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<journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id>
<journal-title>Frontiers in Pharmacology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Pharmacol.</abbrev-journal-title>
<issn pub-type="epub">1663-9812</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
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<article-meta>
<article-id pub-id-type="publisher-id">1442002</article-id>
<article-id pub-id-type="doi">10.3389/fphar.2024.1442002</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Pharmacology</subject>
<subj-group>
<subject>Original Research</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>A disproportionality analysis of low molecular weight heparin in the overall population and in pregnancy women using the FDA adverse event reporting system (FAERS) database</article-title>
<alt-title alt-title-type="left-running-head">Xu et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fphar.2024.1442002">10.3389/fphar.2024.1442002</ext-link>
</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Xu</surname>
<given-names>Huanying</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
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</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Xu</surname>
<given-names>Ningning</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
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<role content-type="https://credit.niso.org/contributor-roles/Writing - review &#x26; editing/"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Yingju</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
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<contrib contrib-type="author">
<name>
<surname>Zou</surname>
<given-names>Haoxi</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<uri xlink:href="https://loop.frontiersin.org/people/2411566/overview"/>
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<contrib contrib-type="author" corresp="yes">
<name>
<surname>Wu</surname>
<given-names>Suzhen</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
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<aff id="aff1">
<sup>1</sup>
<institution>Foshan Clinical Medical School of Guangzhou University of Chinese Medicine</institution>, <addr-line>Foshan</addr-line>, <addr-line>Guangdong</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>TCM Gynecology Department</institution>, <institution>Foshan Fosun Chancheng Hospital</institution>, <addr-line>Foshan</addr-line>, <addr-line>Guangdong</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/469926/overview">Tomoya Tachi</ext-link>, Nagoya City University, Japan</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/442389/overview">Yoshihiro Noguchi</ext-link>, Gifu Pharmaceutical University, Japan</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/628348/overview">Jessian Munoz</ext-link>, Texas Children&#x2019;s Hospital, United States</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Suzhen Wu, <email>fswszm@163.com</email>
</corresp>
<fn fn-type="equal" id="fn001">
<label>
<sup>&#x2020;</sup>
</label>
<p>These authors have contributed equally to this work</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>12</day>
<month>08</month>
<year>2024</year>
</pub-date>
<pub-date pub-type="collection">
<year>2024</year>
</pub-date>
<volume>15</volume>
<elocation-id>1442002</elocation-id>
<history>
<date date-type="received">
<day>01</day>
<month>06</month>
<year>2024</year>
</date>
<date date-type="accepted">
<day>29</day>
<month>07</month>
<year>2024</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2024 Xu, Xu, Wang, Zou and Wu.</copyright-statement>
<copyright-year>2024</copyright-year>
<copyright-holder>Xu, Xu, Wang, Zou and Wu</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>Low molecular weight heparin (LMWH) is extensively utilized as an anticoagulant for the prevention and management of various thrombotic conditions. However, despite the widespread use of LMWH in clinical indications, its adverse events (AEs) have not received substantial attention, and there is a lack of systematic and comprehensive AE studies. This study aims to evaluate AE signals associated with LMWH in the overall population and in pregnancy women from the FDA Adverse Event Reporting System database.</p>
</sec>
<sec>
<title>Methods</title>
<p>We used the Standardized MedDRA Query to identify pregnancy-related AE reports. Disproportionality analyses were employed to identify LMWH-related AE by calculating the reporting odds ratios (ROR), proportional reporting ratios (PRR), bayesian confidence propagation neural network (BCPNN), and the empirical Bayesian geometric mean (EBGM).</p>
</sec>
<sec>
<title>Results</title>
<p>For the overall population, the significantly reported adverse signals in SOCs were pregnancy, puerperium, and perinatal conditions, vascular disorders, blood and lymphatic system disorders, and product issues. The five strongest AEs signal of LMWH-related were anti factor X antibody positive (n &#x3d; 6, ROR 506.70, PRR 506.65, IC 8.31, EBGM 317.03), heparin-induced thrombocytopenia test positive (n &#x3d; 19, ROR 263.10, PRR 263.02, IC 7.65, EBGM 200.79), anti factor X activity increased (n &#x3d; 10, ROR 255.93, PRR 255.89, IC 7.62, EBGM 196.61), heparin-induced thrombocytopenia test (n &#x3d; 14, ROR 231.85, PRR 231.80, IC 7.51, EBGM 182.09), and spontaneous heparin-induced thrombocytopenia syndrome (n &#x3d; 3, ROR 230.31, PRR 230.30, IC 7.50, EBGM 181.16). For pregnancy women, the five strongest AEs signals of LMWH-related included sternal fracture (n &#x3d; 3, ROR 243.44, PRR 243.35, IC 6.61, EBGM 97.94), syringe issue (n &#x3d; 12, ROR 97.49, PRR 97.34, IC 5.94, EBGM 61.21), bleeding time prolonged (n &#x3d; 3, ROR 97.38, PRR 97.34, IC 5.94, EBGM 61.21), spinal compression fracture (n &#x3d; 10, ROR 90.24, PRR 90.13, IC 5.87, EBGM 58.30), and injection site haematoma (n &#x3d; 19, ROR 79.23, PRR 79.04, IC 5.74, EBGM 53.47). Additionally, unexpected AEs associated with LMWH in pregnancy women were observed, including premature baby death, placental necrosis, abortion, antiphospholipid syndrome, systolic dysfunction, compartment syndrome, body height decreased, rubella antibody positive, and ultrasound doppler abnormal.</p>
</sec>
<sec>
<title>Conclusion</title>
<p>This study identified unexpected AE signals of LMWH-relate in pregnancy women. Our study could provide valuable evidence for the clinical practice of LMWH, especially for identifying AEs and ensuring safe usage in pregnancy women.</p>
</sec>
</abstract>
<kwd-group>
<kwd>low molecular weight heparin</kwd>
<kwd>disproportionality analysis</kwd>
<kwd>adverse events</kwd>
<kwd>pregnancy-related reports</kwd>
<kwd>FAERS</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Drugs Outcomes Research and Policies</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>Unfractionated heparin has been recognized as a significant anticoagulant and antithrombotic agent for nearly a century, originating from Jay McLean&#x2019;s discovery in 1916 (<xref ref-type="bibr" rid="B21">Hogwood et al., 2023</xref>). Its clinical use began in the 1930s through developments by Erik Jorpes in Sweden and Charles Best in Canada (<xref ref-type="bibr" rid="B35">Mulloy et al., 2016</xref>). In the 1970s, researchers began modifying unfractionated heparin to enhance its pharmacological properties, leading to the development of low molecular weight heparin (LMWH) (<xref ref-type="bibr" rid="B25">Johnson et al., 1976</xref>). LMWHs are derived by depolymerizing unfractionated heparin (average molecular weight 15,000&#x2013;19,000&#xa0;Da) into smaller molecules (average molecular weight 3,500&#x2013;6,000&#xa0;Da) (<xref ref-type="bibr" rid="B58">Wang et al., 2022</xref>). Compared to unfractionated heparin, LMWH offers advantages such as increased bioavailability, longer half-lives, reduced dosing frequency, prolonged action, and a lower incidence of adverse effects. The development of LMWH began in the 1980s, with the first clinical trials conducted during this period. Enoxaparin, with an average molecular weight of 4,500&#xa0;Da, was among the earliest LMWH approved for medical use, receiving initial approval in France in 1985. Subsequently, the Food and Drug Administration (FDA) approved enoxaparin in the United States in 1993, marking the widespread adoption of LMWH across various medical indications (<xref ref-type="bibr" rid="B55">Thompson, 2010</xref>).</p>
<p>LMWH is extensively utilized in clinical settings to prevent and manage various thrombotic conditions. They are frequently prescribed for ailments including deep vein thrombosis, pulmonary embolism, acute coronary syndrome, and as prophylaxis in high-risk surgical procedures (<xref ref-type="bibr" rid="B35">Mulloy et al., 2016</xref>). Beyond these conventional uses, LMWH has been investigated for their therapeutic potential in diverse applications (<xref ref-type="bibr" rid="B58">Wang et al., 2022</xref>), such as anti-cancer treatments (<xref ref-type="bibr" rid="B31">Ma et al., 2020</xref>), anti-viral therapies (<xref ref-type="bibr" rid="B57">Vitiello and Ferrara, 2023</xref>), anti-inflammatory interventions (<xref ref-type="bibr" rid="B29">Litov et al., 2021</xref>; <xref ref-type="bibr" rid="B57">Vitiello and Ferrara, 2023</xref>), antiphospholipid syndrome (<xref ref-type="bibr" rid="B45">Sammaritano, 2020</xref>), and recurrent spontaneous abortion (<xref ref-type="bibr" rid="B19">Hamulyak et al., 2020</xref>). Nevertheless, similar to all medications, LMWHs can potentially induce adverse reactions.</p>
<p>The most significant complication associated with LMWH treatment is bleeding, particularly when LMWHs are used for the treatment and prophylaxis of thromboembolic disorders. Clinically, the estimated incidence of bleeding ranges from 6% to 14%, which is higher than the rates observed in most clinical trials (<xref ref-type="bibr" rid="B35">Mulloy et al., 2016</xref>). However, the risk of bleeding is challenging to determine due to multiple factors, including the dosage and duration of heparin treatment, patient indications, the procedures undertaken, and any comedications (<xref ref-type="bibr" rid="B21">Hogwood et al., 2023</xref>). In addition, heparin-induced thrombocytopenia (HIT) is a potentially life-threatening complication that can occur after exposure to heparin, with a risk of 0.2% with LMWH (<xref ref-type="bibr" rid="B32">Martel et al., 2005</xref>). Thrombocytopenia is a rare complication that often goes unnoticed, overlooked, and does not receive timely and effective intervention especially when it is associated with LMWHs, because of its safety, ease of administration, and low incidence rate (<xref ref-type="bibr" rid="B41">Sahu et al., 2020</xref>). Other risks include skin lesions (<xref ref-type="bibr" rid="B47">Schindewolf et al., 2018</xref>), osteoporosis (<xref ref-type="bibr" rid="B20">Hardcastle et al., 2019</xref>; <xref ref-type="bibr" rid="B51">Signorelli et al., 2019</xref>; <xref ref-type="bibr" rid="B27">Li et al., 2022</xref>), with some reported incidence of alopecia (<xref ref-type="bibr" rid="B46">Sarris et al., 2003</xref>), hyperkalemia (<xref ref-type="bibr" rid="B54">Thomas et al., 2008</xref>; <xref ref-type="bibr" rid="B56">van der Heiden et al., 2022</xref>) and elevation of liver enzymes (<xref ref-type="bibr" rid="B18">Hahn et al., 2015</xref>; <xref ref-type="bibr" rid="B26">Leo et al., 2019</xref>).</p>
