26 ). Unfortunately, there is no validated screening tool for pregnant patients and common sepsis screening tools such as qSOFA and SIRS have various levels of sensitivity and specificity, decreasing the reliability of the usage of a single screening tool for maternal sepsis diagnosis ( 13 , 26 – 29 ). While examining and evaluating a pregnant patient for sepsis, the sociocultural background of the patient should always be kept in mind to make an accurate diagnosis. Since Asian/Pacific Islander or Hispanic patients have been shown at higher risk for maternal sepsis, interpretation services or health providers that can communicate through the patient’s native language could potentially improve the timely diagnosis of sepsis by overcoming communication problems. We found that listeriosis constituted a strong risk for sepsis development in pregnant patients as well as leading to poor fetal and neonatal outcomes. Patients should be educated on possible transmission routes of listeriosis. On the other hand, physicians should increase their clinical suspicion for listeriosis in pregnant patients and treat according to the guidelines if needed ( 30 ). Additionally, we found that pyelonephritis during pregnancy increased the risk for maternal sepsis development in pregnant patients. It is known that pregnant patients experiencing urinary tract infections (UTIs) have a higher risk for developing pyelonephritis, therefore pregnant individuals should be screened for UTIs and treated carefully ( 31 ). To date, there is no consensus for the usage of a validated sepsis screening tool for pregnant patients although there are some proposals ( 26 , 28 ). In the future, multicentered prospective studies investigating the efficiency of maternal sepsis screening tools are crucial for their validation. To gain a better understanding regarding the adverse neonatal outcomes, a prospective cohort study should be conducted with patients experiencing sepsis during pregnancy and their neonates to understand specific management factors that may be associated with worse neonatal outcomes. Additionally, biomarkers could be investigated using maternal and infant blood samples. Investigating molecular-level changes occurring in the placenta with maternal sepsis could help us gain a better understanding of the underlying pathophysiology. There are strengths and limitations to our study. Our sample size was large, and the data represent births in the entire state of California, the most populous and diverse state in the U.S. The linkage of the data has been validated and provides multiple sources for a number of variables to ensure data accuracy. However, there are also limitations related to the data such as coding errors that can lead to misclassification bias. However, such bias is generally towards the null leading to Type II error. Thus, the statistically significant findings that we identified may actually represent underestimates of the actual differences in the factors and outcomes identified. Another limitation of this study is that we only investigated sepsis that immediately preceded delivery and did not include pregnant women who had sepsis earlier in the pregnancy that did not lead to delivery during that admission. In order to ascertain whether earlier sepsis impacts placenta-related outcomes such as preeclampsia, preterm birth, or fetal growth restriction, a prospective cohort study may yield more specific findings. Taken together, neonates born to patients with maternal sepsis had a higher risk for a wide range of severe adverse neonatal outcomes including stillbirth and neonatal demise. Neonates born to mothers with sepsis should be closely monitored for these complications. Additionally, we found that certain maternal characteristics and types of infections were linked to increased risk for maternal sepsis in pregnant individuals. Reducing maternal sepsis may improve neonatal outcomes. Declarations Conflict of Interest Disclosures: The authors report no conflict of interest. Funding/Support: Dr. Stephanie L. Gaw was supported by the National Institutes of Health (NIAID K08AI141728). Author Contributions Dr. Gaw and Dr. Caughey conceptualized and designed the study, carried out the initial analysis, critically reviewed and revised the manuscript. Dr. Ozarslan and Dr. Cassidy drafted the initial manuscript, reviewed, and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. References CDC. Trends in pregnancy-related mortality in the United States: 1987–2017 [Internet]. cdc.gov; 2020 [cited 2022 Mar 18]. 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Supplementary Files SupplementalTable1.docx SupplementalTable2.docx SupplementalTable3.docx SupplementalTable4.docx Cite Share Download PDF Status: Published Journal Publication published 22 May, 2023 Read the published version in Journal of Perinatology → Version 1 posted Editorial decision: revise 22 Nov, 2022 Review # 1 received at journal 15 Nov, 2022 Reviewer # 1 agreed at journal 30 Oct, 2022 Reviewers invited by journal 27 Oct, 2022 Submission checks completed at journal 26 Oct, 2022 First submitted to journal 25 Oct, 2022 Editor assigned by journal 25 Oct, 2022 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies 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-2203832","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":147577889,"identity":"248ccc5a-1a16-4d66-9c4f-d33cfb3cd723","order_by":0,"name":"Nida Ozarslan","email":"","orcid":"https://orcid.org/0000-0003-3235-1238","institution":"University