Mediating effect of lipid levels during first trimester of pregnancy between COVID-19 lockdown and gestational diabetes mellitus

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This study aimed to explore the relationship among lockdown, lipid levels change in the first trimester and GDM. Methods This was a population-based observational cohort study. Mean values of lipid levels were compared by Wilcoxon rank-sum test. Logistic regression analysis was used to analyze the effects of lockdown and lipid profile on GDM. Mediation analysis was performed to identify whether blood lipid level mediated the association between lockdown and GDM. Results A total of 3997 pregnant women were included, among whom 614 (15.36%) were defined as GDM group and 3383 (84.64%) were defined as non-GDM group. Women who experienced lockdown in the first trimester had higher levels of serum total cholesterol (TC), TG, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) (p < 0.001) than others. Besides, experiencing lockdown (OR 1.84, 95% CI 1.50-2.26) and higher level of TG (OR 1.34, 95% CI 1.16-1.55) during the first trimester were both significantly and independently associated with the risk of GDM by multivariate logistic regression analysis. Furthermore, mediation analysis was conducted to explore the potential relationship among lockdown, lipid levels change during the first trimester and GDM,which showed TG played a mediating role in the association between lockdown and GDM (p < 0.001). Conclusions Pregnant women who experienced lockdown had higher levels of TC, TG HDL and LDL in the first trimester.TG had a mediating effect between lockdown and GDM, indicating that lockdown which brought physical inactivity and poor diet in early pregnancy may have an effect on the development of GDM by affecting lipid profile. Therefore, exercise and diet interventions in early pregnancy could help prevent GDM. Gestational diabetes mellitus Triglycerides COVID-19 lockdown Mediation analysis Intervention Figures Figure 1 Figure 2 Background Gestational diabetes mellitus (GDM) is one of the most common complications for pregnant women[ 1 ], which can lead to short- and long-term adverse consequences for both mother and offspring[ 2 ]. The reported prevalence of GDM in mainland China was 5.12–33.3%, with a rapid rising trend[ 3 ]. During the outbreak of COVID-19 in recent years, lockdown was an important measure to prevent the spread of infection, thus most residents were confined to their houses. Strikingly, lockdown increased GDM prevalence, especially for pregnant women in the first trimester of gestation[ 4 ]. Changes in environments, behaviors, and the psychological status during the lockdown, such as physical inactivity, low sleep levels, poor diet, and mental health problems might result in a higher risk of GDM[ 5 ]. Lipid metabolism plays an important role in the pathophysiology of GDM[ 6 ]. A growing number of studies suggest that elevated maternal triglycerides (TG) levels were associated with higher risk of GDM[ 3 , 7 ]. Other studies also observed that GDM patients had significantly increased serum total cholesterol (TC) levels and decreased low-density lipoprotein (LDL) concentrations when compared to unaffected patients[ 8 ]. Intriguingly, maternal lipid metabolism could be affected by different kinds of lifestyle including diet and physical activity[ 9 , 10 ]. During the lockdown which might result in physical inactivity and poor diet[ 4 , 11 ], higher TC and TG levels were found in non-pregnant people[ 12 ]. However, the maternal lipid levels affected by lockdown remains unclear. Furthermore, the relationship among lockdown, maternal lipid profile and GDM has not been studied. Therefore, this study aimed to provide a description of lipids profile change affected with lockdown during the first trimester. Furthermore, we sought to conduct a mediation analysis to explore the potential relationship among lockdown, lipid levels change during the first trimester and GDM, which may help further establish lifestyle interventions targeted on lipid metabolism to reduce the risk of GDM. Materials and methods Study design and population This retrospective study was conducted at the Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University. Patients delivered in this hospital between January 2021 and December 2022 were included in this study. The study protocol was approved by the hospital ethics committee. This whole-city lockdown in Shanghai, which officially lasted 63 days (began on 28th March 2022 and ended on 1st June 2022) with much stricter measures, had almost all residents confined to their homes and banned from going out, except for those who provided medical necessities[ 1 ]. We identified the women who experienced lockdown in the first trimester based on the time of less than 13 gestational weeks crossed with this period. According to the hospital policy, pregnant women had to undergo nucleic acid testing before they came to hospital for antenatal care, delivery or follow up. All pregnant women included in this study were SARS-CoV-2 negative during pregnancy. And women were not suggested to receive Anti- SARS-CoV2 vaccine during pregnancy in China. The inclusion criteria were as follows: (a) age ≥ 18 years and < 45 years, (b) singleton pregnancy, (c) first prenatal visit at this Hospital before 12 gestational weeks, (d) full-term pregnancy (≥ 37 gestational weeks), (e) fasting plasma glucose < 5.1 mmol/L in the first prenatal visit test. The exclusion criteria were as follows: (a) a diagnosis of type 1 or type 2 diabetes mellitus before or during pregnancy, (b) a history of severe complications including tumor or other severe diseases during pregnancy. Data collection Clinical data were collected from the medical records by trained staffs. Basic information including age, gravidity, parity, pre-pregnancy body mass index (BMI), delivery mode, gestational age at birth, and birth weight were recorded. Biochemistry tests were performed at first prenatal visit, including blood lipid panels consisting of TC, TG, high-density lipoprotein (HDL) and LDL. All laboratory measurements were performed within 3 days after the first clinical visit using the Hitachi 7180 automatic biochemical analyzer. The samples were stored at 4°C and were analyzed within 4-h after collection. Outcome All pregnant women underwent a 75 g OGTT at 24–28 weeks. Participants were diagnosed with GDM and defined as the GDM group if their PG with a 75 g OGTT met one or more of the following criteria: (a) fasting plasma glucose ≥ 5.1 mmol/L; (b) 1-h plasma glucose ≥ 10.0 mmol/L; and (c) 2-h plasma glucose ≥ 8.5 mmol/L [ 13 , 14 ]. Statistical analyses Continuously distributed variables were presented as mean (standard deviation). Since none of them subject to normal distribution, the Wilcoxon rank-sum test was used. Categorical variables were displayed by counts (percentages) and compared using a chi-square test or Fisher's exact test, where appropriate. Multivariate logistic regression model was performed to analyze the effects of blood lipid profile and lockdown in the first trimester on GDM. Specifically, we define \(Y=1\) if the subject was diagnosed with GDM, and \(Y=0\) , otherwise, the logistic regression model is given by $$P\left(Y=1|{X}_{1},\cdots , {X}_{p}\right)=\frac{\text{exp}\left({\beta }_{0}+{\beta }_{1}{X}_{1}+\cdots +{\beta }_{10}{X}_{10}\right)}{1+\text{exp}\left({\beta }_{0}+{\beta }_{1}{X}_{1}+\cdots +{\beta }_{10}{X}_{10}\right) },$$ where there were 10 covariates incorporated in the model, including the continuous variables: age ( \({X}_{1}\) ) and blood lipid panels in the first trimester TC ( \({X}_{2}\) ), TG ( \({X}_{3}\) ), HDL ( \({X}_{4}\) ), LDL ( \({X}_{5}\) ). We also introduced three dummy variables to indicate the BMI classification. \({X}_{6}=1\) represented underweight (BMI < 18.5), \({X}_{7}=1\) represented overweight (BMI 25-27.9), \({X}_{8}=1\) represented obesity (BMI \(\ge\) 28), and the normal weight (BMI 18.5–24.9) was defined as the baseline one. Besides, \({X}_{9}=1\) represented that the woman was multiparous and \({X}_{10}=1\) indicated lockdown in the first trimester. Furthermore, preliminary analysis showed that women who experienced lockdown in the first trimester had higher levels of TC, TG, HDL and LDL (p < 0.001) than others, which indicated that a mediation pathway might be possible from lockdown in the first trimester, the blood lipid profiles, to GDM (Figure S1 ). Thus, mediation analysis was conducted to determine whether blood lipid profile could mediate the relationship between lockdown in the first trimester and GDM. The corresponding mediation model is $$P\left(Y=1|\varvec{X},\varvec{M},A\right)=\frac{\text{exp}\left({\beta }_{0}+\alpha A+{\varvec{\beta }}^{T}\varvec{M}+{\varvec{\beta }}_{X}^{T}\varvec{X}\right)}{1+\text{exp}\left({\beta }_{0}+\alpha A+{\varvec{\beta }}^{T}\varvec{M}+{\varvec{\beta }}_{X}^{T}\varvec{X}\right)},$$ $${M}_{\varvec{j}}={\gamma }_{0j}+{\gamma }_{j}A+{\varvec{\gamma }}_{Xj}^{T}\varvec{X}+{\epsilon }_{j}, j=1,\cdots , 4,$$ where the response \(Y\) was taken to be the diagnosis of GDM, the potential mediators in \(\varvec{M}\) were TC ( \({M}_{1}\) ), TG ( \({M}_{2}\) ), HDL ( \({M}_{3}\) ), LDL ( \({M}_{4}\) ), the exposure variable \(A=1\) if the subject experienced lockdown in the first trimester, and 0, otherwise; and the confounding covariates \(\varvec{X}\) were age, BMI and multiparous; the random errors \({\epsilon }_{i}\) had mean zero and constant variance, and was independent of \(\varvec{X}\) and \(A\) . In this model, we referred \(\alpha\) to the direct effect, the mediation effect (or indirect effect) of the exposure on the outcome mediated through the mediator was approximately equal to \(\beta \gamma\) on the log-odds-ratio scale[ 15 ]. The significance tests of regression coefficients \(\alpha\) , \(\varvec{\beta }\) and \(\varvec{\gamma }\) can be implemented using Wald \({\chi }^{2}\) -test or \(t\) -test. In this study, of interest is to test whether there exists significant mediation effect or not, which can be formulated as the hypothesis testing problem \({H}_{0}: \beta \gamma =0\) versus \({H}_{1}:\beta \gamma \ne 0.\) Two popular tests, the Wald-type Sobel’s test [ 16 ] and the joint significance test (also known as the MaxP test)[ 17 ] were applied here to detect the mediation effect. The two testing procedures were easy to understand and implement, and hence had been widely used by applied researchers. All analyses were performed using R software, with a significance level of p < 0.05. Results Characteristics of study subjects After screening, 3997 pregnant women were included in this study (Fig. 1 ). Among them, 614 (15.36%) were defined as the GDM group, while 3383 (84.64%) were defined as the non-GDM group. From Table 1, pregnant women in the GDM group were significantly older, had higher proportions of overweight and obesity, and lower gestational age at birth compared to the non-GDM group (p < 0.001). Furthermore, the GDM group had higher rate of lockdown experience in the first trimester (p < 0.001) than non-GDM group (Table 1). Besides, the results of blood lipid profile plotted in Fig. 2 A showed that GDM group had higher levels of TC, TG and LDL (p < 0.001) than non-GDM group in the first trimester. For further studying the effects of lockdown on the blood lipid profile in the first trimester, we presented the box-plots of the blood lipid profile in Fig. 2 B. The results indicated that women experiencing lockdown in the first trimester had higher levels of TC, TG, HDL and LDL (p < 0.001) than others. Thus, these results provided us with strong evidence for exploring the mediation effects of blood lipid profile as shown in Figure S1 . Association between clinical characteristics and blood lipid profile and the risk of GDM The results of multivariate logistic regression analysis are summarized in Table 2, which revealed that age (OR 1.06, 95% CI 1.03–1.09), TG (OR 1.34, 95% CI 1.16–1.55) and lockdown in the first trimester (OR 1.84, 95% CI 1.50–2.26) were significantly associated with the risk of GDM, whereas no significant associations were observed for TC, LDL, and HDL. Underweight (OR 0.39, 95% CI 0.26–0.60) and obesity (OR 1.69, 95% CI 1.05–2.74) were associated with the risk of GDM, compared with normal weight. Effect of lockdown on GDM mediated through blood lipid profile in the first trimester of pregnancy First trimester lipid parameters, lockdown and GDM are known to be interrelated. Therefore, we explored whether the first trimester lipid parameters played a mediating role in the association between lockdown and GDM. The testing results were presented in Table 3 . The results of Sobel’s test and the MaxP test were consistent. The following conclusions were identified: (i) the exposure \(A\) (lockdown in the first trimester) had a significant effect on the mediators \(\varvec{M}\) (TC, TG, HDL and LDL) since all \({p}_{\gamma }<0.001\) ; (ii) the mediator \({M}_{2}\) (TG) had a significant effect on the outcome \(Y\) (GDM), while the effects of TC, HDL and LDL on GDM were not significant; (iii) the mediator TG played an important role in mediating the effect of lockdown during the first trimester on GDM due to its \(MaxP<0.001\) and the 95% confidence interval of \({T}_{Sobel}\) did not include zero; but significant mediation effects of TG, HDL and LDL were not detected. Discussion A total of 3997 pregnant women were included in the final analysis, among whom 614 (15.36%) were defined as the GDM group and 3383 (84.64%) were defined as the non-GDM group. Women who experienced lockdown in the first trimester had higher levels of TC, TG, HDL and LDL (p < 0.001) than others. Besides, experiencing lockdown (OR 1.84, 95% CI 1.50–2.26) and higher level of TG (OR 1.34, 95% CI 1.16–1.55) during the first trimester were both significantly and independently associated with the risk of GDM by multivariate logistic regression analysis. Thus, mediation analysis was used to explore the effect of lockdown on GDM mediated through TG levels. As a result, TG had a significant mediating effect (p < 0.001), whereas the mediating effects of TC, HDL, and LDL could not be considered significant. Therefore, it was concluded that the lockdown had an important effect on the development of GDM by affecting TG levels. Among type 2 diabetes people, the dyslipidemia is often an early manifestation, occurring even before overt diabetes develops[ 18 ]. As early in pregnancy, lipid metabolic profiles differed between women with and without GDM[ 19 ]. Recent studies have found higher TG concentrations