{"paper_id":"bc4e8680-3693-49a1-90a3-ef86318be373","body_text":"Meng et al. \nReproductive Biology and Endocrinology           (2023) 21:17  \nhttps://doi.org/10.1186/s12958-023-01068-8\nREVIEW\n© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco \nmmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nOpen Access\nReproductive Biology\nand Endocrinology\nInfluence of Vitamin D supplementation \non reproductive outcomes of infertile patients: \na systematic review and meta-analysis\nXiangqian Meng1, Jiayao Zhang2, Qi Wan1, Jihua Huang3, Tingting Han3, Ting Qu3*† and Lin‑lin Yu4*† \nAbstract \nBackground Low vitamin D status has been associated with an increased risk for infertility. Recent evidence regard‑\ning the efficacy of vitamin D supplementation in improving reproductive outcomes is inconsistent. Therefore, this \nsystematic review was conducted to investigate whether vitamin D supplementation could improve the reproductive \noutcomes of infertile patients and evaluate how the parameters of vitamin D supplementation affected the clinical \npregnancy rate.\nMethods We searched seven electronic databases (CNKI, Cqvip, Wanfang, PubMed, Medline, Embase, and Cochrane \nLibrary) up to March 2022. Randomized and cohort studies were collected to assess the reproductive outcomes differ‑\nence between the intervention (vitamin D) vs. the control (placebo or none). Mantel‑Haenszel random effects models \nwere used. Effects were reported as odds ratio (OR) and their 95% confidence interval (CI). PROSPERO database regis‑\ntration number: CRD42022304018.\nResults Twelve eligible studies (n = 2352) were included: 9 randomized controlled trials (RCTs, n = 1677) and 3 cohort \nstudies (n = 675). Pooled results indicated that infertile women treated with vitamin D had a significantly increased \nclinical pregnancy rate compared with the control group (OR: 1.70, 95% CI: 1.24–2.34; I2 = 63%, P = 0.001). However, \nthe implantation, biochemical pregnancy, miscarriage, and multiple pregnancy rates had no significant difference \n(OR: 1.86, 95% CI: 1.00–3.47; I2 = 85%, P = 0.05; OR: 1.49; 0.98–2.26; I2 = 63%, P = 0.06; OR: 0.98, 95% CI: 0.63–1.53; \nI2 = 0%, P = 0.94 and OR: 3.64, 95% CI: 0.58–11.98; I2 = 68%, P = 0.21). The improvement of clinical pregnancy rate \nin the intervention group was influenced by the vitamin D level of patients, drug type, the total vitamin D dosage, \nthe duration, administration frequency, and daily dosage of vitamin D supplementation. The infertile women (vita‑\nmin D level < 30 ng/mL) treated with the multicomponent drugs including vitamin D (10,000–50,000 IU or 50,000–\n500,000 IU), or got vitamin D 1000–10,000 IU daily, lasting for 30–60 days could achieve better pregnancy outcome.\nConclusion To the best of our knowledge, this is the first meta‑analysis systematically investigated that moderate \ndaily dosing of vitamin D supplementation could improve the clinical pregnancy rate of infertile women and reported \nthe effects of vitamin D supplementation parameters on pregnancy outcomes. A larger sample size and high‑quality \n†Ting Qu and Lin‑lin Yu contributed equally to this work.\n*Correspondence:\nTing Qu\n543103775@qq.com\nLin‑lin Yu\n17069596@qq.com\nFull list of author information is available at the end of the article\n\nPage 2 of 16Meng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \nRCTs are necessary to optimize the parameters of vitamin D supplementation to help more infertile patients benefit \nfrom this therapy.\nKeywords Vitamin D, Supplementation, Reproductive outcomes, Infertile women, Clinical pregnancy rate\nIntroduction\nInfertility is a widespread health problem across the \nworld. Approximately 9.3–16.7% of the females of child-\nbearing age suffered from infertility [1, 2]. In recent years, \nan increasing number of infertile women seek assistance \nfrom assisted reproductive techniques (ARTs) [3]. How -\never, the efficacy of improvement in ARTs slowed down \nrecently [4]. It is still necessary to improve the effective -\nness of ARTs. Vitamin D, a steroid hormone, has five \ncompounds in which vitamin  D2 (ergocalciferol) and \nvitamin  D3 (cholecalciferol) are vital members associated \nwith reproductive health [5]. Previous research found \nthat 1α-hydroxylase (vitamin D enzymes) and vitamin D \nreceptors were expressed in human first-trimester and \ndecidua [6, 7]. Vitamin D receptors and 1,25(OH) 2D3 \nregulated the transcription of HOXA10 which was the \nkey target gene associated with implantation [6–8]. \nAccumulating evidence from prospective random and \ncohort observational studies proposed that vitamin D \ninsufficiency or deficiency was related to infertility [9]. It \nis proposed that vitamin D status might influence initial \nembryo implantation by regulating the immunology cells \n(natural killer cells, dendritic cells, macrophages, and T \ncells) in uterine and decidua tissue [6, 7]. However, recent \ninterest focused on the association between vitamin D \nlevels and ART outcomes, but not on the influence of \nvitamin D supplementation on reproduction [9]. The ani-\nmal experiment found the injection of vitamin  D3 could \ninduce the decidualization of rat endometrial cells [10]. \nIn human clinical trials, some studies found vitamin D \nsupplementation improved the reproductive outcomes \nof infertile women [11, 12], but other research showed \nthe failed influence of vitamin D treatment on pregnancy \noutcomes [13, 14]. Whether vitamin D supplements \ncould contribute to successful ARTs outcomes of infer -\ntile women was still uncertain. Similarly, the dosage and \nduration of vitamin D supplementation varied greatly \nin the previous reports [13, 15]. The high concentration \nof serum vitamin D could result in hypervitaminosis D \n(vitamin D poisoning) which was associated with nausea, \nvomiting, weakness, disturbed digestion, and elevated \nblood and tissue calcium levels [16–18]. Considering \nappropriate vitamin D supplementation for overall health \nbenefits, it is of great significance to investigate the fertil -\nity effect of parameters of vitamin D supplementation.