<p>Over the past several decades, the safety and efficacy of LMWH for the prevention and treatment of thrombotic conditions have been confirmed. To date, LMWH is also used in many high-risk patients, including severe renal impairment, advanced cancer, COVID-19 critically ill, and other critically ill patients (<xref ref-type="bibr" rid="B58">Wang et al., 2022</xref>). With the expansion of clinical indications of LMWH, we should pay more attention to whether there are new adverse reactions or whether the incidence of adverse reactions is increased. Additionally, there is increasing use of LMWH in pregnancy-related diseases, especially in recurrent miscarriage and <italic>in vitro</italic> fertilization, to improve pregnancy outcomes in patients (<xref ref-type="bibr" rid="B19">Hamulyak et al., 2020</xref>; <xref ref-type="bibr" rid="B23">Jiang et al., 2021</xref>), although its efficacy remains controversial (<xref ref-type="bibr" rid="B48">Schleussner et al., 2015</xref>; <xref ref-type="bibr" rid="B60">Yang XL. et al., 2018</xref>; <xref ref-type="bibr" rid="B36">Quenby et al., 2023</xref>). However, the safety of LMWH in pregnancy women and the monitoring of adverse reactions has not received high attention. In addition to common adverse reactions such as vaginal bleeding, oral mucosal hemorrhage, ecchymosis, and skin reactions at the injection site, there is limited clinical data on adverse event (AE) regarding abnormal fetal development, birth defects, premature delivery, abortion, and placental dysfunction potentially associated with the use of LMWH in pregnancy women. At present, due to the limited pre-clinical data, there is a lack of systematic and comprehensive adverse drug reaction studies based on real-world and big data of LMWH-related adverse events (AEs), including those on pregnancy women. Therefore, the comprehensive collection and analysis of AEs of LMWH is crucial to provide researchers with a thorough reference, promoting improvements in LMWH drug development and a comprehensive understanding of its safety.</p>
<p>This study intends to analyze the real-world AE signals of LMWH using the FDA Adverse Event Reporting System (FAERS) database, with a specific focus on AE signals related to LMWH in pregnancy women. First, we analyzed the AE signals of LMWH in the overall population. Then, we examined the AE signals of LMWH in the subgroup of pregnancy women. These analyses will provide insights into the AE signals of LMWH in the overall population and the subgroup of pregnancy women. Our aim is to identify AEs, reduce the risk of these reactions, and regulate the rational clinical use of LMWH.</p>
</sec>
<sec sec-type="materials|methods" id="s2">
<title>2 Materials and methods</title>
<sec id="s2-1">
<title>2.1 Study design and data source</title>
<p>The study sourced AE data from the FAERS, a publicly accessible database established in 2004. FAERS aggregates reports uploaded by healthcare professionals, pharmaceutical manufacturers, patients, and others, providing a standardized and voluminous dataset updated quarterly (<xref ref-type="bibr" rid="B61">Zhou and Hultgren, 2020</xref>). Recognized globally, FAERS serves as a pivotal reporting system and can be downloaded free from FAERS&#x2019; official website.</p>
<p>In this study, AE data associated with LMWH used in the overall population from 1 January 2004, to 31 March 2024, were obtained from the FAERS database, enabling a comprehensive analysis of adverse reactions related to these anticoagulants. A total of 17,627,340 AE reports were collected from FAERS, with 20,870 attributed to LMWH in the overall population. A total of 52,373,206 AEs were extracted from FAERS, of which 61,949 were associated with LMWH use in the overall population (<xref ref-type="fig" rid="F1">Figure 1</xref>). The annual distribution of LMWH-related AE reports in the overall population was illustrated in <xref ref-type="fig" rid="F2">Figure 2A</xref>.</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>The flow diagram of selecting LMWH-related AEs in the overall population from FAERS database. Abbreviation: BCPNN, bayesian confidence propagation neural network; EBGM, empirical bayesian geometric mean; LMWH, low molecular weight heparin; MGPS, multi-item gama poisson shrinker; PTs, preferred terms; PS, primary suspect; PRR, proportional reporting ratio; ROR, reporting odds ratio.</p>
</caption>
<graphic xlink:href="fphar-15-1442002-g001.tif"/>
</fig>
<fig id="F2" position="float">
<label>FIGURE 2</label>
<caption>
<p>Annual distribution of LMWH-related AE reports. <bold>(A)</bold>, Annual distribution of LMWH-related AE reports in the overall population. <bold>(B)</bold>, Annual distribution of LMWH-related AE reports in pregnancy women. Abbreviation: AE, adverse event.</p>
</caption>
<graphic xlink:href="fphar-15-1442002-g002.tif"/>
</fig>
</sec>
<sec id="s2-2">
<title>2.2 Standardization of drug names and adverse reactions</title>
<p>For data with the same primary-id in the DEMO table, only the most recent report based on the date was retained. Relationships between data sets were established using the primary-id field. In addition, the Medical Dictionary for Regulatory Activities (MedDRA 27.0) was used to match the preferred terms (PTs) for LMWH adverse reactions and also listed the system organ classes (SOCs) that corresponded to these PTs.</p>
<p>In this study, all types of LMWH were extracted from the FAERS database, including enoxaparin, nadroparin, dalteparin, tinzaparin, bemiparin, reviparin, parnaparin, and LMWH. Data for each type of LMWH were obtained by searching for the drug name, its brand names, and product active ingredients, as listed in <xref ref-type="sec" rid="s11">Supplementary Table S1</xref>. In this study, reports identifying LMWH as the primary suspect (PS) associated with AEs were extracted. These reports covered various pieces of clinical characteristics such as gender, age, reported countries, reporter, reporting time, indication, onset time of events, and outcomes of AEs.</p>
</sec>
<sec id="s2-3">
<title>2.3 Pregnancy-related report retrieval</title>
<p>Subgroup disproportionality analyses have been conducted due to the potential bias when analyzing the association between drugs and pregnancy outcomes in datasets in which the majority of reports are from non-pregnant women (<xref ref-type="bibr" rid="B8">Beyer-Westendorf et al., 2020</xref>; <xref ref-type="bibr" rid="B43">Sakai et al., 2022a</xref>). Since there is no dedicated field to identify reports from pregnant women in the spontaneous reporting database, efforts are being made to identify such reports using the Standardized MedDRA Query (SMQ) (<xref ref-type="bibr" rid="B44">Sakai et al., 2017</xref>; <xref ref-type="bibr" rid="B50">Sessa et al., 2019</xref>; <xref ref-type="bibr" rid="B43">Sakai et al., 2022a</xref>; <xref ref-type="bibr" rid="B42">Sakai et al., 2022b</xref>). In the current study, we utilized previously described method to identify reports of pregnancy women in the FAERS (<xref ref-type="bibr" rid="B43">Sakai et al., 2022a</xref>).</p>
<p>Between Q1 of 2004 and Q1 of 2024, a total of 17,627,340 records were collected from FAERS, after removed duplication records (<xref ref-type="fig" rid="F3">Figure 3</xref>). To obtain pregnancy-related reports, we used SMQ codes 20000077, 20000186, 20000190, 20000191, 20000192, and 20000193 in the adverse event fields, resulting in a total of 378,027 records. The breakdown of the SMQ codes were shown in <xref ref-type="sec" rid="s11">Supplementary Table S2</xref>. SMQ codes 20000186, 20000190, and 20000193 were used to extract the cases that include terms related to mothers during pregnancy in the indication fields, with a total of 63,753 records. Because the same patients met multiple criteria both in the adverse event fields and in the indication fields, 393,067 patients were included after removing duplicate records.</p>
<fig id="F3" position="float">
<label>FIGURE 3</label>
<caption>
<p>The flow diagram of selecting LMWH-related AEs in pregnancy women from FAERS database. PTs<sup>&#x2a;</sup>: maternal exposure during delivery (10071407), foetal exposure during delivery (10071409), maternal exposure before pregnancy (10071406), maternal exposure during pregnancy (10071408), fetal exposure during pregnancy (10071404), exposure during pregnancy (10073513), maternal exposure timing unspecified (10071415), foetal exposure timing unspecified (10071405), maternal drugs affecting foetus (10026923), drug exposure before pregnancy (10064998). PTs<sup>&#xb6;</sup>: paternal drugs affecting the fetus (10050425), exposure via father (10071403), paternal exposure during pregnancy (10080091), paternal exposure timing unspecified (10080092), paternal exposure before pregnancy (10080093), and maternal exposure via partner during pregnancy (10084938). Abbreviation: BCPNN, bayesian confidence propagation neural network; EBGM, empirical bayesian geometric mean; LMWH, low molecular weight heparin; MGPS, multi-item gama poisson shrinker; PTs, preferred terms; PS, primary suspect; PRR, proportional reporting ratio; ROR, reporting odds ratiop; SMQ, standard MedDRA query.</p>
</caption>
<graphic xlink:href="fphar-15-1442002-g003.tif"/>
</fig>
<p>Cases that included PTs in <xref ref-type="sec" rid="s11">Supplementary Table S3</xref> or cases in which the administration route was transplacental were defined as definitive pregnancy-related reports. After removing duplicate records, a total of 248,568 definitive pregnancy-related records remained. In addition to definitive pregnancy-related reports, 93,897 reports were excluded due to treatment of medical conditions in children, ineligible gender and age, and paternal exposure (<xref ref-type="fig" rid="F3">Figure 3</xref>). After removing duplicates, 50,602 records were included for other reports. Ultimately, 299,170 reports obtained through these processes were considered pregnancy-related and were selected for our final analysis, with 2,298 attributed to LMWH in pregnancy women. A total of 1,279,728 pregnancy-related AEs were extracted, of which 7,840 were associated with LMWH in pregnancy women (shown in <xref ref-type="fig" rid="F3">Figure 3</xref>). The annual distribution of LMWH-related AE reports in pregnancy women was illustrated in <xref ref-type="fig" rid="F2">Figure 2B</xref>.</p>
</sec>
<sec id="s2-4">
<title>2.4 Signals analysis algorithms</title>
<p>In our study, we employed disproportionality analysis, a commonly utilized method in pharmacovigilance studies, to identify potential signals between drugs and AEs (<xref ref-type="bibr" rid="B24">Jiang et al., 2024</xref>). This widely adopted data mining approach assesses the correlation between drugs and AEs by comparing the observed frequencies in exposed and non-exposed populations through a 2 &#xd7; 2 contingency table (shown in <xref ref-type="sec" rid="s11">Supplementary Table S4</xref>) (<xref ref-type="bibr" rid="B13">Du et al., 2024</xref>). In this study, we simultaneously employed multiple methods for detecting drug adverse event signals, including the reporting odds ratios (ROR) (<xref ref-type="bibr" rid="B40">Rothman et al., 2004</xref>), proportional reporting ratios (PRR) (<xref ref-type="bibr" rid="B16">Evans et al., 2001</xref>), bayesian confidence propagation neural network (BCPNN) (<xref ref-type="bibr" rid="B6">Bate et al., 2002</xref>), and the empirical Bayesian geometric mean (EBGM) (<xref ref-type="bibr" rid="B24">Jiang et al., 2024</xref>). The calculate formula of disproportionate measurement and the criteria for signal detection are outlined in <xref ref-type="sec" rid="s11">Supplementary Table S5</xref>. In our study, the four methods of ROR, PRR, BCPNN and EBGM are combined to detect signals, and the threshold is set as follows: a &#x2265; 3, lower limit of ROR 95% confidence interval is greater than 1, PRR &#x2265; 2, chi-square value &#x2265; 4, IC-2SD &#x3e; 0, and EBGM05 &#x3e; 2. The larger the values of ROR, PRR, BCPNN, and EBGM were, the stronger AE signals were, indicating a stronger statistical relationship between the target drug and the target AEs. Statistical analysis was performed using the SAS 9.4.</p>
</sec>
</sec>
<sec sec-type="results" id="s3">
<title>3 Results</title>
<sec id="s3-1">
<title>3.1 Basic information about AEs of LMWH</title>
<p>The basic characteristics of AE reports for LMWH are summarized in <xref ref-type="table" rid="T1">Table 1</xref>. For LMWH in the overall population, female respondents contributed 48.94% of AE reports for LMWH. Most AE reports came from individuals aged 65 and older, although a significant number had unknown ages. Consumer reports were pharmacist (29.45%), and the majority of reports countries was United States (43.84%). Subcutaneous injection (46.73%) was the primary method of administration for LMWH. Serious AE outcomes for LMWH mainly consisted of other serious conditions (41.31%), hospitalization (36.42%), death (14.35%), and life-threatening situations (6.97%). The median time of AEs occurrence was 6.00 (2.00, 17.00) days for LMWH. For LMWH in pregnancy women, a significant number of reports had unknown ages (50.83%). Consumer reports primarily came from physicians (20.80%), and the majority of reports were from the United States (21.15%), although a significant number had unknown countries of report (36.03%). Subcutaneous injection (30.64%) was the primary method of administration for LMWH in pregnancy women. Serious AE outcomes for LMWH used in pregnancy mainly consisted of other serious conditions (62.84%), hospitalization (23.59%), and congenital anomalies (9.57%). The median time to AE occurrence was 15.00 (0.00, 146.00) days for LMWH in pregnancy women.</p>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>Characteristics of AEs reports associated with LMWH.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Characteristics</th>