were associated with higher GDM risk in the first trimester, but not FPG[ 8 , 20 ]. A potential mechanism underlying this phenomenon might be that patients at risk of GDM usually associate with higher levels of insulin resistance (IR), whereby elevated plasma insulin concentrations would enhance very-low‐density lipoprotein (VLDL) synthesis, and lead to the increase in serum TG levels[ 18 ]. Accordingly, TG is the most sensitive lipid index to IR among the common lipid profiles such as TC, TG, HDL and LDL, and was identified as a reliable risk factor for GDM [ 21 ]. This study also found that GDM group had higher levels of TC, TG and LDL (p < 0.001) than non-GDM group in the first trimester, whereas only TG (OR 1.34, 95% CI 1.16–1.55) was associated with the risk of GDM. Diet and exercise could influence maternal lipid profiles. As other researchers reported, a cholesterol-lowering diet[ 22 ] and moderate-intensity aerobic exercise[ 23 ] from early pregnancy may benefit triglyceride levels[ 24 , 25 ]. Moreover, an increasing number of studies have also suggested that the risk of GDM may be reduced by diet, exercise, and lifestyle intervention, particularly when started during the first or early in the second trimester[ 26 ]. On the contrary, lockdown confined most residents to their houses in order to prevent the spread of infection, thus resulted in insufficient dietary supplement and limited physical activity for pregnant women. This study indicated for the first time that women experiencing lockdown in the first trimester had higher levels of TC, TG, HDL and LDL (p < 0.001) than others. In addition, lockdown increased GDM prevalence for pregnant women in the first trimester of gestation (OR 1.84, 95% CI 1.50–2.26). From that, we speculated that the poor diet and physical inactivity during lockdown may disturb the normal glycometabolism and lead to GDM, especially the first trimester of pregnancy may be the window for sensitive exposure. Therefore, this study conducted a mediation analysis to explore the potential relationship among lockdown, lipid levels change and GDM, and verified that elevated TG levels during the first trimester caused by lockdown was responsible for increased GDM incidence. Thus, lifestyle behavior interventions in early pregnancy with a focus on lowering triglyceride levels may help to prevent GDM and reduce the consequent health risks for women and children. To the best of our knowledge, this was the first study to provide a description of maternal lipids profile change affected with lockdown during the first trimester. Our findings showed that women who experienced lockdown in the first trimester had higher levels of TC, TG, HDL and LDL than others. Moreover, a mediation analysis focused on the potential relationship among lockdown, lipid levels change during the first trimester and GDM, which suggests that lockdown had an important effect on the development of GDM by affecting TG levels. However, several limitations of this analysis should be acknowledged. First, this was a hospital-based retrospective study which might affect the power and generality of our investigation. Second, data on type of poor diet and physical inactivity among women who experienced lockdown were lacking in this study, thus more investigation and further analysis exploring targeted interventions with a focus on lowering triglyceride levels could help reduce the rate of GDM. Conclusions Pregnant women who experienced lockdown had higher levels of TC, TG HDL and LDL in the first trimester. Furthermore, TG had a mediating effect between lockdown and GDM which indicated lifestyle behavior may have an effect on the development of GDM by affecting lipid profile. Therefore, exercise and diet interventions in early pregnancy are essential components of GDM management. Declarations Acknowledgments The authors would like to express thanks to all the participants. Author Contributions Jing Peng: study design, data analysis, interpretation and manuscript writing; Bo Jiao: study design, data collection and manuscript writing; Zhen Huang: data analysis, interpretation and manuscript writing; Feixue Shao: data acquisition and interpretation; Yuan Liu: data acquisition, data interpretation and manuscript revision; Cunjie Lin: study design, data analysis, critical manuscript revision; Xiaolin Hua: study design, data interpretation and manuscript revision. Funding This study was funded by the Academic Leader of of the Health Discipline of the Shanghai Municipal Health Commission (2022XD004), Shanghai 2023 "Science and Technology Innovation Action Plan" Medical Innovation Research Project (23Y11909400), 2024 Hainan Health Science and Technology Innovation Joint project (SQ2023WSJK0189) and Jin Ye Seed Fund of Hainan Branch, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University (JYZZ-YJ-02). Data Availability Statement The datasets utilized and/or analyzed during the current study are available from the corresponding author upon reasonable request. Ethics approval and consent to participate The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the ethics committee of Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University (KS23310, 19 Sep 2023). Competing interests The authors declare no competing interests. Informed Consent Statement Not applicable. Author details Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China； Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China； Department of Obstetrics and Gynecology, Hainan Branch, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya 572022, China； Center for Applied Statistics and School of Statistics, Renmin University of China, Beijing 100872, China. References Zhou FY, Li C, Qin KZ, Luo C, Huang HF, Wu YT. Delivery and neonatal outcomes of pregnant women during the Shanghai lockdown: A retrospective analysis. Front Pediatr. 2023;11:992908. McIntyre HD, Catalano P, Zhang C, Desoye G, Mathiesen ER, Damm P. Gestational diabetes mellitus. Nat Rev Dis Primers. 2019;5(1):47. 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Khoury J, Henriksen T, Christophersen B, Tonstad S. Effect of a cholesterol-lowering diet on maternal, cord, and neonatal lipids, and pregnancy outcome: a randomized clinical trial. Am J Obstet Gynecol. 2005;193(4):1292–301. Strom CJ, McDonald SM, Remchak MM, Kew KA, Rushing BR, Houmard JA et al. The Influence of Maternal Aerobic Exercise, Blood DHA and EPA Concentrations on Maternal Lipid Profiles. Int J Environ Res Public Health. 2022;19(6). Bartels HC, Kennelly MA, Killeen SL, Lindsay KL, Crowley RK, McAuliffe FM. An mHealth-Supported antenatal lifestyle intervention may be associated with improved maternal sleep in pregnancy: Secondary analysis from the PEARS trial. BJOG. 2022;129(13):2195–202. Butler CL, Williams MA, Sorensen TK, Frederick IO, Leisenring WM. Relation between maternal recreational physical activity and plasma lipids in early pregnancy. Am J Epidemiol. 2004;160(4):350–9. ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 15. Management of Diabetes in Pregnancy: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S254–66. Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx Table2.xlsx Table3.docx FigureS1.jpg Figure S1. Flowchart of data preparation. