Maternal Concentrations of Vitamin D Metabolites in Response to High-Dose Oral Vitamin D During First Trimester Pregnancy: A Randomized Controlled Trial

Maternal Concentrations of Vitamin D Metabolites in Response to High-Dose Oral Vitamin D During First Trimester Pregnancy: A Randomized Controlled Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Maternal Concentrations of Vitamin D Metabolites in Response to High-Dose Oral Vitamin D During First Trimester Pregnancy: A Randomized Controlled Trial Inayah Syafitri, Rima Irwinda, Yudianto Budi Saroyo, Yuditiya Purwosunu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4126201/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Jul, 2025 Read the published version in BMC Nutrition → Version 1 posted 4 You are reading this latest preprint version Abstract Vitamin D deficiency has become a common problem globally. The present study aimed to evaluate the effects of different vitamin D3 regimens on maternal concentrations of vitamin D metabolites during pregnancy. This randomized controlled trial was registered at ClinicalTrials.gov (NCT06054919) on 22nd September 2023. Subjects were ≤ 14 weeks gestation pregnant women with vitamin D deficient or insufficient (25(OH)D < 30 ng/ml]. Two intervention groups were randomly assigned: 5,000 IU of vitamin D3 daily or 50,000 IU weekly of vitamin D3. Maternal blood samples were collected before and after four weeks of intervention to assess changes in serum concentrations of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH) 2 D), vitamin D binding protein (VDBP), and 24,25-dihydroxyvitamin D (24,25(OH)2D). Sixty subjects were randomized into two groups, and eight subjects were dropped out. There were no differences in the baseline demographics or baseline levels of any of the vitamin D metabolites between the two groups. In the 50,000 group, the 25(OH)D levels increased from 15.3 ± 4.7 ng/mL to 26.9 ± 6.1 ng/mL (p < 0.001) and 34.6% of the subjects achieved vitamin D sufficiency. While in the 5,000 group, the 25(OH)D levels increased from 14.5 ± 4.3 ng/mL to 27.9 ± 9.3 ng/mL (p < 0.001) and 23.1% of the subjects achieved vitamin D sufficiency. Both groups showed an increasing trend in the total levels of 25(OH)D, 1,25(OH)2D, VDBP, and 24,25(OH)2D. However, the increment of all vitamin D metabolites were not significantly different between two groups. Vitamin D3 50,000 IU weekly is equally effective and safe as 5,000 IU daily in increasing vitamin D levels in pregnant women with vitamin D deficient or insufficient. 1 25-dihydroxyvitamin D 25-hydroxyvitamin D 24 25-dihydroxyvitamin D first trimester pregnancy vitamin D Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Vitamin D deficiency has become a common problem globally and is associated with adverse maternal and neonatal health outcomes. It has been estimated that 18–84% of pregnant women worldwide are vitamin D deficient [ 1 ]. Despite being located in a warm climate region, Indonesia has a high prevalence of vitamin D deficiency. A study conducted in Jakarta revealed that 99.6% of first-trimester pregnant women had vitamin D deficiency and insufficiency [(25(OH)D) 99% are transported in the blood bound to VDBP. In the liver, vitamin D3 is converted into 25(OH)D, which is the primary vitamin D compound in the circulation. In the renal proximal tubules of the kidney, 1α-hydroxylase hydroxylates 25(OH)D to yield 1,25(OH) 2 D. This kidney-generated 1,25(OH) 2 D plays a crucial role in mediating the classical functions of vitamin D in calcium homeostasis and bone mineralization. The production of 1,25(OH) 2 D from 25(OH)D occurs in immune cells, the skin, the placenta and other tissues and may contribute to health in nonpregnant and pregnant women. Both 1,25(OH) 2 D and 25(OH)D are inactivated by CYP24A1, to 1,24,25-trihydroxyvitamin D and 24,25-dihydroxyvitamin D [ 3 , 4 ]. Adequate vitamin D intake is essential for maternal and fetal health during pregnancy. Recent work has emphasized the importance of vitamin D in pregnancy and the placenta. The human placenta expresses all the components required for vitamin D signaling. Vitamin D regulates key target genes associated with implantation, trophoblast invasion, and implantation tolerance. Vitamin D also plays an important role in promoting the shift to a T-helper 2-dominated immune response pattern, which is vital for successful pregnancy outcomes. Vitamin D has immune-modulatory and anti-inflammatory effects that are important for preventing microbial invasion intrauterine. Maternal vitamin D deficiency has been associated with adverse pregnancy outcomes such as preterm labor, preeclampsia, gestational diabetes mellitus, and fetal growth restriction [ 5 – 8 ]. According to the 2010 Institute of Medicine Report, the recommended daily allowance of vitamin D during pregnancy is 600 IU. However, this amount may not be enough to maintain sufficient vitamin D in pregnant women [ 9 , 10 ]. Recent studies have shown that pregnant women should take 4,000 IU/day of vitamin D3 starting from 12–16 weeks of gestation to achieve sufficient vitamin D levels. The Endocrine Society Clinical Practice Guideline recommends treating all vitamin D deficient adults with 50,000 IU of vitamin D3 once a week for 8 weeks, or an equivalent daily dose of 6,000 IU of vitamin D3, to achieve a blood level of 25(OH)D above 30 ng/ml [ 11 , 12 ]. However, there are no available data regarding vitamin D therapy in pregnant women in Indonesia. The present study aimed to evaluate the effects of different vitamin D3 regimens on maternal 25(OH)D, 1,25(OH) 2 D, VDBP, and 24,25(OH) 2 D concentrations during pregnancy. Methods We conducted a randomized controlled trial of vitamin D therapy of 5,000 IU daily or 50,000 IU weekly during pregnancy. The study was conducted at Cipto Mangunkusumo National Center General Hospital and Koja District Hospital in Jakarta, Indonesia, within a period of 1 year All the pregnant women were screened for eligibility when they presented to the clinic for antenatal care visits and were offered enrolment if they met the following inclusion criteria: gestational age of ≤ 14 weeks, vitamin D deficient or insufficient (25(OH)D < 30 ng/ml], and a positive fetal heart rate from ultrasound examination. Individuals were not eligible if they had any of the following exclusion criteria: multiple pregnancy, pregnancy with congenital anomaly, hyperemesis gravidarum, diarrhea, complicated medical history (hypertension, diabetes mellitus, heart, kidney, or liver disease), or use of any dietary supplement containing vitamin D prior to enrolment. Informed consent was obtained from all participants. This study was approved by the Ethical Committee for Research in Humans from the Faculty of Medicine University of Indonesia (257/UN.2F1/ETIK/PPM.00.02/2023) and was registered at ClinicalTrials.gov (NCT06054919) on 22nd September 2023. Participants were randomly assigned to one of two parallel intervention groups. The allocation was concealed based on a computer-generated list with a 1:1 allocation ratio. The groups received either vitamin D3 (cholecalciferol) 5,000 IU (Imedco) daily or 50,000 IU (Imedco) weekly. The randomization list was developed using permuted blocks of size 6. All participants were provided with a standard prenatal multivitamin (Emineton) that contained fumarate Fe 90 mg, folic acid 0.4 mg, vitamin B6 3 mg, vitamin B12 5 mcg, sulphate cupric 0.35 mg, sulphate cobalt 0.15 mg, sulphate mangan 5 mcg, vitamin C 60 mg, vitamin E 5 mg, and phosphate calcium 60 mg. Both groups received the intervention for four weeks. At the beginning of the study, participants underwent baseline blood tests to measure serum concentrations of 25(OH)D, 1,25(OH) 2 D, VDBP, and 24,25(OH) 2 D. A medical history, physical, and ultrasound examination were also performed. Additionally, they were asked to complete a questionnaire about sunlight exposure. Throughout the study, weekly follow-up was conducted to evaluate their adherence to the supplement regimen and to monitor any symptoms related to interventions. Maternal self-report and capsule counts were used to assess adherence. After four weeks of interventions, maternal venous blood was collected to assess changes in serum concentrations of 25(OH)D, 1,25(OH) 2 D, VDBP, and 24,25(OH) 2 D. The study had safety thresholds in place to prevent