of California, San Francisco","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nida","middleName":"","lastName":"Ozarslan","suffix":""},{"id":147577890,"identity":"cd18a0cb-4eed-4140-8ee9-394c58807195","order_by":1,"name":"Stephanie Gaw","email":"","orcid":"https://orcid.org/0000-0003-0891-6964","institution":"University of California, San Francisco","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stephanie","middleName":"","lastName":"Gaw","suffix":""},{"id":147577891,"identity":"35c57f7b-b4cd-4982-bf51-2f460849089a","order_by":2,"name":"Arianna Cassidy","email":"","orcid":"","institution":"University of California, San Francisco","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Arianna","middleName":"","lastName":"Cassidy","suffix":""},{"id":147577892,"identity":"a07c83cd-164b-4e5d-a7e0-1d6b2123aeeb","order_by":3,"name":"Aaron Caughey","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYJACZiCWY5CAs4nUYky6lsQGorXwt58xfl1QcTi9X7r9mQRDhXViAyEtEmdyzKxnnDmcO3POGTMJhjPphLUYMOSYGfO2Hc7dcCOHTYKx7TARWvjfALX8O5xucCP9mQTjP2K0SOQYP+ZtOJxgcCPBTIKxgQgtEjeelTHzHEs3nDkjx9gi4Vi6MUEt/P3Jmz/z1FjL80ukP7zxocZalqAWIGADxkgzhJlAhHIQYP7AwFBHpNpRMApGwSgYkQAAk708VEkxc/MAAAAASUVORK5CYII=","orcid":"","institution":"Oregon Health \u0026 Sciences University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Aaron","middleName":"","lastName":"Caughey","suffix":""}],"badges":[],"createdAt":"2022-10-25 22:05:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2203832/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2203832/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41372-023-01696-3","type":"published","date":"2023-05-22T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":28478241,"identity":"7ccde4e6-dbf4-4184-a1da-fb2cb540501d","added_by":"auto","created_at":"2022-10-31 21:16:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":129777,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelationship between maternal characteristics and maternal sepsis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariable logistic regression was performed adjusting for maternal age, parity, race/ethnicity, education, insurance status, degree of prenatal care, gestational age, and twin gestation. Statistical significance was determined by a P-value of \u0026lt;0.05 and 95% confidence intervals (CI) that did not cross one, indicated by grey-filled circles.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2203832/v1/eeabc30ae7778b1e1a48e0d7.png"},{"id":28478240,"identity":"e3d70f88-74c3-4032-81a2-d5d22634b09b","added_by":"auto","created_at":"2022-10-31 21:16:14","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":92657,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelationship between type of maternal infections and maternal sepsis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariable logistic regression was performed adjusting for maternal age, parity, race/ethnicity, education, insurance status, degree of prenatal care, gestational age, and twin gestation. Statistical significance was determined by a P-value of \u0026lt;0.05 and 95% confidence intervals (CI) that did not cross one, indicated by grey-filled circles.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2203832/v1/782517597238c95deea0470f.png"},{"id":28478246,"identity":"ff88f1ac-852e-4061-875f-75481b44ebea","added_by":"auto","created_at":"2022-10-31 21:16:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":158610,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelationship between type of neonatal outcomes and maternal sepsis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariable logistic regression was performed adjusting for maternal age, parity, race/ethnicity, education, insurance status, degree of prenatal care, gestational age, and twin gestation. Statistical significance was determined by a P-value of \u0026lt;0.05 and 95% confidence intervals (CI) that did not cross one, indicated by grey-filled circles.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2203832/v1/cea2e6e07411d6a48dcebb90.png"},{"id":37363105,"identity":"9121d4e2-6aba-4f16-8751-05ec2430ba0a","added_by":"auto","created_at":"2023-05-23 07:10:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":765271,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2203832/v1/5e7c1b4c-73a6-45e0-92d1-6565f4f977e5.pdf"},{"id":28478320,"identity":"8b6985b7-cf44-4e4a-9f97-246809800a6c","added_by":"auto","created_at":"2022-10-31 21:21:14","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15443,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementalTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-2203832/v1/d18312bec824c3bc9f00899f.docx"},{"id":28478245,"identity":"3a8e5ec8-dfcb-4f80-aa3d-adb5944235dc","added_by":"auto","created_at":"2022-10-31 21:16:15","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13604,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-2203832/v1/ce3692dd7a923ab4903cc8ef.docx"},{"id":28478321,"identity":"7f3d938a-3092-4d30-8a5c-066259c5cfee","added_by":"auto","created_at":"2022-10-31 21:21:15","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":13184,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable3.docx","url":"https://assets-eu.researchsquare.com/files/rs-2203832/v1/04e0575f3d0bfdb8cc6245d0.docx"},{"id":28478322,"identity":"04505b16-5288-4704-a605-a6dd91370131","added_by":"auto","created_at":"2022-10-31 21:21:21","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":13518,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable4.docx","url":"https://assets-eu.researchsquare.com/files/rs-2203832/v1/504c55a83a9ec4372812da82.