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4354112","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":299285242,"identity":"b6a383b7-1e7f-4dc0-a55c-296c16075b48","order_by":0,"name":"Jing Peng","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai","correspondingAuthor":false,"prefix":"","firstName":"Jing","middleName":"","lastName":"Peng","suffix":""},{"id":299285243,"identity":"12447b60-c222-4d58-a237-3e3c70f0994a","order_by":1,"name":"Bo Jiao","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Hainan Branch, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya","correspondingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Jiao","suffix":""},{"id":299285244,"identity":"42f70c67-d48f-49fe-9adc-54fa26c5818d","order_by":2,"name":"Zhen Huang","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai","correspondingAuthor":false,"prefix":"","firstName":"Zhen","middleName":"","lastName":"Huang","suffix":""},{"id":299285246,"identity":"f598fcb0-96a1-4672-a8c1-781ed713be55","order_by":3,"name":"Feixue Shao","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai","correspondingAuthor":false,"prefix":"","firstName":"Feixue","middleName":"","lastName":"Shao","suffix":""},{"id":299285248,"identity":"04458dc6-3796-473c-9273-51f0501180de","order_by":4,"name":"Yuan Liu","email":"","orcid":"","institution":"Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Liu","suffix":""},{"id":299285251,"identity":"f34b69ef-6163-4fe7-a773-f0584ec02477","order_by":5,"name":"Cunjie Lin","email":"","orcid":"","institution":"Center for Applied Statistics and School of Statistics, Renmin University of China, Beijing","correspondingAuthor":false,"prefix":"","firstName":"Cunjie","middleName":"","lastName":"Lin","suffix":""},{"id":299285255,"identity":"41c0fd9d-832a-4f21-87cd-dab57559df18","order_by":6,"name":"Xiaolin Hua","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYBACAxCRwMAgwwakmRkqJOTkidXCA9FyxsLYsIEYLUDAAyKYGdsqEhkOENBiLpH8TOJBjQ0Pn3QD8+fCeRIJjA3MDx/dwKPFckaasUHCsTQeNpkDbNIzt0nksTOwGRvn4HPYjQTDBwlsh3nYJBLYmHm3SRQzNvCwSePXkv7hQMI/sBbmz7xzJBIbDhDUkmP4ILENrIVBmreBGC1n3hQbJPalgR0mzXNMwtiwmZBfjqdvk/zxzUZOfgbQYTw1dXLy7M0PH+PTggT4P0BoZuKUj4JRMApGwSjAAwAQe0Gx3Yy57AAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai","correspondingAuthor":true,"prefix":"","firstName":"Xiaolin","middleName":"","lastName":"Hua","suffix":""}],"badges":[],"createdAt":"2024-05-01 11:52:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4354112/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4354112/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56157425,"identity":"f9e820ae-e669-4d7a-9f00-1d933e605b51","added_by":"auto","created_at":"2024-05-09 08:36:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":660124,"visible":true,"origin":"","legend":"\u003cp\u003eScheme of mediation analysis.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4354112/v1/db227598319cd618fe1b59a7.jpg"},{"id":56156941,"identity":"d58c1ae4-76d5-4d1b-8ccd-d0b2a759c436","added_by":"auto","created_at":"2024-05-09 08:28:24","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":428292,"visible":true,"origin":"","legend":"\u003cp\u003eA: box-plots of blood lipid profile in the first trimester for GDM group and non-GDM groups. GDM group had higher levels of TC, TG and LDL (p \u0026lt; 0.001) than non-GDM group in the first trimester; B: box-plots of blood lipid profile in the first trimester for lockdown and non-lockdown groups. Pregnant women who experienced lockdown had higher levels of TC, TG, HDL, and LDL (p \u0026lt; 0.001) in the first trimester than others.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4354112/v1/7cad982a69b35cf738e0491d.jpg"},{"id":75770601,"identity":"b2489cbe-e0ce-4855-91bf-f9e5212e5b61","added_by":"auto","created_at":"2025-02-08 05:38:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1729792,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4354112/v1/3ea8ad7b-41ca-4557-9735-7f9a95e39f63.pdf"},{"id":56156328,"identity":"30e32c42-3bd7-4daa-afb9-8aba2c7cd983","added_by":"auto","created_at":"2024-05-09 08:20:22","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11516,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4354112/v1/28458a61e03586832c8931ec.xlsx"},{"id":56156333,"identity":"733e3c76-597e-410f-8fe7-93fa4ee78d6b","added_by":"auto","created_at":"2024-05-09 08:20:23","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":11452,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4354112/v1/6b91690fc8fc1b608e00ec75.xlsx"},{"id":56157951,"identity":"59229a65-27cc-4628-a355-6483eaef195b","added_by":"auto","created_at":"2024-05-09 08:44:34","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":17207,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4354112/v1/43b0dde45b47c70d482c9b24.docx"},{"id":56157427,"identity":"dc3a5ccb-e5fa-4ce3-b5b3-baba1dfa4a14","added_by":"auto","created_at":"2024-05-09 08:36:24","extension":"jpg","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":186458,"visible":true,"origin":"","legend":"\u003cp\u003eFigure S1. Flowchart of data preparation.\u003c/p\u003e","description":"","filename":"FigureS1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4354112/v1/3a53e240c50e28203e28d8c9.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mediating effect of lipid levels during first trimester of pregnancy between COVID-19 lockdown and gestational diabetes mellitus","fulltext":[{"header":"Background","content":"\u003cp\u003eGestational diabetes mellitus (GDM) is one of the most common complications for pregnant women[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], which can lead to short- and long-term adverse consequences for both mother and offspring[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The reported prevalence of GDM in mainland China was 5.12\u0026ndash;33.3%, with a rapid rising trend[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. During the outbreak of COVID-19 in recent years, lockdown was an important measure to prevent the spread of infection, thus most residents were confined to their houses. Strikingly, lockdown increased GDM prevalence, especially for pregnant women in the first trimester of gestation[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Changes in environments, behaviors, and the psychological status during the lockdown, such as physical inactivity, low sleep levels, poor diet, and mental health problems might result in a higher risk of GDM[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eLipid metabolism plays an important role in the pathophysiology of GDM[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. A growing number of studies suggest that elevated maternal triglycerides (TG) levels were associated with higher risk of GDM[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Other studies also observed that GDM patients had significantly increased serum total cholesterol (TC) levels and decreased low-density lipoprotein (LDL) concentrations when compared to unaffected patients[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Intriguingly, maternal lipid metabolism could be affected by different kinds of lifestyle including diet and physical activity[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. During the lockdown which might result in physical inactivity and poor diet[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], higher TC and TG levels were found in non-pregnant people[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, the maternal lipid levels affected by lockdown remains unclear. Furthermore, the relationship among lockdown, maternal lipid profile and GDM has not been studied.