The Role of 1-Deoxysphingolipids and Polyamines in the Pathogenesis of Placental Syndrome

The Role of 1-Deoxysphingolipids and Polyamines in the Pathogenesis of Placental Syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Role of 1-Deoxysphingolipids and Polyamines in the Pathogenesis of Placental Syndrome Filiz Yarsilikal Guleroglu, Ali Cetin, Goknil Pelin Coskun, Meltem Caliskan, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5405039/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Jan, 2025 Read the published version in BMC Pregnancy and Childbirth → Version 1 posted 10 You are reading this latest preprint version Abstract Background: Placental syndrome mainly composed of preeclampsia and fetal growth restriction have an impact on the health of mother and baby dyads. While impaired placentation is central to their pathophysiology, the underlying molecular mechanisms remain incompletely understood. This study investigates the association between placental syndrome and metabolic alterations in 1-deoxysphingolipids (1-deoxySLs) and polyamines, along with their regulatory enzymes. Methods: This prospective case-control study involved 26 healthy pregnant women and 17 with placental syndrome. Blood samples were collected from maternal, uterine venous, and umbilical cord veins. Levels of 1-deoxySL, spermine, and spermidine as well as related enzymes of polyamine metabolism such as ornithine decarboxylase (ODC), spermidine/spermine N1-acetyltransferase (SSAT), polyamine oxidase (PAO), and spermine oxidase (SMO) were measured using the techniques of LC-MS and ELISA, respectively. Results: Women with placental syndrome had significantly higher levels of 1-deoxySL, spermine, and spermidine in all blood samples compared to the healthy pregnancy group. Additionally, ODC and SSAT levels were reduced significantly in the placental syndrome group, while PAO and SMO levels showed no significant differences. Strong positive correlations were found between the studied enzymes and biomolecules in healthy pregnancies, which were notably weaker in the placental syndrome group. Conclusion: This study demonstrates significantly altered levels of 1-deoxySL and polyamines, with corresponding enzyme activity changes, in placental syndrome compared to healthy pregnancies. The disrupted correlations between these biomolecules suggest alterations in their metabolic pathways and potential utility as biomarkers. Further mechanistic studies are warranted to elucidate their role in placental syndrome pathophysiology. Placental syndrome preeclampsia fetal growth restriction 1-deoxysphingolipids polyamines 1. Introduction Preeclampsia and fetal growth restriction (FGR) and belong to placental syndrome having adverse effects on mother and fetus dyads and present many management problems in antenatal care. These syndromes are believed to arise from abnormal placentation leading to uteroplacental blood flow insufficiency and endothelial dysfunction ( 1 ). Preeclampsia, a multisystemic disease, presents with new-onset hypertension with or without proteinuria during the second half of pregnancy and has an incidence of 3–5% in all pregnancies worldwide ( 2 ). Preeclampsia, encompassing subtypes like eclampsia and HELLP syndrome, represents a prominent factor in maternal and fetal morbidity and mortality and also contributes significantly to enduring maternal cardiovascular complications. ( 3 – 5 ). FGR is the inadequacy of the fetus to utilize the full capacity allowed by its genetic profile, which is commonly ascribed to placental dysfunction and results in adverse newborn outcomes and future health risks ( 6 ). The pathogenesis of placental syndrome involves complex interactions of genetic, immunological, and environmental factors. The placenta, crucial for fetal development, undergoes extensive vascular remodeling during pregnancy to ensure sufficient blood supply to the growing fetus. Inadequate remodeling of uterine spiral arteries, a hallmark of placental syndrome, leads to high-resistance blood flow and placental ischemia ( 7 ). This condition initiates a cascade of pathological events, leading to increased anti-angiogenic factors in the systemic circulation, thereby exacerbating endothelial dysfunction and contributing to the clinical manifestations of preeclampsia and FGR ( 3 , 8 ). There is increasing interest in the roles of sphingolipids and polyamines and related enzymes in understanding these syndromes' pathogenesis. 1-Deoxysphingolipids (1-deoxySLs) are a distinct type of sphingolipids lacking the typical 1-hydroxyl group, leading to unique structural and functional properties ( 9 ). These lipids significantly contribute to cellular dysfunction due to their cytotoxic properties. They disrupt membrane integrity and interfere with cellular signaling pathways, leading to apoptosis and inflammation ( 10 ). Polyamines, including spermidine and spermine, are small organic cations that are mandatory for the process of cell differentiation, proliferation, and apoptosis ( 11 , 12 ). They modulate gene expression, signal transduction, and ion channel functions by interacting with nucleic acids and proteins ( 13 ). These molecules are essential for maintaining cellular homeostasis. They are involved in various physiological and pathological processes from basic cellular function to complex immune responses ( 14 ). The enzymes ornithine decarboxylase (ODC), spermidine/spermine N1-acetyltransferase (SSAT), polyamine oxidase (PAO), and spermine oxidase (SMO) have significant roles in the metabolism of polyamines. These enzymes are key to upholding cellular processes and achieving homeostasis ( 15 ). Despite understanding the roles of 1-deoxySL and polyamines in various cellular processes, their specific roles in the pathogenesis of placental syndrome remain insufficiently explored. Studies suggest that these biomolecules hold promise for early diagnosis and therapeutic interventions ( 16 ). Previous studies have shown the potential of 1-deoxySL or polyamines as biomarkers in diseases such as metabolic and neurodegenerative disorders ( 17 , 18 ). Measurements of maternal and fetal blood levels of these biomolecules can provide critical information about placental health and function. Filling this gap could provide important insights into the molecular mechanisms underlying these conditions and help develop effective diagnostic and therapeutic strategies. Early detection of such novel biomarkers could lead to timely interventions, reducing the severity and incidence of preeclampsia and FGR. Understanding the metabolic alterations in 1-deoxySLs and polyamine pathways may provide insights into potential biomarkers. This study examines the relationship between placental syndrome and the metabolic profiles of 1-deoxySLs, polyamines, and their regulatory enzymes, aiming to characterize their patterns in maternal-fetal circulation. 2. Material and Methods 2.1. Study Participants This study, designed as an observational case-control investigation, was performed in the Gynecology and Obstetrics Services at Haseki Training and Research Hospital. Women who underwent cesarean section with a diagnosis of placental syndrome (preeclampsia and/or late FGR) were eligible for the study. Institutional human research ethics committee approval was obtained from Haseki Training and Research Hospital before the study (Approval No: 210–2023, dated 22.11.2023). The research adhered strictly to the study protocol, crafted consistent with the principles outlined in the Declaration of Helsinki and the latest institutional guidelines. Pregnant women attending antenatal care who were deemed eligible and invited to participate in the study were enrolled only after providing informed written consent. The study included two groups of women: 26 with healthy pregnancies and 17 with placental syndrome. Criteria for inclusion in the placental syndrome group were confirmation of the diagnosis of placental syndrome by prepartum, intrapartum, and postpartum findings; gestational age between 28–41 weeks; gestational age confirmed in the first trimester; late FGR with a gestational age > 32 weeks; absence of acute fetal distress; absence of maternal diabetes mellitus; absence of chronic hypertension; no lipid metabolism disorders; and no chronic kidney disease. The diagnosis of placental syndrome, including preeclampsia and/or late FGR, was based on the clinical, biochemical, and ultrasonographic assessments and course of pregnancy. For the diagnosis of preeclampsia, the findings were confirmed gestational age greater than 20 weeks, high blood pressure (≥ 140/90 mmHg), and proteinuria (urinary total protein/creatinine ratio > 30 or + 1 on urine dipstick) ( 19 ). Late FGR was diagnosed considering the gestational age over 32 weeks with an ultrasonographically determined fetal weight less than the 10th percentile ( 20 ). 2.2. Blood Sample Collection Peripheral Venous Blood Sample A 3-mL antecubital blood sample was taken before cesarean section. Uterine Venous Blood Sample Blood sampling from venous plexus vessels in the broad ligament during cesarean section offers insights into the changes in placental-derived mediators ( 21 ). During cesarean section, a 3-mL blood sample was obtained from the veins in the uterine venous plexus (the largest diameter vein from the part of the vein 5 cm below the fallopian tube) which runs parallel to the uterine wall in the ligamentum latum. During blood collection, the 25G needle needed to make a 30-degree angle with the vein. Umbilical Cord Venous Blood Sample A 3-mL blood sample was drawn after the delivery of the baby. Venous blood samples were divided into two equal parts. Samples were collected in yellow-capped tubes with a gel separator for serum separation, while samples were collected in purple-capped tubes containing EDTA for plasma separation. After allowing the serum samples to clot at room temperature for 30 min, they were centrifuged at 3,000 rpm for 10 min to extract the serum. Their serum samples were carefully aliquoted into separate cryotubes with a capacity of 0.5 mL and preserved at -80°C until the biochemical analysis took place. Samples for plasma were immediately stored in 0.5-mL cryotubes and preserved at -80°C until LC-MS assays. 2.3. Biochemical Analyses 2.3.1. ODC, SSAT, PAO, and SMO Measurements with ELISA Serum ODC, SSAT, PAO, and SMO levels were measured from maternal, uterine, and umbilical cord venous samples using commercial ELISA kits (ODC, SSAT, and SMO from BT LAB, China; PAO from MyBioSource, USA) according to the manufacturer's protocols, without diluting the serum samples. The standard solution was serially diluted from an initial concentration of 80 ng/mL to 1.25 ng/mL for ODC, from 40 ng/mL to 0.625 ng/mL for SSAT, from 32 ng/mL to 0.5 ng/mL for SMO and from 5000 pg/mL to 78 pg/mL for PAO. The tests in the ODC, SSAT, and SMO kits exhibited a coefficient of variation ranging from 8–10% for both within-assay and between-assay variability. The coefficient of variation for PAO, both within and between assays, ranged from 10 to 12%. 2.3.2. 1-DeoxySLs, Spermine, and Spermidine Measurements with LC-MS Samples were prepared according to the literature ( 22 , 23 ). Sphingolipids were hydrolyzed before the analysis. All the samples were prepared according to the assay protocol in the supplementary file (see supplementary). All sphingolipids were analyzed using LC-MS instrument (Agilent Infinity 1260). Polyamine measurements were performed according to the calibration curve ( 24 – 26 ). 2.4. Statistical Analysis Considering that three separate numerical data sets could be compared, for sample size calculation, the effect size was 0.7, the p-value was 0.05 and the power value was 0.80, and the sample size was calculated as 26 participants with consideration given to potential drop-outs. With IBM SPSS v26 (USA), all statistical evaluations were performed. The mean (standard deviation), median (minimum-maximum), or count (%) of study variables were calculated. After normality tests of biomolecule data, with the Mann-Whitney test, inter-group comparisons were performed, and with repeated measures ANOVA test followed by post hoc Bonferroni test, within-group comparisons were made. The chi-square test was employed to analyze categorical data, and the Pearson correlation test was utilized to explore the relationships between relevant variables. Statistical significance was assigned to p-values below 0.05. 