\nThere are lack of conclusive results and a compre -\nhensive review regarding the actual fertility benefits of \nvitamin D supplementation and the potential effects of \nits parameters. Therefore, in this systematic review and \nmeta-analysis, our purpose was to evaluate whether vita -\nmin D supplementation could influence the reproductive \noutcomes of infertile women, and provide practical guid -\nance on the parameters of vitamin D supplementation to \nensure infertile patients could receive proper treatment \nand improve the treatment effectiveness for future trials.\nMethods\nThis systematic review and meta-analysis followed the \nPreferred Reporting Items for Systematic Reviews and \nMeta-Analyses (PRISMA) guidelines. The protocol of \nthis study was prospectively registered with the registra -\ntion number CRD42022304018 at PROSPERO. The insti-\ntutional review board approval was not required because \nall data were published previously.\nSearch strategy\nEnglish-language databases PubMed, Medline, Embase, \nand Cochrane Library and Chinese-language databases \nCNKI, Cqvip, and Wanfang were searched. The search \nstrategy was devised for each outcome (Supplemen -\ntal Search strategy, available online). Searches time was \nrestricted to studies published up to March 2022. Ref -\nerences from the selected articles, including relevant \nreview papers, were reviewed to identify all relevant \nstudies. Conference abstracts and prospective trial regis -\ntries were also searched for relevant items.\nInclusion and exclusion criteria\nData were carefully extracted by 2 investigators inde -\npendently. Any inconsistent opinions were resolved \nby discussion or with the help of a further investigator. \nThe infertile women undergoing ART (IVF, ICSI, fresh \nembryo transfer, and frozen embryo transfer) who had \nvitamin D supplementation were recruited. Study char -\nacteristics [authors’ last name(s), year of publication, \ncountry, and population (number of cases and controls)], \nspecific details about the interventions and reproductive \noutcome measures (implantation rate, biochemical preg -\nnancy rate, clinical pregnancy rate, miscarriage rate, and \nmultiple pregnancy rate) were recorded and summarized. \nExclusion criteria were: (1) reviews and case reports; \n(2) duplicate publications; (3) data were not available or \ncould not be extracted for the study groups; and (4) no \nappropriate case or control group.\n\nPage 3 of 16\nMeng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \n \nQuality assessment\nQuality assessment was evaluated by 2 investigators inde-\npendently. Any inconsistent opinions were arbitrated by a \nthird investigator. The risk of bias for RCTs was evaluated \nusing Cochrane’s tool. The quality score of cohort studies \nwas assessed using Newcastle-Ottawa Scale. The quality \nscores of studies ranged from 0 to 9 points and included \nthree aspects: selection, comparability, and exposure.\nStatistical Analysis\nThe extracted data were analyzed with Review Manager \n5.3 software (Cochrane Collaboration, Oxford, U.K.). The \nMantel-Haenszel method random-effects models were \nused for meta-analysis. The effect sizes were expressed as \nodds ratios (ORs) and calculated using their 95% confi -\ndence intervals (CIs). Summary ORs and 95% CIs were \nassessed graphically with forest plots. The Heterogeneity \nwas quantified using the I 2 value. To examine the poten -\ntial heterogeneity sources, subgroup meta-analyses were \nperformed according to the vitamin D level of patients, \ndrug type, the total vitamin D dosage, and the duration, \nadministration frequency, and daily dosage of vitamin D \nsupplementation. Publication bias was evaluated using \na funnel plot. To evaluate whether there was any study \naffecting the stability of the results, STATA 17.0 software \nwas used for the sensitivity analysis (leave one out). A \nP-value <0.05 was considered statistically significant.\nResults\nThe PRISMA flow diagram of the study process is pre -\nsented in Fig.  1. The search strategy yielded 700 publica -\ntions (58 from CNKI, 13 from Cqvip, 66 from Wanfang, \n96 from PubMed, 96 from Medline, and 146 from other \nsources), of which 313 were removed as duplicates. After \nrecords screening, 209 studies were excluded for not ful -\nfilling the experiment criteria. The full manuscripts of \n28 articles were evaluated. In two publications the full \ntext was not accessible, and two of those were excluded \nfor full-text duplication. Seven articles were removed \nfor not meeting the inclusion criteria. Thus, a total of 12 \npublications with available full texts remained. Finally, \nwe recruited 2548 infertile patients who met the eligibil -\nity criteria for quantitative data synthesis in twelve stud -\nies: nine RCT studies (n = 1773) and three clinical trial \nFig. 1 Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) flowcharts\n\nPage 4 of 16Meng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \nstudies (n = 775) for investigating the effect of vitamin D \nsupplementation on reproductive outcomes. A detailed \nsummary of the included study characteristics is shown \nin Table 1 and Supplemental Tables S1 and S2.