\u003c/p\u003e \u003cp\u003eTherefore, this study aimed to provide a description of lipids profile change affected with lockdown during the first trimester. Furthermore, we sought to conduct a mediation analysis to explore the potential relationship among lockdown, lipid levels change during the first trimester and GDM, which may help further establish lifestyle interventions targeted on lipid metabolism to reduce the risk of GDM.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted at the Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University. Patients delivered in this hospital between January 2021 and December 2022 were included in this study. The study protocol was approved by the hospital ethics committee.\u003c/p\u003e \u003cp\u003eThis whole-city lockdown in Shanghai, which officially lasted 63 days (began on 28th March 2022 and ended on 1st June 2022) with much stricter measures, had almost all residents confined to their homes and banned from going out, except for those who provided medical necessities[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. We identified the women who experienced lockdown in the first trimester based on the time of less than 13 gestational weeks crossed with this period. According to the hospital policy, pregnant women had to undergo nucleic acid testing before they came to hospital for antenatal care, delivery or follow up. All pregnant women included in this study were SARS-CoV-2 negative during pregnancy. And women were not suggested to receive Anti- SARS-CoV2 vaccine during pregnancy in China.\u003c/p\u003e \u003cp\u003eThe inclusion criteria were as follows: (a) age\u0026thinsp;\u0026ge;\u0026thinsp;18 years and \u0026lt;\u0026thinsp;45 years, (b) singleton pregnancy, (c) first prenatal visit at this Hospital before 12 gestational weeks, (d) full-term pregnancy (\u0026ge;\u0026thinsp;37 gestational weeks), (e) fasting plasma glucose\u0026thinsp;\u0026lt;\u0026thinsp;5.1 mmol/L in the first prenatal visit test. The exclusion criteria were as follows: (a) a diagnosis of type 1 or type 2 diabetes mellitus before or during pregnancy, (b) a history of severe complications including tumor or other severe diseases during pregnancy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eClinical data were collected from the medical records by trained staffs. Basic information including age, gravidity, parity, pre-pregnancy body mass index (BMI), delivery mode, gestational age at birth, and birth weight were recorded. Biochemistry tests were performed at first prenatal visit, including blood lipid panels consisting of TC, TG, high-density lipoprotein (HDL) and LDL. All laboratory measurements were performed within 3 days after the first clinical visit using the Hitachi 7180 automatic biochemical analyzer. The samples were stored at 4\u0026deg;C and were analyzed within 4-h after collection.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eOutcome\u003c/h2\u003e \u003cp\u003eAll pregnant women underwent a 75 g OGTT at 24\u0026ndash;28 weeks. Participants were diagnosed with GDM and defined as the GDM group if their PG with a 75 g OGTT met one or more of the following criteria: (a) fasting plasma glucose\u0026thinsp;\u0026ge;\u0026thinsp;5.1 mmol/L; (b) 1-h plasma glucose\u0026thinsp;\u0026ge;\u0026thinsp;10.0 mmol/L; and (c) 2-h plasma glucose\u0026thinsp;\u0026ge;\u0026thinsp;8.5 mmol/L [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eContinuously distributed variables were presented as mean (standard deviation). Since none of them subject to normal distribution, the Wilcoxon rank-sum test was used. Categorical variables were displayed by counts (percentages) and compared using a chi-square test or Fisher's exact test, where appropriate. Multivariate logistic regression model was performed to analyze the effects of blood lipid profile and lockdown in the first trimester on GDM. Specifically, we define \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(Y=1\\)\u003c/span\u003e\u003c/span\u003e if the subject was diagnosed with GDM, and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(Y=0\\)\u003c/span\u003e\u003c/span\u003e, otherwise, the logistic regression model is given by\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$P\\left(Y=1|{X}_{1},\\cdots , {X}_{p}\\right)=\\frac{\\text{exp}\\left({\\beta }_{0}+{\\beta }_{1}{X}_{1}+\\cdots +{\\beta }_{10}{X}_{10}\\right)}{1+\\text{exp}\\left({\\beta }_{0}+{\\beta }_{1}{X}_{1}+\\cdots +{\\beta }_{10}{X}_{10}\\right) },$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003ewhere there were 10 covariates incorporated in the model, including the continuous variables: age (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{1}\\)\u003c/span\u003e\u003c/span\u003e) and blood lipid panels in the first trimester TC (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{2}\\)\u003c/span\u003e\u003c/span\u003e), TG (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{3}\\)\u003c/span\u003e\u003c/span\u003e), HDL (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{4}\\)\u003c/span\u003e\u003c/span\u003e), LDL (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{5}\\)\u003c/span\u003e\u003c/span\u003e). We also introduced three dummy variables to indicate the BMI classification. \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{6}=1\\)\u003c/span\u003e\u003c/span\u003e represented underweight (BMI\u0026thinsp;\u0026lt;\u0026thinsp;18.5), \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{7}=1\\)\u003c/span\u003e\u003c/span\u003e represented overweight (BMI 25-27.9), \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{8}=1\\)\u003c/span\u003e\u003c/span\u003e represented obesity (BMI\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\ge\\)\u003c/span\u003e\u003c/span\u003e 28), and the normal weight (BMI 18.5\u0026ndash;24.9) was defined as the baseline one. Besides, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{9}=1\\)\u003c/span\u003e\u003c/span\u003e represented that the woman was multiparous and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({X}_{10}=1\\)\u003c/span\u003e\u003c/span\u003e indicated lockdown in the first trimester.