The correlation between low serum bile acid levels in the third trimester of pregnancy and maternal and neonatal outcomes: an observational, retrospective case–control study

The correlation between low serum bile acid levels in the third trimester of pregnancy and maternal and neonatal outcomes: an observational, retrospective case–control study | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 7 April 2025 V1 Latest version Share on The correlation between low serum bile acid levels in the third trimester of pregnancy and maternal and neonatal outcomes: an observational, retrospective case–control study Authors : Chuan Feng [email protected] and shou feng 0000-0003-2085-345X Authors Info & Affiliations https://doi.org/10.22541/au.174401646.67148838/v1 182 views 129 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background : Currently, there are more studies on the increase of bile acids during pregnancy, but less attention has been paid to the decrease of bile acids during pregnancy. Research aim : To explore the impact of low bile acid levels during the third trimester of pregnancy on pregnancy and neonatal outcomes. Methods : 429 pregnant women had total bile acid levels of less than 1 µmmol/L in both tests, and these were selected as the study group. 501 pregnant women with normal total bile acid levels in both tests were randomly selected from them as the control group. Results : Compared with the normal control group, the lower bile acid levels were associated with higher age(30.64±4.43 vs 29.27±3.63 years; P <0.001) and smaller gestational age(38.73±1.29 vs 39.34±0.97 weeks; P <0.001). There were significant differences between the two groups in the incidences of gestational diabetes, hypothyroidism and premature rupture of membranes. These conditions were more common in pregnant women with low bile acid levels. Conclusion : Pregnant women with low bile acid levels have a higher incidence of gestational diabetes, hypothyroidism and premature rupture of membranes. The correlation between low serum bile acid levels in the third trimester of pregnancy and maternal and neonatal outcomes: an observational, retrospective case–control study Chuan-Shou Feng*, Cai-Feng Sun Obstetrical department, Changzhou Women and Children Health Hospital Affiliated to Nanjing Medical University, Changzhou, Jiangsu, China. Correspondence: Chuan-Shou Feng, Changzhou Women and Children Health Hospital affiliated to Nanjing Medical University Changzhou, Jiangsu, China, telephone number :13584589498, e-mail: [email protected] . Abstract Background : Currently, there are more studies on the increase of bile acids during pregnancy, but less attention has been paid to the decrease of bile acids during pregnancy. Research aim: To explore the impact of low bile acid levels during the third trimester of pregnancy on pregnancy and neonatal outcomes. Methods: 429 pregnant women had total bile acid levels of less than 1 µmmol/L in both tests, and these were selected as the study group. 501 pregnant women with normal total bile acid levels in both tests were randomly selected from them as the control group. Results: Compared with the normal control group, the lower bile acid levels were associated with higher age( 30.64±4.43 vs 29.27±3.63 years ; P <0.001) and smaller gestational age ( 38.73±1.29 vs 39.34±0.97 weeks ; P <0.001). There were significant differences between the two groups in the incidences of gestational diabetes, hypothyroidism and premature rupture of membranes. These conditions were more common in pregnant women with low bile acid levels. Conclusion: Pregnant women with low bile acid levels have a higher incidence of gestational diabetes, hypothyroidism and premature rupture of membranes. Keywords : Bile acids, Intrahepatic cholestasis of pregnancy, Hypothyroidism, Premature rupture of membranes, Gestational diabetes. Bile acids are synthesized in liver cells and secreted into the intestinal tract, they play significant roles in glucose, fat, and energy metabolism [1-4] , as well as in controlling the growth of intestinal microorganisms [5] . Once these processes are disrupted, it is very likely to lead to the occurrence of liver and gallbladder as well as intestinal diseases. Therefore, people’s interest in bile acids is constantly increasing, and this is also true during pregnancy. Currently, there are more studies on the increase of bile acids during pregnancy, which is intrahepatic cholestasis of pregnancy(ICP). ICP is the most common liver disease during pregnancy. Studies [6-12] have shown that ICP is associated with adverse maternal and fetal outcomes, including a higher risk of preeclampsia, increased risk of post-pregnancy liver and biliary diseases, increased risk of gestational diabetes, preterm birth and fetal asphyxia, etc. But less attention has been paid to the decrease of bile acids during pregnancy. Therefore, on the one hand, we will study the incidence of the low bile acid levels during the third trimester of pregnancy. On the other hand, this study will explore the impact of low bile acid levels during the third trimester of pregnancy on pregnancy and neonatal outcomes. Methods Design A retrospective case–control study was undertaken between March, 2023 and June, 2024 at Changzhou Women and Children Health Hospital affiliated to Nanjing Medical University. All patients signed informed consents, the study design and protocol were reviewed and approved by the Institutional Review