\nStudy characteristics\nThe main characteristics of the included studies are \nshown in Table  1. The publication dates of the eligible \nstudies ranged between 2014 and 2021. The number of \npatients ranged from 74 to 630. Nine studies were RCTs \n[11–15, 19–21], and three studies were nonrandomized \ncohort studies [22–24]. The double-blind method was \nreported in five of the nine RCTs [12, 13, 15, 19, 21]. The \nrisk of bias assessments for the RCTs and cohort stud -\nies are summarized in Supplementary Tables S1 and S2. \nThe studies were conducted in Iran (four studies), China \n(four studies), Italy (two studies), the United Kingdom \n(one study), and Poland (one study). The serum vitamin \nD concentration before supplementation was lower than \n20 ng/mL in 2 studies, lower than 30 ng/mL in 7 studies, \nand not limited in 5 studies. The data on serum vitamin \nD concentration after supplementation were accessible \nin 3 studies. The patients in the case group underwent \nvitamin D supplementation in all 12 studies, were treated \nwith vitamin D only in 6 studies, and were multicompo -\nnent in 6 studies. The patients in the control group were \ntreated with a placebo in 8 studies and without interven -\ntion in 4 studies. The fertilization methods were IVF (one \nstudy), IVF/ICSI (three studies), ICSI (three studies), \nor no information (five studies). All recruited women \nwere infertile and undergoing IVF treatment. Recruited \npatients with PCOS in three studies or a variety of etiol -\nogy in seven studies. The duration of vitamin D supple -\nment was in the range of 1–90 days. The administration \nfrequency of vitamin D was daily in 7 studies, weekly \nin 3 studies, and other 2 in studies. The total vitamin D \ndosage was in the range of 560–600,000 IU. The admin-\nistration route of vitamin D was intramuscular injec -\ntion (one study) or oral administration (ten studies). The \nembryo transfer type was fresh and frozen embryo trans -\nfer (two studies), fresh embryo transfer (one study), fro -\nzen embryo transfer (four studies), or undetermined (five \nstudies).\nEffects of Vitamin D supplementation on the reproductive \noutcomes of infertile patients\nThe implantation rate outcomes were based on the data \nderived from 6 studies (963 cases and 895 controls). The \nimplantation rate had no significant difference between \nthe case and control group (OR: 1.86, 95% CI: 1.00–3.47; \nP = 0.05; heterogeneity; I2 = 85%; Fig. 2A).\nThe biochemical pregnancy rate outcomes were based \non the data derived from seven studies (772 cases and \n711 controls). The biochemical pregnancy rate had no \nsignificant difference in the case group compared with \nthat in the control group (OR: 1.49, 95% CI: 0.98–2.26; \nP = 0.06; heterogeneity; I2 = 63%; Fig. 2B).\nThe clinical pregnancy rate outcomes were based on \nthe data derived from 12 studies (1235 cases and 1117 \ncontrols): nine RCTs and three cohort studies. In RCTs \nstudies, the clinical pregnancy rate was significantly \nhigher in the case group than in the control group \n(OR: 1.49, 95% CI: 1.05–2.11; P = 0.02; heterogeneity; \nI2 = 54%). In cohort studies, the clinical pregnancy rate \nwas significantly higher in the case group than in the \ncontrol group (OR: 2.21, 95% CI: 1.42–3.44; P = 0.0005; \nheterogeneity; I2 = 33%). Overall, the clinical pregnancy \nrate was significantly higher in the case group than in the \ncontrol group in a total of 11 studies (OR: 1.70, 95% CI: \n1.24–2.34; P = 0.001; heterogeneity; I2 = 63%; Fig. 2C).\nThe results of the sensitivity analysis are shown in Sup -\nplemental Fig. S1 and S2. It is suggested that data derived \nfrom Somigliana (2021) may have a remarkable effect on \nthe merger results (Fig. S2) [13]. Somigliana (2021) was \nremoved, the meta-analysis of the effect of vitamin D \nsupplementation on the clinical pregnancy rate of infer -\ntile patients was drawn (Fig. S2) [13]. High heterogeneity \nsuddenly decreased from 63 to 36% (Fig.  2C and S2). The \npooled results still indicated that infertile women treated \nwith vitamin D had a significantly increased clinical preg-\nnancy rate compared with the control group (OR: 1.84, \n95% CI: 1.39–2.43; P < 0.0001; heterogeneity; I2  = 36%; \nFig. S2). And the conclusions of this study were statisti -\ncally reliable.\nHowever, the miscarriage rate outcomes were based on \nthe data derived from seven studies (366 cases and 289 \ncontrols). No difference was found in the miscarriage rate \nbetween the case and control group (OR: 0.98, 95% CI: \n0.63–1.53; P = 0.94; heterogeneity; I2 = 0%; Fig. 2D).\nThe multiple pregnancy rate outcomes were based on \nthe data derived from three studies (332 cases and 319 \ncontrols). The multiple pregnancy rate had no significant \ndifference between the case and control group (OR: 2.64, \n95% CI: 0.58–11.98; P = 0.21; heterogeneity; I2 = 68%; \nFig. 2E).