<th align="left">LMWH used in the overall population, n (%)</th>
<th align="left">LMWH used in pregnancy, n (%)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td colspan="3" align="left">Sex</td>
</tr>
<tr>
<td align="left">Female</td>
<td align="left">10,213 (48.94)</td>
<td align="left">1,830 (79.63)</td>
</tr>
<tr>
<td align="left">Male</td>
<td align="left">7,287 (34.92)</td>
<td align="left">252 (10.97)<xref ref-type="table-fn" rid="Tfn1">
<sup>a</sup>
</xref>
</td>
</tr>
<tr>
<td align="left">Not Specified</td>
<td align="left">3,370 (16.15)</td>
<td align="left">216 (9.40)</td>
</tr>
<tr>
<td colspan="3" align="left">Age, years</td>
</tr>
<tr>
<td align="left">&#x3c;18</td>
<td align="left">337 (1.61)</td>
<td align="left">116 (5.05)</td>
</tr>
<tr>
<td align="left">18&#x2013;44</td>
<td align="left">2,534 (12.14)</td>
<td align="left">993 (43.21)</td>
</tr>
<tr>
<td align="left">45&#x2013;64</td>
<td align="left">3,790 (18.16)</td>
<td align="left">21 (0.91)</td>
</tr>
<tr>
<td align="left">&#x2265;65</td>
<td align="left">6,928 (33.20)</td>
<td align="left">NA</td>
</tr>
<tr>
<td align="left">Not Specified</td>
<td align="left">7,281 (34.89)</td>
<td align="left">1,168 (50.83)</td>
</tr>
<tr>
<td colspan="3" align="left">Reporter</td>
</tr>
<tr>
<td align="left">Consumer</td>
<td align="left">5,172 (24.78)</td>
<td align="left">1,024 (44.56)</td>
</tr>
<tr>
<td align="left">Lawyer</td>
<td align="left">48 (0.23)</td>
<td align="left">3 (0.13)</td>
</tr>
<tr>
<td align="left">Not Specified</td>
<td align="left">1,432 (6.86)</td>
<td align="left">156 (6.79)</td>
</tr>
<tr>
<td align="left">Other health-professional</td>
<td align="left">3,244 (15.54)</td>
<td align="left">337 (14.66)</td>
</tr>
<tr>
<td align="left">Pharmacist</td>
<td align="left">6,146 (29.45)</td>
<td align="left">300 (13.05)</td>
</tr>
<tr>
<td align="left">Physician</td>
<td align="left">4,828 (23.13)</td>
<td align="left">478 (20.80)</td>
</tr>
<tr>
<td colspan="3" align="left">Reported countries<xref ref-type="table-fn" rid="Tfn2">
<sup>b</sup>
</xref>
</td>
</tr>
<tr>
<td align="left">United States</td>
<td align="left">9,149 (43.84)</td>
<td align="left">446 (19.41)</td>
</tr>
<tr>
<td align="left">France</td>
<td align="left">2,556 (12.25)</td>
<td align="left">77 (3.35)</td>
</tr>
<tr>
<td align="left">Not Specified</td>
<td align="left">1,822 (8.73)</td>
<td align="left">828 (36.03)</td>
</tr>
<tr>
<td align="left">United Kingdom</td>
<td align="left">964 (4.62)</td>
<td align="left">48 (2.09)</td>
</tr>
<tr>
<td align="left">Brazil</td>
<td align="left">758 (3.63)</td>
<td align="left">486 (21.15)</td>
</tr>
<tr>
<td colspan="3" align="left">Route<xref ref-type="table-fn" rid="Tfn2">
<sup>b</sup>
</xref>
</td>
</tr>
<tr>
<td align="left">Subcutaneous</td>
<td align="left">9,752 (46.73)</td>
<td align="left">704 (30.64)</td>
</tr>
<tr>
<td align="left">Not Specified</td>
<td align="left">5,304 (25.41)</td>
<td align="left">492 (21.41)</td>
</tr>
<tr>
<td align="left">Unknown</td>
<td align="left">4,330 (20.75)</td>
<td align="left">496 (21.58)</td>
</tr>
<tr>
<td align="left">Transplacental</td>
<td align="left">527 (2.53)</td>
<td align="left">523 (22.76)</td>
</tr>
<tr>
<td align="left">Parenteral</td>
<td align="left">352 (1.69)</td>
<td align="left">40 (1.74)</td>
</tr>
<tr>
<td colspan="3" align="left">Outcomes</td>
</tr>
<tr>
<td align="left">Life-Threatening</td>
<td align="left">1,455 (6.97)</td>
<td align="left">45 (1.96)</td>
</tr>
<tr>
<td align="left">Hospitalization - Initial or Prolonged</td>
<td align="left">7,601 (36.42)</td>
<td align="left">542 (23.59)</td>
</tr>
<tr>
<td align="left">Disability</td>
<td align="left">413 (1.98)</td>
<td align="left">41 (1.78)</td>
</tr>
<tr>
<td align="left">Death</td>
<td align="left">2,995 (14.35)</td>
<td align="left">96 (4.18)</td>
</tr>
<tr>
<td align="left">Congenital Anomaly</td>
<td align="left">237 (1.14)</td>
<td align="left">220 (9.57)</td>
</tr>
<tr>
<td align="left">Required Intervention to Prevent Permanent Impairment/Damage</td>
<td align="left">354 (1.70)</td>
<td align="left">13 (0.57)</td>
</tr>
<tr>
<td align="left">Other</td>
<td align="left">8,622 (41.31)</td>
<td align="left">1,444 (62.84)</td>
</tr>
<tr>
<td colspan="3" align="left">Adverse event occurrence time, days</td>
</tr>
<tr>
<td align="left">Median (Q1, Q3)</td>
<td align="left">6.00 (2.00, 17.00)</td>
<td align="left">15.00 (0.00, 146.00)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="Tfn1">
<label>
<sup>a</sup>
</label>
<p>Gender for male was considered misreporting<sup>.</sup>
</p>
</fn>
<fn id="Tfn2">
<label>
<sup>b</sup>
</label>
<p>Only the top 5 percentages are shown.</p>
</fn>
<fn>
<p>Abbreviations: n, number of adverse events reports.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s3-2">
<title>3.2 Signals detection associated with LMWH in the overall population</title>
<sec id="s3-2-1">
<title>3.2.1 Signals detection in SOCs levels</title>
<p>We compared the AE signals in SOCs for LWMH in the overall population, as shown in <xref ref-type="table" rid="T2">Table 2</xref>. The analysis revealed adverse reactions encompassing 27 SOCs. The proportion of LMWH-related AEs by SOCs was shown in <xref ref-type="fig" rid="F4">Figure 4A</xref>. The top three proportions of LMWH-related AEs by SOCs levels were general disorders and administration site conditions (15.29%), injury, poisoning and procedural complications (11.78%), and gastrointestinal disorders (8.73%). The study findings indicated that the significantly reported adverse signals in SOCs were pregnancy, puerperium, and perinatal conditions (n &#x3d; 1,710, ROR 6.54, PRR 6.39, IC 2.67, EBGM 6.34), vascular disorders (n &#x3d; 4,979, ROR 3.99, PRR 3.75, IC 1.90, EBGM 3.74), blood and lymphatic system disorders (n &#x3d; 3,207, ROR 3.20, PRR 3.09, IC 1.62, EBGM 3.08), and product issues (n &#x3d; 2,334, ROR 2.44, PRR 2.38, IC 1.25, EBGM 2.38).</p>
<table-wrap id="T2" position="float">
<label>TABLE 2</label>
<caption>
<p>Adverse event signals in various system organ classes for LMWH used in the overall population.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">System organ class</th>
<th align="left">Case reports</th>
<th align="left">ROR (95% CI)</th>
<th align="left">PRR (95% CI)</th>
<th align="left">chi_square</th>
<th align="left">IC (IC025)</th>
<th align="left">EBGM (EBGM05)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Pregnancy, puerperium and perinatal conditions<xref ref-type="table-fn" rid="Tfn3">
<sup>a</sup>
</xref>
</td>
<td align="left">1710</td>
<td align="left">6.54 (6.23, 6.86)</td>
<td align="left">6.39 (6.09, 6.69)</td>
<td align="left">7,742.02</td>
<td align="left">2.67 (2.59)</td>
<td align="left">6.34 (6.05)</td>
</tr>
<tr>
<td align="left">Vascular disorders<xref ref-type="table-fn" rid="Tfn3">
<sup>a</sup>
</xref>
</td>
<td align="left">4,979</td>
<td align="left">3.99 (3.88, 4.11)</td>
<td align="left">3.75 (3.65, 3.85)</td>
<td align="left">10,214.15</td>
<td align="left">1.90 (1.86)</td>
<td align="left">3.74 (3.63)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders<xref ref-type="table-fn" rid="Tfn3">
<sup>a</sup>
</xref>
</td>
<td align="left">3,207</td>
<td align="left">3.20 (3.09, 3.32)</td>
<td align="left">3.09 (2.99, 3.19)</td>
<td align="left">4,590.15</td>
<td align="left">1.62 (1.57)</td>
<td align="left">3.08 (2.97)</td>
</tr>
<tr>
<td align="left">Product issues<xref ref-type="table-fn" rid="Tfn3">
<sup>a</sup>
</xref>
</td>
<td align="left">2,334</td>
<td align="left">2.44 (2.34, 2.54)</td>
<td align="left">2.38 (2.29, 2.48)</td>
<td align="left">1896.82</td>
<td align="left">1.25 (1.19)</td>
<td align="left">2.38 (2.28)</td>
</tr>
<tr>
<td align="left">Congenital, familial and genetic disorders</td>
<td align="left">352</td>
<td align="left">1.86 (1.68, 2.07)</td>
<td align="left">1.86 (1.67, 2.06)</td>
<td align="left">139.86</td>
<td align="left">0.89 (0.74)</td>
<td align="left">1.86 (1.67)</td>
</tr>
<tr>
<td align="left">Hepatobiliary disorders</td>
<td align="left">953</td>
<td align="left">1.69 (1.59, 1.80)</td>
<td align="left">1.68 (1.58, 1.79)</td>
<td align="left">265.12</td>
<td align="left">0.75 (0.65)</td>
<td align="left">1.68 (1.58)</td>
</tr>
<tr>
<td align="left">Investigations</td>
<td align="left">4,743</td>
<td align="left">1.26 (1.22, 1.30)</td>
<td align="left">1.24 (1.21, 1.28)</td>
<td align="left">236.06</td>
<td align="left">0.31 (0.27)</td>
<td align="left">1.24 (1.20)</td>
</tr>
<tr>
<td align="left">Renal and urinary disorders</td>
<td align="left">1,431</td>
<td align="left">1.21 (1.14, 1.27)</td>
<td align="left">1.20 (1.14, 1.26)</td>
<td align="left">48.92</td>
<td align="left">0.26 (0.19)</td>
<td align="left">1.20 (1.14)</td>
</tr>
<tr>
<td align="left">Injury, poisoning and procedural complications</td>
<td align="left">7,296</td>
<td align="left">1.18 (1.15, 1.21)</td>
<td align="left">1.16 (1.14, 1.19)</td>
<td align="left">179.12</td>
<td align="left">0.21 (0.18)</td>
<td align="left">1.16 (1.13)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="left">3,126</td>
<td align="left">1.08 (1.04, 1.12)</td>
<td align="left">1.07 (1.04, 1.11)</td>
<td align="left">15.83</td>
<td align="left">0.10 (0.05)</td>
<td align="left">1.07 (1.03)</td>
</tr>
<tr>
<td align="left">Cardiac disorders</td>
<td align="left">1712</td>
<td align="left">1.04 (0.99, 1.09)</td>
<td align="left">1.04 (0.99, 1.09)</td>
<td align="left">2.17</td>
<td align="left">0.05 (&#x2212;0.02)</td>
<td align="left">1.04 (0.99)</td>
</tr>
<tr>
<td align="left">Gastrointestinal disorders</td>
<td align="left">5,406</td>
<td align="left">1.03 (1.00, 1.06)</td>
<td align="left">1.02 (1.00, 1.05)</td>
<td align="left">3.44</td>
<td align="left">0.03 (&#x2212;0.01)</td>
<td align="left">1.02 (1.00)</td>
</tr>
<tr>
<td align="left">Skin and subcutaneous tissue disorders</td>
<td align="left">3,211</td>
<td align="left">0.96 (0.93, 1.00)</td>
<td align="left">0.96 (0.93, 1.00)</td>
<td align="left">4.40</td>
<td align="left">&#x2212;0.05 (&#x2212;0.10)</td>
<td align="left">0.96 (0.93)</td>
</tr>
<tr>
<td align="left">General disorders and administration site conditions</td>
<td align="left">9,471</td>
<td align="left">0.85 (0.84, 0.87)</td>
<td align="left">0.88 (0.86, 0.89)</td>
<td align="left">199.18</td>
<td align="left">&#x2212;0.19 (&#x2212;0.22)</td>
<td align="left">0.88 (0.86)</td>
</tr>
<tr>
<td align="left">Nervous system disorders</td>
<td align="left">4,402</td>
<td align="left">0.82 (0.79, 0.84)</td>
<td align="left">0.83 (0.81, 0.85)</td>
<td align="left">166.41</td>
<td align="left">&#x2212;0.27 (&#x2212;0.31)</td>
<td align="left">0.83 (0.81)</td>
</tr>
<tr>
<td align="left">Surgical and medical procedures</td>
<td align="left">651</td>
<td align="left">0.79 (0.73, 0.85)</td>
<td align="left">0.79 (0.73, 0.86)</td>
<td align="left">35.90</td>
<td align="left">&#x2212;0.34 (&#x2212;0.45)</td>
<td align="left">0.79 (0.73)</td>
</tr>
<tr>
<td align="left">Endocrine disorders</td>
<td align="left">103</td>
<td align="left">0.66 (0.54, 0.80)</td>
<td align="left">0.66 (0.54, 0.80)</td>
<td align="left">18.27</td>
<td align="left">&#x2212;0.60 (&#x2212;0.88)</td>
<td align="left">0.66 (0.54)</td>
</tr>
<tr>
<td align="left">Metabolism and nutrition disorders</td>
<td align="left">822</td>
<td align="left">0.60 (0.56, 0.65)</td>
<td align="left">0.61 (0.57, 0.65)</td>
<td align="left">210.41</td>
<td align="left">&#x2212;0.71 (&#x2212;0.81)</td>
<td align="left">0.61 (0.57)</td>
</tr>
<tr>
<td align="left">Reproductive system and breast disorders</td>
<td align="left">309</td>
<td align="left">0.55 (0.49, 0.61)</td>
<td align="left">0.55 (0.49, 0.62)</td>
<td align="left">113.78</td>
<td align="left">&#x2212;0.86 (&#x2212;1.02)</td>
<td align="left">0.55 (0.49)</td>
</tr>
<tr>
<td align="left">Musculoskeletal and connective tissue disorders</td>
<td align="left">1785</td>
<td align="left">0.54 (0.52, 0.57)</td>
<td align="left">0.56 (0.53, 0.58)</td>
<td align="left">669.83</td>
<td align="left">&#x2212;0.85 (&#x2212;0.92)</td>
<td align="left">0.56 (0.53)</td>
</tr>
<tr>
<td align="left">Immune system disorders</td>