\u003c/p\u003e \u003cp\u003eFurthermore, preliminary analysis showed that women who experienced lockdown in the first trimester had higher levels of TC, TG, HDL and LDL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than others, which indicated that a mediation pathway might be possible from lockdown in the first trimester, the blood lipid profiles, to GDM (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Thus, mediation analysis was conducted to determine whether blood lipid profile could mediate the relationship between lockdown in the first trimester and GDM. The corresponding mediation model is\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv id=\"Equb\" class=\"Equation\"\u003e \u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n$$P\\left(Y=1|\\varvec{X},\\varvec{M},A\\right)=\\frac{\\text{exp}\\left({\\beta }_{0}+\\alpha A+{\\varvec{\\beta }}^{T}\\varvec{M}+{\\varvec{\\beta }}_{X}^{T}\\varvec{X}\\right)}{1+\\text{exp}\\left({\\beta }_{0}+\\alpha A+{\\varvec{\\beta }}^{T}\\varvec{M}+{\\varvec{\\beta }}_{X}^{T}\\varvec{X}\\right)},$$\u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Equc\" class=\"Equation\"\u003e \u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equc\" name=\"EquationSource\"\u003e\n$${M}_{\\varvec{j}}={\\gamma }_{0j}+{\\gamma }_{j}A+{\\varvec{\\gamma }}_{Xj}^{T}\\varvec{X}+{\\epsilon }_{j}, j=1,\\cdots , 4,$$\u003c/div\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003ewhere the response \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(Y\\)\u003c/span\u003e\u003c/span\u003ewas taken to be the diagnosis of GDM, the potential mediators in \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\varvec{M}\\)\u003c/span\u003e\u003c/span\u003e were TC (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({M}_{1}\\)\u003c/span\u003e\u003c/span\u003e), TG (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({M}_{2}\\)\u003c/span\u003e\u003c/span\u003e), HDL (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({M}_{3}\\)\u003c/span\u003e\u003c/span\u003e), LDL (\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({M}_{4}\\)\u003c/span\u003e\u003c/span\u003e), the exposure variable \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(A=1\\)\u003c/span\u003e\u003c/span\u003e if the subject experienced lockdown in the first trimester, and 0, otherwise; and the confounding covariates \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\varvec{X}\\)\u003c/span\u003e\u003c/span\u003e were age, BMI and multiparous; the random errors \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({\\epsilon }_{i}\\)\u003c/span\u003e\u003c/span\u003e had mean zero and constant variance, and was independent of \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\varvec{X}\\)\u003c/span\u003e\u003c/span\u003e and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(A\\)\u003c/span\u003e\u003c/span\u003e. In this model, we referred \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\alpha\\)\u003c/span\u003e\u003c/span\u003e to the direct effect, the mediation effect (or indirect effect) of the exposure on the outcome mediated through the mediator was approximately equal to \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\beta \\gamma\\)\u003c/span\u003e\u003c/span\u003eon the log-odds-ratio scale[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe significance tests of regression coefficients \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\alpha\\)\u003c/span\u003e\u003c/span\u003e, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\varvec{\\beta }\\)\u003c/span\u003e\u003c/span\u003eand \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\varvec{\\gamma }\\)\u003c/span\u003e\u003c/span\u003e can be implemented using Wald \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({\\chi }^{2}\\)\u003c/span\u003e\u003c/span\u003e-test or \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(t\\)\u003c/span\u003e\u003c/span\u003e-test. In this study, of interest is to test whether there exists significant mediation effect or not, which can be formulated as the hypothesis testing problem \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({H}_{0}: \\beta \\gamma =0\\)\u003c/span\u003e\u003c/span\u003eversus \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({H}_{1}:\\beta \\gamma \\ne 0.\\)\u003c/span\u003e\u003c/span\u003eTwo popular tests, the Wald-type Sobel\u0026rsquo;s test [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and the joint significance test (also known as the MaxP test)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] were applied here to detect the mediation effect. The two testing procedures were easy to understand and implement, and hence had been widely used by applied researchers.\u003c/p\u003e \u003cp\u003eAll analyses were performed using R software, with a significance level of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of study subjects\u003c/h2\u003e \u003cp\u003eAfter screening, 3997 pregnant women were included in this study (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among them, 614 (15.36%) were defined as the GDM group, while 3383 (84.64%) were defined as the non-GDM group. From Table\u0026nbsp;1, pregnant women in the GDM group were significantly older, had higher proportions of overweight and obesity, and lower gestational age at birth compared to the non-GDM group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFurthermore, the GDM group had higher rate of lockdown experience in the first trimester (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than non-GDM group (Table\u0026nbsp;1). Besides, the results of blood lipid profile plotted in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eA showed that GDM group had higher levels of TC, TG and LDL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than non-GDM group in the first trimester. For further studying the effects of lockdown on the blood lipid profile in the first trimester, we presented the box-plots of the blood lipid profile in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eB. The results indicated that women experiencing lockdown in the first trimester had higher levels of TC, TG, HDL and LDL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than others. Thus, these results provided us with strong evidence for exploring the mediation effects of blood lipid profile as shown in Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eAssociation between clinical characteristics and blood lipid profile and the risk of GDM\u003c/h2\u003e \u003cp\u003eThe results of multivariate logistic regression analysis are summarized in Table\u0026nbsp;2, which revealed that age (OR 1.06, 95% CI 1.03\u0026ndash;1.09), TG (OR 1.34, 95% CI 1.16\u0026ndash;1.55) and lockdown in the first trimester (OR 1.84, 95% CI 1.50\u0026ndash;2.26) were significantly associated with the risk of GDM, whereas no significant associations were observed for TC, LDL, and HDL. Underweight (OR 0.39, 95% CI 0.26\u0026ndash;0.60) and obesity (OR 1.69, 95% CI 1.05\u0026ndash;2.74) were associated with the risk of GDM, compared with normal weight.\u003c/p\u003e \u003cp\u003e \u003cb\u003eEffect of lockdown on GDM mediated through blood lipid profile in the first trimester of pregnancy\u003c/b\u003e \u003c/p\u003e \u003cp\u003eFirst trimester lipid parameters, lockdown and GDM are known to be interrelated. Therefore, we explored whether the first trimester lipid parameters played a mediating role in the association between lockdown and GDM. The testing results were presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The results of Sobel\u0026rsquo;s test and the MaxP test were consistent. The following conclusions were identified: (i) the exposure \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(A\\)\u003c/span\u003e\u003c/span\u003e(lockdown in the first trimester) had a significant effect on the mediators \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\varvec{M}\\)\u003c/span\u003e\u003c/span\u003e (TC, TG, HDL and LDL) since all \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({p}_{\\gamma }\u0026lt;0.001\\)\u003c/span\u003e\u003c/span\u003e; (ii) the mediator \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({M}_{2}\\)\u003c/span\u003e\u003c/span\u003e (TG) had a significant effect on the outcome \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(Y\\)\u003c/span\u003e\u003c/span\u003e (GDM), while the effects of TC, HDL and LDL on GDM were not significant; (iii) the mediator TG played an important role in mediating the effect of lockdown during the first trimester on GDM due to its \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(MaxP\u0026lt;0.001\\)\u003c/span\u003e\u003c/span\u003e and the 95% confidence interval of \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({T}_{Sobel}\\)\u003c/span\u003e\u003c/span\u003e did not include zero; but significant mediation effects of TG, HDL and LDL were not detected.