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Predictors of antepartum maternal sepsis and effects on neonatal outcomes: a population-based cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMaternal sepsis in pregnancy, which is defined as organ dysfunction resulting from infection during pregnancy, intrapartum, post-abortion, or during the postpartum period, is a significant cause of severe maternal morbidity and mortality. According to the latest CDC data, infection is the second leading cause of pregnancy-related deaths in the United States. at 12.7%, surpassed only by cardiovascular disease (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMaternal sepsis affects 1\u0026ndash;3/10 000 deliveries per year, but the proportion of maternal deaths caused by sepsis ranges between 4.1\u0026ndash;6.2% (\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). According to a 2013 study, between 1998\u0026ndash;2008, the odds for both severe sepsis during pregnancy and sepsis related death increased 10% annually in the U.S. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). A study from the U.S. noted that over 2002\u0026ndash;2015, the rate of maternal sepsis increased from 1.2/10 000 to 3.7/10 000, with an annual increase of almost 7% (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Mortality rates were as high as 20\u0026ndash;28% (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). A 2014 study found maternal sepsis to have a case fatality rate of 4.4 per 100 deliveries (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMaternal diseases causing prenatal inflammation have been linked to adverse neonatal outcomes. Even localized periodontitis, has been linked to adverse pregnancy outcomes like preterm birth (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Interestingly, babies born to patients with pancreatitis had increased odds of being born small for gestational age, developing respiratory distress syndrome, and neonatal jaundice (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Although acute pyelonephritis rates of pregnant patients are similar to non-pregnant females, acute pyelonephritis during pregnancy has been linked to adverse pregnancy outcomes including preterm birth (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Besides unwanted maternal outcomes, maternal sepsis has been associated with poor neonatal outcomes as well. Previous studies have demonstrated an almost-3-fold risk of preterm delivery and a 6- to 8-fold risk of perinatal mortality, as well as an increased risk of neonatal hypoxia/acidosis (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, these data have been limited by smaller sample sizes.\u003c/p\u003e \u003cp\u003eThe impact of maternal sepsis on neonatal outcomes not been studied in diverse, population-based cohorts. The goal of this study was to examine factors associated with maternal sepsis during the antenatal period and examine neonatal outcomes after maternal sepsis.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003eThis is a retrospective cohort study including all deliveries in California between 2005\u0026ndash;2008, recorded in the state birth certificate registry and linked with statewide hospital discharge and death certificate data. The data were derived from linked mother-infant datasets from the California Vital Statistics Birth Certificate Data, Vital Statistics Death Certificate Data, California Patient Discharge Data, and Vital Statistics Fetal Death File. Data linkage was performed by the California Office of Statewide Health Planning and Development (OSHPD) Healthcare Information Resource Center, under the California Health and Human Services Agency (CHHS) using a unique \u0026ldquo;record linkage number\u0026rdquo; specific to the mother-infant pair.\u003c/p\u003e \u003cp\u003eWe obtained human subjects\u0026rsquo; approval from the Institutional Review Board at Oregon Health \u0026amp; Science University, the California Office of Statewide Health Planning and Development (OSHPD), and the Committee for the Protection of Human Subjects (IRB00009487, approved March 13, 2013). The linked dataset did not contain potential patient privacy/identification information, so informed consent was exempted. Our primary exposure of interest was a diagnosis of maternal sepsis and we identified 687 patients with antepartum sepsis using the following International Classification of Diseases, 9th Revision [ICD-9] codes (\u003cb\u003eSupplemental Table\u0026nbsp;1\u003c/b\u003e). A total of 687 cases were identified and these were compared with 2 077 965 control deliveries.\u003c/p\u003e \u003cp\u003eTo focus on antepartum sepsis, we excluded associated codes of postpartum sepsis, endometritis, wound infection, and mastitis. Pregnancies complicated by congenital anomalies and triplet, and higher order gestations were also excluded. Analyses were performed using Stata (version 12, StataCorp; College Station, TX) and R (version 2.13.1, R Foundation for Statistical Computing; Vienna, Austria). Particular maternal characteristics, type of maternal infection, and neonatal outcomes of interest were defined. Specifically, we examined age, race/ethnicity, parity, education, insurance type, number of prenatal care visits, and twin gestation. Advanced maternal age was defined as 35 years and older at time of birth. Parity was stratified into nulliparity and multiparity. The type of inciting maternal infection was delineated as pneumonia, pyelonephritis, chorioamnionitis, fungal infection, and listeriosis. Fetal/neonatal outcomes of interest encompassed preterm delivery, stillbirth, transient tachypnea of newborn (TTN), respiratory distress syndrome, jaundice, small for gestational age (SGA), hypoglycemia, meningitis, neonatal sepsis, shock, retinopathy of prematurity (ROP), neonatal seizures, and neonatal mortality. Preterm delivery was additionally stratified by gestational age; born before 37 weeks, 32 weeks and 28 weeks.