<td align="left">344</td>
<td align="left">0.50 (0.45, 0.56)</td>
<td align="left">0.51 (0.46, 0.56)</td>
<td align="left">166.29</td>
<td align="left">&#x2212;0.98 (&#x2212;1.13)</td>
<td align="left">0.51 (0.46)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">1,594</td>
<td align="left">0.48 (0.46, 0.50)</td>
<td align="left">0.49 (0.47, 0.52)</td>
<td align="left">877.42</td>
<td align="left">&#x2212;1.02 (&#x2212;1.09)</td>
<td align="left">0.49 (0.47)</td>
</tr>
<tr>
<td align="left">Social circumstances</td>
<td align="left">127</td>
<td align="left">0.44 (0.37, 0.53)</td>
<td align="left">0.44 (0.37, 0.53)</td>
<td align="left">89.51</td>
<td align="left">&#x2212;1.17 (&#x2212;1.42)</td>
<td align="left">0.44 (0.37)</td>
</tr>
<tr>
<td align="left">Ear and labyrinth disorders</td>
<td align="left">110</td>
<td align="left">0.41 (0.34, 0.49)</td>
<td align="left">0.41 (0.34, 0.49)</td>
<td align="left">95.39</td>
<td align="left">&#x2212;1.30 (&#x2212;1.56)</td>
<td align="left">0.41 (0.34)</td>
</tr>
<tr>
<td align="left">Neoplasms benign, malignant and unspecified (incl cysts and polyps)</td>
<td align="left">644</td>
<td align="left">0.38 (0.35, 0.41)</td>
<td align="left">0.39 (0.36, 0.42)</td>
<td align="left">635.81</td>
<td align="left">&#x2212;1.36 (&#x2212;1.48)</td>
<td align="left">0.39 (0.36)</td>
</tr>
<tr>
<td align="left">Eye disorders</td>
<td align="left">400</td>
<td align="left">0.32 (0.29, 0.35)</td>
<td align="left">0.33 (0.30, 0.36)</td>
<td align="left">568.69</td>
<td align="left">&#x2212;1.62 (&#x2212;1.76)</td>
<td align="left">0.33 (0.30)</td>
</tr>
<tr>
<td align="left">Psychiatric disorders</td>
<td align="left">727</td>
<td align="left">0.20 (0.18, 0.21)</td>
<td align="left">0.21 (0.19, 0.22)</td>
<td align="left">2,370.27</td>
<td align="left">&#x2212;2.28 (&#x2212;2.39)</td>
<td align="left">0.21 (0.19)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="Tfn3">
<label>
<sup>a</sup>
</label>
<p>indicates satisfies four signal detection methods simultaneously.</p>
</fn>
<fn>
<p>Abbreviations: BCPNN, bayesian confidence propagation neural network; CI, confidence interval; EBGM, empirical bayesian geometric mean; IC, information component; PRR, proportional reporting ratio; ROR, reporting odds ratio.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<fig id="F4" position="float">
<label>FIGURE 4</label>
<caption>
<p>Proportion of LMWH-related AEs by SOCs. <bold>(A)</bold>, Proportion of LMWH-related AEs by SOCs in the overall population. <bold>(B)</bold>, Proportion of LMWH-related AEs by SOC in pregnancy women. The bar plot displays the statistical distribution of LMWH-related AEs across 27 SOC levels. The percentage values indicated in the figure represent the proportion of LMWH-related AEs in each SOC.</p>
</caption>
<graphic xlink:href="fphar-15-1442002-g004.tif"/>
</fig>
</sec>
<sec id="s3-2-2">
<title>3.2.2 Signals detection in PTs levels</title>
<p>The top 50&#xa0;PTs by frequency for LMWH-related AEs in the overall population are illustrated in <xref ref-type="fig" rid="F5">Figure 5A</xref>. The five PTs with the highest frequency of LMWH-related AEs were exposure during pregnancy (n &#x3d; 1,360), hemorrhage (n &#x3d; 1,204), pulmonary embolism (n &#x3d; 927), hematoma (n &#x3d; 756), and death (n &#x3d; 727). Ranked based on ROR, the top 50 PTs for LMWH in the overall population are displayed in <xref ref-type="table" rid="T3">Table 3</xref>. The findings revealed PTs with high signal strength for LMWH in the overall population, including anti factor X antibody positive (n &#x3d; 6, ROR 506.70, PRR 506.65, IC 8.31, EBGM 317.03), heparin-induced thrombocytopenia test positive (n &#x3d; 19, ROR 263.10, PRR 263.02, IC 7.65, EBGM 200.79), anti factor X activity increased (n &#x3d; 10, ROR 255.93, PRR 255.89, IC 7.62, EBGM 196.61), heparin-induced thrombocytopenia test (n &#x3d; 14, ROR 231.85, PRR 231.80, IC 7.51, EBGM 182.09), and spontaneous heparin-induced thrombocytopenia syndrome (n &#x3d; 3, ROR 230.31, PRR 230.30, IC 7.50, EBGM 181.16). Additionally, besides the side effects already mentioned in the instructions, unexpected adverse reactions such as placental necrosis, foetal vascular malperfusion, abortion, premature separation of placenta, premature baby death, nonreassuring fetal heart rate pattern, femoral nerve palsy, angiokeratoma, device safety feature issue, immobilisation prolonged, and removal of foreign body were also observed among the top 50&#xa0;PTs associated with LMWH in the overall population.</p>
<fig id="F5" position="float">
<label>FIGURE 5</label>
<caption>
<p>Top 50 PTs by Frequency for LMWH-related AEs. <bold>(A)</bold>, Top 50 PTs by frequency for LMWH-related AEs in the overall population. <bold>(B)</bold>, Top 50 PTs by frequency for LMWH-related AEs in pregnancy women. The bar plot displays the top 50 PTs by frequency for LMWH-related AEs. The percentages represent the number of case reports under each PT as a percentage of the total sum of all case reports.</p>
</caption>
<graphic xlink:href="fphar-15-1442002-g005.tif"/>
</fig>
<table-wrap id="T3" position="float">
<label>TABLE 3</label>
<caption>
<p>The significant identification of the top 50 PTs of LMWH used in the overall population.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">SOC/PTs</th>
<th align="left">Case reports</th>
<th align="left">ROR (95% CI)</th>
<th align="left">PRR (95% CI)</th>
<th align="left">Chi_<break/>square</th>
<th align="left">IC (IC025)</th>
<th align="left">EBGM (EBGM05)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td colspan="7" align="left">Investigations</td>
</tr>
<tr>
<td align="left">Anti factor X antibody positive</td>
<td align="left">6</td>
<td align="left">506.70 (184.15, 1,394.23)</td>
<td align="left">506.65 (184.14, 1,394.01)</td>
<td align="left">1892.46</td>
<td align="left">8.31 (1.48)</td>
<td align="left">317.03 (115.22)</td>
</tr>
<tr>
<td align="left">Heparin-induced thrombocytopenia test positive</td>
<td align="left">19</td>
<td align="left">263.10 (157.2, 440.33)</td>
<td align="left">263.02 (157.17, 440.14)</td>
<td align="left">3,781.55</td>
<td align="left">7.65 (3.47)</td>
<td align="left">200.79 (119.97)</td>
</tr>
<tr>
<td align="left">Anti factor X activity increased</td>
<td align="left">10</td>
<td align="left">255.93 (126.13, 519.28)</td>
<td align="left">255.89 (126.12, 519.15)</td>
<td align="left">1948.46</td>
<td align="left">7.62 (2.41)</td>
<td align="left">196.61 (96.90)</td>
</tr>
<tr>
<td align="left">Heparin-induced thrombocytopenia test</td>
<td align="left">14</td>
<td align="left">231.85 (128.34, 418.86)</td>
<td align="left">231.80 (128.32, 418.72)</td>
<td align="left">2,524.35</td>
<td align="left">7.51 (2.97)</td>
<td align="left">182.09 (100.79)</td>
</tr>
<tr>
<td align="left">Coagulation factor XII level decreased</td>
<td align="left">3</td>
<td align="left">211.12 (59.57, 748.15)</td>
<td align="left">211.11 (59.57, 748.08)</td>
<td align="left">501.87</td>
<td align="left">7.40 (0.36)</td>
<td align="left">169.08 (47.71)</td>
</tr>
<tr>
<td align="left">Factor Xa activity increased</td>
<td align="left">3</td>
<td align="left">168.89 (48.89, 583.42)</td>
<td align="left">168.88 (48.89, 583.36)</td>
<td align="left">417.23</td>
<td align="left">7.14 (0.38)</td>
<td align="left">140.90 (40.79)</td>
</tr>
<tr>
<td align="left">Fibrinolysis increased</td>
<td align="left">7</td>
<td align="left">203.85 (89.30, 465.36)</td>
<td align="left">203.83 (89.29, 465.27)</td>
<td align="left">1,138.11</td>
<td align="left">7.36 (1.81)</td>
<td align="left">164.39 (72.01)</td>
</tr>
<tr>
<td align="left">Coagulation factor X level increased</td>
<td align="left">3</td>
<td align="left">101.34 (30.59, 335.64)</td>
<td align="left">101.33 (30.60, 335.61)</td>
<td align="left">266.09</td>
<td align="left">6.50 (0.41)</td>
<td align="left">90.58 (27.35)</td>
</tr>
<tr>
<td align="left">Ultrasound Doppler abnormal<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">8</td>
<td align="left">47.25 (23.18, 96.30)</td>
<td align="left">47.24 (23.18, 96.28)</td>
<td align="left">342.91</td>
<td align="left">5.49 (1.94)</td>
<td align="left">44.79 (21.97)</td>
</tr>
<tr>
<td align="left">Rubella antibody positive<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">3</td>
<td align="left">46.91 (14.67, 150.05)</td>
<td align="left">46.91 (14.67, 150.04)</td>
<td align="left">127.71</td>
<td align="left">5.48 (0.41)</td>
<td align="left">44.50 (13.91)</td>
</tr>
<tr>
<td align="left">Anti-platelet antibody positive</td>
<td align="left">8</td>
<td align="left">42.76 (21.02, 87.00)</td>
<td align="left">42.76 (21.02, 86.99)</td>
<td align="left">310.51</td>
<td align="left">5.35 (1.92)</td>
<td align="left">40.74 (20.02)</td>
</tr>
<tr>
<td colspan="7" align="left">Injury, poisoning and procedural complications</td>
</tr>
<tr>
<td align="left">Exposure via blood</td>
<td align="left">6</td>
<td align="left">187.67 (77.48, 454.56)</td>
<td align="left">187.65 (77.48, 454.48)</td>
<td align="left">911.40</td>
<td align="left">7.26 (1.55)</td>
<td align="left">153.71 (63.46)</td>
</tr>
<tr>
<td align="left">Foreign body in skin or subcutaneous tissue<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">5</td>
<td align="left">127.95 (49.95, 327.77)</td>
<td align="left">127.94 (49.95, 327.72)</td>
<td align="left">546.89</td>
<td align="left">6.80 (1.25)</td>
<td align="left">111.24 (43.43)</td>
</tr>
<tr>
<td align="left">Exposure via contaminated device</td>
<td align="left">3</td>
<td align="left">74.51 (22.88, 242.61)</td>
<td align="left">74.51 (22.88, 242.59)</td>
<td align="left">199.92</td>
<td align="left">6.10 (0.42)</td>
<td align="left">68.55 (21.05)</td>
</tr>
<tr>
<td align="left">Cardiac valve replacement complication</td>
<td align="left">16</td>
<td align="left">60.06 (36.17, 99.74)</td>
<td align="left">60.05 (36.16, 99.70)</td>
<td align="left">867.36</td>
<td align="left">5.81 (3.00)</td>
<td align="left">56.13 (33.80)</td>
</tr>
<tr>
<td align="left">Scrotal haematoma</td>
<td align="left">5</td>
<td align="left">49.68 (20.16, 122.43)</td>
<td align="left">49.67 (20.16, 122.41)</td>
<td align="left">225.21</td>
<td align="left">5.55 (1.22)</td>
<td align="left">46.97 (19.06)</td>
</tr>
<tr>
<td align="left">Extradural haematoma</td>
<td align="left">62</td>
<td align="left">45.61 (35.32, 58.90)</td>
<td align="left">45.57 (35.29, 58.83)</td>
<td align="left">2,564.10</td>
<td align="left">5.44 (4.32)</td>
<td align="left">43.28 (33.52)</td>
</tr>
<tr>
<td align="left">Post procedural pulmonary embolism</td>
<td align="left">10</td>
<td align="left">43.09 (22.82, 81.35)</td>
<td align="left">43.08 (22.82, 81.33)</td>
<td align="left">391.11</td>
<td align="left">5.36 (2.25)</td>
<td align="left">41.04 (21.74)</td>
</tr>
<tr>
<td align="left">Wound haematoma</td>
<td align="left">6</td>
<td align="left">41.53 (18.30, 94.27)</td>
<td align="left">41.53 (18.30, 94.25)</td>
<td align="left">226.20</td>
<td align="left">5.31 (1.48)</td>
<td align="left">39.63 (17.46)</td>
</tr>
<tr>
<td colspan="7" align="left">Gastrointestinal disorders</td>
</tr>
<tr>
<td align="left">Abdominal wall haematoma</td>
<td align="left">255</td>
<td align="left">145.99 (127.79, 166.78)</td>
<td align="left">145.39 (127.33, 166.02)</td>
<td align="left">31,196.88</td>
<td align="left">6.96 (6.20)</td>
<td align="left">124.18 (108.71)</td>
</tr>
<tr>
<td align="left">Retroperitoneal haemorrhage</td>
<td align="left">314</td>
<td align="left">133.18 (118.21, 150.04)</td>
<td align="left">132.51 (117.68, 149.21)</td>
<td align="left">35,424.89</td>
<td align="left">6.84 (6.22)</td>
<td align="left">114.67 (101.78)</td>
</tr>
<tr>
<td align="left">Intra-abdominal haematoma</td>
<td align="left">149</td>
<td align="left">113.62 (95.74, 134.84)</td>
<td align="left">113.35 (95.55, 134.47)</td>
<td align="left">14,629.22</td>
<td align="left">6.64 (5.66)</td>
<td align="left">100.05 (84.31)</td>
</tr>
<tr>
<td align="left">Retroperitoneal haematoma</td>
<td align="left">210</td>
<td align="left">102.08 (88.44, 117.82)</td>
<td align="left">101.74 (88.19, 117.37)</td>
<td align="left">18,695.35</td>
<td align="left">6.51 (5.78)</td>
<td align="left">90.91 (78.76)</td>
</tr>
<tr>
<td align="left">Abdominal wall haemorrhage</td>
<td align="left">21</td>
<td align="left">85.28 (54.44, 133.60)</td>
<td align="left">85.25 (54.43, 133.53)</td>
<td align="left">1,588.24</td>
<td align="left">6.28 (3.47)</td>