3. Results Although the study was initially planned to include 26 participants per group, due to exclusion criteria and time constraints, the study was completed with 26 and 17 participants in the women with healthy pregnancy and placental syndrome, respectively. Among these participants with placental syndrome, 7 (41.2%) had isolated preeclampsia, 4 (23.5%) had isolated FGR, and 6 (35.3%) were diagnosed with both preeclampsia and FGR. Comparative analysis of biomolecular markers between these subgroups was not performed due to limited sample sizes in each category. Table 1 displays the fundamental clinical characteristics of both the healthy pregnancy and placental syndrome groups. Upon analysis, the median age of the healthy pregnancy group was found to be significantly lower than that of the placental syndrome group (28.5 [21–41] vs. 32.5 [21–44], respectively; p = 0.029). The median gestational age at delivery was notably higher in the healthy pregnancy group compared to the placental syndrome group (38 [35–40] vs. 36 [32–39] weeks; p = 0.001). Additionally, the median birth weight was significantly greater in the healthy pregnancy group than in the placental syndrome group (3160 [2350–4660] vs. 2475 [1290–3470] grams; p = 0.001). Other variables, including gravidity, parity, ethnicity, education level, history of placental syndrome, including family history, smoking, mode of conception, body mass index, fetal sex, APGAR score, and umbilical cord blood gas pH values, showed no significant differences (p > 0.05). Table 1 Basic clinical characteristics of healthy pregnancy and placental syndrome groups. Healthy pregnancy (n = 26) Placental syndrome (n = 17) Significance Age (years) 28.5 ( 21 – 41 ) 32.5 (21–44) p = 0.029 Gravidity 3 ( 1 – 8 ) 3 ( 1 – 9 ) p > 0.05 Parity 2 (0–5) 2 (0–6) p > 0.05 Ethnicity Turkish citizen Immigrant 20 (76.9%) 6 (23.1%) 15 (88.2%) 2 (11.8%) p > 0.05 Education Status Illiterate Primary education High School University 6 (23.1%) 15 (57.7%) 4 (15.4%) 1 (3.8%) 3 (17.6%) 8 (47.1%) 5 (29.4%) 1 (5.9%) p > 0.05 Body Mass Index (Kg/m 2 ) 27.8 (20.5–46) 29.9 (23.3–46.6) p > 0.05 History of Placental Syndrome Yes No 1 (3.8%) 25 (96.2%) 6 (35.3%) 11 (64.7%) p > 0.05 Familial History of Placental Syndrome Yes No 2 (7.7%) 24 (92.3%) 3 (17.6%) 14 (82.4%) p > 0.05 Smoking Yes No 3 (11.5%) 23 (88.5%) 1 (5.9%) 16 (94.1%) p > 0.05 Conception Natural ART 26 (100%) 0 15 (88.2%) 2 (11.8%) p > 0.05 Gestational Age at Delivery (weeks) 38 ( 35 – 40 ) 36 ( 32 – 39 ) P = 0.001 Fetal gender Female Male 10 (38.5%) 16 (61.5%) 10 (58.8%) 7 (41.2%) p > 0.05 Birth Weight (g) 3160 (2350–4660) 2475 (1290–3470) p = 0.001 APGAR Score Minute 1 Minute 5 8.5 ( 5 – 9 ) 9 ( 7 – 10 ) 9 ( 5 – 9 ) 10 ( 7 – 10 ) p > 0.05 Umbilical Cord Blood pH 7.3 (7.2–7.4) 7.3 (7.3–7.4) p > 0.05 NICU Admission Yes No 4 (15.4%) 22 (84.6%) 9 (52.9%) 8 (47.1%) p > 0.05 Data are presented as median (minimum-maximum) and number (%). ART, assisted reproductive techniques; NICU, neonatal intensive care unit. Table 2 summarizes the hematological and biochemical results for both the healthy pregnancy and placental syndrome groups. There were no significant differences between the groups in terms of median values for baseline hematological parameters, creatinine, aspartate aminotransferase, and lactate dehydrogenase (p > 0.05). However, median uric acid levels were significantly elevated in the placental syndrome group compared to the healthy pregnancy group (5 [3–14] vs. 3.6 [2.5–4.2]; p = 0.002). Conversely, the median alanine aminotransferase levels were significantly higher in the healthy pregnancy group compared to the placental syndrome group (13 [6–23] vs. 9.5 [2–34]; p = 0.044). Table 2 Hematologic and biochemical findings of healthy pregnancy and placental syndrome groups. Healthy pregnancy (n = 26) Placental syndrome (n = 17) Significance Protein/creatine in spot urine 0.26 (0.1–1.4) White blood cell count (10 3 uL) 11.2 (5.5–20) 10.8 (7.1–14.6) p > 0.05 Red blood cell count (10 6 uL) 3.9 (2.9–4.7) 3.6 (2.4–4.8) p > 0.05 Hemoglobin (g/dl) 11.3 (7.3–12.7) 10.5 (7.8–12.1) p > 0.05 Hematocrit (%) 33.8 (23.9–39.3) 31.9 (24.1–36.3) p > 0.05 Platelet (10 3 uL) 215 (124–385) 208 (146–395) p > 0.05 Neutrophil (10 3 uL) 9 (3.1–17.8) 8.1 (4.2–12.5) p > 0.05 Lymphocyte (10 3 uL) 1.3 (0.6–2.2) 1.6 (0.7-3) p > 0.05 Creatine (mg/dl) 0.5 (0.3–0.6) 0.5 (0.3–0.7) p > 0.05 Uric Acid (mg/dl) 3.6 (2.5–4.2) 5 ( 3 – 14 ) p = 0.02 AST (U/L) 18 ( 6 – 31 ) 17 (13–50) p > 0.05 ALT (U/L) 13 ( 6 – 23 ) 9.5 ( 2 – 34 ) p = 0.044 LDH (U/L) 185 (125–224) 231 (140–623) p > 0.05 Data are shown as median (minimum-maximum). AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase. Table 3 presents the levels of ODC, SSAT, PAO, and SMO in maternal, uterine venous, and umbilical cord blood samples of healthy pregnancy and placental syndrome groups. Inter- and intra-group comparisons were performed for all the enzyme levels. Median ODC levels were significantly higher in the maternal, uterine venous, and umbilical cord blood samples of the healthy pregnancy group compared to the placental syndrome group [maternal blood: 135 (73–726) vs. 108 (15–309); (p = 0.022), uterine venous blood: 121 (41–758) vs. 78 (15–245); (p = 0.011), and umbilical cord blood: 165 (68–719) vs. 117 (0.3–391); (p = 0.018), respectively]. In intra-group comparisons, no significant difference was found between maternal blood, uterine venous blood, and umbilical cord blood in healthy pregnancy and placental syndrome groups (p > 0.05). Median SSAT levels were significantly higher in the maternal, uterine venous, and umbilical cord blood samples of the healthy pregnancy group compared to the placental syndrome group [maternal blood: 8 (3.7–28.5) vs. 6.7 (4.1–10.3); (p = 0.037), uterine venous blood: 6.7 (2.6–26.8) vs. 6 (4.3–10.3); (p = 0.032), and umbilical cord blood: 9.3 (6.3–25.9) vs. 6.6 (5.2–16.1); (p = 0.021), respectively]. In intra-group comparisons, no significant difference was found between maternal blood, uterine venous blood, and umbilical cord blood in healthy pregnancy and placental syndrome groups (p > 0.05). No significant difference was found in PAO levels in inter-group comparisons (p > 0.05). However, in intra-group comparisons, umbilical cord blood median PAO levels were statistically higher in the healthy pregnancy group and placental syndrome group compared to maternal and uterine venous blood levels (p = 0.001). No significant difference was found in SMO levels in the healthy pregnancy group and the placental syndrome group in inter-group and intra-group comparisons (p > 0.05). Table 3 ODC, SSAT, PAO, and SMO levels in maternal, uterine venous, and umbilical cord blood samples of healthy pregnancy and placental syndrome groups. Healthy pregnancy (n = 26) Placental syndrome (n = 17) Inter-group significance ODC (ng/mL) Maternal blood Uterine venous blood Umbilical cord blood 13.5 (7.3–72.6) 12.1 (4.1–75.8) 16.5 (6.8–71.9) 10.8 (1.5–30.9) a 7.8 (1.5–24.5) b 11.7 (0.3–39.1) c P = 0.022 P = 0.011 P = 0.018 Intra-group significance P = 0.355 P = 0.239 SSAT (ng/mL) Maternal blood Uterine venous blood Umbilical cord blood 8 (3.7–28.5) 6.7 (2.6–26.8) 9.3 (6.3–25.9) 6.7 (4.1–10.3) d 6 (4.3–10.3) e 6.6 (5.2–16.1) f P = 0.037 P = 0.032 P = 0.021 Intra-group significance P = 0.638 P = 0.11 PAO (pg/mL) Maternal blood Uterine venous blood Umbilical cord blood 413.1(37-2719.3) 180.6 (19.8-2001.5) 3500.9 (168.3-7793.6) * 237.5 (19.7-3669.1) 248.6 (37-3310.4) 4825.8 (1155.3-8580.4) ** P = 0.863 P = 0.689 P = 0.535 Intra-group significance P = 0.001 P = 0.001 SMO (ng/mL) Maternal blood Uterine venous blood Umbilical cord blood 6.3 (0.98-30) 5.6 (0.6–30.6) 6 (0.8–29.4) 4.9 (3.5–11) 5.2 (3.5–12.3) 5.9 (4.1–18.5) P = 0.069 P = 0.123 P = 0.242 Intra-group significance P = 0.993 P = 0.236 Data are shown as median (minimum-maximum). Maternal, uterine venous, and umbilical cord blood enzyme levels of healthy pregnancy and placental syndrome groups were compared by the Mann-Whitney test. Maternal, uterine venous, and umbilical cord blood enzyme levels within the healthy pregnancy and placental syndrome groups were compared using repeated measures ANOVA followed by post hoc Bonferroni test for pairwise comparisons. a,b,c,d,e,f The median enzyme levels were significantly lower in the placental syndrome group compared to healthy pregnancies. *,** The median PAO levels in umbilical cord blood were significantly higher than maternal and uterine venous blood levels in both groups. ODC, Ornithine Decarboxylase; SSAT, Spermidine/Spermine N1-acetyltransferase; PAO, Polyamine Oxidase; SMO, Spermine Oxidase. Table 4 illustrates the correlation coefficients for ODC, SSAT, PAO, and SMO levels across the study groups. In the healthy pregnancy group, ODC levels exhibited strong positive correlations with both SSAT (r = 0.866, p = 0.001) and SMO (r = 0.780, p = 0.001), and SSAT levels were similarly correlated with SMO (r = 0.789, p = 0.001). No significant correlations were detected between ODC and PAO, SSAT and PAO, or PAO and SMO (p > 0.05). Conversely, in the placental syndrome group, significant positive correlations were observed between ODC and SSAT (r = 0.439, p = 0.001) as well as between ODC and SMO (r = 0.464, p = 0.001). Other pairings did not show significant correlations (p > 0.05). Table 4 Correlation coefficients of ODC, SSAT, PAO, and SMO levels in all blood samples of healthy pregnancy and placental syndrome groups. ODC SSAT PAO SMO Healthy pregnancy (n = 26) ODC (ng/mL) - 0.866 p = 0.001 0.059 p > 0.05 0.780 p = 0.001 SSAT (ng/mL) - 0.083 p > 0.05 0.789 p = 0.001 PAO (pg/mL) - -0.030 p > 0.05 SMO (ng/mL) - Placental syndrome (n = 17) ODC (ng/mL) - 0.439 p = 0.001 0.007 p > 0.05 0.464 p = 0.001 SSAT (ng/mL) - 0.039 p > 0.05 0.325 p = 0.020 PAO (pg/mL) - -0.101 p > 0.05 SMO (ng/mL) - Maternal, uterine venous, and umbilical cord blood samples were pooled to analyze the relationship between enzyme levels using the Pearson correlation test. ODC, Ornithine Decarboxylase; SSAT, Spermidine/Spermine N1-acetyltransferase; PAO, Polyamine Oxidase; SMO, Spermine Oxidase. Table 5 is composed of the levels of 1-deoxySL, spermine, and spermidine in maternal, uterine venous, and umbilical cord blood samples of healthy pregnancy and placental syndrome groups. Inter- and intra-group comparisons were made for 1-deoxySL, spermine, and spermidine levels. Median 1-deoxySL levels were significantly higher in the maternal, uterine venous, and umbilical cord blood samples of the placental syndrome group compared to the healthy pregnancy group [maternal blood: 583 (547–673) vs. 489 (445–535); (p < 0.001), uterine venous blood: 441 (321–489) vs. 383 (345–432); (p < 0.001), and umbilical cord blood: 557 (345–672) vs. 256 (103–321); (p < 0.001), respectively]. In intra-group comparisons in the healthy pregnancy group showed significantly higher median 1-deoxySL levels in maternal blood compared to uterine venous and umbilical cord blood (p < 0.001), and higher levels in uterine venous blood compared to umbilical cord blood (p < 0.001). In the placental syndrome group, the median 1-deoxySL levels in uterine venous blood were significantly lower than the maternal and umbilical cord blood levels (p < 0.001). In the placental syndrome group, median spermine levels were significantly higher in maternal blood, uterine venous blood and umbilical cord blood samples compared to the healthy pregnancy group [maternal blood: 68 (43.2–79.3) vs. 47.2 (39.2–50.2); p < 0.001, uterine venous blood: 62.2 (34.6–69.4) vs. 37.4 (29.5–39.2), 47.2 (39.2–50.2); p < 0.001, and umbilical cord blood: 56.8 (49.4–89.4) vs. 22.8 (16.3–29.7); p < 0.001, respectively]. In intra-group comparisons, the healthy pregnancy group showed significantly higher median spermine levels in maternal blood compared to uterine venous and umbilical cord blood (p < 0.001), and higher levels in uterine venous blood compared to umbilical cord blood. In the placental syndrome group, the median spermine levels in maternal blood were significantly higher than uterine venous and umbilical cord blood levels (p = 0.004). In the placental syndrome group, median spermidine levels were significantly higher in maternal blood, uterine venous blood and umbilical cord blood samples compared to the healthy pregnancy group [maternal blood: 77.4 (34.6–90.3) vs. 67.6 (57.3–79.3); p = 0.005, uterine venous blood: 73 (23.5–78.8) vs. 66 (55.4–75.3); p < 0.01, and umbilical cord blood: 64.7 (23.8–90.4) vs. 51.2 (43.4–65.4); p < 0.001, respectively]. In intra-group comparisons, the healthy pregnancy group showed significantly lower median spermidine levels in umbilical cord blood compared to maternal and uterine venous blood (p < 0.001). In the placental syndrome group, the median spermidine levels in maternal blood were also statistically higher than uterine venous and umbilical cord blood levels (p = 0.005). Table 5 1-Deoxysphingolipids, spermine, and spermidine levels in maternal, uterine venous, and umbilical cord blood samples of healthy pregnancy and placental syndrome groups. Healthy pregnancy (n = 26) Placental syndrome (n = 17) Inter-group significance 1-deoxySL (ng/mL) Maternal blood Uterine venous blood Umbilical cord blood 48.9 (44.5–53.5) * 38.3 (34.5–43.2) ** 25.6 (10.3–32.1) 58.3 (54.7–67.3) a 44.1 (32.1–48.9) b,*** 55.7 (34.5–67.2) c P < 0.001 P < 0.001 P < 0.001 Intra-group significance P < 0.001 P < 0.001 Spermine (ng/mL) Maternal blood Uterine venous blood Umbilical cord blood 47.2 (39.2–50.2) # 37.4 (29.5–39.2) $ 22.8 (16.3–29.7) 68 (43.2–79.3) d,† 62.2 (34.6–69.4) e 56.8 (49.4–89.4) f P < 0.001 P < 0.001 P < 0.001 Intra-group significance P < 0.001 P = 0.004 Spermidine (ng/mL) Maternal blood Uterine venous blood Umbilical cord blood 67.6 (57.3–79.3) 66 (55.4–75.3) 51.2 (43.4–65.4) & 77.4 (34.6–90.3) g,~ 73 (23.5–78.8) h 64.7 (23.8–90.4) i P = 0.005 P < 0.010 P < 0.001 Intra-group significance P < 0.001 P = 0.005 Data are shown as median (minimum-maximum). Maternal, uterine venous, and umbilical cord blood enzyme levels of healthy pregnancy and placental syndrome groups were compared by the Mann-Whitney test. Maternal, uterine venous, and umbilical cord blood enzyme levels within the healthy pregnancy and placental syndrome groups were compared using repeated measures ANOVA followed by post hoc Bonferroni test for pairwise comparisons. a,b,c,d,e,f,g,h, i Median 1-deoxySL levels were significantly higher in the placental syndrome group compared to healthy pregnancies. * Maternal blood median 1- 1-deoxySL levels were significantly higher than uterine venous and umbilical cord blood levels. ** Uterine venous blood median 1-deoxySL levels were significantly higher than umbilical cord blood levels. *** Uterine venous blood median 1-deoxySL levels were significantly lower than maternal and umbilical cord blood levels. # The median spermine levels in maternal blood were significantly higher than uterine venous and umbilical cord blood levels. $ The median spermine levels in uterine venous blood were significantly higher than in umbilical cord blood. † The median spermine levels in maternal blood were significantly higher than uterine venous and umbilical cord blood levels. & The median spermidine levels in umbilical cord blood were significantly lower than in maternal and uterine venous blood. ~ Maternal blood median spermidine levels were significantly higher than uterine venous and umbilical cord blood levels. 