hypervitaminosis D, which was defined as a serum concentration of 25(OH)D ≥ 100 ng/mL. The concentrations of different forms of vitamin D in the blood were measured using various tests. Serum 25(OH)D was quantified by direct competitive Chemiluminescence Immunoassay (CLIA) using LIAISON®. Serum 1,25(OH) 2 D was quantified by Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) using ImmuTube®. Serum VDBP was quantified by Enzyme-Linked Immunosorbent Assay (ELISA) using Quantikine®. Serum 24,25(OH) 2 D was quantified by Acquity I Class Binary Solvent Manager FTN, Xevo TQXS Tandem Mass Spectrometry (Waters Corporation). All of these laboratory tests were conducted at the Prodia Laboratory in Jakarta. Results Sixty pregnant women who were eligible to participate were randomly assigned to two groups as shown in Fig. 1 . However, after allocation, 5 subjects discontinued participation for any specific reason, and 3 subjects dropped out due to COVID-19 infection. As a result, 52 patients completed the study and were available for analysis. Of these 52 participants, 26 were in the 5,000 group and the other 26 were in the 50,000 group. The median maternal age and gestational age of the study participants were 30 years and 8 weeks, respectively. The distribution of demographics was equal between the control and treatment groups. Approximately half of the study participants (55.8%) were obese, and 35 (67.3%) were multiparous. All of the subjects had low sun exposure scores (< 33.6). Table 1 shows that demographic data were equally distributed between the two groups. Table 1 Baseline demographic characteristics of the study participants Variable All subjects (n = 52) 50,000 IU weekly (n = 26) 5,000 IU daily (n = 26) p-value Age (years) 30 (22–42) 29 (26–42) 30 (22–39) 0.978 Gestational age (weeks) 8 (6–11) 9 (6–11) 8 (6–11) 0.158 Parity Nulliparity Multiparity 17 (32.7%) 35 (67.3%) 8 (30.7%) 18 (69.2%) 9 (34.6%) 17 (65.3%) 0.768 BMI (kg/m 2 ) Underweight (< 18.5) Normal (18.5–22.9) Overweight (23–24.9) Obesity (≥ 25) 26.23 ± 5.36 2 (3.8%) 14 (26.9%) 7 (13.5%) 29 (55.8%) 25.80 ± 5.50 2 (7.6%) 7 (26.9%) 3 (11.5%) 14 (53.8%) 26.60 ± 5.20 0 (0%) 7 (26.9%) 4 (15.3%) 15 (57.6%) 0.699 Sun exposure score Low (< 33.6) Moderate (33.6–44.7) High (≥ 44.8) 11.98 ± 5.25 52 (100%) 0 (0%) 0 (0%) 12.00 ± 5.02 26 (100%) 0 (0%) 0 (0%) 11.96 ± 5.58 26 (100%) 0 (0%) 0 (0%) 0.979 Table 2 demonstrates that the baseline levels of 25(OH)D, 1,25(OH) 2 D, VDBP, and 24,25(OH) 2 D were equal between 50,000 and 5,000 groups. The baseline 25(OH)D levels were 15.3 ± 4.7 ng/mL and 14.5 ± 4.3 ng/mL in the 50,000 and 5,000 groups, respectively. After four weeks of treatment, the levels of 25(OH)D were significantly improved in both groups, but the increment was not statistically significant (p = 0.649) between two groups. In the 50,000 group, 25(OH)D levels increased from 15.3 ± 4.7 ng/mL to 26.9 ± 6.1 ng/mL (p 30 ng/mL). While in the 5,000 group, the 25(OH)D levels increased from 14.5 ± 4.3 ng/mL to 27.9 ± 9.3 ng/mL (p < 0.001) and 23.1% of the subjects achieved vitamin D sufficiency. Figures 2 and 3 illustrate the individual changes in 25(OH)D levels in groups of 50,000 and 5,000, respectively. Table 2 Comparison 25(OH)D, 1,25(OH) 2 D, VDBP, and 24,25(OH) 2 D levels between two groups Variable 50,000 IU/week Group (n = 26) 5,000 IU/day Group (n = 26) Baseline Follow-up Increment Baseline Follow-up Increment 25(OH)D (ng/mL) 15.3 ± 4.7 a 26.9 ± 6.1 a 10.6 (0.1–30.2) 14.5 ± 4.3 b 27.9 ± 9.3 b 10.8 (4.0–28.6) 1,25(OH) 2 D (pg/mL) 72.9 ± 17.6 84.0 (27.8–218.7) 14.8 (-41.5–151.8) 69.6 ± 23.8 b 84.4 (39.3–141.0) b 20.2 (-50.4–59.2) VDBP (µg/mL) 292.0 (11.0–520.0) 296.0 (168.0–1667.0) c 17.0 (-330.0–1361.0) 280.0 (133.0–524.0) 348.5 (198.0–1205.0) c 45.5 (-166.0–963.0) 24,25(OH) 2 D (pg/mL) 67.0 (12,0–329.0) 194.5 (23.0– 727.0) 140.0 (-151.0–638.0) 115.5 (17.0 − 339.0) 288.0 (85.0–525.0) 195.0 (-144.0–501.0) a p<0.05 in 50,000 group between baseline and follow-up levels b p<0.05 in 5,000 group between baseline and follow-up levels c p<0.05 in follow-up levels between 50,000 and 5,000 groups Both groups showed an increasing trend in the total levels of 1,25(OH) 2 D, VDBP, and 24,25(OH) 2 D. However, we only found a statistically significant difference in the levels of 1,25(OH) 2 D between baseline and follow-up in the 5,000 group (p = 0.042). Additionally, we found a statistically significant difference in the follow-up levels of VDBP between the 50,000 and 5,000 groups (p = 0.013). There was no statistically significant difference in the increment of 1,25(OH) 2 D, VDBP, or 24,25(OH) 2 D between the two groups. Pearson correlation analysis revealed no correlation between baseline levels of 25(OH)D and 1,25(OH) 2 D (r = 0.105, p = 0.458). Discussion To the best of our knowledge, this is the first study to explore the impact of high-dose oral vitamin D on serum vitamin D metabolites among first trimester pregnant women in Indonesia. Among the subjects we studied, 55.8% were obese with a median early pregnancy BMI of 26.23 kg/m2. Previous research conducted in Malaysia (Palaniveloo et al, 2020) revealed that early pregnancy BMI (OR = 2.95, 95% CI = 1.03–8.47) was significantly associated with vitamin D deficiency [ 13 ]. BMI can affect vitamin D metabolism because vitamin D is a fat-soluble vitamin that can be sequestered in adipose tissue, leading to lower bioavailability in the obese state. Alternatively, obesity may suppress the hepatic enzyme 25-hydroxylation of vitamin D to 25(OH)D, thereby reducing bioactivity [ 14 ]. All of the subjects in our study had low sun exposure scores, with a median of sunlight exposure score of 11.98. The sun exposure score was calculated using a validated questionnaire by Hanwell (2010). The daily time spent on the sun and skin exposure over one week was assessed. Previous research in Minangkabau, Indonesia, showed that pregnant women who spent less than one hour outdoors had a tenfold increase in the risk of developing vitamin D deficiency (OR 9.659, CI 95% 1.883–49.550; p-value = 0.007) [ 15 ]. According to a study conducted in Jakarta, Indonesia, our findings are consistent with the fact that 99.6% of first-trimester pregnant women in Jakarta suffer from vitamin D deficiency and insufficiency [ 2 ]. The primary source of vitamin D is sunlight exposure, particularly UVB light, which accounts for 90% of the body's vitamin D requirements. Consequently, inadequate sunlight exposure is the leading cause of vitamin D deficiency. This study revealed that the administration of 50,000 IU/week of vitamin D3 for 4 weeks significantly increased 25(OH)D levels from 15.3 ± 4.7 ng/mL to 26.9 ± 6.1 ng/mL. These results are consistent with a randomized controlled study conducted by Bimson, et al., which demonstrated that giving vitamin D3 50,000 IU/week to treat vitamin D deficiency in pregnant women for 8 weeks significantly increased 25(OH)D levels. However, the 25(OH)D increment in that study was much greater than that in the present study, which was only 30.5 ng/mL [ 16 ]. Additionally, in our study, only 34.6% of the subjects achieved vitamin D sufficiency (> 30 ng/mL) in the 50,000 IU/week group, and the mean follow-up level of 25(OH)D did not reach a sufficient number (26.9 ± 6.1 ng/mL). Bimson, et al. reported that 84.4% of subjects achieved vitamin D sufficiency [ 16 ]. This difference might be attributed to the shorter duration of intervention in our study. A longer duration of study might be needed to evaluate the optimal duration of vitamin D3 therapy. Our study also found that taking a daily dose of 5,000 IU of vitamin D3 for four weeks significantly increased 25(OH)D levels. The levels increased from 14.5 ± 4.3 ng/mL to 27.9 ± 9.3 ng/mL, with an overall increase of 10.8 ng/mL. At the end of the study, only 23.1% of the subjects were able to achieve normal levels of 25(OH)D. Additionally, the final mean 25(OH)D level remained insufficient, at 27.9 ± 9.3 ng/mL. A study conducted by Bokharee et al on pregnant women in Pakistan demonstrated that administering 5,000 IU/day of vitamin D increased 25(OH)D levels by 23.14 ± 11.18 ng/mL in 8 weeks [ 17 ]. Another study by Yap et al found that 90% of pregnant women who took a vitamin D dose of 5,000 IU/day for 12 weeks achieved a sufficient vitamin D concentration of 32 ng/ml [ 18 ]. In our study, although serum 25(OH)D levels increased with