Board of Changzhou Women and Children Health Hospital affiliated to Nanjing Medical University prior to the initiation of the study in March 4, 2025. Sample This study included all cases of low bile acid levels that met the inclusion criteria during the period from March 2023 to June 2024 at Changzhou Maternal and Child Health Care Hospital Affiliated to Nanjing Medical University. Eligibility criteria included: singleton pregnancy, no previous liver or biliary system diseases, natural conception, newborns without chromosomal disorders or structural abnormalities. In our hospital, it is recommended that pregnant women undergo total bile acid tests in the outpatient department during the 28-32 weeks of gestation. If there are no abnormal conditions such as ICP, total bile acid tests should be repeated before delivery. From March 2023 to June 2024, a total of 10,581 pregnant women completed total bile acid tests and delivered in our hospital. Among them, 429 pregnant women had total bile acid levels of less than 1 µmmol/L in both tests, and these were selected as the study group. 501 pregnant women with normal total bile acid levels in both tests were randomly selected from them as the control group. Data collection We faithfully recorded the detailed medical data, including the sociodemographic factors(maternal age, BMI), obstetric characteristics(gestational age at delivery, parity, mode of delivery), complications of pregnancy(gestational hypertension, gestational diabetes, hypothyroidism), maternal outcomes(premature rupture of membrane, preterm birth, abruptio placentae, meconium amniotic fluid, and postpartum haemorrhage), and fetal condition(fetal gender, fetal weight, fetal distress, and stillbirth). Data analysis All statistical analysis were performed using SPSS 23.0, Quantitative data were expressed as Mean ±SD, the difference of quantitative data between the two groups were analyzed by homogeneity test of variances, and t test was used under an equal condition, t ’test should be carried out if the variance of the two groups is not equal. The enumeration data were expressed as rate(%), the chi-square tests were used for comparison between the two groups. P <0.05 was chosen to be statistically significant. Results The trial was carried out from March 2023 to June 2024. During this study period, 10,581 women completed total bile acid tests and delivered in our hospital. A total of 512 pregnant women had total bile acid levels of less than 1 µmmol/L for the first time. Among them, 83 pregnant women had their bile acid levels returned to normal after the second test. Eventually, 429 pregnant women(4.1%) had total bile acid levels of less than 1 µmmol/L in both tests. Meanwhile, 338 pregnant women(3.2%) were diagnosed with intrahepatic cholestasis of pregnancy(ICP) during this period. The baseline demographic characteristics and the clinical features were shown in Table 1 , There was no significant difference in BMI, parity, and neonatal birth weight between the two groups( P >0.05). Compared with the normal control group, the lower bile acid levels were associated with higher age( 30.64±4.43 vs 29.27±3.63 years ; P <0.001) and smaller gestational age ( 38.73±1.29 vs 39.34±0.97 weeks ; P <0.001). The proportion of pregnant women with low bile acid levels giving birth to male infants was higher(61.5%), and the difference was statistically significant ( P <0.05). Compared with the normal control group, the pregnant women in the study group had a higher incidence of hypothyroidism( P <0.001), gestational diabetes( P <0.001) and premature rupture of membranes( P <0.05). However, there were no significant differences in other pregnancy and neonatal outcomes between the two groups. In terms of delivery methods, there were also no significant differences between the two groups( P >0.05)(Table 2). In order to quantify the risk of certain pathological conditions in women with low bile acid levels, we calculated the odds ratios for gestational diabetes, hypothyroidism and premature rupture of membranes, and the results were all statistically significant (Table 3). Discussion Bile acids are synthesized from cholesterol in the liver and undergo modification under the action of intestinal bacteria, thereby generating a group of molecules with a common structure but different numbers and spatial positions of hydroxyl groups on the steroid rings. In the intestinal lumen, bile acids play an important role as lipid-soluble solvents, which is crucial for lipid absorption. Bile acids also regulate various liver and intestinal functions and produce systemic effects such as increased energy consumption and improved insulin sensitivity [13,14] . Regarding the relationship between bile acids and glucose metabolism, animal experiments [3] have shown that mice fed with high-fat diet (HFD) exhibited elevated fasting blood glucose levels and reduced bile acid pool volume, and that insulin resistance was improved after supplementing cholic acid (CA). Multiple studies in humans [15-17] have indicated that the bile acid metabolism profile of pregnant women with gestational diabetes mellitus has undergone significant changes. A nested case-control study [18] revealed an independent association between low bile acid concentration and increased risk of gestational diabetes mellitus. A study in 2021 [19] found that the decline in bile acid levels was associated with the occurrence of gestational diabetes mellitus. Our research