<td align="left">77.53 (49.49)</td>
</tr>
<tr>
<td align="left">Peritoneal haematoma</td>
<td align="left">7</td>
<td align="left">46.55 (21.75, 99.63)</td>
<td align="left">46.54 (21.75, 99.61)</td>
<td align="left">295.66</td>
<td align="left">5.46 (1.74)</td>
<td align="left">44.16 (20.63)</td>
</tr>
<tr>
<td colspan="7" align="left">Pregnancy, puerperium and perinatal conditions</td>
</tr>
<tr>
<td align="left">Placental necrosis<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">3</td>
<td align="left">87.36 (26.61, 286.79)</td>
<td align="left">87.35 (26.61, 286.76)</td>
<td align="left">232.09</td>
<td align="left">6.31 (0.42)</td>
<td align="left">79.26 (24.14)</td>
</tr>
<tr>
<td align="left">Peripartum haemorrhage</td>
<td align="left">3</td>
<td align="left">55.07 (17.13, 177.08)</td>
<td align="left">55.07 (17.13, 177.07)</td>
<td align="left">149.52</td>
<td align="left">5.69 (0.42)</td>
<td align="left">51.76 (16.10)</td>
</tr>
<tr>
<td align="left">Foetal vascular malperfusion<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">6</td>
<td align="left">52.24 (22.90, 119.15)</td>
<td align="left">52.23 (22.90, 119.13)</td>
<td align="left">283.95</td>
<td align="left">5.62 (1.51)</td>
<td align="left">49.25 (21.59)</td>
</tr>
<tr>
<td align="left">Abortion<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">150</td>
<td align="left">51.44 (43.62, 60.67)</td>
<td align="left">51.32 (43.53, 60.51)</td>
<td align="left">6,977.57</td>
<td align="left">5.60 (4.96)</td>
<td align="left">48.44 (41.07)</td>
</tr>
<tr>
<td align="left">Premature separation of placenta<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">59</td>
<td align="left">38.45 (29.62, 49.92)</td>
<td align="left">38.41 (29.59, 49.86)</td>
<td align="left">2056.39</td>
<td align="left">5.20 (4.14)</td>
<td align="left">36.78 (28.33)</td>
</tr>
<tr>
<td colspan="7" align="left">Nervous system disorders</td>
</tr>
<tr>
<td align="left">Spinal cord haematoma</td>
<td align="left">40</td>
<td align="left">141.42 (101.17, 197.68)</td>
<td align="left">141.33 (101.12, 197.51)</td>
<td align="left">4,774.32</td>
<td align="left">6.92 (4.46)</td>
<td align="left">121.21 (86.71)</td>
</tr>
<tr>
<td align="left">Brain stem haematoma</td>
<td align="left">3</td>
<td align="left">64.96 (20.07, 210.21)</td>
<td align="left">64.96 (20.07, 210.19)</td>
<td align="left">175.42</td>
<td align="left">5.92 (0.42)</td>
<td align="left">60.39 (18.66)</td>
</tr>
<tr>
<td align="left">Spinal epidural haemorrhage</td>
<td align="left">4</td>
<td align="left">53.62 (19.52, 147.31)</td>
<td align="left">53.61 (19.52, 147.29)</td>
<td align="left">194.20</td>
<td align="left">5.66 (0.87)</td>
<td align="left">50.47 (18.37)</td>
</tr>
<tr>
<td align="left">Femoral nerve palsy<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">3</td>
<td align="left">47.8 (14.94, 152.97)</td>
<td align="left">47.8 (14.94, 152.95)</td>
<td align="left">130.09</td>
<td align="left">5.50 (0.41)</td>
<td align="left">45.29 (14.15)</td>
</tr>
<tr>
<td colspan="7" align="left">Blood and lymphatic system disorders</td>
</tr>
<tr>
<td align="left">Spontaneous heparin-induced thrombocytopenia syndrome</td>
<td align="left">3</td>
<td align="left">230.31 (64.25, 825.57)</td>
<td align="left">230.30 (64.25, 825.49)</td>
<td align="left">538.14</td>
<td align="left">7.50 (0.35)</td>
<td align="left">181.16 (50.54)</td>
</tr>
<tr>
<td align="left">Autoimmune heparin-induced thrombocytopenia</td>
<td align="left">6</td>
<td align="left">211.13 (86.30, 516.52)</td>
<td align="left">211.11 (86.30, 516.43)</td>
<td align="left">1,003.73</td>
<td align="left">7.40 (1.55)</td>
<td align="left">169.08 (69.11)</td>
</tr>
<tr>
<td align="left">Heparin-induced thrombocytopenia</td>
<td align="left">510</td>
<td align="left">112.78 (102.79, 123.73)</td>
<td align="left">111.86 (102.02, 122.64)</td>
<td align="left">49,482.42</td>
<td align="left">6.63 (6.24)</td>
<td align="left">98.89 (90.14)</td>
</tr>
<tr>
<td colspan="7" align="left">Musculoskeletal and connective tissue disorders</td>
</tr>
<tr>
<td align="left">Haematoma muscle</td>
<td align="left">87</td>
<td align="left">95.54 (76.53, 119.27)</td>
<td align="left">95.41 (76.45, 119.07)</td>
<td align="left">7,302.54</td>
<td align="left">6.42 (5.13)</td>
<td align="left">85.82 (68.75)</td>
</tr>
<tr>
<td align="left">Chest wall haematoma</td>
<td align="left">22</td>
<td align="left">91.55 (58.96, 142.15)</td>
<td align="left">91.51 (58.95, 142.08)</td>
<td align="left">1776.98</td>
<td align="left">6.37 (3.55)</td>
<td align="left">82.66 (53.24)</td>
</tr>
<tr>
<td align="left">Muscle haemorrhage</td>
<td align="left">200</td>
<td align="left">53.08 (46.00, 61.24)</td>
<td align="left">52.91 (45.87, 61.02)</td>
<td align="left">9,585.60</td>
<td align="left">5.64 (5.12)</td>
<td align="left">49.85 (43.20)</td>
</tr>
<tr>
<td colspan="7" align="left">Skin and subcutaneous tissue disorders</td>
</tr>
<tr>
<td align="left">Bullous haemorrhagic dermatosis</td>
<td align="left">21</td>
<td align="left">221.74 (137.12, 358.57)</td>
<td align="left">221.66 (137.09, 358.4)</td>
<td align="left">3,653.86</td>
<td align="left">7.46 (3.62)</td>
<td align="left">175.78 (108.70)</td>
</tr>
<tr>
<td align="left">Angiokeratoma<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">5</td>
<td align="left">62.09 (25.04, 153.99)</td>
<td align="left">62.09 (25.04, 153.97)</td>
<td align="left">279.95</td>
<td align="left">5.86 (1.24)</td>
<td align="left">57.91 (23.35)</td>
</tr>
<tr>
<td colspan="7" align="left">Reproductive system and breast disorders</td>
</tr>
<tr>
<td align="left">Pelvic haematoma</td>
<td align="left">43</td>
<td align="left">106.24 (77.36, 145.91)</td>
<td align="left">106.17 (77.32, 145.78)</td>
<td align="left">3,979.43</td>
<td align="left">6.56 (4.46)</td>
<td align="left">94.42 (68.76)</td>
</tr>
<tr>
<td align="left">Uterine haematoma</td>
<td align="left">6</td>
<td align="left">50.67 (22.23, 115.49)</td>
<td align="left">50.67 (22.23, 115.47)</td>
<td align="left">275.58</td>
<td align="left">5.58 (1.51)</td>
<td align="left">47.85 (21.00)</td>
</tr>
<tr>
<td colspan="7" align="left">Product issues</td>
</tr>
<tr>
<td align="left">Device safety feature issue<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">83</td>
<td align="left">208.25 (163.77, 264.82)</td>
<td align="left">207.97 (163.59, 264.40)</td>
<td align="left">13,717.81</td>
<td align="left">7.38 (5.46)</td>
<td align="left">167.07 (131.38)</td>
</tr>
<tr>
<td colspan="7" align="left">Social circumstances</td>
</tr>
<tr>
<td align="left">Immobilisation prolonged<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">8</td>
<td align="left">72.65 (35.28, 149.58)</td>
<td align="left">72.64 (35.28, 149.55)</td>
<td align="left">520.45</td>
<td align="left">6.07 (2.00)</td>
<td align="left">66.96 (32.52)</td>
</tr>
<tr>
<td colspan="7" align="left">Endocrine disorders</td>
</tr>
<tr>
<td align="left">Adrenal haematoma</td>
<td align="left">4</td>
<td align="left">68.94 (24.88, 191.03)</td>
<td align="left">68.93 (24.88, 191.01)</td>
<td align="left">247.58</td>
<td align="left">6.00 (0.88)</td>
<td align="left">63.81 (23.03)</td>
</tr>
<tr>
<td colspan="7" align="left">Surgical and medical procedures</td>
</tr>
<tr>
<td align="left">Removal of foreign body<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">5</td>
<td align="left">54.84 (22.19, 135.50)</td>
<td align="left">54.83 (22.19, 135.48)</td>
<td align="left">248.14</td>
<td align="left">5.69 (1.23)</td>
<td align="left">51.55 (20.86)</td>
</tr>
<tr>
<td colspan="7" align="left">General disorders and administration site conditions</td>
</tr>
<tr>
<td align="left">Premature baby death<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">4</td>
<td align="left">49.68 (18.12, 136.18)</td>
<td align="left">49.67 (18.12, 136.16)</td>
<td align="left">180.17</td>
<td align="left">5.55 (0.87)</td>
<td align="left">46.97 (17.13)</td>
</tr>
<tr>
<td colspan="7" align="left">Cardiac disorders</td>
</tr>
<tr>
<td align="left">Nonreassuring foetal heart rate pattern<xref ref-type="table-fn" rid="Tfn4">
<sup>a</sup>
</xref>
</td>
<td align="left">9</td>
<td align="left">45.24 (23.14, 88.47)</td>
<td align="left">45.24 (23.14, 88.45)</td>
<td align="left">369.54</td>
<td align="left">5.43 (2.11)</td>
<td align="left">42.99 (21.98)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="Tfn4">
<label>
<sup>a</sup>
</label>
<p>indicates unexpected AE, not mentioned in the instructions.</p>
</fn>
<fn>
<p>Abbreviations: BCPNN, bayesian confidence propagation neural network; CI, confidence interval; EBGM, empirical bayesian geometric mean; IC, information component; PRR, proportional reporting ratio; ROR, reporting odds ratio.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
</sec>
<sec id="s3-3">
<title>3.3 Signals detection associated with LMWH in pregnancy women</title>
<sec id="s3-3-1">
<title>3.3.1 Signals detection in SOCs levels</title>
<p>We compared the AE signals in SOCs for LWMH in pregnancy women, shown in <xref ref-type="table" rid="T4">Table 4</xref>. The occurrence of LMWH-related AEs among the pregnancy women encompassed 27 SOCs. Among pregnancy women, the top three proportions of LMWH-related AEs by SOCs level were injury, poisoning, and procedural complications (34.32%), pregnancy, puerperium, and perinatal conditions (21.19%), and general disorders and administration site conditions (7.36%), shown in <xref ref-type="fig" rid="F4">Figure 4B</xref>. The significantly reported adverse signals in SOCs were product issues (n &#x3d; 105, ROR 2.99, PRR 2.97, IC 1.55, EBGM 2.93), vascular disorders (n &#x3d; 240, ROR 2.79, PRR 2.74, IC 1.44, EBGM 2.71), and blood and lymphatic system disorders (n &#x3d; 131, ROR 2.07, PRR 2.05, IC 1.03, EBGM 2.04).</p>
<table-wrap id="T4" position="float">
<label>TABLE 4</label>
<caption>
<p>Adverse event signals in various system organ classes for LMWH in pregnancy women.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">System organ class</th>
<th align="left">Case reports</th>
<th align="left">ROR (95% CI)</th>
<th align="left">PRR (95% CI)</th>
<th align="left">chi_square</th>
<th align="left">IC (IC025)</th>
<th align="left">EBGM (EBGM05)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Product issues<xref ref-type="table-fn" rid="Tfn5">
<sup>a</sup>
</xref>
</td>
<td align="left">105</td>
<td align="left">2.99 (2.46, 3.63)</td>
<td align="left">2.97 (2.45, 3.59)</td>
<td align="left">134.91</td>
<td align="left">1.55 (1.24)</td>
<td align="left">2.93 (2.41)</td>
</tr>
<tr>
<td align="left">Vascular disorders<xref ref-type="table-fn" rid="Tfn5">
<sup>a</sup>
</xref>
</td>
<td align="left">240</td>
<td align="left">2.79 (2.45, 3.18)</td>
<td align="left">2.74 (2.41, 3.10)</td>
<td align="left">263.10</td>
<td align="left">1.44 (1.24)</td>
<td align="left">2.71 (2.38)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders<xref ref-type="table-fn" rid="Tfn5">
<sup>a</sup>
</xref>
</td>
<td align="left">131</td>
<td align="left">2.07 (1.74, 2.46)</td>
<td align="left">2.05 (1.73, 2.43)</td>
<td align="left">70.26</td>
<td align="left">1.03 (0.76)</td>
<td align="left">2.04 (1.71)</td>
</tr>
<tr>
<td align="left">Injury, poisoning and procedural complications</td>
<td align="left">2,691</td>
<td align="left">1.63 (1.56, 1.71)</td>
<td align="left">1.41 (1.37, 1.46)</td>
<td align="left">428.14</td>
<td align="left">0.50 (0.43)</td>
<td align="left">1.41 (1.35)</td>
</tr>
<tr>
<td align="left">Surgical and medical procedures</td>
<td align="left">234</td>
<td align="left">1.52 (1.34, 1.74)</td>
<td align="left">1.51 (1.33, 1.71)</td>
<td align="left">40.41</td>
<td align="left">0.59 (0.39)</td>
<td align="left">1.50 (1.32)</td>
</tr>
<tr>
<td align="left">Pregnancy, puerperium and perinatal conditions</td>
<td align="left">1,661</td>
<td align="left">1.51 (1.43, 1.59)</td>
<td align="left">1.40 (1.34, 1.46)</td>
<td align="left">221.02</td>
<td align="left">0.48 (0.40)</td>
<td align="left">1.40 (1.32)</td>
</tr>
<tr>
<td align="left">Investigations</td>
<td align="left">305</td>
<td align="left">1.05 (0.94, 1.18)</td>
<td align="left">1.05 (0.94, 1.17)</td>
<td align="left">0.72</td>
<td align="left">0.07 (&#x2212;0.10)</td>
<td align="left">1.05 (0.93)</td>
</tr>
<tr>
<td align="left">Renal and urinary disorders</td>
<td align="left">59</td>
<td align="left">1.01 (0.78, 1.31)</td>
<td align="left">1.01 (0.79, 1.31)</td>
<td align="left">0.01</td>
<td align="left">0.02 (&#x2212;0.36)</td>