\u003c/p\u003e \u003cp\u003eComparisons were made between cases of sepsis and all other births without a sepsis code, using chi-squared or Fisher\u0026rsquo;s exact test, as appropriate. Multivariable logistic regression was performed adjusting for maternal age, parity, race/ethnicity, education, insurance status, degree of prenatal care, gestational age, and twin gestation. Missing data were excluded from analyses. Statistical significance was determined by a P-value of \u0026lt;\u0026thinsp;0.05 and 95% confidence intervals (CI) that did not cross unity.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the study period, there were 2 078 652 deliveries in California. Among those, we identified 687 (0.03%) cases of antepartum sepsis. These cases were compared to the remaining 2 077 965 control pregnancies. The rate of developing maternal sepsis significantly differed by maternal race/ethnicity (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The highest rate of maternal sepsis was seen in Asian and Black patients with 0.04%, followed by Hispanic patients with 0.03%. Maternal sepsis also showed a significant association with parity, public insurance, and twin gestation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMaternal Demographics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-Sepsis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGeneral\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e687 (0.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 077 965\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAdvanced Maternal Age\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e132 (0.04%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e357 915\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaternal Race\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e140 (0.02%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e564 270\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (0.04%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e105 980\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHispanic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e388 (0.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 126 919\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101 (0.04%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e238 448\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (0.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 806\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 542\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNulliparous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e313 (0.04%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e804 103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiparous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e357 (0.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 267 331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 531\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSome College Education\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e280 (0.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e899 995\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.219\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInsurance Type\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePublic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e364 (0.04%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 001 622\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrivate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e323 (0.03%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 076 343\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFever than 5 Prenatal Care Visits\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (0.07%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e85 429\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTwins\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (0.06%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e58 687\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhen controlling for potential confounders, the incidence of maternal sepsis remained associated with many of the above factors, including Hispanic ethnicity (adjusted odds ratio (aOR) 1.3, CI 1.0-1.6) Asian race (aOR 1.7, CI 1.3\u0026ndash;2.2), nulliparity (aOR 1.5, CI 1.3\u0026ndash;1.8), and having public insurance (aOR 1.3, CI 1.0-1.5) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cb\u003eSupplemental Table\u0026nbsp;2\u003c/b\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe relationship between specific maternal infections and the development of maternal sepsis was investigated (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cb\u003eSupplemental Table\u0026nbsp;3\u003c/b\u003e). Chorioamnionitis, pyelonephritis, pneumonia, listeriosis, and fungal infections were all significantly (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) associated with maternal sepsis. Chorioamnionitis and pyelonephritis were the most common infections leading to sepsis, constituting 21.7% and 13.1% of sepsis cases, respectively. Listeriosis was rare, causing 0.44% of sepsis cases; however, it led to the highest odds of developing sepsis (aOR 83.4, CI 16.9-410.8).