1-deoxySL, 1-Deoxysphingolipids. Table 6 displays the correlation coefficients of 1-deoxySL, spermine, and spermidine levels. In the healthy pregnancy group, there were positive and statistically significant correlations between 1-deoxySL and spermine (r = 0.855, p = 0.001), 1-deoxySL and spermidine (r = 0.630, p = 0.001), and spermine and spermidine (r = 0.585, p = 0.001). Within the placental syndrome group, the analysis revealed a significant positive correlation only between 1-deoxySL and spermine (r = 0.375, p = 0.01). Other variables did not exhibit any significant correlations (p > 0.05). Table 6 Correlation coefficients of 1-Deoxysphingolipids, spermine, and spermidine levels in all blood samples of healthy pregnancy and placental syndrome groups. 1-deoxySL Spermine Spermidine Healthy pregnancy (n = 26) 1-deoxySL (ng/mL) - 0.855 p = 0.001 0.630 p = 0.001 Spermine (ng/mL) - 0.585 p = 0.001 Spermidine (ng/mL) - Placental syndrome (n = 17) 1-deoxySL (ng/mL) - 0.375 p = 0.01 0.223 p > 0.05 Spermine (ng/mL) - 0.083 p > 0.05 Spermidine (ng/mL) - Maternal, uterine venous, and umbilical cord blood samples were pooled to analyze the relationships between 1-deoxySL, spermine, and spermidine levels using the Pearson correlation test. 1-deoxySL, 1-Deoxysphingolipids. 4. Discussion This research focused on the place of 1-deoxySLs, polyamines (spermine and spermidine), and enzymes involved in polyamine metabolism (ODC, SSAT, PAO, and SMO) in the pathogenesis of placental syndrome such as preeclampsia and FGR. The comparison of healthy pregnancies with placental syndrome suggests that these molecules could be pivotal in the course of these syndromes. In terms of clinical features, women in the placental syndrome group were observed to be older, to give birth earlier, and to have lower fetal birth weights. The levels of ODC and SSAT were reduced in all the blood samples of pregnant women with placental syndrome. The comparison of the biomolecule levels in the blood samples of healthy and placental syndrome patients revealed that there is partial distinction between the two groups. ODC, SSAT, and SMO levels in blood samples were comparable, however, PAO levels in umbilical cord blood were higher than in maternal and uterine venous blood in both groups. These results may imply the suppression of polyamine biosynthesis in placental syndrome and that alterations in the mentioned enzymes are involved in the development of these syndromes. The current research revealed the following biomarkers to be higher in all the blood samples of the placental syndrome group: 1-deoxySL, spermine, and spermidine. These biomolecules were discovered to have varying levels of presence in healthy pregnancies as opposed to the ones affected by placental syndrome in maternal, uterine venous, and umbilical cord blood. 1-DeoxySL has been identified to have high levels that lead to cell membrane damage and interfere with signaling pathways that are lethal to cells. These may be higher in the placental syndrome group and may therefore be implicated in the pathogenesis of these syndromes. Higher levels of spermine and spermidine affect cellular stress and inflammation which is not beneficial for the placenta. The coefficients of ODC, SSAT, and SMO were significantly higher in the healthy pregnancy group than in the placental syndrome group. Therefore, the coefficients of positive correlations between 1-deoxySL, spermine, and spermidine were significantly lower in patients with placental syndrome. These findings indicate that disturbances in polyamine metabolism can be considered one of the key factors in the pathogenesis of placental syndrome. Recently, there has been a growing interest in studying the biological functions and potential pathological effects of 1-deoxySLs ( 27 ). Elevated 1-deoxySLs are thought to negatively affect cellular functions, particularly by disrupting membrane structure and signaling pathways, leading to cell death and various metabolic disorders. Disruptions in 1-deoxySL metabolism have been linked to several pathological conditions, such as cancers ( 28 ), type 2 diabetes ( 29 ), chronic kidney disease ( 27 ), retinopathy ( 30 ), non-alcoholic fatty liver disease ( 31 ), and hereditary sensory and autonomic neuropathy type 1 ( 32 ). While studies on 1-deoxySLs in pregnancy are limited, existing data suggest that these molecules may have significant adverse effects, particularly in the context of diabetes and metabolic disorders. A study by Khan et al. ( 33 ) revealed that plasma sphingoid bases 1-deoxysphinganine and 1-deoxysphingosine levels showed a significant positive correlation with glucose load during the oral glucose tolerance test (OGTT) during pregnancy. These findings indicate that another sphingoid base, 1-deoxySL, can be used as a potential biomarker in the diagnosis of gestational diabetes and may make significant contributions to increasing the accuracy of OGTT. Our biochemical analyses revealed elevated 1-deoxySL levels in maternal, uterine venous, and umbilical cord blood samples from the placental syndrome group. This increase indicates a possible disruption in lipid metabolism pathways, contributing to endothelial dysfunction and placental dysfunction observed in preeclampsia and FGR. Our findings are consistent with the study by Del Gaudio et al. ( 34 ), which explored sphingolipid metabolism in the feto-placental vasculature under preeclamptic conditions. Their research identified a distinct lipid remodeling characterized by sphingomyelin accumulation and disrupted sphingosine-1-phosphate signaling in chorionic arteries. This metabolic shift may impair endothelial function, affecting vascular homeostasis. These results support the role of 1-deoxySL and polyamine imbalances in preeclampsia, emphasizing the significance of sphingolipid dysregulation in the pathogenesis of placental disorders​​. Polyamines, including spermidine, spermine, and putrescine, are ubiquitous in all living cells. They are integral to gene expression and protein synthesis, affecting cell division, apoptosis, oxidative stress, angiogenesis, and intercellular communication ( 35 ). Therefore, polyamines are vital from the earliest stages of embryonic development through to the successful conclusion of pregnancy in mammals, promoting positive outcomes. Polyamine synthesis initiates with the conversion of L-ornithine into putrescine, which is subsequently converted into spermidine and spermine. Enzymes involved in polyamine metabolism, such as ODC, play critical roles in their biosynthesis, while SSAT, PAO, and SMO are essential for their catabolism, maintaining cellular homeostasis, and regulating polyamine levels ( 36 ). Unlike the findings of Mendez et al. ( 37 ), who reported significantly increased PAO activity in preeclamptic patients, our study found no significant differences in PAO levels between the placental syndrome and healthy pregnancy groups. While Mendez's study focused solely on PAO activity in maternal serum of preeclamptic women, our research provided a more comprehensive analysis by examining multiple polyamine pathway components across maternal, uterine venous, and umbilical cord blood samples. Our study revealed reduced ODC and SSAT levels and elevated polyamines (spermine and spermidine) in placental syndrome cases, suggesting a broader dysregulation of polyamine metabolism. These contrasting findings regarding PAO levels might be explained by differences in methodology, patient populations, or the broader spectrum of placental syndrome included in our study, emphasizing the need for further research to fully understand the role of polyamine metabolism in pregnancy complications. In another study Gong et al. ( 38 ) investigated the impact of placental polyamine metabolism on fetal development, particularly in the context of FGR and preeclampsia, and how these processes differ by fetal sex using multi-omics analyses and targeted experiments. The authors suggested that the placenta exhibits sex-dependent functional differences, which are associated with the risks of placental complications. Their results indicated that polyamine metabolism differs by fetal sex in the placenta and influences the risk of preeclampsia and FGR. Hiramatsu et al. ( 39 ) examined the levels of polyamines in amniotic fluid, maternal plasma, and urine to understand their roles during pregnancy. Their findings supported increased plasma levels of putrescine, spermidine, and spermine in the third trimester, correlating with estradiol and progesterone levels. The same study found increased putrescine and spermine levels in urine as the pregnancy progressed, while initially high levels of putrescine and spermidine in amniotic fluid decreased in other trimesters. Their data showed that polyamines reflect fetal and maternal metabolic changes and are affected by elevated hormones during pregnancy. The authors concluded that polyamines in amniotic fluid could be used as biochemical indicators of fetal growth and that monitoring polyamine levels could evaluate both fetal and maternal health during pregnancy. Considering the research findings mentioned above and our study's results, the observed changes in polyamines and their regulatory enzymes, ODC and SSAT, indicate a disruption in polyamine metabolism, suggesting that these biomolecules play roles in abnormal placental development and dysfunction. In this study, uterine venous blood samples were collected in addition to peripheral maternal blood, as it was thought to better reflect the placental metabolic state. This method aimed to measure placental metabolites more directly. Although this technique is less commonly used in the literature ( 40 , 41 ), it could be valuable in understanding how much the placenta contributes to elevated or reduced metabolites in maternal blood and in understanding placental metabolism. Our findings suggest that collecting blood samples from the uterine venous plexus is a successful technique for understanding placental metabolism. In our study, especially 1-deoxySL, spermine, and spermidine levels in uterine venous blood samples were significantly lower in pregnancies with placental syndrome, emphasizing the accuracy and value of this method. This may contribute to a better understanding of placental metabolism in future studies. This study is subject to various limitations, mainly related to the relatively small sample size, which complicates drawing definitive conclusions from the findings and restricts their applicability to a wider population. In addition, only healthy pregnancies and pregnancies with placental syndrome were compared, excluding other pregnancy complications. The lack of long-term follow-up prevented the assessment of the persistence of biochemical changes and their impact on long-term outcomes. Furthermore, this study did not address a broader metabolite profile that may play a role in the pathogenesis of placental syndrome. However, the strengths of the study include comprehensive clinical and biochemical analyses providing a broad perspective on the pathophysiology of placental syndrome, identification of innovative biomarkers, and a multidisciplinary approach combining clinical and laboratory findings. These aspects contribute to the novelty and relevance of the study's findings. 