\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eA total of 3997 pregnant women were included in the final analysis, among whom 614 (15.36%) were defined as the GDM group and 3383 (84.64%) were defined as the non-GDM group. Women who experienced lockdown in the first trimester had higher levels of TC, TG, HDL and LDL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than others. Besides, experiencing lockdown (OR 1.84, 95% CI 1.50\u0026ndash;2.26) and higher level of TG (OR 1.34, 95% CI 1.16\u0026ndash;1.55) during the first trimester were both significantly and independently associated with the risk of GDM by multivariate logistic regression analysis. Thus, mediation analysis was used to explore the effect of lockdown on GDM mediated through TG levels. As a result, TG had a significant mediating effect (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas the mediating effects of TC, HDL, and LDL could not be considered significant. Therefore, it was concluded that the lockdown had an important effect on the development of GDM by affecting TG levels.\u003c/p\u003e \u003cp\u003eAmong type 2 diabetes people, the dyslipidemia is often an early manifestation, occurring even before overt diabetes develops[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. As early in pregnancy, lipid metabolic profiles differed between women with and without GDM[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Recent studies have found higher TG concentrations were associated with higher GDM risk in the first trimester, but not FPG[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. A potential mechanism underlying this phenomenon might be that patients at risk of GDM usually associate with higher levels of insulin resistance (IR), whereby elevated plasma insulin concentrations would enhance very-low‐density lipoprotein (VLDL) synthesis, and lead to the increase in serum TG levels[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Accordingly, TG is the most sensitive lipid index to IR among the common lipid profiles such as TC, TG, HDL and LDL, and was identified as a reliable risk factor for GDM [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This study also found that GDM group had higher levels of TC, TG and LDL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than non-GDM group in the first trimester, whereas only TG (OR 1.34, 95% CI 1.16\u0026ndash;1.55) was associated with the risk of GDM.\u003c/p\u003e \u003cp\u003eDiet and exercise could influence maternal lipid profiles. As other researchers reported, a cholesterol-lowering diet[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and moderate-intensity aerobic exercise[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] from early pregnancy may benefit triglyceride levels[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Moreover, an increasing number of studies have also suggested that the risk of GDM may be reduced by diet, exercise, and lifestyle intervention, particularly when started during the first or early in the second trimester[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. On the contrary, lockdown confined most residents to their houses in order to prevent the spread of infection, thus resulted in insufficient dietary supplement and limited physical activity for pregnant women. This study indicated for the first time that women experiencing lockdown in the first trimester had higher levels of TC, TG, HDL and LDL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than others. In addition, lockdown increased GDM prevalence for pregnant women in the first trimester of gestation (OR 1.84, 95% CI 1.50\u0026ndash;2.26). From that, we speculated that the poor diet and physical inactivity during lockdown may disturb the normal glycometabolism and lead to GDM, especially the first trimester of pregnancy may be the window for sensitive exposure. Therefore, this study conducted a mediation analysis to explore the potential relationship among lockdown, lipid levels change and GDM, and verified that elevated TG levels during the first trimester caused by lockdown was responsible for increased GDM incidence. Thus, lifestyle behavior interventions in early pregnancy with a focus on lowering triglyceride levels may help to prevent GDM and reduce the consequent health risks for women and children.\u003c/p\u003e \u003cp\u003eTo the best of our knowledge, this was the first study to provide a description of maternal lipids profile change affected with lockdown during the first trimester. Our findings showed that women who experienced lockdown in the first trimester had higher levels of TC, TG, HDL and LDL than others. Moreover, a mediation analysis focused on the potential relationship among lockdown, lipid levels change during the first trimester and GDM, which suggests that lockdown had an important effect on the development of GDM by affecting TG levels. However, several limitations of this analysis should be acknowledged. First, this was a hospital-based retrospective study which might affect the power and generality of our investigation. Second, data on type of poor diet and physical inactivity among women who experienced lockdown were lacking in this study, thus more investigation and further analysis exploring targeted interventions with a focus on lowering triglyceride levels could help reduce the rate of GDM.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePregnant women who experienced lockdown had higher levels of TC, TG HDL and LDL in the first trimester. Furthermore, TG had a mediating effect between lockdown and GDM which indicated lifestyle behavior may have an effect on the development of GDM by affecting lipid profile. Therefore, exercise and diet interventions in early pregnancy are essential components of GDM management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express thanks to all the participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJing Peng: study design, data analysis, interpretation and manuscript writing; Bo Jiao: study design, data collection and manuscript writing; Zhen Huang: data analysis, interpretation and manuscript writing; Feixue Shao: data acquisition and interpretation; Yuan Liu: data acquisition, data interpretation and manuscript revision; Cunjie Lin: study design, data analysis, critical manuscript revision; Xiaolin Hua: study design, data interpretation and manuscript revision.