a therapeutic dose of 5,000 IU/day, most of the participants still did not achieve adequate vitamin D status. As a result, a longer intervention duration of high-dose vitamin D is needed for further studies to determine the optimal vitamin D dose and duration for pregnant women. The mean baseline 25(OH)D levels were equivalent between the 5,000 and 50,000 groups (p = 0.552). After receiving intervention for four weeks, there was a significant increase in 25(OH)D levels in both groups. However, there was no significant difference in delta 25(OH)D levels between the two groups (p = 0.694). These findings are consistent with previous research indicating that a weekly dose of vitamin D2 or D3 at 50,000 IU for eight weeks is equivalent to a daily dose of vitamin D2 or D3 at 6,000 IU in achieving serum 25(OH)D levels of more than 30 ng/mL in adults with vitamin D deficiency [ 12 ]. Although 25(OH)D is not the biologically active form of vitamin D, 25(OH)D is the major circulating form of vitamin D with a half-life of approximately 2–3 weeks [ 12 ]. A pharmacokinetic study showed that the level of 25(OH)D continues to rise through day 14 and by day 28 after administering a single dose of 50,000 IU of vitamin D3 [ 19 ]. This finding indicates the potential of intermittent high doses of vitamin D therapy, as shown in this study. Weekly vitamin D therapy potentially improves patient compliance with long-term therapy. The initial 1,25(OH) 2 D levels were the same in both 5,000 and 50,000 groups (p = 0.580). After 4 weeks of intervention, the 5,000 group showed a significant increase in 1,25(OH) 2 D levels, while the 50,000 group showed no significant change. However, in terms of increment 1,25(OH) 2 D, there was no significant difference between the two groups (p = 0.641). This finding is consistent with previous studies showing that vitamin D supplementation was effective at increasing 25(OH)D levels but did not alter 1,25(OH) 2 D levels [ 20 , 21 ]. In addition, this study showed no correlation between 25(OH)D and 1,25(OH) 2 D levels. This finding is consistent with previous studies [ 22 , 23 ]. The concentration of 1,25(OH) 2 D in the bloodstream is tightly regulated by various factors, including parathyroid hormone, calcium, phosphate, and the growth factor FGF23 [ 24 ]. This study found that the administration of vitamin D3 for 4 weeks increased VDBP levels in both groups, with the follow-up level being greater in the 5,000 group than in the 50,000 group (348.5 vs 296.0 µg/mL; p = 0 .042). Total VDBP levels increase during pregnancy, which indicates an increase in the amount of 1,25(OH) 2 D bound to VDBP to prevent pregnant women from developing hypercalcemia. The higher follow-up level found in the 5,000 group might reflect the significant increase in the 1,25(OH) 2 D level that was found only in the 5,000 group. However, using linear regression, no relationship was observed between circulating VDBP and 1,25(OH) 2 D (r = 0,180, p = 0,201). This finding is consistent with a previous study showing that the level of DBP is not influenced by serum vitamin D level, even if it is deficient [ 25 ]. At the end of our study, no signs or symptoms of vitamin D toxicity, such as anorexia, diarrhea, constipation, nausea, or vomiting, were observed. The highest 25(OH)D levels recorded were 46.3 ng/mL in the group receiving 50,000 IU and 47.3 ng/mL in the group receiving 5,000 IU. These levels were below the limit for hypervitaminosis D (≥ 100 ng/mL). Additionally, no remarkable allergic reactions or side effects were observed in either group. These findings are consistent with previous research by Bimson et al., who reported that administering vitamin D3 50,000 IU/week for 8 weeks to treat vitamin D deficiency during pregnancy is both effective and safe [ 16 ]. Therefore, this research supports that vitamin D3 doses of 5,000 IU/day and 50,000 IU/week given for 4 weeks can be considered safe and tolerable for pregnant women in the first trimester with vitamin D deficiency and insufficiency. This study has certain limitations. First, we did not assess the nutritional intake of each subject which is a confounding factor in this study. Additionally, we did not measure the levels of PTH, calcium, or phosphate, which affect the concentration of 1,25(OH) 2 D in the bloodstream. Furthermore, the duration of the intervention was not long enough to determine the optimal duration of therapy Despite the aforementioned shortcomings, this study is the first to explore the impact of vitamin D therapy on serum vitamin D metabolites among pregnant women in Indonesia. The findings of the current study may provide the basis for formulating guidelines and recommendations for vitamin D therapy among pregnant women in Indonesia. Conclusion Vitamin D3 50,000 IU weekly is equally effective and safe as 5,000 IU daily in increasing vitamin D levels in pregnant women with vitamin D deficient or insufficient. Future research with larger samples and longer duration is needed to determine the optimal duration of the therapy required to achieve vitamin D sufficiency. Abbreviations 1,25(OH) 2 D 1,25-dihydroxyvitamin D 24,25(OH)2D 24,25-dihydroxyvitamin D 25(OH)D 25-hydroxyvitamin D LC-MS/MS Liquid Chromatography-tandem Mass Spectrometry ELISA Enzyme-Linked Immunosorbent Assay VDBP Vitamin D binding protein Declarations Acknowledgments The authors would like to express gratitude to all participants and all the medical staff in the Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Indonesia/Cipto Mangunkusumo National General Hospital. Author Contributions I.S., R.I., and N.W. designed and conducted the study. I.S. and R.I. collected and analyzed the data. I.S. and R.I. wrote the manuscript. Y.B.S., Y.P., and N.W. revised and are responsible for all the content. All authors have read and agreed to the published version of the manuscript. Funding This research was funded by a 2020 Ministry of Research, Technology and Higher Education of Republic of Indonesia Grant. Data Availability Statement The data used in this study can be requested from the corresponding author upon reasonable request. Ethics considerations and approval The study was conducted according to the guidelines of the Declaration of Helsinki, and was approved by the Ethical Committee for Research in Humans from the Faculty of Medicine, Universitas Indonesia ((257/UN.2F1/ETIK/PPM.00.02/2023), and was registered at ClinicalTrials.gov (NCT06054919). Consent to Participate Informed consent was obtained from all subjects involved in the study. Consent for publication Not Applicable. Conflicts of Interest The authors declare that there are no conflicts of interest related to this study. 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D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73–8. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D Supplementation during Pregnancy: Double Blind, Randomized Clinical Trial of Safety and Effectiveness. J Bone Min Res. 2011;26(10):2341–57. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Jul, 2025 Read the published version in BMC Nutrition → Version 1 posted Editorial decision: Revision requested 02 Apr, 2024 Submission checks completed at journal 28 Mar, 2024 Editor assigned by journal 28 Mar, 2024 First submitted to journal 18 Mar, 2024 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. 