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWhen examining outcomes of the pregnancy, septic patients had significantly higher rates of preterm delivery, as compared to non-septic patients, 27.1% vs. 10.1% respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The rates of deliveries prior to 32 weeks (12.8% vs. 1.4%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and before 28 weeks (6.0% vs. 0.4%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were also increased with maternal sepsis. Patients with maternal sepsis had higher rates of cesarean section compared to non-septic patients, 39.2% and 30.4% respectively (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of Neonatal Complications\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIncidence among patients with sepsis\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;687)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIncidence among patients without sepsis\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;2 078 533)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eShock\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.75%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.01%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePreterm Delivery\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;37 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27.07%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.11%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;32 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.81%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.38%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;28 weeks\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.97%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.39%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeonatal Demise\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.64%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStillbirth\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.49%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.34%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTransient Tachypnea of Newborn\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4.66%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.19%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRespiratory Distress Syndrome\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7.71%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.03%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eJaundice\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26.20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15.72%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmall for Gestational Age\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.15%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.78%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypoglycemia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.33%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.82%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMeningitis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.58%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.01%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeonatal Sepsis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10.04%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.57%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRetinopathy of Prematurity\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.08%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNeonatal Seizure\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.73%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.06%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMaternal sepsis was also related to higher rates of neonatal complications. Sepsis was associated with an increased risk of both fetal (3.5% vs. 0.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and neonatal demise (3.9% vs. 0.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Neonatal seizures were more commonly seen in neonates born to patients with maternal sepsis (0.7% vs. 0.06%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The rates of neonatal infection such as neonatal shock (1.8% vs. 0.01%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), sepsis (10.0% vs. 1.6%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and meningitis (0.6% vs. 0.01%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), were higher in neonates born to patients with maternal sepsis. Other adverse neonatal outcomes such as respiratory distress syndrome (7.7% vs. 1.0%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), transient tachypnea of newborn (4.7% vs. 2.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), small for gestational age (9.5% vs. 6.5%, p\u0026thinsp;=\u0026thinsp;0.003), hypoglycemia (2.3% vs. 0.8%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), jaundice (26.2% vs. 15.7%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and retinopathy of prematurity (1.3% vs. 0.1%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were all more commonly seen with maternal sepsis.