\nEffects of the parameters of vitamin D supplementation \non the clinical pregnancy rates of infertile patients\nThe clinical pregnancy rate in studies with different vitamin D \nlevels of infertile patients\nNo significant difference was found in the clinical preg -\nnancy rate between the case and control groups when \nthe vitamin D level in the serum of infertile patients was \nlower than 20 ng/mL or had no limited (OR: 0.84, 95% \nCI: 0.48–1.49; P = 0.56; heterogeneity; I2 = 35%; or OR: \n1.27, 95%CI: 0.94–1.72; P = 0.12; heterogeneity; I2 = 0%). \n\nPage 5 of 16\nMeng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \n \nTable 1 main characteristics of the included studies\nAuthor Year Country Study design Serum Vitamin \nD concentration \nbefore / after \nsupplementary (ng/\nml)\nRecruited \npatients \nnumber\nTreatment(s) Control Fertilization Disease Duration of \nVitamin D \nsupplement\nCase Control\nAbedi 2019 Iran Double‑Blind \nRandomized \nPlacebo‑Con‑\ntrolled Trial\n13.6 ± 6.6/37.1 ± 7.7 \nvs 12.7 ± 6.4/14.4 ± 6.6\n54 54 Vitamin D placebo ICSI Infertile couples \nwho had Vitamin \nD level below \n30 ng/ml without \nsymptom of Vita‑\nmin D deficiency\nSix weeks\nAflatoonian 2014 Iran Randomized con‑\ntrolled trial\nbelow 30 57 57 Vitamin D – IVF/ICSI Infertile women \nundergo IVF/ICSI\nSix‑eight weeks\nDoryanizadeh 2021 Iran Double‑Blind \nRandomized \nClinical Trial\n27.5 ± 1.8 vs 27.6 ± 1.8 51 44 Calcitriol (Vitamin \nD3)\nplacebo – Infertile women Four weeks\nEspinola 2021 Italy Randomized and \ncontrolled pilot \nstudy\n25.4 (6.7; 16.0–\n40.0)/33.2(4.3; \n23.3–40.4) vs 23.9 (4.9; \n14.0–35.6) /24.3(5.2; \n16.1–36.4)\n60 60 Myo‑Inositol \n(600 mg), folic \nacid (200 mg), \nmelatonin \n(1.0 mg) and \nvitamin D3 \n(50 μg, 2000 IU) as \ncholecalciferol\nMyo‑Inositol \n(600 mg), folic \nAcid (200 mg), \nmelatonin \n(1.0 mg), folic \nacid (200 μg)\n– Infertile women \nof different etiol‑\nogy\nFrom the day of \nhCG administra‑\ntion until 14 days \nafter embryo \ntransfer\nFatemi 2017 Iran Double‑Blind \nRandomized \nPlacebo‑Con‑\ntrolled Trial\nbelow 30 52 53 Vitamin E, \n400 mg/day dl \nalpha tocoph‑\nerylacetate and \nvitamin D3\nplacebo ICSI PCOS Eight weeks\nKermack 2019 United Kingdom Double‑blinded \nrandomized\ncontrolled trial\n74.33 ± vs \n71.62 ± 24.69 nmol/L/ \n154.63 ± 1.56 nmol/L \nvs. 68.50 ± 1.51\n55 56 EPA(800 mg), \nDHA (1200 mg), \nor vitamin D in \nolive oil\nSunflower seed \noil\nIVF or IVF‑ICSI Women under‑\ngoing IVF\nSix weeks\nLan 2018 China Clinical trial below 30 37 37 Vitamin D2 – – Infertile women \nwho had failed \nto undergo IVF \nfresh embryo \ntransplantation\nSix weeks at least\nSomigliana 2021 Italy Randomized \nsuperiority \ndouble‑blind pla‑\ncebo controlled \nclinical trial\n20.0(15.5–23.6) vs \n19.9(14.6–23.9)\n308 322 Vitamin D3 \ndiluted in olive oil\nplacebo (the \nolive oil)\nClassical IVF and \nICSI\nWomen under‑\ngoing IVF\nA single adminis‑\ntration\n\nPage 6 of 16Meng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \nTable 1 (continued)\nAuthor Year Country Study design Serum Vitamin \nD concentration \nbefore / after \nsupplementary (ng/\nml)\nRecruited \npatients \nnumber\nTreatment(s) Control Fertilization Disease Duration of \nVitamin D \nsupplement\nCase Control\nTang 2017 China Randomized con‑\ntrolled trial\n– 235 155 Multivitamin tab‑\nlets (elevit)pearl/\ndaily orally\n– IVF‑ET Infertile women Ninety days\nWdowiak 2020 Poland Randomized con‑\ntrolled trial\n– 50 50 600 mg MI, \n200 μg folic acid, \n1 mg melatonin, \n50 μg equiva‑\nlent to 2000 IU \nvitamin D3\nplacebo ICSI Infertile women Three months\nZhao 2019 China Clinical trial – 190 115 25OH‑VD – – PCOS and insulin \nresistance\nTwo‑three months\nZhuang 2019 China Clinical trial – 204 192 Vitamin D \ncombined with \nmetformin and \nclomiphene\nmetformin and \nclomiphene\n– Patients with \nPCOS combined \nwith infertility\nThree consecutive \nmenstrual cycles\n\nPage 7 of 16\nMeng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \n \nTable 1 (continued)\nAuthor Administration \nfrequency of \nVitamin D\nTotal \nVitamin D \ndosage (IU)\nAdministration \nroute\nAge (years) BMI (kg/m2) Duration of infertility Transfer type Stage of \nembryo\nOutcome measures\nAbedi 50,000 units/week 300,000 Oral administra‑\ntion\n18–38(31.9 ± 4.2/30.8 ± 4.4) 18–30(23.9 ± 2.1/23.8 ± 1.9) 77.4 ± 22.1/68.1 ± 19.3 months – – Biochemical and clini‑\ncal pregnancy rate\nAflatoonian 50,000/week 300,000‑\n400,000\nOral administra‑\ntion\n28.45 ± 3.74/29.56 ± 4.68 26.87 ± 1.77/26.29 ± 1.67 – Frozen embryo \ntransfer\nEmbryos \nA/B/C\nBiochemical and clini‑\ncal pregnancy rate\nDoryanizadeh Two 0.25 μg daily 560 Oral administra‑\ntion\n20–40(32.5 ± 4.9/31.6 ± 4.9) 25.3 ± 3.2/24.9 ± 3.4 7.0 ± 4.7/7.1 ± 4.8 years Frozen embryo \ntransfer\n– Biochemical and \nclinical pregnancy rate, \nmiscarriage rate and \npregnancy continued \nuntil week 20\nEspinola 50 μg, 2000 IU daily 42,000 Oral administra‑\ntion\n≤ 42[34.7 (6.7;22–42)/35.9 \n(3.7;27.0–42.0)]\n18.5–24.9[21.9 (2.1;17.6–\n28.4)/22.0 (2.3;17.6–27.5)]\n3.7 (1.8;1.0–9.0)/3.6 (2.1;1.0–\n10.0) years\nFresh embryo \ntransfer\nBlastocysts \ngraded A/B\nImplantation rate, \nBiochemical and \nclinical pregnancy rate, \nmiscarriage rate, multi‑\nple pregnancy rate\nFatemi 50,000 IU/one in two \nweeks‑3300 IU/daily\n200,000 Oral administra‑\ntion\n18–\n38(28.07 ± 4.21/28.13 ± 3.73)\n20–\n34(26.53 ± 2.99/26.13 ± 3.58)\n61.61 ± 43.62/66.46 ± 36.31 \nmonths\nFresh and \nfrozen embryo \ntransfer\nEmbryo with \ngood mor‑\nphologic\nImplantation rate, Bio‑\nchemical and clinical \npregnancy rate, multi‑\nple pregnancy rate\nKermack 10 μg, 400 IU daily 16,800 Oral administra‑\ntion\n18–41(33.3 ± 4.1/33.4 ± 4.3) 18–32(24.3 ± 3.1/25.0 ± 3.9) – – Embryo with \nhighest\nmorphologic \nscore\nImplantation, clinical \npregnancy and live \nbith rate\nLan 10 ml (50 mg)/one \ntime in two weeks\n45,000 Intramuscular \ninjection\n– – – Frozen embryos – Implantation and clini‑\ncal pregnancy rate\nSomigliana 600,000 IU 600,000 Oral administra‑\ntion\n18–39[35.0(32.0–\n37.0)/35.0(33.0–37.0)]\n18–25[20.8(19.5–\n22.5)/21.1(19.7–22.9)]\n3(2–4)/2.5(2–4) years Fresh and fro‑\nzen embryos\nBlastocyst \nStage (Day 5)\nBiochemical and \nclinical pregnancy rate, \nmiscarriage rate, multi‑\nple pregnancy rate and \nlive birth rate\nTang Vitamin D 500 IU/\ndaily\n45,000 Oral administra‑\ntion\n24–43(32.5 ± 3.2)/23–\n42(31.8 ± 3.0)\n– 1–12(4.2 ± 1.4)/1–11(4.0 ± 1.2) \nyears\n– – Clinical pregnancy, and \nmiscarriage rate\nWdowiak 50 μg equivalent to \n2000 IU vitamin D3 \nas cholecalciferol/\ndaily\n168,000 Oral administra‑\ntion\n20–35(31 ± 3.11/31.2 ± 3.03) 24.76 ± 2.94/25.11 ± 2.39 – – – Clinical pregnancy rate\nZhao – – – 31.2 ± 4.3/32.1 ± 4.2,32.0 ± 3.\n4/31.6 ± 6.9\n22.4 ± 2.4/24.7 ± 4.7, \n23.5 ± 3.8/24.1 ± 4.4\n3.8 ± 2.3/3.1 ± 3.2,3.7 ± 1.0/\n3.4 ± 2.2\nFrozen embryos – Implantation and clini‑\ncal pregnancy rate\nZhuang 3000 IU daily, 5 days/\nmenstrual cycle\n45,000 Oral administra‑\ntion\n26.33 ± 4.05/25.64 ± 4.78 27.53 ± 4.13/27.28 ± 3.56 3.87 ± 2.44/3.52 ± 2.56 – – Pregnancy rate\n\nPage 8 of 16Meng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \nWhen the vitamin D level in serum before treatment was \nlower than 30 ng/mL, the clinical pregnancy rate was sig -\nnificantly increased in the case group than in the control \ngroup (OR: 2.06, 95% CI: 1.32–3.22; P = 0.001; heteroge-\nneity; I2 = 58%; Fig. 3).\nThe clinical pregnancy rate in studies with different drug \ntypes\nWhen the infertile patients were treated with vitamin D \nonly, the clinical pregnancy rate had no significant dif -\nference between the case and control groups (OR: 1.67, \n95% CI: 0.98–2.82; P = 0.06; heterogeneity; I2 = 66%). \nHowever, if the patients got multicomponent drug con -\ntained vitamin D, the clinical pregnancy rate was signifi -\ncantly higher in the case group than in the control group \n(OR: 1.75, 95% CI: 1.18–2.59; P = 0.005; heterogeneity; \nI2 = 53%; Fig. 4).\nThe results of the sensitivity analysis are shown in Sup -\nplemental Fig. S3 and S4. It is suggested that data derived \nfrom Somigliana (2021) might have a remarkable effect \non the merger results (Fig. S3) [13]. Somigliana (2021) \nwas removed, meta-analysis of the effect of vitamin D \nsupplementation on the clinical pregnancy rate in the \nsubgroup of vitamin D only supplementation was drawn \n(Fig. S3) [13]. The high heterogeneity suddenly decreased \nfrom 66 to 20% (Fig.  4 and S4). The pooled results indi -\ncated that infertile women treated with vitamin D only \nhad a significantly increased clinical pregnancy rate com-\npared with the control group (OR: 1.97, 95% CI: 1.26–\n3.09; P < 0.003; heterogeneity; I2 = 20%; Fig. S4).\nThe clinical pregnancy rate in studies with different total \ndosages of vitamin D supplementation\nThere was no significant difference in the clinical preg -\nnancy rate between the case and control groups when \nthe total vitamin D dosage was lower than 10,000 IU or \nhigher than 500,000 IU (OR: 3.01, 95% CI: 1.00–9.11; \nP = 0.05; or OR: 0.86, 95% CI: 0.62–1.18; P  = 0.34). \nCompared with the control group, the clinical preg -\nnancy rate increased significantly in the case group \nwhen the infertile patients were treated with 10,000–\n50,000 IU or 50,000–500,000 IU vitamin D during the \nwhole supplementation (OR: 1.69, 95% CI: 1.06–2.71; \nP = 0.03; heterogeneity; I2 = 62%; or OR: 2.12, 95% CI: \n1.29–3.49; P = 0.003; heterogeneity; I2 = 14%; Fig. 5).\nThe clinical pregnancy rate in studies with different \nduration of vitamin D supplementation\nThe clinical pregnancy rate was similar in the case \ngroup compared with the control group when the \nduration of vitamin D supplementation was shorter \nthan 30 days (OR: 1.45, 95% CI: 0.67–3.13; P  = 0.34; \nheterogeneity; I2 = 69%). When the vitamin D sup -\nplementation lasted for 30–60 days or 60–90 days, the \nFig. 2 Meta‑analyses of the effect of vitamin D supplementation on the reproductive outcomes of infertile patients A Implantation; B Biochemical \npregnancy; C Clinical pregnancy; D Miscarriage; E Multiple pregnancy\n\nPage 9 of 16\nMeng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \n \nclinical pregnancy rate was significantly higher in the \ncase group than in the control group (OR: 2.00, 95% \nCI: 1.07–3.76; P  = 0.03; heterogeneity; I2 = 54%; or \nOR: 1.70, 95% CI: 1. 16–2.49; P  = 0.007; heterogeneity; \nI2 = 52%; Fig. 6).\nThe clinical pregnancy rate in studies with different \nadministration frequencies of vitamin D supplementation\nThe clinical pregnancy rate was significantly higher in the \ncase group compared with the control group when vita -\nmin D supplementation was given every day or weekly \n(OR: 1.83, 95% CI: 1.26–2.64; P = 0.001; heterogeneity; \nI2 = 49%; or OR: 2.16, 95% CI: 0.95–4.92; P = 0.07; het-\nerogeneity; I2 = 49%). When the vitamin D was admin -\nistrated at one time or other frequency, the clinical \npregnancy rate was similar in the case group compared \nwith the control group (OR: 1.10, 95% CI: 0.61–2.00; \nP = 0.74; heterogeneity; I2 = 69%; Fig. 7).