<td align="left">1.01 (0.78)</td>
</tr>
<tr>
<td align="left">Cardiac disorders</td>
<td align="left">148</td>
<td align="left">0.96 (0.82, 1.14)</td>
<td align="left">0.96 (0.82, 1.13)</td>
<td align="left">0.19</td>
<td align="left">&#x2212;0.05 (&#x2212;0.29)</td>
<td align="left">0.97 (0.82)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="left">235</td>
<td align="left">0.95 (0.84, 1.09)</td>
<td align="left">0.95 (0.84, 1.08)</td>
<td align="left">0.52</td>
<td align="left">&#x2212;0.07 (&#x2212;0.26)</td>
<td align="left">0.96 (0.84)</td>
</tr>
<tr>
<td align="left">Reproductive system and breast disorders</td>
<td align="left">98</td>
<td align="left">0.95 (0.78, 1.16)</td>
<td align="left">0.95 (0.78, 1.16)</td>
<td align="left">0.26</td>
<td align="left">&#x2212;0.07 (&#x2212;0.37)</td>
<td align="left">0.95 (0.78)</td>
</tr>
<tr>
<td align="left">Hepatobiliary disorders</td>
<td align="left">43</td>
<td align="left">0.93 (0.69, 1.25)</td>
<td align="left">0.93 (0.69, 1.25)</td>
<td align="left">0.25</td>
<td align="left">&#x2212;0.11 (&#x2212;0.55)</td>
<td align="left">0.93 (0.69)</td>
</tr>
<tr>
<td align="left">Skin and subcutaneous tissue disorders</td>
<td align="left">133</td>
<td align="left">0.75 (0.63, 0.89)</td>
<td align="left">0.75 (0.64, 0.89)</td>
<td align="left">11.07</td>
<td align="left">&#x2212;0.41 (&#x2212;0.66)</td>
<td align="left">0.75 (0.63)</td>
</tr>
<tr>
<td align="left">General disorders and administration site conditions</td>
<td align="left">577</td>
<td align="left">0.72 (0.66, 0.78)</td>
<td align="left">0.74 (0.68, 0.80)</td>
<td align="left">58.03</td>
<td align="left">&#x2212;0.43 (&#x2212;0.56)</td>
<td align="left">0.74 (0.68)</td>
</tr>
<tr>
<td align="left">Nervous system disorders</td>
<td align="left">239</td>
<td align="left">0.68 (0.60, 0.78)</td>
<td align="left">0.69 (0.61, 0.78)</td>
<td align="left">34.25</td>
<td align="left">&#x2212;0.53 (&#x2212;0.72)</td>
<td align="left">0.69 (0.61)</td>
</tr>
<tr>
<td align="left">Metabolism and nutrition disorders</td>
<td align="left">64</td>
<td align="left">0.64 (0.50, 0.82)</td>
<td align="left">0.64 (0.50, 0.82)</td>
<td align="left">12.85</td>
<td align="left">&#x2212;0.64 (&#x2212;0.99)</td>
<td align="left">0.64 (0.50)</td>
</tr>
<tr>
<td align="left">Endocrine disorders</td>
<td align="left">8</td>
<td align="left">0.60 (0.30, 1.21)</td>
<td align="left">0.60 (0.30, 1.21)</td>
<td align="left">2.07</td>
<td align="left">&#x2212;0.72 (&#x2212;1.62)</td>
<td align="left">0.61 (0.30)</td>
</tr>
<tr>
<td align="left">Immune system disorders</td>
<td align="left">26</td>
<td align="left">0.59 (0.40, 0.87)</td>
<td align="left">0.59 (0.40, 0.87)</td>
<td align="left">7.44</td>
<td align="left">&#x2212;0.76 (&#x2212;1.29)</td>
<td align="left">0.59 (0.40)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">130</td>
<td align="left">0.55 (0.46, 0.65)</td>
<td align="left">0.56 (0.47, 0.66)</td>
<td align="left">46.96</td>
<td align="left">&#x2212;0.84 (&#x2212;1.09)</td>
<td align="left">0.56 (0.47)</td>
</tr>
<tr>
<td align="left">Eye disorders</td>
<td align="left">29</td>
<td align="left">0.51 (0.35, 0.73)</td>
<td align="left">0.51 (0.35, 0.73)</td>
<td align="left">13.94</td>
<td align="left">&#x2212;0.98 (&#x2212;1.48)</td>
<td align="left">0.51 (0.35)</td>
</tr>
<tr>
<td align="left">Ear and labyrinth disorders</td>
<td align="left">12</td>
<td align="left">0.49 (0.28, 0.87)</td>
<td align="left">0.50 (0.28, 0.87)</td>
<td align="left">6.18</td>
<td align="left">&#x2212;1.01 (&#x2212;1.76)</td>
<td align="left">0.50 (0.28)</td>
</tr>
<tr>
<td align="left">Neoplasms benign, malignant and unspecified (incl cysts and polyps)</td>
<td align="left">14</td>
<td align="left">0.44 (0.26, 0.75)</td>
<td align="left">0.44 (0.26, 0.75)</td>
<td align="left">9.71</td>
<td align="left">&#x2212;1.16 (&#x2212;1.86)</td>
<td align="left">0.45 (0.26)</td>
</tr>
<tr>
<td align="left">Congenital, familial and genetic disorders</td>
<td align="left">306</td>
<td align="left">0.44 (0.40, 0.50)</td>
<td align="left">0.47 (0.42, 0.52)</td>
<td align="left">204.45</td>
<td align="left">&#x2212;1.10 (&#x2212;1.26)</td>
<td align="left">0.47 (0.42)</td>
</tr>
<tr>
<td align="left">Musculoskeletal and connective tissue disorders</td>
<td align="left">136</td>
<td align="left">0.43 (0.37, 0.51)</td>
<td align="left">0.44 (0.38, 0.52)</td>
<td align="left">98.72</td>
<td align="left">&#x2212;1.17 (&#x2212;1.41)</td>
<td align="left">0.44 (0.38)</td>
</tr>
<tr>
<td align="left">Gastrointestinal disorders</td>
<td align="left">148</td>
<td align="left">0.43 (0.36, 0.50)</td>
<td align="left">0.44 (0.37, 0.51)</td>
<td align="left">111.30</td>
<td align="left">&#x2212;1.19 (&#x2212;1.42)</td>
<td align="left">0.44 (0.37)</td>
</tr>
<tr>
<td align="left">Social circumstances</td>
<td align="left">12</td>
<td align="left">0.32 (0.18, 0.56)</td>
<td align="left">0.32 (0.18, 0.57)</td>
<td align="left">17.23</td>
<td align="left">&#x2212;1.63 (&#x2212;2.36)</td>
<td align="left">0.32 (0.18)</td>
</tr>
<tr>
<td align="left">Psychiatric disorders</td>
<td align="left">56</td>
<td align="left">0.15 (0.11, 0.19)</td>
<td align="left">0.15 (0.12, 0.20)</td>
<td align="left">274.65</td>
<td align="left">&#x2212;2.70 (&#x2212;3.06)</td>
<td align="left">0.15 (0.12)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="Tfn5">
<label>
<sup>a</sup>
</label>
<p>indicates satisfies four signal detection methods simultaneously.</p>
</fn>
<fn>
<p>Abbreviations: BCPNN, bayesian confidence propagation neural network; CI, confidence interval; EBGM, empirical bayesian geometric mean; IC, information component; PRR, proportional reporting ratio; ROR, reporting odds ratio.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="s3-3-2">
<title>3.3.2 Signals detection in PTs levels</title>
<p>The five PTs with the highest frequency of LMWH-related AEs were exposure during pregnancy (n &#x3d; 1,360), maternal exposure during pregnancy (n &#x3d; 408), abortion spontaneous (n &#x3d; 306), foetal exposure during pregnancy (n &#x3d; 273), and premature baby (n &#x3d; 248), shown in <xref ref-type="fig" rid="F5">Figure 5B</xref>. Ranked based on ROR, the top 50 PTs for LMWH in pregnancy women are displayed in <xref ref-type="table" rid="T5">Table 5</xref>. The five strongest signals for LMWH-related among the pregnancy women included sternal fracture (n &#x3d; 3, ROR 243.44, PRR 243.35, IC 6.61, EBGM 97.94), syringe issue (n &#x3d; 12, ROR 97.49, PRR 97.34, IC 5.94, EBGM 61.21), bleeding time prolonged (n &#x3d; 3, ROR 97.38, PRR 97.34, IC 5.94, EBGM 61.21), spinal compression fracture (n &#x3d; 10, ROR 90.24, PRR 90.13, IC 5.87, EBGM 58.30), and injection site haematoma (n &#x3d; 19, ROR 79.23, PRR 79.04, IC 5.74, EBGM 53.47). Additionally, unexpected AEs associated with LMWH in pregnancy women were observed, including premature baby death, placental necrosis, abortion, antiphospholipid syndrome, systolic dysfunction, compartment syndrome, body height decreased, rubella antibody positive, and ultrasound doppler abnormal.</p>
<table-wrap id="T5" position="float">
<label>TABLE 5</label>
<caption>
<p>The significant identification of the top 50&#xa0;PTs of LMWH in pregnancy women.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="center">SOC/PTs</th>
<th align="center">Case reports</th>
<th align="center">ROR (95% CI)</th>
<th align="center">PRR (95% CI)</th>
<th align="center">chi_square</th>
<th align="center">IC (IC025)</th>
<th align="center">EBGM (EBGM05)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td colspan="7" align="left">Injury, poisoning and procedural complications</td>
</tr>
<tr>
<td align="left">Sternal fracture</td>
<td align="right">3</td>
<td align="left">243.44 (40.67, 1,457.14)</td>
<td align="left">243.35 (40.67, 1,456.18)</td>
<td align="right">289.62</td>
<td align="left">6.61 (0.09)</td>
<td align="left">97.94 (16.36)</td>
</tr>
<tr>
<td align="left">Spinal compression fracture</td>
<td align="right">10</td>
<td align="left">90.24 (41.64, 195.56)</td>
<td align="left">90.13 (41.62, 195.18)</td>
<td align="right">566.62</td>
<td align="left">5.87 (2.20)</td>
<td align="left">58.30 (26.90)</td>
</tr>
<tr>
<td align="left">Cardiac valve replacement complication</td>
<td align="right">11</td>
<td align="left">59.57 (29.84, 118.9)</td>
<td align="left">59.48 (29.82, 118.66)</td>
<td align="right">462.83</td>
<td align="left">5.45 (2.31)</td>
<td align="left">43.79 (21.94)</td>
</tr>
<tr>
<td align="left">Spinal fracture</td>
<td align="right">11</td>
<td align="left">55.84 (28.14, 110.83)</td>
<td align="left">55.77 (28.12, 110.59)</td>
<td align="right">440.30</td>
<td align="left">5.38 (2.30)</td>
<td align="left">41.76 (21.04)</td>
</tr>
<tr>
<td align="left">Femur fracture</td>
<td align="right">5</td>
<td align="left">21.36 (8.4, 54.28)</td>
<td align="left">21.35 (8.40, 54.22)</td>
<td align="right">85.69</td>
<td align="left">4.25 (0.98)</td>
<td align="left">18.98 (7.47)</td>
</tr>
<tr>
<td align="left">Incorrect dose administered by device</td>
<td align="right">3</td>
<td align="left">20.29 (6.11, 67.38)</td>
<td align="left">20.28 (6.11, 67.33)</td>
<td align="right">48.88</td>
<td align="left">4.18 (0.23)</td>
<td align="left">18.14 (5.46)</td>
</tr>
<tr>
<td align="left">Recalled product administered</td>
<td align="right">3</td>
<td align="left">18.73 (5.67, 61.88)</td>
<td align="left">18.72 (5.67, 61.83)</td>
<td align="right">45.11</td>
<td align="left">4.08 (0.22)</td>
<td align="left">16.89 (5.11)</td>
</tr>
<tr>
<td align="left">Product storage error</td>
<td align="right">13</td>
<td align="left">13.81 (7.83, 24.33)</td>
<td align="left">13.78 (7.83, 24.27)</td>
<td align="right">142.09</td>
<td align="left">3.68 (1.99)</td>
<td align="left">12.78 (7.25)</td>
</tr>
<tr>
<td colspan="7" align="left">General disorders and administration site conditions</td>
</tr>
<tr>
<td align="left">Injection site haematoma</td>
<td align="right">19</td>
<td align="left">79.23 (45.76, 137.15)</td>
<td align="left">79.04 (45.7, 136.7)</td>
<td align="right">984.40</td>
<td align="left">5.74 (3.13)</td>
<td align="left">53.47 (30.89)</td>
</tr>
<tr>
<td align="left">Injury associated with device</td>
<td align="right">7</td>
<td align="left">29.14 (13.03, 65.18)</td>
<td align="left">29.12 (13.03, 65.08)</td>
<td align="right">161.15</td>
<td align="left">4.63 (1.53)</td>
<td align="left">24.84 (11.11)</td>
</tr>
<tr>
<td align="left">Injection site haemorrhage</td>
<td align="right">23</td>
<td align="left">24.62 (15.87, 38.19)</td>
<td align="left">24.55 (15.84, 38.04)</td>
<td align="right">451.32</td>
<td align="left">4.42 (2.90)</td>
<td align="left">21.45 (13.83)</td>
</tr>
<tr>
<td align="left">Injection site bruising</td>
<td align="right">46</td>
<td align="left">19.70 (14.49, 26.77)</td>
<td align="left">19.59 (14.44, 26.58)</td>
<td align="right">724.18</td>
<td align="left">4.14 (3.25)</td>
<td align="left">17.58 (12.94)</td>
</tr>
<tr>
<td align="left">Injection site discolouration</td>
<td align="right">8</td>
<td align="left">15.84 (7.66, 32.75)</td>
<td align="left">15.83 (7.66, 32.70)</td>
<td align="right">101.25</td>
<td align="left">3.86 (1.52)</td>
<td align="left">14.51 (7.02)</td>
</tr>
<tr>
<td align="left">Application site pain</td>
<td align="right">3</td>
<td align="left">14.32 (4.40, 46.63)</td>
<td align="left">14.31 (4.40, 46.6)</td>
<td align="right">34.14</td>
<td align="left">3.73 (0.18)</td>
<td align="left">13.23 (4.06)</td>
</tr>
<tr>
<td align="left">Premature baby death<xref ref-type="table-fn" rid="Tfn6">
<sup>a</sup>
</xref>
</td>
<td align="right">4</td>
<td align="left">10.64 (3.87, 29.28)</td>
<td align="left">10.64 (3.87, 29.25)</td>
<td align="right">32.78</td>
<td align="left">3.33 (0.49)</td>
<td align="left">10.04 (3.65)</td>
</tr>
<tr>
<td colspan="7" align="left">Vascular disorders</td>
</tr>
<tr>
<td align="left">Peripheral ischaemia</td>
<td align="right">4</td>
<td align="left">59.02 (18.79, 185.4)</td>
<td align="left">58.99 (18.79, 185.23)</td>
<td align="right">167.23</td>
<td align="left">5.44 (0.71)</td>
<td align="left">43.53 (13.86)</td>
</tr>
<tr>
<td align="left">Embolism</td>
<td align="right">9</td>
<td align="left">52.20 (24.63, 110.67)</td>
<td align="left">52.15 (24.61, 110.47)</td>
<td align="right">341.67</td>
<td align="left">5.31 (1.99)</td>
<td align="left">39.70 (18.73)</td>
</tr>
<tr>
<td align="left">Pelvic venous thrombosis</td>
<td align="right">3</td>
<td align="left">17.39 (5.29, 57.21)</td>