5. Conclusions In conclusion, this study demonstrates significant alterations in the levels of 1-deoxySLs and polyamines in patients with placental syndrome compared to healthy pregnancies. Notable differences were observed in both absolute levels and molecular interactions between the groups, with elevated 1-deoxySL, spermine, and spermidine levels in the placental syndrome cohort. Additionally, we found significant differences in the activity of enzymes such as ODC and SSAT. Changes in 1-deoxySLs and polyamine levels may have potential utility as biomarkers to monitor placental syndrome, though further validation studies are needed to assess their diagnostic and prognostic value. Abbreviations 1-deoxySLs 1-deoxysphingolipids ODC Ornithine decarboxylase SSAT Spermidine/spermine N1-acetyltransferase PAO Polyamine oxidase SMO Spermine oxidase FGR Fetal growth restriction Declarations Ethics approval and consent to participate The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethical Committee of the Haseki Training and Research Hospital. In addition, before conducting the surveys, the informed consent was obtained from all study participants by the researchers. Acknowledgments The authors would like to thank all participants in this study for their contribution. Funding This work was supported by the Health Institutes of Turkey (TÜSEB; Grant No. 31482). Author contributions All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by FYG, YT, GPC, MC, FK, CB, RM, ST, MNA, TC, and AC. The manuscript was written by FYG, AO, and AC. FYG and AC analyzed and interpreted the data. Disclosure Statement During the preparation of this work, the authors used AI-assisted technologies (QuillBot AI) in order to improve readability and language. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. Consent for publication Not applicable. Competing interests The authors declare no competing interests. Availability of data and materials The corresponding author can provide the datasets used and/or analyzed in this study upon request. Clinical trial number Not applicable. References Stevens D, Schiffer V, Severens-Rijvers C, de Nobrega Teixeira J, van Haren A, Spaanderman M, et al. The association between decidual vasculopathy and abnormal uterine artery Doppler measurement. Acta Obstet Gynecol Scand. 2022;101(8):910–6. Wang Y, Li B, Zhao Y. Inflammation in Preeclampsia: Genetic Biomarkers, Mechanisms, and Therapeutic Strategies. 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16:17:22","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20468,"visible":true,"origin":"","legend":"","description":"","filename":"LCMSsupplemantary.docx","url":"https://assets-eu.researchsquare.com/files/rs-5405039/v1/0a69e8097e2138c7e885f4e0.docx"},{"id":69925520,"identity":"010683dc-6bf8-43e2-9318-ccbb1e99a861","added_by":"auto","created_at":"2024-11-26 16:17:22","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":20468,"visible":true,"origin":"","legend":"","description":"","filename":"LCMSsupplemantary.docx","url":"https://assets-eu.researchsquare.com/files/rs-5405039/v1/690da33df413e914240fd508.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Role of 1-Deoxysphingolipids and Polyamines in the Pathogenesis of Placental Syndrome","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePreeclampsia and fetal growth restriction (FGR) and belong to placental syndrome having adverse effects on mother and fetus dyads and present many management problems in antenatal care. These syndromes are believed to arise from abnormal placentation leading to uteroplacental blood flow insufficiency and endothelial dysfunction (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Preeclampsia, a multisystemic disease, presents with new-onset hypertension with or without proteinuria during the second half of pregnancy and has an incidence of 3\u0026ndash;5% in all pregnancies worldwide (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Preeclampsia, encompassing subtypes like eclampsia and HELLP syndrome, represents a prominent factor in maternal and fetal morbidity and mortality and also contributes significantly to enduring maternal cardiovascular complications. (\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). FGR is the inadequacy of the fetus to utilize the full capacity allowed by its genetic profile, which is commonly ascribed to placental dysfunction and results in adverse newborn outcomes and future health risks (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe pathogenesis of placental syndrome involves complex interactions of genetic, immunological, and environmental factors. The placenta, crucial for fetal development, undergoes extensive vascular remodeling during pregnancy to ensure sufficient blood supply to the growing fetus. Inadequate remodeling of uterine spiral arteries, a hallmark of placental syndrome, leads to high-resistance blood flow and placental ischemia (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). This condition initiates a cascade of pathological events, leading to increased anti-angiogenic factors in the systemic circulation, thereby exacerbating endothelial dysfunction and contributing to the clinical manifestations of preeclampsia and FGR (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere is increasing interest in the roles of sphingolipids and polyamines and related enzymes in understanding these syndromes' pathogenesis. 1-Deoxysphingolipids (1-deoxySLs) are a distinct type of sphingolipids lacking the typical 1-hydroxyl group, leading to unique structural and functional properties (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). These lipids significantly contribute to cellular dysfunction due to their cytotoxic properties. They disrupt membrane integrity and interfere with cellular signaling pathways, leading to apoptosis and inflammation (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePolyamines, including spermidine and spermine, are small organic cations that are mandatory for the process of cell differentiation, proliferation, and apoptosis (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). They modulate gene expression, signal transduction, and ion channel functions by interacting with nucleic acids and proteins (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). These molecules are essential for maintaining cellular homeostasis. They are involved in various physiological and pathological processes from basic cellular function to complex immune responses (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The enzymes ornithine decarboxylase (ODC), spermidine/spermine N1-acetyltransferase (SSAT), polyamine oxidase (PAO), and spermine oxidase (SMO) have significant roles in the metabolism of polyamines. These enzymes are key to upholding cellular processes and achieving homeostasis (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite understanding the roles of 1-deoxySL and polyamines in various cellular processes, their specific roles in the pathogenesis of placental syndrome remain insufficiently explored. Studies suggest that these biomolecules hold promise for early diagnosis and therapeutic interventions (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Previous studies have shown the potential of 1-deoxySL or polyamines as biomarkers in diseases such as metabolic and neurodegenerative disorders (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Measurements of maternal and fetal blood levels of these biomolecules can provide critical information about placental health and function. Filling this gap could provide important insights into the molecular mechanisms underlying these conditions and help develop effective diagnostic and therapeutic strategies. Early detection of such novel biomarkers could lead to timely interventions, reducing the severity and incidence of preeclampsia and FGR. Understanding the metabolic alterations in 1-deoxySLs and polyamine pathways may provide insights into potential biomarkers. This study examines the relationship between placental syndrome and the metabolic profiles of 1-deoxySLs, polyamines, and their regulatory enzymes, aiming to characterize their patterns in maternal-fetal circulation.\u003c/p\u003e"},{"header":"2. Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Study Participants\u003c/h2\u003e \u003cp\u003eThis study, designed as an observational case-control investigation, was performed in the Gynecology and Obstetrics Services at Haseki Training and Research Hospital. Women who underwent cesarean section with a diagnosis of placental syndrome (preeclampsia and/or late FGR) were eligible for the study. Institutional human research ethics committee approval was obtained from Haseki Training and Research Hospital before the study (Approval No: 210\u0026ndash;2023, dated 22.11.2023). The research adhered strictly to the study protocol, crafted consistent with the principles outlined in the Declaration of Helsinki and the latest institutional guidelines. Pregnant women attending antenatal care who were deemed eligible and invited to participate in the study were enrolled only after providing informed written consent.\u003c/p\u003e \u003cp\u003eThe study included two groups of women: 26 with healthy pregnancies and 17 with placental syndrome. Criteria for inclusion in the placental syndrome group were confirmation of the diagnosis of placental syndrome by prepartum, intrapartum, and postpartum findings; gestational age between 28\u0026ndash;41 weeks; gestational age confirmed in the first trimester; late FGR with a gestational age\u0026thinsp;\u0026gt;\u0026thinsp;32 weeks; absence of acute fetal distress; absence of maternal diabetes mellitus; absence of chronic hypertension; no lipid metabolism disorders; and no chronic kidney disease.\u003c/p\u003e \u003cp\u003eThe diagnosis of placental syndrome, including preeclampsia and/or late FGR, was based on the clinical, biochemical, and ultrasonographic assessments and course of pregnancy. For the diagnosis of preeclampsia, the findings were confirmed gestational age greater than 20 weeks, high blood pressure (\u0026ge;\u0026thinsp;140/90 mmHg), and proteinuria (urinary total protein/creatinine ratio\u0026thinsp;\u0026gt;\u0026thinsp;30 or +\u0026thinsp;1 on urine dipstick) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Late FGR was diagnosed considering the gestational age over 32 weeks with an ultrasonographically determined fetal weight less than the 10th percentile (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Blood Sample Collection\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003ePeripheral Venous Blood Sample\u003c/strong\u003e \u003cp\u003eA 3-mL antecubital blood sample was taken before cesarean section.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eUterine Venous Blood Sample\u003c/strong\u003e \u003cp\u003eBlood sampling from venous plexus vessels in the broad ligament during cesarean section offers insights into the changes in placental-derived mediators (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). During cesarean section, a 3-mL blood sample was obtained from the veins in the uterine venous plexus (the largest diameter vein from the part of the vein 5 cm below the fallopian tube) which runs parallel to the uterine wall in the ligamentum latum. During blood collection, the 25G needle needed to make a 30-degree angle with the vein.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eUmbilical Cord Venous Blood Sample\u003c/strong\u003e \u003cp\u003eA 3-mL blood sample was drawn after the delivery of the baby.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eVenous blood samples were divided into two equal parts. Samples were collected in yellow-capped tubes with a gel separator for serum separation, while samples were collected in purple-capped tubes containing EDTA for plasma separation. After allowing the serum samples to clot at room temperature for 30 min, they were centrifuged at 3,000 rpm for 10 min to extract the serum. Their serum samples were carefully aliquoted into separate cryotubes with a capacity of 0.5 mL and preserved at -80\u0026deg;C until the biochemical analysis took place. Samples for plasma were immediately stored in 0.5-mL cryotubes and preserved at -80\u0026deg;C until LC-MS assays.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Biochemical Analyses\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1. ODC, SSAT, PAO, and SMO Measurements with ELISA\u003c/h2\u003e \u003cp\u003eSerum ODC, SSAT, PAO, and SMO levels were measured from maternal, uterine, and umbilical cord venous samples using commercial ELISA kits (ODC, SSAT, and SMO from BT LAB, China; PAO from MyBioSource, USA) according to the manufacturer's protocols, without diluting the serum samples. The standard solution was serially diluted from an initial concentration of 80 ng/mL to 1.25 ng/mL for ODC, from 40 ng/mL to 0.625 ng/mL for SSAT, from 32 ng/mL to 0.5 ng/mL for SMO and from 5000 pg/mL to 78 pg/mL for PAO. The tests in the ODC, SSAT, and SMO kits exhibited a coefficient of variation ranging from 8\u0026ndash;10% for both within-assay and between-assay variability. The coefficient of variation for PAO, both within and between assays, ranged from 10 to 12%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.3.2. 