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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-4126201","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":284850841,"identity":"48832b1c-7ccd-4a31-93e9-8115e8c88a47","order_by":0,"name":"Inayah Syafitri","email":"","orcid":"","institution":"Universitas Indonesia/Cipto- Mangunkusumo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Inayah","middleName":"","lastName":"Syafitri","suffix":""},{"id":284850842,"identity":"c70671a9-f8cf-4b8c-82b8-cbeeaade54b7","order_by":1,"name":"Rima Irwinda","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYDACZhBhwMDABiI/MDAkkKaFcQZRWpCAATMPMVrM27kTPzAU3Evsk27e+Nm2zS6Pn72B8cPHHNxaZA7zbpZgMChObJM5Viyd25ZcLNlzgFly5jbcWiSYeTcAtSTktknkGAC1MCduuJHAxsyLX8vmH1Atxr8t2+qJ0rINZouZNGPbYeK0WCQYJNS3SaSVWfacO544s+dgM36/8J/dfOPDnwRj+RnJm2/8KKtO7GdvPvjhIx4tYJAAYzCygckGAupRwB9SFI+CUTAKRsFIAQDm9EsTW9JNMAAAAABJRU5ErkJggg==","orcid":"","institution":"Universitas Indonesia/Cipto-Mangunkusumo Hospital","correspondingAuthor":true,"prefix":"","firstName":"Rima","middleName":"","lastName":"Irwinda","suffix":""},{"id":284850843,"identity":"8aea55c5-4aae-4142-8d9d-d3f02041e02e","order_by":2,"name":"Yudianto Budi Saroyo","email":"","orcid":"","institution":"Universitas Indonesia/Cipto-Mangunkusumo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yudianto","middleName":"Budi","lastName":"Saroyo","suffix":""},{"id":284850844,"identity":"3949556a-670c-48f5-ad27-d4bd4efadc0a","order_by":3,"name":"Yuditiya Purwosunu","email":"","orcid":"","institution":"Universitas Indonesia/Cipto-Mangunkusumo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuditiya","middleName":"","lastName":"Purwosunu","suffix":""},{"id":284850845,"identity":"2086acc1-5926-44bc-a5dc-ca2cb2252b72","order_by":4,"name":"Noroyono Wibowo","email":"","orcid":"","institution":"Universitas Indonesia/Cipto-Mangunkusumo Hospital","correspondingAuthor":false,"prefix":"","firstName":"Noroyono","middleName":"","lastName":"Wibowo","suffix":""}],"badges":[],"createdAt":"2024-03-18 23:59:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4126201/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4126201/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40795-025-01104-3","type":"published","date":"2025-07-04T15:57:58+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":53964044,"identity":"af27c983-1254-4650-9b74-0535ec62218e","added_by":"auto","created_at":"2024-04-02 18:55:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":83572,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of the subjects throughout the study\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4126201/v1/6c08332d2bbfbe60b06c5054.png"},{"id":53963463,"identity":"e363a8e8-feb1-4a74-ab81-1a273277080b","added_by":"auto","created_at":"2024-04-02 18:47:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":10361,"visible":true,"origin":"","legend":"\u003cp\u003eThe individual change of 25(OH)D level in 50,000 group\u003c/p\u003e","description":"","filename":"Onlinedrawingimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4126201/v1/c8c9f4af43bd372f550cb189.png"},{"id":53963464,"identity":"d1cd6c4f-a16c-49af-8782-8823916227f1","added_by":"auto","created_at":"2024-04-02 18:47:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":8424,"visible":true,"origin":"","legend":"\u003cp\u003eThe individual change of 25(OH)D level in 5,000 group\u003c/p\u003e","description":"","filename":"Onlinedrawingimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4126201/v1/8b1c09ad6abb50fcaf78b966.png"},{"id":53963466,"identity":"1794b33d-1e9b-4a6f-9d60-7435d39e4772","added_by":"auto","created_at":"2024-04-02 18:47:06","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":214858,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plot correlation between baseline levels of 25(OH)D and 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4126201/v1/0e682ef8482d6a56fcd68600.jpeg"},{"id":86179134,"identity":"4522be4e-7ee3-4df3-81b9-c86b502f196f","added_by":"auto","created_at":"2025-07-07 16:16:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":890070,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4126201/v1/c04a969d-6748-4279-abb9-7c44ce9bb903.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Maternal Concentrations of Vitamin D Metabolites in Response to High-Dose Oral Vitamin D During First Trimester Pregnancy: A Randomized Controlled Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVitamin D deficiency has become a common problem globally and is associated with adverse maternal and neonatal health outcomes. It has been estimated that 18\u0026ndash;84% of pregnant women worldwide are vitamin D deficient [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite being located in a warm climate region, Indonesia has a high prevalence of vitamin D deficiency. A study conducted in Jakarta revealed that 99.6% of first-trimester pregnant women had vitamin D deficiency and insufficiency [(25(OH)D)\u0026thinsp;\u0026lt;\u0026thinsp;30 ng/ml] [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVitamin D and its metabolites are hydrophobic, and \u0026gt;\u0026thinsp;99% are transported in the blood bound to VDBP. In the liver, vitamin D3 is converted into 25(OH)D, which is the primary vitamin D compound in the circulation. In the renal proximal tubules of the kidney, 1α-hydroxylase hydroxylates 25(OH)D to yield 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD. This kidney-generated 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD plays a crucial role in mediating the classical functions of vitamin D in calcium homeostasis and bone mineralization. The production of 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD from 25(OH)D occurs in immune cells, the skin, the placenta and other tissues and may contribute to health in nonpregnant and pregnant women. Both 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD and 25(OH)D are inactivated by CYP24A1, to 1,24,25-trihydroxyvitamin D and 24,25-dihydroxyvitamin D [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAdequate vitamin D intake is essential for maternal and fetal health during pregnancy. Recent work has emphasized the importance of vitamin D in pregnancy and the placenta. The human placenta expresses all the components required for vitamin D signaling. Vitamin D regulates key target genes associated with implantation, trophoblast invasion, and implantation tolerance. Vitamin D also plays an important role in promoting the shift to a T-helper 2-dominated immune response pattern, which is vital for successful pregnancy outcomes. Vitamin D has immune-modulatory and anti-inflammatory effects that are important for preventing microbial invasion intrauterine. Maternal vitamin D deficiency has been associated with adverse pregnancy outcomes such as preterm labor, preeclampsia, gestational diabetes mellitus, and fetal growth restriction [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to the 2010 Institute of Medicine Report, the recommended daily allowance of vitamin D during pregnancy is 600 IU. However, this amount may not be enough to maintain sufficient vitamin D in pregnant women [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Recent studies have shown that pregnant women should take 4,000 IU/day of vitamin D3 starting from 12\u0026ndash;16 weeks of gestation to achieve sufficient vitamin D levels. The Endocrine Society Clinical Practice Guideline recommends treating all vitamin D deficient adults with 50,000 IU of vitamin D3 once a week for 8 weeks, or an equivalent daily dose of 6,000 IU of vitamin D3, to achieve a blood level of 25(OH)D above 30 ng/ml [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, there are no available data regarding vitamin D therapy in pregnant women in Indonesia. The present study aimed to evaluate the effects of different vitamin D3 regimens on maternal 25(OH)D, 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD, VDBP, and 24,25(OH)\u003csub\u003e2\u003c/sub\u003eD concentrations during pregnancy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe conducted a randomized controlled trial of vitamin D therapy of 5,000 IU daily or 50,000 IU weekly during pregnancy. The study was conducted at Cipto Mangunkusumo National Center General Hospital and Koja District Hospital in Jakarta, Indonesia, within a period of 1 year All the pregnant women were screened for eligibility when they presented to the clinic for antenatal care visits and were offered enrolment if they met the following inclusion criteria: gestational age of \u0026le;\u0026thinsp;14 weeks, vitamin D deficient or insufficient (25(OH)D\u0026thinsp;\u0026lt;\u0026thinsp;30 ng/ml], and a positive fetal heart rate from ultrasound examination. Individuals were not eligible if they had any of the following exclusion criteria: multiple pregnancy, pregnancy with congenital anomaly, hyperemesis gravidarum, diarrhea, complicated medical history (hypertension, diabetes mellitus, heart, kidney, or liver disease), or use of any dietary supplement containing vitamin D prior to enrolment. Informed consent was obtained from all participants. This study was approved by the Ethical Committee for Research in Humans from the Faculty of Medicine University of Indonesia (257/UN.2F1/ETIK/PPM.00.02/2023) and was registered at ClinicalTrials.gov (NCT06054919) on 22nd September 2023.