\u003c/p\u003e \u003cp\u003eEven after controlling for potential confounders including gestational age, the associations between maternal sepsis and adverse neonatal outcomes persisted (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, \u003cb\u003eSupplemental Table\u0026nbsp;4\u003c/b\u003e). Maternal sepsis increased the risk of neonatal demise (aOR 4.2, CI 2.2-8.), neonatal seizure (aOR 8.9, CI 3.3\u0026ndash;23.9), and neonatal infections such as shock (aOR 142.0, CI 73.6-274.2), sepsis (aOR 4.8, CI 3.6\u0026ndash;6.4) and meningitis (aOR 31.2, CI 9.8\u0026ndash;99.0). Odds were also higher for developing neonatal complications including transient tachypnea of newborn (aOR 1.5, CI 1.0- 2.3), small for gestational age (aOR 1.1, CI 1.1\u0026ndash;1.9), neonatal hypoglycemia (aOR 1.9, CI 1.1\u0026ndash;3.3), jaundice (aOR 1.5, CI 1.3\u0026ndash;1.9), and retinopathy of prematurity (aOR 5.9, CI 2.7\u0026ndash;13.1) with maternal sepsis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our study, we found that maternal sepsis increased the risk of fetal and neonatal mortality and morbidities such as meningitis, sepsis, and shock. Other adverse neonatal outcomes were also more commonly seen in patients with maternal sepsis such as preterm delivery and small for gestational age. Preterm delivery associated with maternal sepsis would be predicted to lead to neonatal complications. However, the association between maternal sepsis and neonatal complications persisted even when controlling for gestational age. Additionally, we have previously reported antepartum sepsis as a risk factor for placental dysfunction (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This suggests that there may be some effect from maternal sepsis itself that impacts the neonate beyond the expected consequences of preterm birth.\u003c/p\u003e \u003cp\u003eThe distribution of various infections among pregnant patients in our sample with sepsis was investigated. The most common was chorioamnionitis, at 21.7%, and the least common was listeriosis, at 0.44%. In a multicenter case-control study, chorioamnionitis was also the most common cause of maternal sepsis, but not specified as antepartum sepsis (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). It was shown that neonates born to patients with chorioamnionitis had a higher risk for NICU admissions, asphyxia at delivery requiring resuscitation, intraventricular hemorrhage, respiratory distress syndrome, and intrauterine infection (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). A prospective cohort study investigating pregnancies complicated with clinical chorioamnionitis, maternal fever or histological chorioamnionitis revealed that prenatal inflammation reduced the protective effect of advanced gestational age and constituted a risk factor for adverse neonatal outcomes (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlthough listeriosis was rare, it was associated with the highest odds for the development of maternal sepsis. Pregnant patients were found to be 16\u0026ndash;18 times more likely to experience listeriosis compared to non-pregnant females, and pregnant patients constituted 16\u0026ndash;27% of all listeriosis cases (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). According to a national prospective cohort study conducted in France, maternal listeriosis led to adverse pregnancy outcomes including preterm birth, neonatal listeriosis, fetal and neonatal death in more than 80% of affected pregnancies (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Two separate studies from China reported 57.1% and 73% fetal-neonatal mortality rates due to maternal listeriosis (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In an observational study conducted in New Zealand, listeriosis during pregnancy resulted in the hospitalization of all infected pregnant patients and one-third of these pregnancies resulted in intrauterine death or stillbirth, proving the severity of listeriosis (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In parallel, a study investigating seven pregnant patients with listeriosis, all pregnancies were complicated with preterm delivery (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe show that in a large cohort of deliveries in California, certain maternal characteristics and specific infections pose an increased risk of developing sepsis prior to delivery. Maternal race/ethnicity was significantly associated with sepsis, with Asian/Pacific Islander and Hispanic patients at greatest risk. Such findings are unlikely to have a biological underpinning, but rather identify socio-cultural differences as well as inculcated systemic racism within society and the health system leading to such health inequities. Thus, it was not surprising that another group at increased risk of developing sepsis were those with public insurance who similarly may face challenges in accessing care.