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Academic Leader of of the Health Discipline of the Shanghai Municipal Health Commission (2022XD004), Shanghai 2023 \u0026quot;Science and Technology Innovation Action Plan\u0026quot; Medical Innovation Research Project (23Y11909400), 2024 Hainan Health Science and Technology Innovation Joint project (SQ2023WSJK0189) and Jin Ye Seed Fund of Hainan Branch, Shanghai Children\u0026apos;s Medical Center, School of Medicine, Shanghai Jiao Tong University (JYZZ-YJ-02).\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets utilized and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by\u0026nbsp;the ethics committee of Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University (KS23310, 19 Sep 2023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eDepartment of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China；\u003c/li\u003e\n \u003cli\u003eShanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China；\u003c/li\u003e\n \u003cli\u003eDepartment of Obstetrics and Gynecology, Hainan Branch, Shanghai Children\u0026apos;s Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya 572022, China；\u003c/li\u003e\n \u003cli\u003eCenter for Applied Statistics and School of Statistics, Renmin University of China, Beijing 100872, China.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhou FY, Li C, Qin KZ, Luo C, Huang HF, Wu YT. 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Geneva: World Health Organization Copyright \u0026copy; World Health Organization 2013.; 2013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eValeri L, Vanderweele TJ. Mediation analysis allowing for exposure-mediator interactions and causal interpretation: theoretical assumptions and implementation with SAS and SPSS macros. Psychol Methods. 2013;18(2):137\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSobel ME. Asymptotic Confidence Intervals for Indirect Effects in Structural Equation Models. Sociol Methodol. 1982;13:290\u0026ndash;312.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMacKinnon DP, Lockwood CM, Hoffman JM, West SG, Sheets V. A comparison of methods to test mediation and other intervening variable effects. Psychol Methods. 2002;7(1):83\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBahiru E, Hsiao R, Phillipson D, Watson KE. Mechanisms and Treatment of Dyslipidemia in Diabetes. Curr Cardiol Rep. 2021;23(4):26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen Q, Francis E, Hu G, Chen L. Metabolomic profiling of women with gestational diabetes mellitus and their offspring: Review of metabolomics studies. J Diabetes Complications. 2018;32(5):512\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Y, Lan X, Cai C, Li R, Gao Y, Yang L, et al. Associations between Maternal Lipid Profiles and Pregnancy Complications: A Prospective Population-Based Study. Am J Perinatol. 2021;38(8):834\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShen L, Wang D, Huang Y, Ye L, Zhu C, Zhang S, et al. Longitudinal trends in lipid profiles during pregnancy: Association with gestational diabetes mellitus and longitudinal trends in insulin indices. Front Endocrinol (Lausanne). 2022;13:1080633.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhoury J, Henriksen T, Christophersen B, Tonstad S. Effect of a cholesterol-lowering diet on maternal, cord, and neonatal lipids, and pregnancy outcome: a randomized clinical trial. Am J Obstet Gynecol. 2005;193(4):1292\u0026ndash;301.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStrom CJ, McDonald SM, Remchak MM, Kew KA, Rushing BR, Houmard JA et al. The Influence of Maternal Aerobic Exercise, Blood DHA and EPA Concentrations on Maternal Lipid Profiles. Int J Environ Res Public Health. 2022;19(6).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBartels HC, Kennelly MA, Killeen SL, Lindsay KL, Crowley RK, McAuliffe FM. An mHealth-Supported antenatal lifestyle intervention may be associated with improved maternal sleep in pregnancy: Secondary analysis from the PEARS trial. BJOG. 2022;129(13):2195\u0026ndash;202.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButler CL, Williams MA, Sorensen TK, Frederick IO, Leisenring WM. Relation between maternal recreational physical activity and plasma lipids in early pregnancy. Am J Epidemiol. 2004;160(4):350\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, et al. 15. Management of Diabetes in Pregnancy: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S254\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Gestational diabetes mellitus, Triglycerides, COVID-19 lockdown, Mediation analysis, Intervention","lastPublishedDoi":"10.21203/rs.3.rs-4354112/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4354112/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e Higher triglycerides (TG) levels are associated with gestational diabetes mellitus (GDM) and higher prevalence of GDM was found in women experiencing COVID-19 pandemic lockdown in early pregnancy. This study aimed to explore the relationship among lockdown, lipid levels change in the first trimester and GDM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThis was a population-based observational cohort study. Mean values of lipid levels were compared by Wilcoxon rank-sum test. Logistic regression analysis was used to analyze the effects of lockdown and lipid profile on GDM. Mediation analysis was performed to identify whether blood lipid level mediated the association between lockdown and GDM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e A total of 3997 pregnant women were included, among whom 614 (15.36%) were defined as GDM group and 3383 (84.64%) were defined as non-GDM group. Women who experienced lockdown in the first trimester had higher levels of serum total cholesterol (TC), TG, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) (p \u0026lt; 0.001) than others. Besides, experiencing lockdown (OR 1.84, 95% CI 1.50-2.26) and higher level of TG (OR 1.34, 95% CI 1.16-1.55) during the first trimester were both significantly and independently associated with the risk of GDM by multivariate logistic regression analysis. Furthermore, mediation analysis was conducted to explore the potential relationship among lockdown, lipid levels change during the first trimester and GDM,which showed TG played a mediating role in the association between lockdown and GDM (p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003ePregnant women who experienced lockdown had higher levels of TC, TG HDL and LDL in the first trimester.TG had a mediating effect between lockdown and GDM, indicating that lockdown which brought physical inactivity and poor diet in early pregnancy may have an effect on the development of GDM by affecting lipid profile. Therefore, exercise and diet interventions in early pregnancy could help prevent GDM.\u003c/p\u003e","manuscriptTitle":"Mediating effect of lipid levels during first trimester of pregnancy between COVID-19 lockdown and gestational diabetes mellitus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-09 08:20:08","doi":"10.21203/rs.3.rs-4354112/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5e1a3791-e397-4227-b698-3e0a21448333","owner":[],"postedDate":"May 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-08T05:38:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-09 08:20:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4354112","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4354112","identity":"rs-4354112","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}