\u003c/p\u003e \u003cp\u003eParticipants were randomly assigned to one of two parallel intervention groups. The allocation was concealed based on a computer-generated list with a 1:1 allocation ratio. The groups received either vitamin D3 (cholecalciferol) 5,000 IU (Imedco) daily or 50,000 IU (Imedco) weekly. The randomization list was developed using permuted blocks of size 6. All participants were provided with a standard prenatal multivitamin (Emineton) that contained fumarate Fe 90 mg, folic acid 0.4 mg, vitamin B6 3 mg, vitamin B12 5 mcg, sulphate cupric 0.35 mg, sulphate cobalt 0.15 mg, sulphate mangan 5 mcg, vitamin C 60 mg, vitamin E 5 mg, and phosphate calcium 60 mg. Both groups received the intervention for four weeks.\u003c/p\u003e \u003cp\u003eAt the beginning of the study, participants underwent baseline blood tests to measure serum concentrations of 25(OH)D, 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD, VDBP, and 24,25(OH)\u003csub\u003e2\u003c/sub\u003eD. A medical history, physical, and ultrasound examination were also performed. Additionally, they were asked to complete a questionnaire about sunlight exposure. Throughout the study, weekly follow-up was conducted to evaluate their adherence to the supplement regimen and to monitor any symptoms related to interventions. Maternal self-report and capsule counts were used to assess adherence. After four weeks of interventions, maternal venous blood was collected to assess changes in serum concentrations of 25(OH)D, 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD, VDBP, and 24,25(OH)\u003csub\u003e2\u003c/sub\u003eD. The study had safety thresholds in place to prevent hypervitaminosis D, which was defined as a serum concentration of 25(OH)D\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/mL.\u003c/p\u003e \u003cp\u003eThe concentrations of different forms of vitamin D in the blood were measured using various tests. Serum 25(OH)D was quantified by direct competitive Chemiluminescence Immunoassay (CLIA) using LIAISON\u0026reg;. Serum 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD was quantified by Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS) using ImmuTube\u0026reg;. Serum VDBP was quantified by Enzyme-Linked Immunosorbent Assay (ELISA) using Quantikine\u0026reg;. Serum 24,25(OH)\u003csub\u003e2\u003c/sub\u003eD was quantified by Acquity I Class Binary Solvent Manager FTN, Xevo TQXS Tandem Mass Spectrometry (Waters Corporation). All of these laboratory tests were conducted at the Prodia Laboratory in Jakarta.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eSixty pregnant women who were eligible to participate were randomly assigned to two groups as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. However, after allocation, 5 subjects discontinued participation for any specific reason, and 3 subjects dropped out due to COVID-19 infection. As a result, 52 patients completed the study and were available for analysis. Of these 52 participants, 26 were in the 5,000 group and the other 26 were in the 50,000 group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe median maternal age and gestational age of the study participants were 30 years and 8 weeks, respectively. The distribution of demographics was equal between the control and treatment groups. Approximately half of the study participants (55.8%) were obese, and 35 (67.3%) were multiparous. All of the subjects had low sun exposure scores (\u0026lt;\u0026thinsp;33.6). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows that demographic data were equally distributed between the two groups.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline demographic characteristics of the study participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll subjects\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;52)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50,000 IU weekly\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5,000 IU daily\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (22\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (26\u0026ndash;42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (22\u0026ndash;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.978\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age (weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (6\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (6\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (6\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.158\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity\u003c/p\u003e \u003cp\u003eNulliparity\u003c/p\u003e \u003cp\u003eMultiparity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (32.7%)\u003c/p\u003e \u003cp\u003e35 (67.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (30.7%)\u003c/p\u003e \u003cp\u003e18 (69.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (34.6%)\u003c/p\u003e \u003cp\u003e17 (65.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.768\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003e\u003cem\u003eUnderweight\u003c/em\u003e (\u0026lt;\u0026thinsp;18.5)\u003c/p\u003e \u003cp\u003eNormal (18.5\u0026ndash;22.9)\u003c/p\u003e \u003cp\u003e\u003cem\u003eOverweight\u003c/em\u003e (23\u0026ndash;24.9) Obesity (\u0026ge;\u0026thinsp;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.23\u0026thinsp;\u0026plusmn;\u0026thinsp;5.36\u003c/p\u003e \u003cp\u003e2 (3.8%)\u003c/p\u003e \u003cp\u003e14 (26.9%)\u003c/p\u003e \u003cp\u003e7 (13.5%)\u003c/p\u003e \u003cp\u003e29 (55.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.80\u0026thinsp;\u0026plusmn;\u0026thinsp;5.50\u003c/p\u003e \u003cp\u003e2 (7.6%)\u003c/p\u003e \u003cp\u003e7 (26.9%)\u003c/p\u003e \u003cp\u003e3 (11.5%)\u003c/p\u003e \u003cp\u003e14 (53.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.60\u0026thinsp;\u0026plusmn;\u0026thinsp;5.20\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e7 (26.9%)\u003c/p\u003e \u003cp\u003e4 (15.3%)\u003c/p\u003e \u003cp\u003e15 (57.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.699\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSun exposure score\u003c/p\u003e \u003cp\u003eLow (\u0026lt;\u0026thinsp;33.6)\u003c/p\u003e \u003cp\u003eModerate (33.6\u0026ndash;44.7)\u003c/p\u003e \u003cp\u003eHigh (\u0026ge;\u0026thinsp;44.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.98\u0026thinsp;\u0026plusmn;\u0026thinsp;5.25\u003c/p\u003e \u003cp\u003e52 (100%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.00\u0026thinsp;\u0026plusmn;\u0026thinsp;5.02\u003c/p\u003e \u003cp\u003e26 (100%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.96\u0026thinsp;\u0026plusmn;\u0026thinsp;5.58\u003c/p\u003e \u003cp\u003e26 (100%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.979\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e demonstrates that the baseline levels of 25(OH)D, 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD, VDBP, and 24,25(OH)\u003csub\u003e2\u003c/sub\u003eD were equal between 50,000 and 5,000 groups. The baseline 25(OH)D levels were 15.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 ng/mL and 14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 ng/mL in the 50,000 and 5,000 groups, respectively. After four weeks of treatment, the levels of 25(OH)D were significantly improved in both groups, but the increment was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.649) between two groups. In the 50,000 group, 25(OH)D levels increased from 15.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 ng/mL to 26.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1 ng/mL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 34.6% of the subjects achieved vitamin D sufficiency (\u0026gt;\u0026thinsp;30 ng/mL). While in the 5,000 group, the 25(OH)D levels increased from 14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 ng/mL to 27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 ng/mL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 23.1% of the subjects achieved vitamin D sufficiency. Figures\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e illustrate the individual changes in 25(OH)D levels in groups of 50,000 and 5,000, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison 25(OH)D, 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD, VDBP, and 24,25(OH)\u003csub\u003e2\u003c/sub\u003eD levels between two groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e50,000 IU/week Group (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c10\" namest=\"c7\"\u003e \u003cp\u003e5,000 IU/day Group (n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFollow-up\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIncrement\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFollow-up\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eIncrement\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e25(OH)D (ng/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e26.