\nThe clinical pregnancy rate in studies with different \ndosages of vitamin D supplementation daily\nThe clinical pregnancy rate was similar in the case group \ncompared with the control group when the dosage of \nvitamin D supplementation daily was lower than 1000 IU \n(OR: 1.28, 95% CI: 0.78–2.10; P = 0.33; heterogeneity; \nI2 = 33%). When the dosage of vitamin D supplementa -\ntion daily ranged from 1000 to 10,000 IU, the clinical \npregnancy rate was significantly higher in the case group \nthan in the control group (OR: 2.17, 95% CI: 1.63–2.89; \nP < 0.00001; heterogeneity; I2 = 0%). Compared with the \ncontrol group, the clinical pregnancy rate was the same \nFig. 3 Forrest plot for the effect of vitamin D supplementation on the clinical pregnancy rate in studies with different vitamin D level of infertile \npatients\n\nPage 10 of 16Meng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \nin the case group when the dosage of vitamin D supple -\nmentation daily was higher than 10,000 IU (OR: 1.87, 95% \nCI: 0.33–10.48; P = 0.48; heterogeneity; I2 = 87%; Fig. 8).\nDiscussion\nThis study demonstrated that vitamin D supplementa -\ntion successfully improved the clinical pregnancy rate \nof infertile women, but failed to significantly alter the \nimplantation and biochemical pregnancy rate. However, \nwe found that the results were significantly influenced by \nthe article reported by Somigliana et al. [13]. When the \ndata from this article was removed, the implantation and \nbiochemical pregnancy rate significantly increased [13]. \nThe alteration might be caused by its research design \n[13]. Somigliana et  al. designed that the patients took a \nsingle oral dose of 600,000 IU [13]. This single dosage was \nmuch higher than the maximum dose of supplementa -\ntion for vitamin D-deficient adults recommended by the \nScientific Advisory Committee on Nutrition (SACN) \nwhich should not exceed 4000 IU/day or suggested by \nthe National Institute for Health and Care Excellence \n(NICE) 50,000 IU per week for 6 weeks (300,000 IU in \ntotal) [25, 26]. Even though vitamin D supplementa -\ntion was suggested as a safe and well-tolerated interven -\ntion, the drug dosage of clinical intervention still needed \ncareful consideration [16, 27–29]. Especially, the previous \nreports proposed that there were toxicity and counter -\nproductive influence when serum vitamin D concentra -\ntions greater than 150 ng/mL (greater than 374 nmol/L) \n[16, 27, 28, 30]. Even previous articles showed that large \nbolus vitamin D dose could be cleared within a week, \nachieving little or no detectable effect on circulating the \nvitamin D status [31, 32]. All of these reasons could be \nused to explain the results bias caused by Somigliana \net  al. [13]. Increased clinical pregnancy rate might be \nassociated with successful implantation, not resulting \nfrom reducing the risk of miscarriage. The results sup -\nported the hypothesis that vitamin D exerted pivotal \neffects on initial embryo implantation, the early tropho -\nblast invasion, and the decidualization of endometrium, \nnot on the second-trimester loss for infertile women \nundergoing IVF treatment [33, 34].\nMany previous reports proposed that the low level of \nvitamin D was related to poor implantation and infertility \n[9, 35]. The cut-off value of serum vitamin D was adopted \nby the Endocrine Society [36]. The serum 25-hydroxy \nvitamin  D3 concentration of <20 ng/mL was considered \nvitamin D deficiency, 21–29 ng/mL was considered insuf-\nficient, and > 30 ng/mL was considered replete [36]. We \nseparated the recruited population according to these \nFig. 4 Forrest plot for the effect of vitamin D supplementation on the clinical pregnancy rate in studies with different drug type\n\nPage 11 of 16\nMeng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \n \nvitamin D levels into three groups and tried to check \nwhether the vitamin D level before the supplementation \ncould affect the reproductive outcomes of the vitamin D \ntreatment. Only the patients whose vitamin D level was \nlower than 30 ng/mL could benefit from the supplemen -\ntation, neither the vitamin D concentration in serum \nlower than 20 ng/mL nor non-limited. These results could \nbe explained by the hypothesis that individuals with dif -\nferent genotypes of vitamin D-related genes had different \nresponses to vitamin D supplementation [37]. Polymor -\nphism in several vitamin D genes (CYP2R1, CYP27A1, \nCYP27B1, CYP24A1, VDBP , and VDR) had been associ -\nated with vitamin D metabolism and regulated the activ -\nity of vitamin D [37]. Single nucleotide polymorphisms \n(SNP) in GC (rs4588 and rs7041), VDR (rs10735810), \nand CYP27B1 (rs10877012) also were reported asso -\nciated with vitamin D status [38, 39]. GC (rs4588 and \nrs2282679) were associated with lower vitamin D status \nboth before and after vitamin D supplementation [37]. So \nthe patients with vitamin D status lower than 20 ng/mL \nmight carry related genes with poor vitamin D response, \nno significant benefit was provided. Overall, vitamin D \nsupplementation was encouraged for infertile patients \nwith vitamin D status lower than 30 ng/mL.