<td align="left">17.38 (5.29, 57.16)</td>
<td align="right">41.84</td>
<td align="left">3.98 (0.21)</td>
<td align="left">15.80 (4.80)</td>
</tr>
<tr>
<td align="left">Thrombosis</td>
<td align="right">52</td>
<td align="left">14.19 (10.68, 18.86)</td>
<td align="left">14.11 (10.64, 18.71)</td>
<td align="right">582.89</td>
<td align="left">3.71 (3.00)</td>
<td align="left">13.06 (9.83)</td>
</tr>
<tr>
<td align="left">Haematoma</td>
<td align="right">18</td>
<td align="left">13.30 (8.22, 21.52)</td>
<td align="left">13.27 (8.21, 21.45)</td>
<td align="right">188.86</td>
<td align="left">3.63 (2.26)</td>
<td align="left">12.35 (7.63)</td>
</tr>
<tr>
<td align="left">Ischaemia</td>
<td align="right">3</td>
<td align="left">9.55 (2.98, 30.59)</td>
<td align="left">9.54 (2.98, 30.57)</td>
<td align="right">21.67</td>
<td align="left">3.18 (0.09)</td>
<td align="left">9.07 (2.83)</td>
</tr>
<tr>
<td colspan="7" align="left">Investigations</td>
</tr>
<tr>
<td align="left">Bleeding time prolonged</td>
<td align="right">3</td>
<td align="left">97.38 (23.27, 407.53)</td>
<td align="left">97.34 (23.27, 407.24)</td>
<td align="right">178.78</td>
<td align="left">5.94 (0.19)</td>
<td align="left">61.21 (14.63)</td>
</tr>
<tr>
<td align="left">Body height decreased<xref ref-type="table-fn" rid="Tfn6">
<sup>a</sup>
</xref>
</td>
<td align="right">3</td>
<td align="left">54.10 (14.64, 199.86)</td>
<td align="left">54.08 (14.64, 199.71)</td>
<td align="right">117.22</td>
<td align="left">5.35 (0.24)</td>
<td align="left">40.81 (11.05)</td>
</tr>
<tr>
<td align="left">Rubella antibody positive<xref ref-type="table-fn" rid="Tfn6">
<sup>a</sup>
</xref>
</td>
<td align="right">3</td>
<td align="left">23.18 (6.91, 77.74)</td>
<td align="left">23.18 (6.91, 77.68)</td>
<td align="right">55.70</td>
<td align="left">4.35 (0.24)</td>
<td align="left">20.40 (6.08)</td>
</tr>
<tr>
<td align="left">Ultrasound Doppler abnormal<xref ref-type="table-fn" rid="Tfn6">
<sup>a</sup>
</xref>
</td>
<td align="right">7</td>
<td align="left">21.05 (9.57, 46.27)</td>
<td align="left">21.03 (9.57, 46.20)</td>
<td align="right">118.22</td>
<td align="left">4.23 (1.45)</td>
<td align="left">18.73 (8.52)</td>
</tr>
<tr>
<td align="left">Fibrin D dimer increased</td>
<td align="right">6</td>
<td align="left">14.32 (6.21, 33.02)</td>
<td align="left">14.31 (6.21, 32.97)</td>
<td align="right">68.29</td>
<td align="left">3.73 (1.12)</td>
<td align="left">13.23 (5.74)</td>
</tr>
<tr>
<td colspan="7" align="left">Product issues</td>
</tr>
<tr>
<td align="left">Syringe issue</td>
<td align="right">12</td>
<td align="left">97.49 (47.64, 199.49)</td>
<td align="left">97.34 (47.60, 199.05)</td>
<td align="right">715.13</td>
<td align="left">5.94 (2.49)</td>
<td align="left">61.21 (29.91)</td>
</tr>
<tr>
<td align="left">Needle issue</td>
<td align="right">19</td>
<td align="left">65.74 (38.57, 112.06)</td>
<td align="left">65.58 (38.51, 111.69)</td>
<td align="right">860.54</td>
<td align="left">5.55 (3.09)</td>
<td align="left">46.99 (27.57)</td>
</tr>
<tr>
<td align="left">Product packaging issue</td>
<td align="right">7</td>
<td align="left">51.66 (22.06, 120.98)</td>
<td align="left">51.62 (22.06, 120.80)</td>
<td align="right">263.60</td>
<td align="left">5.30 (1.61)</td>
<td align="left">39.40 (16.83)</td>
</tr>
<tr>
<td align="left">Product availability issue</td>
<td align="right">11</td>
<td align="left">14.53 (7.84, 26.93)</td>
<td align="left">14.51 (7.83, 26.87)</td>
<td align="right">127.01</td>
<td align="left">3.74 (1.85)</td>
<td align="left">13.40 (7.23)</td>
</tr>
<tr>
<td align="left">Device defective</td>
<td align="right">3</td>
<td align="left">11.87 (3.68, 38.36)</td>
<td align="left">11.87 (3.68, 38.33)</td>
<td align="right">27.83</td>
<td align="left">3.48 (0.14)</td>
<td align="left">11.13 (3.45)</td>
</tr>
<tr>
<td colspan="7" align="left">Musculoskeletal and connective tissue disorders</td>
</tr>
<tr>
<td align="left">Osteoporotic fracture</td>
<td align="right">5</td>
<td align="left">73.79 (25.63, 212.42)</td>
<td align="left">73.74 (25.63, 212.19)</td>
<td align="right">246.66</td>
<td align="left">5.67 (1.07)</td>
<td align="left">51.01 (17.72)</td>
</tr>
<tr>
<td align="left">Compartment syndrome<xref ref-type="table-fn" rid="Tfn6">
<sup>a</sup>
</xref>
</td>
<td align="right">3</td>
<td align="left">40.57 (11.45, 143.81)</td>
<td align="left">40.56 (11.45, 143.70)</td>
<td align="right">92.60</td>
<td align="left">5.03 (0.25)</td>
<td align="left">32.65 (9.21)</td>
</tr>
<tr>
<td align="left">Osteoporosis</td>
<td align="right">23</td>
<td align="left">14.28 (9.32, 21.88)</td>
<td align="left">14.24 (9.3, 21.80)</td>
<td align="right">260.38</td>
<td align="left">3.72 (2.51)</td>
<td align="left">13.17 (8.60)</td>
</tr>
<tr>
<td align="left">Osteopenia</td>
<td align="right">8</td>
<td align="left">9.28 (4.55, 18.93)</td>
<td align="left">9.27 (4.55, 18.90)</td>
<td align="right">55.84</td>
<td align="left">3.14 (1.24)</td>
<td align="left">8.82 (4.33)</td>
</tr>
<tr>
<td colspan="7" align="left">Pregnancy, puerperium and perinatal conditions</td>
</tr>
<tr>
<td align="left">Placental necrosis<xref ref-type="table-fn" rid="Tfn6">
<sup>a</sup>
</xref>
</td>
<td align="right">3</td>
<td align="left">17.39 (5.29, 57.21)</td>
<td align="left">17.38 (5.29, 57.16)</td>
<td align="right">41.84</td>
<td align="left">3.98 (0.21)</td>
<td align="left">15.80 (4.80)</td>
</tr>
<tr>
<td align="left">Peripartum haemorrhage</td>
<td align="right">3</td>
<td align="left">12.17 (3.76, 39.35)</td>
<td align="left">12.17 (3.76, 39.32)</td>
<td align="right">28.60</td>
<td align="left">3.51 (0.15)</td>
<td align="left">11.39 (3.52)</td>
</tr>
<tr>
<td align="left">Abortion<xref ref-type="table-fn" rid="Tfn6">
<sup>a</sup>
</xref>
</td>
<td align="right">144</td>
<td align="left">11.36 (9.58, 13.47)</td>
<td align="left">11.17 (9.45, 13.20)</td>
<td align="right">1,249.27</td>
<td align="left">3.39 (3.05)</td>
<td align="left">10.51 (8.87)</td>
</tr>
<tr>
<td colspan="7" align="left">Blood and lymphatic system disorders</td>
</tr>
<tr>
<td align="left">Hypercoagulation</td>
<td align="right">14</td>
<td align="left">22.53 (12.87, 39.41)</td>
<td align="left">22.49 (12.86, 39.31)</td>
<td align="right">252.48</td>
<td align="left">4.31 (2.34)</td>
<td align="left">19.87 (11.36)</td>
</tr>
<tr>
<td align="left">Antiphospholipid syndrome<xref ref-type="table-fn" rid="Tfn6">
<sup>a</sup>
</xref>
</td>
<td align="right">10</td>
<td align="left">17.85 (9.29, 34.31)</td>
<td align="left">17.83 (9.28, 34.24)</td>
<td align="right">143.12</td>
<td align="left">4.01 (1.84)</td>
<td align="left">16.16 (8.41)</td>
</tr>
<tr>
<td align="left">Heparin-induced thrombocytopenia</td>
<td align="right">4</td>
<td align="left">14.76 (5.3, 41.08)</td>
<td align="left">14.75 (5.30, 41.04)</td>
<td align="right">46.99</td>
<td align="left">3.77 (0.59)</td>
<td align="left">13.60 (4.89)</td>
</tr>
<tr>
<td colspan="7" align="left">Nervous system disorders</td>
</tr>
<tr>
<td align="left">Cerebral thrombosis</td>
<td align="right">4</td>
<td align="left">18.55 (6.59, 52.2)</td>
<td align="left">18.54 (6.59, 52.15)</td>
<td align="right">59.57</td>
<td align="left">4.07 (0.64)</td>
<td align="left">16.74 (5.95)</td>
</tr>
<tr>
<td align="left">Ischaemic stroke</td>
<td align="right">5</td>
<td align="left">11.12 (4.49, 27.52)</td>
<td align="left">11.11 (4.49, 27.49)</td>
<td align="right">43.06</td>
<td align="left">3.39 (0.79)</td>
<td align="left">10.46 (4.23)</td>
</tr>
<tr>
<td align="left">Transient ischaemic attack</td>
<td align="right">7</td>
<td align="left">9.63 (4.49, 20.65)</td>
<td align="left">9.62 (4.49, 20.62)</td>
<td align="right">51.07</td>
<td align="left">3.19 (1.12)</td>
<td align="left">9.14 (4.26)</td>
</tr>
<tr>
<td colspan="7" align="left">Cardiac disorders</td>
</tr>
<tr>
<td align="left">Cardiac ventricular thrombosis</td>
<td align="right">11</td>
<td align="left">36.47 (18.96, 70.16)</td>
<td align="left">36.42 (18.94, 70.01)</td>
<td align="right">309.46</td>
<td align="left">4.90 (2.22)</td>
<td align="left">29.93 (15.56)</td>
</tr>
<tr>
<td align="left">Systolic dysfunction<xref ref-type="table-fn" rid="Tfn6">
<sup>a</sup>
</xref>
</td>
<td align="right">3</td>
<td align="left">11.07 (3.44, 35.64)</td>
<td align="left">11.06 (3.44, 35.62)</td>
<td align="right">25.70</td>
<td align="left">3.38 (0.13)</td>
<td align="left">10.42 (3.23)</td>
</tr>
<tr>
<td colspan="7" align="left">Skin and subcutaneous tissue disorders</td>
</tr>
<tr>
<td align="left">Livedo reticularis</td>
<td align="right">3</td>
<td align="left">9.55 (2.98, 30.59)</td>
<td align="left">9.54 (2.98, 30.57)</td>
<td align="right">21.67</td>
<td align="left">3.18 (0.09)</td>
<td align="left">9.07 (2.83)</td>
</tr>
<tr>
<td colspan="7" align="left">Respiratory, thoracic and mediastinal disorders</td>
</tr>
<tr>
<td align="left">Pulmonary thrombosis</td>
<td align="right">4</td>
<td align="left">19.67 (6.97, 55.55)</td>
<td align="left">19.66 (6.97, 55.49)</td>
<td align="right">63.20</td>
<td align="left">4.14 (0.65)</td>
<td align="left">17.65 (6.25)</td>
</tr>
<tr>
<td colspan="7" align="left">Reproductive system and breast disorders</td>
</tr>
<tr>
<td align="left">Uterine haematoma</td>
<td align="right">5</td>
<td align="left">12.30 (4.95, 30.53)</td>
<td align="left">12.29 (4.95, 30.50)</td>
<td align="right">48.21</td>
<td align="left">3.52 (0.83)</td>
<td align="left">11.50 (4.63)</td>
</tr>
<tr>
<td colspan="7" align="left">Gastrointestinal disorders</td>
</tr>
<tr>
<td align="left">Abdominal wall haematoma</td>
<td align="right">3</td>
<td align="left">24.34 (7.23, 81.94)</td>
<td align="left">24.33 (7.23, 81.88)</td>
<td align="right">58.37</td>
<td align="left">4.41 (0.24)</td>
<td align="left">21.29 (6.33)</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="Tfn6">
<label>
<sup>a</sup>
</label>
<p>indicates unexpected AE, not mentioned in the instructions.</p>
</fn>
<fn>
<p>Abbreviations: BCPNN, bayesian confidence propagation neural network; CI, confidence interval; EBGM, empirical bayesian geometric mean; IC, information component; PRR, proportional reporting ratio; ROR, reporting odds ratio.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</sec>
</sec>
</sec>
<sec sec-type="discussion" id="s4">
<title>4 Discussion</title>
<p>Our pharmacovigilance analysis of the FAERS database comprehensively and systematically revealed the safety signals of LMWH. For the overall population, significant AEs at SOC levels included pregnancy, puerperium, and perinatal conditions; vascular disorders; blood and lymphatic system disorders; and product issues. The five strongest AE signals were anti factor X antibody positive, heparin-induced thrombocytopenia test positive, anti factor X activity increased, heparin-induced thrombocytopenia test, and spontaneous heparin-induced thrombocytopenia syndrome. Besides the side effects of bleeding, hematoma, and HIT mentioned in the drug&#x2019;s instructions, unexpected AEs such as placental necrosis, foetal vascular malperfusion, abortion, premature separation of placenta, premature baby death, nonreassuring fetal heart rate pattern, femoral nerve palsy, angiokeratoma, device safety feature issue, immobilisation prolonged, and removal of foreign body were also observed. Additionally, for pregnancy women, significant AEs at SOC levels included product issues, vascular disorders, and blood and lymphatic system disorders. The five strongest AE signals were sternal fracture, syringe issue, prolonged bleeding time, spinal compression fracture, and injection site hematoma. Unexpected AEs associated with LMWH in pregnancy women were observed, including premature baby death, placental necrosis, abortion, antiphospholipid syndrome, systolic dysfunction, compartment syndrome, decreased body height, positive rubella antibody, and abnormal ultrasound doppler results.</p>