1-DeoxySLs, Spermine, and Spermidine Measurements with LC-MS\u003c/h2\u003e \u003cp\u003eSamples were prepared according to the literature (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Sphingolipids were hydrolyzed before the analysis. All the samples were prepared according to the assay protocol in the supplementary file (see supplementary). All sphingolipids were analyzed using LC-MS instrument (Agilent Infinity 1260). Polyamine measurements were performed according to the calibration curve (\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Statistical Analysis\u003c/h2\u003e \u003cp\u003eConsidering that three separate numerical data sets could be compared, for sample size calculation, the effect size was 0.7, the p-value was 0.05 and the power value was 0.80, and the sample size was calculated as 26 participants with consideration given to potential drop-outs.\u003c/p\u003e \u003cp\u003eWith IBM SPSS v26 (USA), all statistical evaluations were performed. The mean (standard deviation), median (minimum-maximum), or count (%) of study variables were calculated. After normality tests of biomolecule data, with the Mann-Whitney test, inter-group comparisons were performed, and with repeated measures ANOVA test followed by post hoc Bonferroni test, within-group comparisons were made. The chi-square test was employed to analyze categorical data, and the Pearson correlation test was utilized to explore the relationships between relevant variables. Statistical significance was assigned to p-values below 0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eAlthough the study was initially planned to include 26 participants per group, due to exclusion criteria and time constraints, the study was completed with 26 and 17 participants in the women with healthy pregnancy and placental syndrome, respectively. Among these participants with placental syndrome, 7 (41.2%) had isolated preeclampsia, 4 (23.5%) had isolated FGR, and 6 (35.3%) were diagnosed with both preeclampsia and FGR. Comparative analysis of biomolecular markers between these subgroups was not performed due to limited sample sizes in each category.\u003c/p\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e displays the fundamental clinical characteristics of both the healthy pregnancy and placental syndrome groups. Upon analysis, the median age of the healthy pregnancy group was found to be significantly lower than that of the placental syndrome group (28.5 [21\u0026ndash;41] vs. 32.5 [21\u0026ndash;44], respectively; p\u0026thinsp;=\u0026thinsp;0.029). The median gestational age at delivery was notably higher in the healthy pregnancy group compared to the placental syndrome group (38 [35\u0026ndash;40] vs. 36 [32\u0026ndash;39] weeks; p\u0026thinsp;=\u0026thinsp;0.001). Additionally, the median birth weight was significantly greater in the healthy pregnancy group than in the placental syndrome group (3160 [2350\u0026ndash;4660] vs. 2475 [1290\u0026ndash;3470] grams; p\u0026thinsp;=\u0026thinsp;0.001). Other variables, including gravidity, parity, ethnicity, education level, history of placental syndrome, including family history, smoking, mode of conception, body mass index, fetal sex, APGAR score, and umbilical cord blood gas pH values, showed no significant differences (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab1\" style=\"width: 818px;\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBasic clinical characteristics of healthy pregnancy and placental syndrome groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth style=\"width: 276.294px;\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003eHealthy pregnancy\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003ePlacental syndrome\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003eSignificance\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e28.5 (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e32.5 (21\u0026ndash;44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eGravidity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e3 (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eParity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e2 (0\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e2 (0\u0026ndash;6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eEthnicity\u003c/p\u003e\n \u003cp\u003eTurkish citizen\u003c/p\u003e\n \u003cp\u003eImmigrant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e20 (76.9%)\u003c/p\u003e\n \u003cp\u003e6 (23.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e15 (88.2%)\u003c/p\u003e\n \u003cp\u003e2 (11.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eEducation Status\u003c/p\u003e\n \u003cp\u003eIlliterate\u003c/p\u003e\n \u003cp\u003ePrimary education\u003c/p\u003e\n \u003cp\u003eHigh School\u003c/p\u003e\n \u003cp\u003eUniversity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (23.1%)\u003c/p\u003e\n \u003cp\u003e15 (57.7%)\u003c/p\u003e\n \u003cp\u003e4 (15.4%)\u003c/p\u003e\n \u003cp\u003e1 (3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (17.6%)\u003c/p\u003e\n \u003cp\u003e8 (47.1%)\u003c/p\u003e\n \u003cp\u003e5 (29.4%)\u003c/p\u003e\n \u003cp\u003e1 (5.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eBody Mass Index (Kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e27.8 (20.5\u0026ndash;46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e29.9 (23.3\u0026ndash;46.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eHistory of Placental Syndrome\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (3.8%)\u003c/p\u003e\n \u003cp\u003e25 (96.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6 (35.3%)\u003c/p\u003e\n \u003cp\u003e11 (64.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eFamilial History of Placental\u003c/p\u003e\n \u003cp\u003eSyndrome\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e2 (7.7%)\u003c/p\u003e\n \u003cp\u003e24 (92.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e3 (17.6%)\u003c/p\u003e\n \u003cp\u003e14 (82.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eSmoking\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (11.5%)\u003c/p\u003e\n \u003cp\u003e23 (88.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (5.9%)\u003c/p\u003e\n \u003cp\u003e16 (94.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eConception\u003c/p\u003e\n \u003cp\u003eNatural\u003c/p\u003e\n \u003cp\u003eART\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26 (100%)\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15 (88.2%)\u003c/p\u003e\n \u003cp\u003e2 (11.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eGestational Age at\u003c/p\u003e\n \u003cp\u003eDelivery (weeks)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e38 (\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e36 (\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eFetal gender\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (38.5%)\u003c/p\u003e\n \u003cp\u003e16 (61.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (58.8%)\u003c/p\u003e\n \u003cp\u003e7 (41.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eBirth Weight (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e3160 (2350\u0026ndash;4660)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e2475 (1290\u0026ndash;3470)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eAPGAR Score\u003c/p\u003e\n \u003cp\u003eMinute 1\u003c/p\u003e\n \u003cp\u003eMinute 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8.5 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e\n \u003cp\u003e10 (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eUmbilical Cord Blood pH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e7.3 (7.2\u0026ndash;7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e7.3 (7.3\u0026ndash;7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 276.294px;\" align=\"left\"\u003e\n \u003cp\u003eNICU Admission\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 191.706px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (15.4%)\u003c/p\u003e\n \u003cp\u003e22 (84.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 201px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (52.9%)\u003c/p\u003e\n \u003cp\u003e8 (47.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 124px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 793px;\" colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eData are presented as median (minimum-maximum) and number (%). ART, assisted reproductive techniques; NICU, neonatal intensive care unit.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes the hematological and biochemical results for both the healthy pregnancy and placental syndrome groups. There were no significant differences between the groups in terms of median values for baseline hematological parameters, creatinine, aspartate aminotransferase, and lactate dehydrogenase (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, median uric acid levels were significantly elevated in the placental syndrome group compared to the healthy pregnancy group (5 [3\u0026ndash;14] vs. 3.6 [2.5\u0026ndash;4.2]; p\u0026thinsp;=\u0026thinsp;0.002). Conversely, the median alanine aminotransferase levels were significantly higher in the healthy pregnancy group compared to the placental syndrome group (13 [6\u0026ndash;23] vs. 9.5 [2\u0026ndash;34]; p\u0026thinsp;=\u0026thinsp;0.044).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eHematologic and biochemical findings of healthy pregnancy and placental syndrome groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHealthy pregnancy\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePlacental syndrome\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSignificance\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProtein/creatine in spot urine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.26 (0.1\u0026ndash;1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWhite blood cell count\u003c/p\u003e\n \u003cp\u003e(10\u003csup\u003e3\u003c/sup\u003e uL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.2 (5.5\u0026ndash;20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.8 (7.1\u0026ndash;14.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRed blood cell count (10\u003csup\u003e6\u003c/sup\u003e uL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9 (2.9\u0026ndash;4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.6 (2.4\u0026ndash;4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHemoglobin (g/dl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.3 (7.3\u0026ndash;12.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.5 (7.8\u0026ndash;12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHematocrit (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.8 (23.9\u0026ndash;39.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.9 (24.1\u0026ndash;36.