\nThe previous article showed that a short period of die -\ntary intervention containing omega-3 Fas and vitamin D \ncould improve the quality of embryo cleavage [21]. Our \nresults showed that the individual components (vita -\nmin D only) resulting in improved clinical pregnancy \nrate might be underdetermined. The multicomponent \nFig. 5 Forrest plot for the effect of vitamin D supplementation on the clinical pregnancy rate in studies with different total dosages of vitamin D \nsupplementation\n\nPage 12 of 16Meng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \nincluding Myo-Inositol, folic acid, melatonin vitamin \nE and D ect, improved the pregnancy rate which con -\nfirmed that not vitamin D exerted a positive influence \non reproductive outcomes independently but synergis -\ntically. However, the sensitivity analysis (the exclusion \nof the study by Somigliana et  al.) showed that infertile \nwomen treated with vitamin D only also had a signifi -\ncantly increased clinical pregnancy rate compared with \nthe control group [13]. More researches about the effect \nof vitamin D supplementation on the clinical pregnancy \nrate with different drug type were needed.\nVitamin D is a fat-soluble steroid hormone, has lipo -\nphilic nature, and distributes in adipose tissue [40, 41]. \nVitamin D has a slow turnover in the body with a half-\nlife of approximately 2 months [40, 42]. Vitamin D could \nbe metabolized by 25-hydroxylase, a liver enzyme, into \n25(OH) D which has a half-life of 15 days [40, 42]. The \n(25(OH)D) again could be converted into calcitriol or \n1,25(OH)2 D by enzyme CYP27B1 [40, 42]. 1,25(OH)2 D \nhas a half-life of 15 hours [40, 43]. The pharmacokinetics \nof vitamin D can impact the effects of vitamin D sup -\nplementation, so the dosing regimen of vitamin D sup -\nplementation had to be taken into consideration. To \nmaximize the chance of achieving pregnancy and mini -\nmize and minimize the detrimental and toxicity effects \nof vitamin D supplementation, we set the subgroup of \ntotal vitamin D dosage, duration, administration fre -\nquency, and daily vitamin D dosage to confirm the suit -\nable intervention. When the total vitamin D dosage was \ntoo low (lower than 10,000 IU) or too high (higher than \n500,000 IU), the clinical pregnancy rate had no signifi -\ncant increase. The total vitamin D dosage ranged from \n10,000–500,000 IU might be proper for infertile patients. \nThe infertile patients could achieve better reproductive \noutcomes when they got vitamin D (1,000–10,000 IU) \nsupplementation every day that lasts for more than \n30 days. In comparison to the vitamin D administrated \nweekly or at others interverals (monthly or longer inter -\nvals), this study yielded only positive results for daily \ntreatment. That could be explained by the hypothesis \nFig. 6 Forrest plot for the effect of vitamin D supplementation on the clinical pregnancy rate in studies with different duration of vitamin D \nsupplementation\n\nPage 13 of 16\nMeng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \n \nthat only daily vitamin D supplementation could main -\ntain stable circulating concentrations over time [31, 44]. \nThe infertile patients treated with vitamin D dose var -\nied from 1000-10,000 IU daily could benefit from the \nsupplementation. A dose lower than 1000 IU or higher \nthan 10,000 IU daily failed to show that vitamin D could \nimprove the clinical pregnancy rate of infertile patients. \nThese results indicated that patients treated with a \nsmall daily dose might still be at risk of vitamin D defi -\nciency, so the improvement had failed. This finding was \nconsistent with the past researches that approximately \n280 IU/d or 400 IU/d dose for several months had mini -\nmal, or even no effect on the circulating vitamin D [44, \n45]. While large bolus dosing with vitamin D caused a \ndramatic fluctuation circulating 25(OH) D levels, which \nhave little benefit, or even be adverse [46, 47]. That \nmight be because the sudden increased vitamin D lev -\nels caused by the bolus vitamin D could trigger counter -\nvailing factors. Low response to bolus dosing of vitamin \nD leaded to increase of vitamin D level not as expected \n[48, 49]. 24-hydroxylase (CYP24A1) up-regulated by the \nbolus dosing of vitamin D could significantly increase \n24,25(OH)2D3, down-regulate 1,25(OH) 2D and inhibits \nimmune-modulation for weeks or even months [48– 50]. \nWe summarized and discussed that moderate daily dos -\ning of vitamin D supplementation was an appropriate \ndosing regimen. A suitable vitamin D dosing regimen \ncould have positive effects on the clinical pregnancy rate \nof infertile patients.\nEven though several clinical parameters were ana -\nlyzed to figure out which parameter might regulate the \nreproductive outcomes, several limitations still existed \nin our study. The limitations mainly originated from \nthe clinical heterogeneity of the included publications, \nincluding the different ethnicities, uncertain vitamin \nD status before and after vitamin D supplementa -\ntion, duration of vitamin D supplementation, and the \nrecruited infertile women of different etiology. Even \nthough vitamin D supplementation was thought a safe \nand low-cost treatment, we still found the variation \nFig. 7 Forrest plot for the effect of vitamin D supplementation on the clinical pregnancy rate in studies with different administration frequency of \nvitamin D supplementation\n\nPage 14 of 16Meng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \nof vitamin D supplementation was quite large. Proper \ndoses of vitamin D supplementation should be deter -\nmined. Furthermore, infertile women in 3 articles had \nbeen shown that their serum vitamin D level got sig -\nnificantly increased after the intervention. The lack of \nvitamin D data after the intervention might mean it \nwas possible vitamin D insufficient or deficiency was \nnot changed, and the full effect of the intervention was \nnot elicited. It is necessary to