<p>The most important complication associated with heparin treatment is bleeding, resulting directly from the potency of heparin as an anticoagulant. As we know, all antithrombotic carry the risk of bleeding as a complication (<xref ref-type="bibr" rid="B49">Schulman et al., 2008</xref>). The incidence of bleeding under heparin therapy is hard to define, as it depends on numerous parameters including the indication, dosage, duration of heparin application, baseline status of the patient, procedure that the patient undergoes, and co-medication (<xref ref-type="bibr" rid="B2">Alban, 2012</xref>). In all patients treated with antithrombotic therapy, increased age, and renal damage are strong independent baseline predictors of major bleeding (<xref ref-type="bibr" rid="B28">Lim et al., 2006</xref>; <xref ref-type="bibr" rid="B10">Clark, 2008</xref>; <xref ref-type="bibr" rid="B15">Eikelboom et al., 2009</xref>). In general, bleeding can occur at any site during therapy. Major bleeds are rare adverse events, but hematomas are commonly observed (<xref ref-type="bibr" rid="B2">Alban, 2012</xref>). An estimate of the incidence of bleeding clinically is between 6% and 14% (<xref ref-type="bibr" rid="B35">Mulloy et al., 2016</xref>).</p>
<p>HIT is a life-threatening severe nonbleeding adverse reaction caused by LMWH (<xref ref-type="bibr" rid="B12">Dhakal et al., 2018</xref>). Nonbleeding complications of heparins are induced by binding of heparin molecules to proteins other than antithrombin and to cells, which is generally more pronounced with unfractionated heparin (with an incidence of about 2.5%) than with LMWH(with an incidence of about 0.2%) (<xref ref-type="bibr" rid="B21">Hogwood et al., 2023</xref>). HIT can be divided into type I and type II. Type I is an early-onset, mild thrombocytopenia that does not lead to thromboembolism, whereas type II is immune-mediated and clinically severe, causing both thrombocytopenia and thromboembolism (<xref ref-type="bibr" rid="B4">Arepally and Padmanabhan, 2021</xref>), with approximately 50% of patients developing arterial or venous thrombosis usually occurring 5&#x2013;10&#xa0;days after starting heparin therapy (<xref ref-type="bibr" rid="B5">Barcellona et al., 2020</xref>; <xref ref-type="bibr" rid="B52">Singh et al., 2020</xref>; <xref ref-type="bibr" rid="B30">Liu et al., 2023</xref>). The immunologic nature of the more serious type II HIT is due to the generation of antibodies that recognize complexes of heparin and PLT factor 4. PLT factor 4 is a positively charged protein released from the &#x3b1;-granules of activated platelets and combines with the negatively charged heparin through electrostatic interaction of the vascular epidermis to form a complex (<xref ref-type="bibr" rid="B21">Hogwood et al., 2023</xref>; <xref ref-type="bibr" rid="B34">Mongirdiene et al., 2023</xref>), which results in thrombocytopenia and increases the risk of venous and arterial thromboses (<xref ref-type="bibr" rid="B3">Arepally, 2017</xref>; <xref ref-type="bibr" rid="B39">Rollin et al., 2022</xref>). In this study, we found HIT was the strongest signal, followed by spontaneous haematoma and autoimmune heparin&#x2212;induced thrombocytopenia in blood and lymphatic system disorders. Ranked based on ROR, the top 6 PTs for LMWH were anti factor x antibody positive, heparin-induced thrombocytopenia test positive, anti factor x activity increased, heparin-induced thrombocytopenia test, factor xa activity increased, and spontaneous heparin-induced thrombocytopenia. Our findings were consistent with previous reports (<xref ref-type="bibr" rid="B30">Liu et al., 2023</xref>).</p>
<p>LMWHs are increasingly used during pregnancy, either as prophylaxis for venous thromboembolism or as an effective treatment of acute venous thromboembolism in pregnancy (<xref ref-type="bibr" rid="B7">Bates et al., 2018</xref>; <xref ref-type="bibr" rid="B9">Bistervels et al., 2022</xref>). Other clinically practiced indications for LMWH use in pregnancy-related diseases include unexplained recurrent miscarriage, thrombophilia, autoimmune disease, and <italic>in vitro</italic> fertilization to improve pregnancy rates and outcomes. In addition, early studies suggested an association between placenta&#x2010;mediated complications in pregnancy and women with thrombophilia or an increased risk of developing thrombosis (<xref ref-type="bibr" rid="B37">Rodger et al., 2010</xref>). As a result, physicians have prescribed heparin as prophylaxis to prevent placenta-mediated pregnancy complications (<xref ref-type="bibr" rid="B14">Duffett and Rodger, 2015</xref>; <xref ref-type="bibr" rid="B11">Cruz-Lemini et al., 2022</xref>; <xref ref-type="bibr" rid="B62">Zullino et al., 2022</xref>). However, the evidence that LMWH can reduce the risk of placenta-mediated pregnancy complications including late pregnancy loss, placental abruption, pre-eclampsia, small-for-gestational-age neonate, and fetal growth restriction, is controversial (<xref ref-type="bibr" rid="B33">Mastrolia et al., 2016</xref>; <xref ref-type="bibr" rid="B38">Rodger et al., 2016</xref>). Although there is no evidence that heparins cross the placenta, and consequently no fetal or neonatal complication has been reported (<xref ref-type="bibr" rid="B14">Duffett and Rodger, 2015</xref>), the safety issues should cause our concern, especially regarding abnormal fetal development, birth defects, premature delivery, abortion, and placental dysfunction.</p>
<p>In our study, besides side effects of hematoma and bruising or haemorrhage at the injection site, unexpected AEs about fetal induced by LMWH in pregnancy women were observed, including premature baby death, placental necrosis, abortion, and abnormal ultrasound doppler results. Previous reports indicated that treatment with a prophylactic dose of LMWH during pregnancy was related to an increased risk of prematurity complications (<xref ref-type="bibr" rid="B22">Isma et al., 2010</xref>). While fetal risk was low in LMWH exposed pregnancies (<xref ref-type="bibr" rid="B53">Sogaard et al., 2022</xref>), and neonatal death related to LMWH was limited, our findings should be cautiously explored. Large studies are needed to better confirm the findings. In addition, caesarean section is an important risk factor for <italic>postpartum</italic> venous thrombosis in pregnant women. However, due to the lack of evidence, the benefits of pharmacologic thromboprophylaxis such as LMWH in preventing the occurrence of venous thrombosis in caesarean section patients remain controversial (<xref ref-type="bibr" rid="B59">Yang R. et al., 2018</xref>). Results from a previous meta-analysis showed that LMWH was associated with no obvious decrease in the risk of thrombus after caesarean section compared with UHF and negative control. However, LMWH was observed to be associated with a definite increase in the risk of bleeding or hematomas after caesarean section in comparison to negative control (<xref ref-type="bibr" rid="B59">Yang R. et al., 2018</xref>). Similarly, our study found the AE of uterine haematoma, peripartum haemorrhage for LMWH use in pregnancy women. Contrary, recent research suggested that the use of LMWH was not associated with increased critical obstetric bleeding among women with caesarean section (<xref ref-type="bibr" rid="B1">Akaishi et al., 2024</xref>). Due to inconsistent findings, large studies are needed to better confirm the safety of LMWH for women undergoing caesarean section.</p>
<p>It is worth noting that fractures and osteoporosis are the most significant AE signals related to LMWH in pregnancy women in this study. Data on the effects of LMWH on bone loss and fractures in pregnant women are limited. Some reports have shown that at least 3&#xa0;months of LMWH use was associated with bone loss and fractures in the pregnancy women, with more significant reductions observed in patients receiving enoxaparin for more than 1&#xa0;year (<xref ref-type="bibr" rid="B51">Signorelli et al., 2019</xref>). However, an observational cohort study of 152 pregnant women found that prolonged use of LMWH during pregnancy was not related to a subsequent decrease in BMD (measured by dual-energy X-ray absorptiometry 4&#x2013;7&#xa0;years after the last delivery), osteopenia, osteoporosis, or osteoporotic fractures (<xref ref-type="bibr" rid="B17">Galambosi et al., 2016</xref>). Therefore, based on current literature findings, long-term LMWH exposure during pregnancy may have some negative effect on BMD. Large sample sizes and long-term follow-up studies are needed to better confirm the association between bone loss and LMWH in pregnant women.</p>
<p>Our study has several limitations. Firstly, adverse event reports are voluntary and come from a variety of sources, resulting in varying degrees of underreporting, delayed reporting, misreporting, and incomplete information, which may introduce bias into the measurement of the disproportionality report. Secondly, disproportionality analysis alone can be a useful step in identifying safety signals; however, it cannot formally establish causation or measure incidence due to limitations such as lack of detailed patient exposure data, reporting biases, and confounding factors. Thirdly, our study cannot directly explain the mechanism underlying the development of some unexpected adverse reactions caused by LMWHs, which requires specific mechanisms to be studied through cell and animal experiments in the future. Finally, the lack of multivariable analyses controlling for other clinical factors such as age, comorbidities, or other factors, makes it challenging to implicate the specific role of LMWH in the development of adverse reactions. Considering the above limitations and other potential biases, we need to interpret the results more cautiously, and further clinical study evaluations are required to confirm these associations.</p>
</sec>
<sec sec-type="conclusion" id="s5">
<title>5 Conclusion</title>
<p>In conclusion, the significant AEs at SOC levels related to LMWH were pregnancy, puerperium, and perinatal conditions, vascular disorders, blood and lymphatic system disorders, and product issues. Bleeding, hematoma, and HIT are common AEs for which patients should be monitored. Additionally, the five strongest AE signals for LMWH-related in pregnancy women were sternal fracture, syringe issue, prolonged bleeding time, spinal compression fracture, and injection site hematoma. Unexpected AEs associated with LMWH in pregnancy women were observed, including premature baby death, placental necrosis, abortion, antiphospholipid syndrome, systolic dysfunction, compartment syndrome, decreased body height, positive rubella antibody, and abnormal ultrasound doppler results. Our study could provide valuable evidence for the clinical practice of LMWH, especially for identifying AEs and ensuring safe usage in pregnancy women.</p>
</sec>
</body>
<back>
<sec sec-type="data-availability" id="s6">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/<xref ref-type="sec" rid="s11">Supplementary Material</xref>, further inquiries can be directed to the corresponding authors.</p>
</sec>
<sec id="s7">
<title>Author contributions</title>
<p>HX: Data curation, Formal Analysis, Investigation, Writing&#x2013;original draft, Writing&#x2013;review and editing. NX: Formal Analysis, Visualization, Writing&#x2013;original draft, Writing&#x2013;review and editing. YW: Formal Analysis, Visualization, Writing&#x2013;review and editing. HZ: Formal Analysis, Writing&#x2013;review and editing. SW: Conceptualization, Methodology, Writing&#x2013;review and editing.</p>
</sec>
<sec sec-type="funding-information" id="s8">
<title>Funding</title>
<p>The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was funded by the Guangdong TCM Anti-aging Engineering Technology Research Center (No. 2022E040), Guangdong Famous Traditional Chinese Medicine Inheritance Studio Construction Program, Foshan Anti-aging Engineering Technology Research Center, and Foshan Traditional Chinese Medicine Clinical Science and Technology Innovation Base Construction Program.</p>
</sec>
<ack>
<p>The authors would like to thank the FAERS database for freely providing the open-source data. The authors would like to thank the experts who provided valuable suggestions for the development of this article.</p>
</ack>
<sec sec-type="COI-statement" id="s9">
<title>Conflict of interest</title>
<p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p>
</sec>
<sec sec-type="disclaimer" id="s10">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec id="s11">
<title>Supplementary material</title>
<p>The Supplementary Material for this article can be found online at: <ext-link ext-link-type="uri" xlink:href="https://www.frontiersin.org/articles/10.3389/fphar.2024.1442002/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fphar.2024.1442002/full&#x23;supplementary-material</ext-link>
</p>
<supplementary-material xlink:href="Table1.DOCX" id="SM1" mimetype="application/DOCX" xmlns:xlink="http://www.w3.org/1999/xlink"/>
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