\u003c/p\u003e \u003cp\u003eAccording to the World Health Organization, the frequency of infection-related maternal deaths around the world is much greater than previously estimated (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Considering the adverse fetal and maternal outcomes of sepsis during pregnancy, early recognition of maternal sepsis is crucial. It has been shown that the administration of antibiotics within the first hour of diagnosis (deemed the golden hour) drastically reduces mortality rates in sepsis (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Unfortunately, there is no validated screening tool for pregnant patients and common sepsis screening tools such as qSOFA and SIRS have various levels of sensitivity and specificity, decreasing the reliability of the usage of a single screening tool for maternal sepsis diagnosis (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan additionalcitationids=\"CR27 CR28\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). While examining and evaluating a pregnant patient for sepsis, the sociocultural background of the patient should always be kept in mind to make an accurate diagnosis. Since Asian/Pacific Islander or Hispanic patients have been shown at higher risk for maternal sepsis, interpretation services or health providers that can communicate through the patient\u0026rsquo;s native language could potentially improve the timely diagnosis of sepsis by overcoming communication problems.\u003c/p\u003e \u003cp\u003eWe found that listeriosis constituted a strong risk for sepsis development in pregnant patients as well as leading to poor fetal and neonatal outcomes. Patients should be educated on possible transmission routes of listeriosis. On the other hand, physicians should increase their clinical suspicion for listeriosis in pregnant patients and treat according to the guidelines if needed (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Additionally, we found that pyelonephritis during pregnancy increased the risk for maternal sepsis development in pregnant patients. It is known that pregnant patients experiencing urinary tract infections (UTIs) have a higher risk for developing pyelonephritis, therefore pregnant individuals should be screened for UTIs and treated carefully (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo date, there is no consensus for the usage of a validated sepsis screening tool for pregnant patients although there are some proposals (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In the future, multicentered prospective studies investigating the efficiency of maternal sepsis screening tools are crucial for their validation. To gain a better understanding regarding the adverse neonatal outcomes, a prospective cohort study should be conducted with patients experiencing sepsis during pregnancy and their neonates to understand specific management factors that may be associated with worse neonatal outcomes. Additionally, biomarkers could be investigated using maternal and infant blood samples. Investigating molecular-level changes occurring in the placenta with maternal sepsis could help us gain a better understanding of the underlying pathophysiology.\u003c/p\u003e \u003cp\u003eThere are strengths and limitations to our study. Our sample size was large, and the data represent births in the entire state of California, the most populous and diverse state in the U.S. The linkage of the data has been validated and provides multiple sources for a number of variables to ensure data accuracy. However, there are also limitations related to the data such as coding errors that can lead to misclassification bias. However, such bias is generally towards the null leading to Type II error. Thus, the statistically significant findings that we identified may actually represent underestimates of the actual differences in the factors and outcomes identified. Another limitation of this study is that we only investigated sepsis that immediately preceded delivery and did not include pregnant women who had sepsis earlier in the pregnancy that did not lead to delivery during that admission. In order to ascertain whether earlier sepsis impacts placenta-related outcomes such as preeclampsia, preterm birth, or fetal growth restriction, a prospective cohort study may yield more specific findings.\u003c/p\u003e \u003cp\u003eTaken together, neonates born to patients with maternal sepsis had a higher risk for a wide range of severe adverse neonatal outcomes including stillbirth and neonatal demise. Neonates born to mothers with sepsis should be closely monitored for these complications. Additionally, we found that certain maternal characteristics and types of infections were linked to increased risk for maternal sepsis in pregnant individuals. Reducing maternal sepsis may improve neonatal outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures:\u003c/strong\u003e The authors report no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support:\u003c/strong\u003e Dr. Stephanie L. Gaw was supported by the National Institutes of Health (NIAID K08AI141728).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Gaw and Dr. Caughey conceptualized and designed the study, carried out the initial analysis, critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eDr. Ozarslan and Dr. Cassidy drafted the initial manuscript, reviewed, and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCDC. Trends in pregnancy-related mortality in the United States: 1987\u0026ndash;2017 [Internet]. cdc.gov; 2020 [cited 2022 Mar 18]. 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J Perinatol. 2018 Jan;38(1):26\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonet M, Brizuela V, Abalos E, Cuesta C, Baguiya A, Chamillard M, et al. Frequency and management of maternal infection in health facilities in 52 countries (GLOSS): a 1-week inception cohort study. Lancet Glob Health. 