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet (10\u003csup\u003e3\u003c/sup\u003e uL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e215 (124\u0026ndash;385)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e208 (146\u0026ndash;395)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNeutrophil (10\u003csup\u003e3\u003c/sup\u003e uL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (3.1\u0026ndash;17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.1 (4.2\u0026ndash;12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymphocyte (10\u003csup\u003e3\u003c/sup\u003e uL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.3 (0.6\u0026ndash;2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.6 (0.7-3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCreatine (mg/dl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5 (0.3\u0026ndash;0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.5 (0.3\u0026ndash;0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUric Acid (mg/dl)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.6 (2.5\u0026ndash;4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAST (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (13\u0026ndash;50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALT (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.5 (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.044\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLDH (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e185 (125\u0026ndash;224)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e231 (140\u0026ndash;623)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eData are shown as median (minimum-maximum). AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e presents the levels of ODC, SSAT, PAO, and SMO in maternal, uterine venous, and umbilical cord blood samples of healthy pregnancy and placental syndrome groups. Inter- and intra-group comparisons were performed for all the enzyme levels. Median ODC levels were significantly higher in the maternal, uterine venous, and umbilical cord blood samples of the healthy pregnancy group compared to the placental syndrome group [maternal blood: 135 (73\u0026ndash;726) vs. 108 (15\u0026ndash;309); (p\u0026thinsp;=\u0026thinsp;0.022), uterine venous blood: 121 (41\u0026ndash;758) vs. 78 (15\u0026ndash;245); (p\u0026thinsp;=\u0026thinsp;0.011), and umbilical cord blood: 165 (68\u0026ndash;719) vs. 117 (0.3\u0026ndash;391); (p\u0026thinsp;=\u0026thinsp;0.018), respectively]. In intra-group comparisons, no significant difference was found between maternal blood, uterine venous blood, and umbilical cord blood in healthy pregnancy and placental syndrome groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Median SSAT levels were significantly higher in the maternal, uterine venous, and umbilical cord blood samples of the healthy pregnancy group compared to the placental syndrome group [maternal blood: 8 (3.7\u0026ndash;28.5) vs. 6.7 (4.1\u0026ndash;10.3); (p\u0026thinsp;=\u0026thinsp;0.037), uterine venous blood: 6.7 (2.6\u0026ndash;26.8) vs. 6 (4.3\u0026ndash;10.3); (p\u0026thinsp;=\u0026thinsp;0.032), and umbilical cord blood: 9.3 (6.3\u0026ndash;25.9) vs. 6.6 (5.2\u0026ndash;16.1); (p\u0026thinsp;=\u0026thinsp;0.021), respectively]. In intra-group comparisons, no significant difference was found between maternal blood, uterine venous blood, and umbilical cord blood in healthy pregnancy and placental syndrome groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). No significant difference was found in PAO levels in inter-group comparisons (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, in intra-group comparisons, umbilical cord blood median PAO levels were statistically higher in the healthy pregnancy group and placental syndrome group compared to maternal and uterine venous blood levels (p\u0026thinsp;=\u0026thinsp;0.001). No significant difference was found in SMO levels in the healthy pregnancy group and the placental syndrome group in inter-group and intra-group comparisons (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eODC, SSAT, PAO, and SMO levels in maternal, uterine venous, and umbilical cord blood samples of healthy pregnancy and placental syndrome groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHealthy pregnancy\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePlacental syndrome\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eInter-group\u003c/p\u003e\n \u003cp\u003esignificance\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eODC (ng/mL)\u003c/p\u003e\n \u003cp\u003eMaternal blood\u003c/p\u003e\n \u003cp\u003eUterine venous blood\u003c/p\u003e\n \u003cp\u003eUmbilical cord blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13.5 (7.3\u0026ndash;72.6)\u003c/p\u003e\n \u003cp\u003e12.1 (4.1\u0026ndash;75.8)\u003c/p\u003e\n \u003cp\u003e16.5 (6.8\u0026ndash;71.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10.8 (1.5\u0026ndash;30.9)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e7.8 (1.5\u0026ndash;24.5)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e11.7 (0.3\u0026ndash;39.1)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.022\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.011\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntra-group significance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.355\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.239\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSSAT (ng/mL)\u003c/p\u003e\n \u003cp\u003eMaternal blood\u003c/p\u003e\n \u003cp\u003eUterine venous blood\u003c/p\u003e\n \u003cp\u003eUmbilical cord blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8 (3.7\u0026ndash;28.5)\u003c/p\u003e\n \u003cp\u003e6.7 (2.6\u0026ndash;26.8)\u003c/p\u003e\n \u003cp\u003e9.3 (6.3\u0026ndash;25.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6.7 (4.1\u0026ndash;10.3)\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e6 (4.3\u0026ndash;10.3)\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e6.6 (5.2\u0026ndash;16.1)\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.037\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.032\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntra-group significance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.638\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePAO (pg/mL)\u003c/p\u003e\n \u003cp\u003eMaternal blood\u003c/p\u003e\n \u003cp\u003eUterine venous blood\u003c/p\u003e\n \u003cp\u003eUmbilical cord blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e413.1(37-2719.3)\u003c/p\u003e\n \u003cp\u003e180.6 (19.8-2001.5)\u003c/p\u003e\n \u003cp\u003e3500.9 (168.3-7793.6)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e237.5 (19.7-3669.1)\u003c/p\u003e\n \u003cp\u003e248.6 (37-3310.4)\u003c/p\u003e\n \u003cp\u003e4825.8 (1155.3-8580.4)\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.863\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.689\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.535\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntra-group significance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMO (ng/mL)\u003c/p\u003e\n \u003cp\u003eMaternal blood\u003c/p\u003e\n \u003cp\u003eUterine venous blood\u003c/p\u003e\n \u003cp\u003eUmbilical cord blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6.3 (0.98-30)\u003c/p\u003e\n \u003cp\u003e5.6 (0.6\u0026ndash;30.6)\u003c/p\u003e\n \u003cp\u003e6 (0.8\u0026ndash;29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4.9 (3.5\u0026ndash;11)\u003c/p\u003e\n \u003cp\u003e5.2 (3.5\u0026ndash;12.3)\u003c/p\u003e\n \u003cp\u003e5.9 (4.1\u0026ndash;18.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.069\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.123\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.242\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntra-group significance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.993\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.236\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eData are shown as median (minimum-maximum). Maternal, uterine venous, and umbilical cord blood enzyme levels of healthy pregnancy and placental syndrome groups were compared by the Mann-Whitney test. Maternal, uterine venous, and umbilical cord blood enzyme levels within the healthy pregnancy and placental syndrome groups were compared using repeated measures ANOVA followed by post hoc Bonferroni test for pairwise comparisons.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea,b,c,d,e,f\u003c/sup\u003e The median enzyme levels were significantly lower in the placental syndrome group compared to healthy pregnancies.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e*,**\u003c/sup\u003e The median PAO levels in umbilical cord blood were significantly higher than maternal and uterine venous blood levels in both groups.\u003c/p\u003e\n \u003cp\u003eODC, Ornithine Decarboxylase; SSAT, Spermidine/Spermine N1-acetyltransferase; PAO, Polyamine Oxidase; SMO, Spermine Oxidase.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e illustrates the correlation coefficients for ODC, SSAT, PAO, and SMO levels across the study groups. In the healthy pregnancy group, ODC levels exhibited strong positive correlations with both SSAT (r\u0026thinsp;=\u0026thinsp;0.866, p\u0026thinsp;=\u0026thinsp;0.001) and SMO (r\u0026thinsp;=\u0026thinsp;0.780, p\u0026thinsp;=\u0026thinsp;0.001), and SSAT levels were similarly correlated with SMO (r\u0026thinsp;=\u0026thinsp;0.789, p\u0026thinsp;=\u0026thinsp;0.001). No significant correlations were detected between ODC and PAO, SSAT and PAO, or PAO and SMO (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Conversely, in the placental syndrome group, significant positive correlations were observed between ODC and SSAT (r\u0026thinsp;=\u0026thinsp;0.439, p\u0026thinsp;=\u0026thinsp;0.001) as well as between ODC and SMO (r\u0026thinsp;=\u0026thinsp;0.464, p\u0026thinsp;=\u0026thinsp;0.001). Other pairings did not show significant correlations (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCorrelation coefficients of ODC, SSAT, PAO, and SMO levels in all blood samples of healthy pregnancy and placental syndrome groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eODC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSSAT\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePAO\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSMO\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" align=\"left\"\u003e\n \u003cp\u003eHealthy pregnancy (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eODC (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.866\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.780\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSSAT (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.789\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePAO (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.030\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMO (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" align=\"left\"\u003e\n \u003cp\u003ePlacental syndrome (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eODC (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.439\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.464\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSSAT (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.039\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.325\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePAO (pg/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.101\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMO (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" align=\"left\"\u003e\n \u003cp\u003eMaternal, uterine venous, and umbilical cord blood samples were pooled to analyze the relationship between enzyme levels using the Pearson correlation test. ODC, Ornithine Decarboxylase; SSAT, Spermidine/Spermine N1-acetyltransferase; PAO, Polyamine Oxidase; SMO, Spermine Oxidase.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e is composed of the levels of 1-deoxySL, spermine, and spermidine in maternal, uterine venous, and umbilical cord blood samples of healthy pregnancy and placental syndrome groups. Inter- and intra-group comparisons were made for 1-deoxySL, spermine, and spermidine levels. Median 1-deoxySL levels were significantly higher in the maternal, uterine venous, and umbilical cord blood samples of the placental syndrome group compared to the healthy pregnancy group [maternal blood: 583 (547\u0026ndash;673) vs. 489 (445\u0026ndash;535); (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), uterine venous blood: 441 (321\u0026ndash;489) vs. 383 (345\u0026ndash;432); (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and umbilical cord blood: 557 (345\u0026ndash;672) vs. 256 (103\u0026ndash;321); (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), respectively]. In intra-group comparisons in the healthy pregnancy group showed significantly higher median 1-deoxySL levels in maternal blood compared to uterine venous and umbilical cord blood (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and higher levels in uterine venous blood compared to umbilical cord blood (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In the placental syndrome group, the median 1-deoxySL levels in uterine venous blood were significantly lower than the maternal and umbilical cord blood levels (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In the placental syndrome group, median spermine levels were significantly higher in maternal blood, uterine venous blood and umbilical cord blood samples compared to the healthy pregnancy group [maternal blood: 68 (43.2\u0026ndash;79.3) vs. 47.2 (39.2\u0026ndash;50.2); p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, uterine venous blood: 62.2 (34.6\u0026ndash;69.4) vs. 37.4 (29.5\u0026ndash;39.2), 47.2 (39.2\u0026ndash;50.2); p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, and umbilical cord blood: 56.8 (49.4\u0026ndash;89.4) vs. 22.8 (16.3\u0026ndash;29.7); p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively]. In intra-group comparisons, the healthy pregnancy group showed significantly higher median spermine levels in maternal blood compared to uterine venous and umbilical cord blood (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and higher levels in uterine venous blood compared to umbilical cord blood. In the placental syndrome group, the median spermine levels in maternal blood were significantly higher than uterine venous and umbilical cord blood levels (p\u0026thinsp;=\u0026thinsp;0.004). In the placental syndrome group, median spermidine levels were significantly higher in maternal blood, uterine venous blood and umbilical cord blood samples compared to the healthy pregnancy group [maternal blood: 77.4 (34.6\u0026ndash;90.3) vs. 67.6 (57.3\u0026ndash;79.3); p\u0026thinsp;=\u0026thinsp;0.005, uterine venous