also discovered that pregnant women with low bile acid levels had a higher incidence of gestational diabetes mellitus. However, some studies [20,21] have found that elevated bile acids, which is the condition of ICP, may be associated with the occurrence of GDM, and can be regarded as one of the potential risk factors. A meta-analysis [22] also found that pregnant women with moderate to severe ICP had a higher risk of developing GDM. This association may be caused by multiple potential mechanisms. A significant increase in serum bile acids can lead to severe hepatocyte damage and subsequent metabolic disorders [23] , including impaired glucose metabolism, insulin resistance, and lipid metabolism disorders [24]. Elevated bile acid levels can also reduce pancreaticβ-cell function and increase insulin resistance, both of which are related to the occurrence of GDM [25] . Moreover, severe ICP can trigger an inflammatory response, which further exacerbate insulin resistance [26] . Multiple in vivo experiments have shown that thyroid hormones can affect bile acid synthesis [27-29] . In hyperthyroidism, multiple studies have found [30,31] that bile acid synthesis is induced. In patients with hypothyroidism, Ellis et al. [32] found that T3 leads to a dose-dependent reduction in bile acid production, with the level dropping to 44% of the control group level. Angelin et al. [33] also found that the bile acid level in patients with hypothyroidism is lower. In our study, we found that the incidence of hypothyroidism is higher in pregnant women with low bile acid levels, confirming the above viewpoints. Our research also found that the incidence of premature rupture of membranes (PROM) in the group of pregnant women with low bile acid levels was higher than that in the normal control group. We speculate that it might be because bile acid is involved in lipid metabolism, when bile acid levels are low, lipid metabolism absorption is affected, ultimately leading to changes in the stability of the fetal membranes and causing PROM. Further research is needed to explore the specific mechanism. Conclusion Pregnant women with low bile acid levels have a higher incidence of gestational diabetes, hypothyroidism and premature rupture of membranes. Therefore, we should pay more attention to pregnant women with low bile acid levels. Acknowledgments We thank ping feng for her help on information collection. Funding None. Availability of data and materials Not applicable Authors’ contributions The manuscript has been read and approved by all authors and all authors contributed to the manuscript. CSF and CFS conceived and designed the study. CSF undertook collection, cleaning, analysis and interpretation of the data and wrote the earlier manuscript drafts. CFS revised subsequent manuscript drafts, reviewed records, and prepared tables and figures. CSF supervised all aspects of the study. Ethics approval and consent to participate All patients signed informed consents, and the study design and protocol were reviewed and approved by the Institutional Review Board of Changzhou Women and Children Health Hospital affiliated to Nanjing Medical University prior to the initiation of the study in March 4, 2025. Consent for publication Not applicable. Competing interests The authors declare that they have no financial or nonfinancial conflicts of interest related to the subject matter or materials discussed in the manuscript. References 1. Chavez-Talavera, O., Tailleux, A., et al. Bile acid control of metabolism and inflammation in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic fatty liver disease. Gastroenterology. 2017, 152, 1679–1694 [e3]. 2. Li, T., Chiang, J.Y. Bile acids as metabolic regulators. 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Arvidsson, et al. Monitoring hepatic cholesterol 7alpha-hydroxylase activity by assay of the stable bile acid intermediate 7alpha-hydroxy-4-cholesten- 3-one in peripheral blood. J. Lipid Res. 2003, 44: 859 – 866 . 31. Bonde Y, Breuer O, et al. Thyroid hormone reduces PCSK9 and stimulates bile acid synthesis in humans. J Lipid Res. 2014 Nov;55(11):2408-15. 32. Ellis EC. Suppression of bile acid synthesis by thyroid hormone in primary human hepatocytes. World J Gastroenterol. 2006 Aug 7;12(29):4640-5. 33. Angelin B, Einarsson K, Leijd B. Bile acid metabolism in hypothyroid subjects: response to substitution therapy. Eur J Clin Invest 1983; 13: 99-106 Supplementary Material File (table 1.docx) Download 13.31 KB File (table 2.docx) Download 13.96 KB File (table 3.docx) Download 12.25 KB Information & Authors Information Version history V1 Version 1 07 April 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords diabetes in pregnancy epidemiology: perinatal maternal medicine Authors Affiliations Chuan Feng [email protected] Changzhou Women and Children's Hospital View all articles by this author shou feng 0000-0003-2085-345X Changzhou Women and Children's Hospital View all articles by this author Metrics & Citations Metrics Article Usage 182 views 129 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Chuan Feng, shou feng. The correlation between low serum bile acid levels in the third trimester of pregnancy and maternal and neonatal outcomes: an observational, retrospective case–control study. Authorea . 07 April 2025. DOI: https://doi.org/10.22541/au.174401646.67148838/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. 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