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.6\u003c/p\u003e \u003cp\u003e(0.1\u0026ndash;30.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10.8\u003c/p\u003e \u003cp\u003e(4.0\u0026ndash;28.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1,25(OH)\u003c/b\u003e\u003csub\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sub\u003e\u003cb\u003eD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e(pg/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.9\u0026thinsp;\u0026plusmn;\u0026thinsp;17.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e84.0\u003c/p\u003e \u003cp\u003e(27.8\u0026ndash;218.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.8\u003c/p\u003e \u003cp\u003e(-41.5\u0026ndash;151.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e69.6\u0026thinsp;\u0026plusmn;\u0026thinsp;23.8 \u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e84.4\u003c/p\u003e \u003cp\u003e(39.3\u0026ndash;141.0)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e20.2\u003c/p\u003e \u003cp\u003e(-50.4\u0026ndash;59.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVDBP (\u0026micro;g/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e292.0\u003c/p\u003e \u003cp\u003e(11.0\u0026ndash;520.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e296.0\u003c/p\u003e \u003cp\u003e(168.0\u0026ndash;1667.0)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17.0\u003c/p\u003e \u003cp\u003e(-330.0\u0026ndash;1361.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e280.0\u003c/p\u003e \u003cp\u003e(133.0\u0026ndash;524.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e348.5\u003c/p\u003e \u003cp\u003e(198.0\u0026ndash;1205.0)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e45.5\u003c/p\u003e \u003cp\u003e(-166.0\u0026ndash;963.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e24,25(OH)\u003c/b\u003e\u003csub\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sub\u003e\u003cb\u003eD (pg/mL)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.0\u003c/p\u003e \u003cp\u003e(12,0\u0026ndash;329.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e194.5\u003c/p\u003e \u003cp\u003e(23.0\u0026ndash; 727.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e140.0\u003c/p\u003e \u003cp\u003e(-151.0\u0026ndash;638.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e115.5\u003c/p\u003e \u003cp\u003e(17.0 \u0026minus;\u0026thinsp;339.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003e288.0\u003c/p\u003e \u003cp\u003e(85.0\u0026ndash;525.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e195.0\u003c/p\u003e \u003cp\u003e(-144.0\u0026ndash;501.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e\u003cem\u003ep\u0026lt;0.05 in 50,000 group between baseline and follow-up levels\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003cem\u003ep\u0026lt;0.05 in 5,000 group between baseline and follow-up levels\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003e\u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e\u003cem\u003ep\u0026lt;0.05 in follow-up levels between 50,000 and 5,000 groups\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBoth groups showed an increasing trend in the total levels of 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD, VDBP, and 24,25(OH)\u003csub\u003e2\u003c/sub\u003eD. However, we only found a statistically significant difference in the levels of 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD between baseline and follow-up in the 5,000 group (p\u0026thinsp;=\u0026thinsp;0.042). Additionally, we found a statistically significant difference in the follow-up levels of VDBP between the 50,000 and 5,000 groups (p\u0026thinsp;=\u0026thinsp;0.013). There was no statistically significant difference in the increment of 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD, VDBP, or 24,25(OH)\u003csub\u003e2\u003c/sub\u003eD between the two groups.\u003c/p\u003e \u003cp\u003ePearson correlation analysis revealed no correlation between baseline levels of 25(OH)D and 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD (r\u0026thinsp;=\u0026thinsp;0.105, p\u0026thinsp;=\u0026thinsp;0.458).\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003e To the best of our knowledge, this is the first study to explore the impact of high-dose oral vitamin D on serum vitamin D metabolites among first trimester pregnant women in Indonesia. Among the subjects we studied, 55.8% were obese with a median early pregnancy BMI of 26.23 kg/m2. Previous research conducted in Malaysia (Palaniveloo et al, 2020) revealed that early pregnancy BMI (OR\u0026thinsp;=\u0026thinsp;2.95, 95% CI\u0026thinsp;=\u0026thinsp;1.03\u0026ndash;8.47) was significantly associated with vitamin D deficiency [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. BMI can affect vitamin D metabolism because vitamin D is a fat-soluble vitamin that can be sequestered in adipose tissue, leading to lower bioavailability in the obese state. Alternatively, obesity may suppress the hepatic enzyme 25-hydroxylation of vitamin D to 25(OH)D, thereby reducing bioactivity [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAll of the subjects in our study had low sun exposure scores, with a median of sunlight exposure score of 11.98. The sun exposure score was calculated using a validated questionnaire by Hanwell (2010). The daily time spent on the sun and skin exposure over one week was assessed. Previous research in Minangkabau, Indonesia, showed that pregnant women who spent less than one hour outdoors had a tenfold increase in the risk of developing vitamin D deficiency (OR 9.659, CI 95% 1.883\u0026ndash;49.550; p-value\u0026thinsp;=\u0026thinsp;0.007) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. According to a study conducted in Jakarta, Indonesia, our findings are consistent with the fact that 99.6% of first-trimester pregnant women in Jakarta suffer from vitamin D deficiency and insufficiency [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The primary source of vitamin D is sunlight exposure, particularly UVB light, which accounts for 90% of the body's vitamin D requirements. Consequently, inadequate sunlight exposure is the leading cause of vitamin D deficiency.\u003c/p\u003e \u003cp\u003eThis study revealed that the administration of 50,000 IU/week of vitamin D3 for 4 weeks significantly increased 25(OH)D levels from 15.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 ng/mL to 26.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1 ng/mL. These results are consistent with a randomized controlled study conducted by Bimson, et al., which demonstrated that giving vitamin D3 50,000 IU/week to treat vitamin D deficiency in pregnant women for 8 weeks significantly increased 25(OH)D levels. However, the 25(OH)D increment in that study was much greater than that in the present study, which was only 30.5 ng/mL [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Additionally, in our study, only 34.6% of the subjects achieved vitamin D sufficiency (\u0026gt;\u0026thinsp;30 ng/mL) in the 50,000 IU/week group, and the mean follow-up level of 25(OH)D did not reach a sufficient number (26.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1 ng/mL). Bimson, et al. reported that 84.4% of subjects achieved vitamin D sufficiency [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. This difference might be attributed to the shorter duration of intervention in our study. A longer duration of study might be needed to evaluate the optimal duration of vitamin D3 therapy.