blood: 73 (23.5\u0026ndash;78.8) vs. 66 (55.4\u0026ndash;75.3); p\u0026thinsp;\u0026lt;\u0026thinsp;0.01, and umbilical cord blood: 64.7 (23.8\u0026ndash;90.4) vs. 51.2 (43.4\u0026ndash;65.4); p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively]. In intra-group comparisons, the healthy pregnancy group showed significantly lower median spermidine levels in umbilical cord blood compared to maternal and uterine venous blood (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In the placental syndrome group, the median spermidine levels in maternal blood were also statistically higher than uterine venous and umbilical cord blood levels (p\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e1-Deoxysphingolipids, spermine, and spermidine levels in maternal, uterine venous, and umbilical cord blood samples of healthy pregnancy and placental syndrome groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHealthy pregnancy\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePlacental syndrome (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eInter-group\u003c/p\u003e\n \u003cp\u003esignificance\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1-deoxySL (ng/mL)\u003c/p\u003e\n \u003cp\u003eMaternal blood\u003c/p\u003e\n \u003cp\u003eUterine venous blood\u003c/p\u003e\n \u003cp\u003eUmbilical cord blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e48.9 (44.5\u0026ndash;53.5)\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e38.3 (34.5\u0026ndash;43.2)\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e25.6 (10.3\u0026ndash;32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e58.3 (54.7\u0026ndash;67.3)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e44.1 (32.1\u0026ndash;48.9)\u003csup\u003eb,***\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e55.7 (34.5\u0026ndash;67.2)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntra-group significance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpermine (ng/mL)\u003c/p\u003e\n \u003cp\u003eMaternal blood\u003c/p\u003e\n \u003cp\u003eUterine venous blood\u003c/p\u003e\n \u003cp\u003eUmbilical cord blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e47.2 (39.2\u0026ndash;50.2)\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e37.4 (29.5\u0026ndash;39.2)\u003csup\u003e$\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e22.8 (16.3\u0026ndash;29.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e68 (43.2\u0026ndash;79.3)\u003csup\u003ed,\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e62.2 (34.6\u0026ndash;69.4)\u003csup\u003ee\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e56.8 (49.4\u0026ndash;89.4)\u003csup\u003ef\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntra-group significance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpermidine (ng/mL)\u003c/p\u003e\n \u003cp\u003eMaternal blood\u003c/p\u003e\n \u003cp\u003eUterine venous blood\u003c/p\u003e\n \u003cp\u003eUmbilical cord blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e67.6 (57.3\u0026ndash;79.3)\u003c/p\u003e\n \u003cp\u003e66 (55.4\u0026ndash;75.3)\u003c/p\u003e\n \u003cp\u003e51.2 (43.4\u0026ndash;65.4)\u003csup\u003e\u0026amp;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e77.4 (34.6\u0026ndash;90.3)\u003csup\u003eg,~\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e73 (23.5\u0026ndash;78.8)\u003csup\u003eh\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e64.7 (23.8\u0026ndash;90.4)\u003csup\u003ei\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.005\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.010\u003c/p\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntra-group significance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eData are shown as median (minimum-maximum). Maternal, uterine venous, and umbilical cord blood enzyme levels of healthy pregnancy and placental syndrome groups were compared by the Mann-Whitney test. Maternal, uterine venous, and umbilical cord blood enzyme levels within the healthy pregnancy and placental syndrome groups were compared using repeated measures ANOVA followed by post hoc Bonferroni test for pairwise comparisons.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003ea,b,c,d,e,f,g,h, i\u003c/sup\u003e Median 1-deoxySL levels were significantly higher in the placental syndrome group compared to healthy pregnancies.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e*\u003c/sup\u003e Maternal blood median 1- 1-deoxySL levels were significantly higher than uterine venous and umbilical cord blood levels.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e**\u003c/sup\u003e Uterine venous blood median 1-deoxySL levels were significantly higher than umbilical cord blood levels.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e***\u003c/sup\u003e Uterine venous blood median 1-deoxySL levels were significantly lower than maternal and umbilical cord blood levels.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e#\u003c/sup\u003e The median spermine levels in maternal blood were significantly higher than uterine venous and umbilical cord blood levels.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e$\u003c/sup\u003e The median spermine levels in uterine venous blood were significantly higher than in umbilical cord blood.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e The median spermine levels in maternal blood were significantly higher than uterine venous and umbilical cord blood levels.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e\u0026amp;\u003c/sup\u003e The median spermidine levels in umbilical cord blood were significantly lower than in maternal and uterine venous blood.\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e~\u003c/sup\u003e Maternal blood median spermidine levels were significantly higher than uterine venous and umbilical cord blood levels. 1-deoxySL, 1-Deoxysphingolipids.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e displays the correlation coefficients of 1-deoxySL, spermine, and spermidine levels. In the healthy pregnancy group, there were positive and statistically significant correlations between 1-deoxySL and spermine (r\u0026thinsp;=\u0026thinsp;0.855, p\u0026thinsp;=\u0026thinsp;0.001), 1-deoxySL and spermidine (r\u0026thinsp;=\u0026thinsp;0.630, p\u0026thinsp;=\u0026thinsp;0.001), and spermine and spermidine (r\u0026thinsp;=\u0026thinsp;0.585, p\u0026thinsp;=\u0026thinsp;0.001). Within the placental syndrome group, the analysis revealed a significant positive correlation only between 1-deoxySL and spermine (r\u0026thinsp;=\u0026thinsp;0.375, p\u0026thinsp;=\u0026thinsp;0.01). Other variables did not exhibit any significant correlations (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCorrelation coefficients of 1-Deoxysphingolipids, spermine, and spermidine levels in all blood samples of healthy pregnancy and placental syndrome groups.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e1-deoxySL\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSpermine\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSpermidine\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eHealthy pregnancy (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1-deoxySL (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.855\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.630\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpermine (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.585\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpermidine (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003ePlacental syndrome (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1-deoxySL (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.375\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.223\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpermine (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.083\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;\u0026gt;\u0026thinsp;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSpermidine (ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" align=\"left\"\u003e\n \u003cp\u003eMaternal, uterine venous, and umbilical cord blood samples were pooled to analyze the relationships between 1-deoxySL, spermine, and spermidine levels using the Pearson correlation test. 1-deoxySL, 1-Deoxysphingolipids.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis research focused on the place of 1-deoxySLs, polyamines (spermine and spermidine), and enzymes involved in polyamine metabolism (ODC, SSAT, PAO, and SMO) in the pathogenesis of placental syndrome such as preeclampsia and FGR. The comparison of healthy pregnancies with placental syndrome suggests that these molecules could be pivotal in the course of these syndromes. In terms of clinical features, women in the placental syndrome group were observed to be older, to give birth earlier, and to have lower fetal birth weights. The levels of ODC and SSAT were reduced in all the blood samples of pregnant women with placental syndrome. The comparison of the biomolecule levels in the blood samples of healthy and placental syndrome patients revealed that there is partial distinction between the two groups. ODC, SSAT, and SMO levels in blood samples were comparable, however, PAO levels in umbilical cord blood were higher than in maternal and uterine venous blood in both groups. These results may imply the suppression of polyamine biosynthesis in placental syndrome and that alterations in the mentioned enzymes are involved in the development of these syndromes.\u003c/p\u003e \u003cp\u003eThe current research revealed the following biomarkers to be higher in all the blood samples of the placental syndrome group: 1-deoxySL, spermine, and spermidine. These biomolecules were discovered to have varying levels of presence in healthy pregnancies as opposed to the ones affected by placental syndrome in maternal, uterine venous, and umbilical cord blood. 1-DeoxySL has been identified to have high levels that lead to cell membrane damage and interfere with signaling pathways that are lethal to cells. These may be higher in the placental syndrome group and may therefore be implicated in the pathogenesis of these syndromes. Higher levels of spermine and spermidine affect cellular stress and inflammation which is not beneficial for the placenta.\u003c/p\u003e \u003cp\u003eThe coefficients of ODC, SSAT, and SMO were significantly higher in the healthy pregnancy group than in the placental syndrome group. Therefore, the coefficients of positive correlations between 1-deoxySL, spermine, and spermidine were significantly lower in patients with placental syndrome. These findings indicate that disturbances in polyamine metabolism can be considered one of the key factors in the pathogenesis of placental syndrome.\u003c/p\u003e \u003cp\u003eRecently, there has been a growing interest in studying the biological functions and potential pathological effects of 1-deoxySLs (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Elevated 1-deoxySLs are thought to negatively affect cellular functions, particularly by disrupting membrane structure and signaling pathways, leading to cell death and various metabolic disorders. Disruptions in 1-deoxySL metabolism have been linked to several pathological conditions, such as cancers (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), type 2 diabetes (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), chronic kidney disease (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), retinopathy (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e), non-alcoholic fatty liver disease (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), and hereditary sensory and autonomic neuropathy type 1 (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). While studies on 1-deoxySLs in pregnancy are limited, existing data suggest that these molecules may have significant adverse effects, particularly in the context of diabetes and metabolic disorders. A study by Khan et al. (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e) revealed that plasma sphingoid bases 1-deoxysphinganine and 1-deoxysphingosine levels showed a significant positive correlation with glucose load during the oral glucose tolerance test (OGTT) during pregnancy. These findings indicate that another sphingoid base, 1-deoxySL, can be used as a potential biomarker in the diagnosis of gestational diabetes and may make significant contributions to increasing the accuracy of OGTT. Our biochemical analyses revealed elevated 1-deoxySL levels in maternal, uterine venous, and umbilical cord blood samples from the placental syndrome group. This increase indicates a possible disruption in lipid metabolism pathways, contributing to endothelial dysfunction and placental dysfunction observed in preeclampsia and FGR.