2020 May;8(5):e661\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N Engl J Med. 2017 Jun 8;376(23):2235\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShields A, de Assis V, Halscott T. Top 10 Pearls for the Recognition, Evaluation, and Management of Maternal Sepsis. Obstet Gynecol. 2021 Aug;138(2):289\u0026ndash;304.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEscobar MF, Echavarr\u0026iacute;a MP, Zambrano MA, Ramos I, Kusanovic JP. Maternal sepsis. Am J Obstet Gynecol MFM. 2020 Aug;2(3):100149.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerafim R, Gomes JA, Salluh J, P\u0026oacute;voa P. A Comparison of the Quick-SOFA and Systemic Inflammatory Response Syndrome Criteria for the Diagnosis of Sepsis and Prediction of Mortality. Chest. 2018 Mar;153(3):646\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCagino SG, Burke AA, Letner DR, Leizer JM, Zelig CM. Quick Sequential Organ Failure Assessment: Modifications for Identifying Maternal Morbidity and Mortality in Obstetrical Patients. Am J Perinatol. 2022 Jan;39(01):001\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonet M, Nogueira Pileggi V, Rijken MJ, Coomarasamy A, Lissauer D, Souza JP, et al. Towards a consensus definition of maternal sepsis: results of a systematic review and expert consultation. Reprod Health. 2017 Dec;14(1):67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmerican College of Obstetricians and Gynecologists. Management of pregnant women with presumptive exposure to Listeria monocytogenes. Comm Opin No 614. 2014 Dec;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlaser AP, Schaeffer AJ. Urinary Tract Infection and Bacteriuria in Pregnancy. Urol Clin North Am. 2015 Nov;42(4):547\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"infection, pregnancy, neonate, antenatal infection, neonatal complication, antenatal sepsis, maternal infection","lastPublishedDoi":"10.21203/rs.3.rs-2203832/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2203832/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\n\u003cp\u003eTo examine the relationship between maternal sepsis, type of infection, and short-term neonatal outcomes.\u003c/p\u003e\n\u003ch2\u003eStudy Design\u003c/h2\u003e\n\u003cp\u003eWe conducted a retrospective cohort study investigating pregnancies between 2005 and 2008 in California with antepartum maternal sepsis diagnosis. Comparisons were made between sepsis cases and all other births without sepsis, using chi-squared or Fisher’s exact test. Multivariable logistic regression (MLR) was performed, adjusting for maternal characteristics.\u003c/p\u003e\n\u003ch2\u003eResults\u003c/h2\u003e\n\u003cp\u003eMLR analyses indicated that specific maternal characteristics increased the odds of maternal sepsis. Chorioamnionitis, pneumonia, pyelonephritis, listeriosis, and fungal infection were all significantly associated with maternal sepsis (p \u0026lt; 0.001). Neonates born to patients with maternal sepsis had a higher risk of developing certain neonatal complications.\u003c/p\u003e\n\u003ch2\u003eConclusion\u003c/h2\u003e\n\u003cp\u003eMaternal sepsis was associated with neonatal complications. Efforts to reduce maternal sepsis may improve neonatal outcomes. Further studies are required for a better understanding of these associations and whether prevention or more rapid diagnosis and treatment can lower these risks.\u003c/p\u003e","manuscriptTitle":"Predictors of antepartum maternal sepsis and effects on neonatal outcomes: a population-based cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-10-31 21:16:13","doi":"10.21203/rs.3.rs-2203832/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2022-11-22T12:18:28+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2022-11-15T22:20:12+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2022-10-30T18:16:13+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2022-10-27T19:45:19+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2022-10-26T10:02:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Perinatology","date":"2022-10-25T22:03:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-10-25T22:03:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-perinatology","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"jp","sideBox":"Learn more about [Journal of Perinatology](http://www.nature.com/jp/)","snPcode":"41372","submissionUrl":"https://mts-jper.nature.com/cgi-bin/main.plex","title":"Journal of Perinatology","twitterHandle":"@jperinatology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"1f5222ce-c6ed-4b5b-a5e5-4327cf858c47","owner":[],"postedDate":"October 31st, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":16551685,"name":"Health sciences/Medical research/Outcomes research"},{"id":16551686,"name":"Health sciences/Risk factors"},{"id":16551687,"name":"Health sciences/Diseases/Infectious diseases"}],"tags":[],"updatedAt":"2023-05-23T07:10:20+00:00","versionOfRecord":{"articleIdentity":"rs-2203832","link":"https://doi.org/10.1038/s41372-023-01696-3","journal":{"identity":"journal-of-perinatology","isVorOnly":false,"title":"Journal of Perinatology"},"publishedOn":"2023-05-22 04:00:00","publishedOnDateReadable":"May 22nd, 2023"},"versionCreatedAt":"2022-10-31 21:16:13","video":"","vorDoi":"10.1038/s41372-023-01696-3","vorDoiUrl":"https://doi.org/10.1038/s41372-023-01696-3","workflowStages":[]},"version":"v1","identity":"rs-2203832","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2203832","identity":"rs-2203832","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}