\u003c/p\u003e \u003cp\u003eOur study also found that taking a daily dose of 5,000 IU of vitamin D3 for four weeks significantly increased 25(OH)D levels. The levels increased from 14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 ng/mL to 27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 ng/mL, with an overall increase of 10.8 ng/mL. At the end of the study, only 23.1% of the subjects were able to achieve normal levels of 25(OH)D. Additionally, the final mean 25(OH)D level remained insufficient, at 27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 ng/mL. A study conducted by Bokharee et al on pregnant women in Pakistan demonstrated that administering 5,000 IU/day of vitamin D increased 25(OH)D levels by 23.14\u0026thinsp;\u0026plusmn;\u0026thinsp;11.18 ng/mL in 8 weeks [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Another study by Yap et al found that 90% of pregnant women who took a vitamin D dose of 5,000 IU/day for 12 weeks achieved a sufficient vitamin D concentration of 32 ng/ml [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our study, although serum 25(OH)D levels increased with a therapeutic dose of 5,000 IU/day, most of the participants still did not achieve adequate vitamin D status. As a result, a longer intervention duration of high-dose vitamin D is needed for further studies to determine the optimal vitamin D dose and duration for pregnant women.\u003c/p\u003e \u003cp\u003eThe mean baseline 25(OH)D levels were equivalent between the 5,000 and 50,000 groups (p\u0026thinsp;=\u0026thinsp;0.552). After receiving intervention for four weeks, there was a significant increase in 25(OH)D levels in both groups. However, there was no significant difference in delta 25(OH)D levels between the two groups (p\u0026thinsp;=\u0026thinsp;0.694). These findings are consistent with previous research indicating that a weekly dose of vitamin D2 or D3 at 50,000 IU for eight weeks is equivalent to a daily dose of vitamin D2 or D3 at 6,000 IU in achieving serum 25(OH)D levels of more than 30 ng/mL in adults with vitamin D deficiency [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough 25(OH)D is not the biologically active form of vitamin D, 25(OH)D is the major circulating form of vitamin D with a half-life of approximately 2\u0026ndash;3 weeks [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. A pharmacokinetic study showed that the level of 25(OH)D continues to rise through day 14 and by day 28 after administering a single dose of 50,000 IU of vitamin D3 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This finding indicates the potential of intermittent high doses of vitamin D therapy, as shown in this study. Weekly vitamin D therapy potentially improves patient compliance with long-term therapy.\u003c/p\u003e \u003cp\u003eThe initial 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD levels were the same in both 5,000 and 50,000 groups (p\u0026thinsp;=\u0026thinsp;0.580). After 4 weeks of intervention, the 5,000 group showed a significant increase in 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD levels, while the 50,000 group showed no significant change. However, in terms of increment 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD, there was no significant difference between the two groups (p\u0026thinsp;=\u0026thinsp;0.641). This finding is consistent with previous studies showing that vitamin D supplementation was effective at increasing 25(OH)D levels but did not alter 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD levels [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In addition, this study showed no correlation between 25(OH)D and 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD levels. This finding is consistent with previous studies [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The concentration of 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD in the bloodstream is tightly regulated by various factors, including parathyroid hormone, calcium, phosphate, and the growth factor FGF23 [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study found that the administration of vitamin D3 for 4 weeks increased VDBP levels in both groups, with the follow-up level being greater in the 5,000 group than in the 50,000 group (348.5 vs 296.0 \u0026micro;g/mL; p\u0026thinsp;=\u0026thinsp;0 .042). Total VDBP levels increase during pregnancy, which indicates an increase in the amount of 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD bound to VDBP to prevent pregnant women from developing hypercalcemia. The higher follow-up level found in the 5,000 group might reflect the significant increase in the 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD level that was found only in the 5,000 group. However, using linear regression, no relationship was observed between circulating VDBP and 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD (r\u0026thinsp;=\u0026thinsp;0,180, p\u0026thinsp;=\u0026thinsp;0,201). This finding is consistent with a previous study showing that the level of DBP is not influenced by serum vitamin D level, even if it is deficient [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAt the end of our study, no signs or symptoms of vitamin D toxicity, such as anorexia, diarrhea, constipation, nausea, or vomiting, were observed. The highest 25(OH)D levels recorded were 46.3 ng/mL in the group receiving 50,000 IU and 47.3 ng/mL in the group receiving 5,000 IU. These levels were below the limit for hypervitaminosis D (\u0026ge;\u0026thinsp;100 ng/mL). Additionally, no remarkable allergic reactions or side effects were observed in either group. These findings are consistent with previous research by Bimson et al., who reported that administering vitamin D3 50,000 IU/week for 8 weeks to treat vitamin D deficiency during pregnancy is both effective and safe [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, this research supports that vitamin D3 doses of 5,000 IU/day and 50,000 IU/week given for 4 weeks can be considered safe and tolerable for pregnant women in the first trimester with vitamin D deficiency and insufficiency.\u003c/p\u003e \u003cp\u003eThis study has certain limitations. First, we did not assess the nutritional intake of each subject which is a confounding factor in this study. Additionally, we did not measure the levels of PTH, calcium, or phosphate, which affect the concentration of 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD in the bloodstream. Furthermore, the duration of the intervention was not long enough to determine the optimal duration of therapy Despite the aforementioned shortcomings, this study is the first to explore the impact of vitamin D therapy on serum vitamin D metabolites among pregnant women in Indonesia. The findings of the current study may provide the basis for formulating guidelines and recommendations for vitamin D therapy among pregnant women in Indonesia.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eVitamin D3 50,000 IU weekly is equally effective and safe as 5,000 IU daily in increasing vitamin D levels in pregnant women with vitamin D deficient or insufficient. Future research with larger samples and longer duration is needed to determine the optimal duration of the therapy required to achieve vitamin D sufficiency.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e1,25(OH)\u003csub\u003e2\u003c/sub\u003eD\u0026nbsp; \u0026nbsp; \u0026nbsp;1,25-dihydroxyvitamin D\u003csub\u003e\u0026nbsp;\u003c/sub\u003e\u003c/p\u003e\n\u003cp\u003e24,25(OH)2D\u0026nbsp; \u0026nbsp;24,25-dihydroxyvitamin D\u003c/p\u003e\n\u003cp\u003e25(OH)D\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;25-hydroxyvitamin D\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLC-MS/MS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Liquid Chromatography-tandem Mass\u0026nbsp;Spectrometry\u003c/p\u003e\n\u003cp\u003eELISA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Enzyme-Linked Immunosorbent Assay\u003c/p\u003e\n\u003cp\u003eVDBP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Vitamin D binding protein\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to express gratitude to all participants and all the medical staff in the Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Indonesia/Cipto Mangunkusumo National General Hospital.