\u003c/p\u003e \u003cp\u003eOur findings are consistent with the study by Del Gaudio et al. (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e), which explored sphingolipid metabolism in the feto-placental vasculature under preeclamptic conditions. Their research identified a distinct lipid remodeling characterized by sphingomyelin accumulation and disrupted sphingosine-1-phosphate signaling in chorionic arteries. This metabolic shift may impair endothelial function, affecting vascular homeostasis. These results support the role of 1-deoxySL and polyamine imbalances in preeclampsia, emphasizing the significance of sphingolipid dysregulation in the pathogenesis of placental disorders​​.\u003c/p\u003e \u003cp\u003ePolyamines, including spermidine, spermine, and putrescine, are ubiquitous in all living cells. They are integral to gene expression and protein synthesis, affecting cell division, apoptosis, oxidative stress, angiogenesis, and intercellular communication (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Therefore, polyamines are vital from the earliest stages of embryonic development through to the successful conclusion of pregnancy in mammals, promoting positive outcomes. Polyamine synthesis initiates with the conversion of L-ornithine into putrescine, which is subsequently converted into spermidine and spermine. Enzymes involved in polyamine metabolism, such as ODC, play critical roles in their biosynthesis, while SSAT, PAO, and SMO are essential for their catabolism, maintaining cellular homeostasis, and regulating polyamine levels (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Unlike the findings of Mendez et al. (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), who reported significantly increased PAO activity in preeclamptic patients, our study found no significant differences in PAO levels between the placental syndrome and healthy pregnancy groups. While Mendez's study focused solely on PAO activity in maternal serum of preeclamptic women, our research provided a more comprehensive analysis by examining multiple polyamine pathway components across maternal, uterine venous, and umbilical cord blood samples. Our study revealed reduced ODC and SSAT levels and elevated polyamines (spermine and spermidine) in placental syndrome cases, suggesting a broader dysregulation of polyamine metabolism. These contrasting findings regarding PAO levels might be explained by differences in methodology, patient populations, or the broader spectrum of placental syndrome included in our study, emphasizing the need for further research to fully understand the role of polyamine metabolism in pregnancy complications. In another study Gong et al. (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) investigated the impact of placental polyamine metabolism on fetal development, particularly in the context of FGR and preeclampsia, and how these processes differ by fetal sex using multi-omics analyses and targeted experiments. The authors suggested that the placenta exhibits sex-dependent functional differences, which are associated with the risks of placental complications. Their results indicated that polyamine metabolism differs by fetal sex in the placenta and influences the risk of preeclampsia and FGR. Hiramatsu et al. (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) examined the levels of polyamines in amniotic fluid, maternal plasma, and urine to understand their roles during pregnancy. Their findings supported increased plasma levels of putrescine, spermidine, and spermine in the third trimester, correlating with estradiol and progesterone levels. The same study found increased putrescine and spermine levels in urine as the pregnancy progressed, while initially high levels of putrescine and spermidine in amniotic fluid decreased in other trimesters. Their data showed that polyamines reflect fetal and maternal metabolic changes and are affected by elevated hormones during pregnancy. The authors concluded that polyamines in amniotic fluid could be used as biochemical indicators of fetal growth and that monitoring polyamine levels could evaluate both fetal and maternal health during pregnancy. Considering the research findings mentioned above and our study's results, the observed changes in polyamines and their regulatory enzymes, ODC and SSAT, indicate a disruption in polyamine metabolism, suggesting that these biomolecules play roles in abnormal placental development and dysfunction.\u003c/p\u003e \u003cp\u003eIn this study, uterine venous blood samples were collected in addition to peripheral maternal blood, as it was thought to better reflect the placental metabolic state. This method aimed to measure placental metabolites more directly. Although this technique is less commonly used in the literature (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e), it could be valuable in understanding how much the placenta contributes to elevated or reduced metabolites in maternal blood and in understanding placental metabolism. Our findings suggest that collecting blood samples from the uterine venous plexus is a successful technique for understanding placental metabolism. In our study, especially 1-deoxySL, spermine, and spermidine levels in uterine venous blood samples were significantly lower in pregnancies with placental syndrome, emphasizing the accuracy and value of this method. This may contribute to a better understanding of placental metabolism in future studies.\u003c/p\u003e \u003cp\u003eThis study is subject to various limitations, mainly related to the relatively small sample size, which complicates drawing definitive conclusions from the findings and restricts their applicability to a wider population. In addition, only healthy pregnancies and pregnancies with placental syndrome were compared, excluding other pregnancy complications. The lack of long-term follow-up prevented the assessment of the persistence of biochemical changes and their impact on long-term outcomes. Furthermore, this study did not address a broader metabolite profile that may play a role in the pathogenesis of placental syndrome. However, the strengths of the study include comprehensive clinical and biochemical analyses providing a broad perspective on the pathophysiology of placental syndrome, identification of innovative biomarkers, and a multidisciplinary approach combining clinical and laboratory findings. These aspects contribute to the novelty and relevance of the study's findings.\u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eIn conclusion, this study demonstrates significant alterations in the levels of 1-deoxySLs and polyamines in patients with placental syndrome compared to healthy pregnancies. Notable differences were observed in both absolute levels and molecular interactions between the groups, with elevated 1-deoxySL, spermine, and spermidine levels in the placental syndrome cohort. Additionally, we found significant differences in the activity of enzymes such as ODC and SSAT. Changes in 1-deoxySLs and polyamine levels may have potential utility as biomarkers to monitor placental syndrome, though further validation studies are needed to assess their diagnostic and prognostic value.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e1-deoxySLs \u0026nbsp;1-deoxysphingolipids\u003c/p\u003e\n\u003cp\u003eODC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Ornithine decarboxylase\u003c/p\u003e\n\u003cp\u003eSSAT \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Spermidine/spermine N1-acetyltransferase\u003c/p\u003e\n\u003cp\u003ePAO \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Polyamine oxidase\u003c/p\u003e\n\u003cp\u003eSMO \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Spermine oxidase\u003c/p\u003e\n\u003cp\u003eFGR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Fetal growth restriction\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethical Committee of the Haseki Training and Research Hospital. In addition, before conducting the surveys, the informed consent was obtained from all study participants by the researchers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all participants in this study for their contribution.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Health Institutes of Turkey (T\u0026Uuml;SEB; Grant No. 31482).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study\u0026apos;s conception and design. Material preparation, data collection, and analysis were performed by FYG, YT, GPC, MC, FK, CB, RM, ST, MNA, TC, and AC. The manuscript was written by FYG, AO, and AC. FYG and AC analyzed and interpreted the data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work, the authors used AI-assisted technologies (QuillBot AI) in order to\u0026nbsp;improve readability and language. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe corresponding author can provide the datasets used and/or analyzed in this study upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStevens D, Schiffer V, Severens-Rijvers C, de Nobrega Teixeira J, van Haren A, Spaanderman M, et al. 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Am J Obstet Gynecol. 2024.\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":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Placental syndrome, preeclampsia, fetal growth restriction, 1-deoxysphingolipids, polyamines","lastPublishedDoi":"10.21203/rs.3.rs-5405039/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5405039/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Placental syndrome mainly composed of preeclampsia and fetal growth restriction have an impact on the health of mother and baby dyads. While impaired placentation is central to their pathophysiology, the underlying molecular mechanisms remain incompletely understood. This study investigates the association between placental syndrome and metabolic alterations in 1-deoxysphingolipids (1-deoxySLs) and polyamines, along with their regulatory enzymes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This prospective case-control study involved 26 healthy pregnant women and 17 with placental syndrome. Blood samples were collected from maternal, uterine venous, and umbilical cord veins. Levels of 1-deoxySL, spermine, and spermidine as well as related enzymes of polyamine metabolism such as ornithine decarboxylase (ODC), spermidine/spermine N1-acetyltransferase (SSAT), polyamine oxidase (PAO), and spermine oxidase (SMO) were measured using the techniques of LC-MS and ELISA, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eWomen with placental syndrome had significantly higher levels of 1-deoxySL, spermine, and spermidine in all blood samples compared to the healthy pregnancy group. Additionally, ODC and SSAT levels were reduced significantly in the placental syndrome group, while PAO and SMO levels showed no significant differences. Strong positive correlations were found between the studied enzymes and biomolecules in healthy pregnancies, which were notably weaker in the placental syndrome group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e This study demonstrates significantly altered levels of 1-deoxySL and polyamines, with corresponding enzyme activity changes, in placental syndrome compared to healthy pregnancies. The disrupted correlations between these biomolecules suggest alterations in their metabolic pathways and potential utility as biomarkers. Further mechanistic studies are warranted to elucidate their role in placental syndrome pathophysiology.\u003c/p\u003e","manuscriptTitle":"The Role of 1-Deoxysphingolipids and Polyamines in the Pathogenesis of Placental Syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-26 16:17:18","doi":"10.21203/rs.3.rs-5405039/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-12-20T06:36:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-16T12:10:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"259340080082663213561961889465974164692","date":"2024-12-09T23:10:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-29T14:25:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"97381549157323227549182529264156071582","date":"2024-11-22T01:33:04+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-22T01:07:28+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-11-11T19:12:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-08T11:28:42+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-08T11:28:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2024-11-06T18:53:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c600ebdf-1c8d-43a4-b84f-d40a1f3d1606","owner":[],"postedDate":"November 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T16:03:22+00:00","versionOfRecord":{"articleIdentity":"rs-5405039","link":"https://doi.org/10.1186/s12884-025-07175-1","journal":{"identity":"bmc-pregnancy-and-childbirth","isVorOnly":false,"title":"BMC Pregnancy and Childbirth"},"publishedOn":"2025-01-22 15:57:52","publishedOnDateReadable":"January 22nd, 2025"},"versionCreatedAt":"2024-11-26 16:17:18","video":"","vorDoi":"10.1186/s12884-025-07175-1","vorDoiUrl":"https://doi.org/10.1186/s12884-025-07175-1","workflowStages":[]},"version":"v1","identity":"rs-5405039","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5405039","identity":"rs-5405039","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}