monitor the response \nto vitamin D supplements. The analysis of subgroups, \naccording to the duration of vitamin D supplementa -\ntion, should not be overlooked. The heterogeneity was \nhigh in all subgroups, so the result might be not reli -\nable. This might possible because the parameter - dura -\ntion was not an independent factor influencing the \nclinical pregnancy rate. The duration of vitamin D sup -\nplementation could be affected by the administration \nfrequencies and total dosages of vitamin D supplemen -\ntation. Patients with different genotypes have different \nresponses to the supplementation, so how the guide \nmedication according to the genotype also should be \npaid attention to. Vitamin D could be self-synthesized \nby the human body, and the level of vitamin D is viti -\nated with the seasons’ change. Whether the vitamin D \nsupplementation should be adjusted according to the \nseasons is to be considered in the future. Recogniz -\ning the limitations of studies included in meta-anal -\nyses may stimulate future studies with better designs \nand methods that will improve available evidence and \ndefinitively define the role of vitamin D in ART.\nConclusion\nOur study provides important evidence to support that \ntaking appropriate vitamin D in combination with other \ncomponents, before pregnancy, can increase reproduc -\ntive outcomes, but not prevent infertile women from \nexperiencing miscarriages. What’s more, women taking \nvitamin D supplements can be affected by the param -\neters of vitamin D. And the infertile patients at risk of \nvitamin D deficiency received moderate daily dosing \nFig. 8 Forrest plot for the effect of vitamin D supplementation on the clinical pregnancy rate in studies with different dosage of vitamin D \nsupplementation daily\n\nPage 15 of 16\nMeng et al. Reproductive Biology and Endocrinology           (2023) 21:17 \n \nof vitamin D supplementation are more likely to have \ngood reproductive outcomes. However, the included \narticles have a small sample size and high heterogene -\nity, so further investigating the mechanism of vitamin \nD treatment acting on the infertile population is still \nnecessary.\nSupplementary Information\nThe online version contains supplementary material available at https:// doi. \norg/ 10. 1186/ s12958‑ 023‑ 01068‑8.\nAdditional files 1: Table S1. Risk of bias assessment of the randomized \ncontrolled trials for meta‑analysis using the Cochrane tool. Table S2. \nQuality assessment of the cohort studies for the meta‑analysis using the \nNewcastle‑Ottawa scale.\nAdditional files 2: Fig. S1. Sensitivity analysis for the effect of vitamin \nD supplementation on clinical pregnancy rate of infertile patients using \nrandom effect model (Odds Ratio).\nAdditional files 3: Fig. S2. Forrest plot for the effect of vitamin D sup‑\nplementation on the clinical pregnancy rate of infertile patients [leave \nSomigliana (2021) out].\nAdditional files 4: Fig. S3. Sensitivity analysis for the effect of vitamin D \nsupplementation on the clinical pregnancy rate in studies of vitamin D \nonly supplementation using random effect model (Odds Ratio).\nAdditional files 5: Fig. S4. Forrest plot for the effect of vitamin D sup‑\nplementation on the clinical pregnancy rate in studies of vitamin D only \nsupplementation [leave Somigliana (2021) out].\nAcknowledgments\nNot applicable.\nAuthors’ contributions\nXiangqian Meng and Jiayao Zhang accomplished the literature search and \nidentified the eligible studies. Qi Wan and Jihua Huang completed the data \nextraction. Tingting Han achieved the assessment of the quality of the litera‑\nture. Ting Qu and Lin‑lin Yu supervised, made the conception and designed \nthe research, wrote the manuscript. All authors reviewed and approved the \nmanuscript.\nFunding\nTing Qu reports grants from the Sichuan Medical Association (Q20055) \nand the Science and Technology Department of Sichuan, China (Grant no. \n2022NSFSC1508).\nAvailability of data and materials\nThe datasets used and/or analyzed during this study are available in this \npublished article and supplementary.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nAll data were collected from published literature.\nCompeting interests\nThe authors have no competing interests to declare.\nAuthor details\n1 Chengdu Xi’nan Gynecological Hospital Co. LTD, Chengdu 610000, Sichuan, \nChina. 2 West China School of Basic Medical Sciences & Forensic Medicine, \nSichuan University, Chengdu 610000, Sichuan, China. 3 Chengdu Jinxin \nResearch Institute for Reproductive Medicine and Genetics, Chengdu 610000, \nSichuan, China. 4 Chengdu Women’s and Children’s Central Hospital, School \nof Medicine, University of Electronic Science and Technology of China, \nChengdu 610000, Sichuan, China. \nReceived: 20 December 2022   Accepted: 23 January 2023\nReferences\n 1. Inal ZO, Inal HA, Gorkem U. Sexual function and depressive symptoms in \nprimary infertile women with vitamin D deficiency undergoing IVF treat‑\nment. Taiwan J Obstetrics Gynecol. 2020;59:91–8.\n 2. Zhou Z, Zheng D, Wu H, Li R, Xu S, Kang Y, et al. Epidemiology of infertility \nin China: a population‑based study. BJOG. 2017;125:432–41.\n 3. Farquhar C, Marjoribanks J. Assisted reproductive technology: An over‑\nview of Cochrane Reviews. 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Rheum Dis Clin N Am. 2012;38:125–39.\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in pub‑\nlished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}