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI.S., R.I., and N.W. designed and conducted the study. I.S. and R.I. collected and analyzed the data. I.S. and R.I. wrote the manuscript. Y.B.S., Y.P., and N.W. revised and are responsible for all the content. All authors have read and agreed to the published version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by a 2020 Ministry of Research, Technology and Higher Education of Republic of Indonesia Grant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used in this study can be requested from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics considerations and approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki, and was approved by the Ethical Committee for Research in Humans from the Faculty of Medicine, Universitas Indonesia ((257/UN.2F1/ETIK/PPM.00.02/2023), and was registered at ClinicalTrials.gov (NCT06054919).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all subjects involved in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no conflicts of interest related to this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYates N, Crew RC, Wyrwoll CS. 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J Am Diet Assoc. 2011;111:524\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr. 2005;135:317\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHollis BW, et al. Vitamin D Supplementation During Pregnancy: Double-Blind, Randomized Clinical Trial of Safety and Effectiveness. J Bone Min Res. 2011;26:2338\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jbmr.498\u003c/span\u003e\u003cspan address=\"10.1002/jbmr.498\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolick MF, et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrin Metab. 2011;96(7):1\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalaniveloo L, et al. Vitamin D status is associated with high BMI, working status and gravidity among pregnant Malaysian women. Malay J Nutr. 2020;26(1):129\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBodnar LM, Catov JM, Roberts JM, Simhan HN. Prepregnancy Obesity Predicts Poor Vitamin D Status in Mothers and Their Neonates. J Nutr. 2007;137(11):2437\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAju AS, Erwinda E, Yusrawati Y, Malik SG, Lipoeto NI. Vitamin D deficiency status and its related risk factors during early pregnancy: a cross-sectional study of pregnant Minangkabau women, Indonesia. BMC Pregnancy Childbirth. 2019;19(1):183.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBimson B, Brustman L, Al Ibraheemi Z, Herrera k, Rosenn B. Can weekly vitamin d dosing adequately treat vitamin d deficiency in pregnancy? Am J Obstet Gynecol January. 2017;216(1):S380\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBokharee N, et al. Daily versus stat vitamin D supplementation during pregnancy; A prospective cohort study. PLoS ONE. 2020;15(4):e0231590.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYap C, et al. Vitamin D supplementation and the effects on glucose metabolism during pregnancy: a randomized controlled trial. Diabetes Care. 2014;37(7):1837\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArmas LAG, Hollis BW, Heaney RP. Vitamin D2 Is Much Less Effective than Vitamin D3 in Humans. J Clin Endocrinol Metab November. 2004;89(11):5387\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLips P, et al. The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. J Clin Endocrinol Metab. 1988;67(4):644\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBiancuzzo RM, Clarke N, Reitz RE, Travison TG, Holick MF. Serum concentrations of 1,25-dihydroxyvitamin D2 and 1,25-dihydroxyvitamin D3 in response to vitamin D2 and vitamin D3 supplementation. J Clin Endocrinol Metab. 2013;98(3):973\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang JCY, et al. The dynamic relationships between the active and catabolic vitamin D metabolites, their ratios, and associations with PTH. Sci Rep. 2019;9(1):6974.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVaes AMM, et al. Dose-response effects of supplementation with calcifediol on serum 25-hydroxyvitamin D status and its metabolites: A randomized controlled trial in older adults. Clin Nutr. 2018;37(3):808\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolick MF, Vitamin. D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D Supplementation during Pregnancy: Double Blind, Randomized Clinical Trial of Safety and Effectiveness. J Bone Min Res. 2011;26(10):2341\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nutrition","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nutn","sideBox":"Learn more about [BMC Nutrition](http://bmcnutr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nutn/default.aspx","title":"BMC Nutrition","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, first trimester pregnancy, vitamin D","lastPublishedDoi":"10.21203/rs.3.rs-4126201/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4126201/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eVitamin D deficiency has become a common problem globally. The present study aimed to evaluate the effects of different vitamin D3 regimens on maternal concentrations of vitamin D metabolites during pregnancy. This randomized controlled trial was registered at ClinicalTrials.gov (NCT06054919) on 22nd September 2023. Subjects were \u0026le;\u0026thinsp;14 weeks gestation pregnant women with vitamin D deficient or insufficient (25(OH)D\u0026thinsp;\u0026lt;\u0026thinsp;30 ng/ml]. Two intervention groups were randomly assigned: 5,000 IU of vitamin D3 daily or 50,000 IU weekly of vitamin D3. Maternal blood samples were collected before and after four weeks of intervention to assess changes in serum concentrations of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)\u003csub\u003e2\u003c/sub\u003eD), vitamin D binding protein (VDBP), and 24,25-dihydroxyvitamin D (24,25(OH)2D). Sixty subjects were randomized into two groups, and eight subjects were dropped out. There were no differences in the baseline demographics or baseline levels of any of the vitamin D metabolites between the two groups. In the 50,000 group, the 25(OH)D levels increased from 15.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7 ng/mL to 26.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1 ng/mL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 34.6% of the subjects achieved vitamin D sufficiency. While in the 5,000 group, the 25(OH)D levels increased from 14.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3 ng/mL to 27.9\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 ng/mL (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and 23.1% of the subjects achieved vitamin D sufficiency. Both groups showed an increasing trend in the total levels of 25(OH)D, 1,25(OH)2D, VDBP, and 24,25(OH)2D. However, the increment of all vitamin D metabolites were not significantly different between two groups. Vitamin D3 50,000 IU weekly is equally effective and safe as 5,000 IU daily in increasing vitamin D levels in pregnant women with vitamin D deficient or insufficient.\u003c/p\u003e","manuscriptTitle":"Maternal Concentrations of Vitamin D Metabolites in Response to High-Dose Oral Vitamin D During First Trimester Pregnancy: A Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-02 18:47:01","doi":"10.21203/rs.3.rs-4126201/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-02T12:02:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-03-28T07:35:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-03-28T07:35:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nutrition","date":"2024-03-18T23:55:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nutrition","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nutn","sideBox":"Learn more about [BMC Nutrition](http://bmcnutr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nutn/default.aspx","title":"BMC Nutrition","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"671b9175-b2e6-4830-a606-9e21e730629c","owner":[],"postedDate":"April 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-07T16:04:29+00:00","versionOfRecord":{"articleIdentity":"rs-4126201","link":"https://doi.org/10.1186/s40795-025-01104-3","journal":{"identity":"bmc-nutrition","isVorOnly":false,"title":"BMC Nutrition"},"publishedOn":"2025-07-04 15:57:58","publishedOnDateReadable":"July 4th, 2025"},"versionCreatedAt":"2024-04-02 18:47:01","video":"","vorDoi":"10.1186/s40795-025-01104-3","vorDoiUrl":"https://doi.org/10.1186/s40795-025-01104-3","workflowStages":[]},"version":"v1","identity":"rs-4126201","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4126201","identity":"rs-4126201","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}