Abstract
Purpose
To review the current literature regarding the role of vitamin D status in pregnancy outcomes in women undergoing assisted reproductive technology (ART) and to assess cost-effectiveness of routine vitamin D deficiency screening and repletion prior to initiation of ART.
Methods
A systematic literature review was conducted using PubMed. Relevant study outcomes were compared among the selected studies. A cost-benefit analysis was performed using a decision tree mathematical model with sensitivity analyses from the perspective of direct societal cost. Published data were used to estimate probabilities and costs in 2014 US dollars.
Results
Thirty-four articles were retrieved, of which eight met inclusion criteria. One study demonstrated a negative relationship between vitamin D status and ART outcomes, while two studies showed no association. The remaining five studies concluded that ART outcomes improved after vitamin D repletion.
Conclusion
The majority of reviewed studies reported a decrement in ART outcomes in patients with vitamin D deficiency. Cost-benefit analyses suggested that screening and supplementing vitamin D prior to ART might be cost effective, but further evidence is needed. Given the absence of Level I evidence regarding vitamin D status and ART outcomes, full endorsement of routine vitamin D screening and supplementation prior to ART is premature.
This is a preview of subscription content, access via your institution.





References
Bouillon R, Carmeliet G, Daci E, Segaert S, Verstuyf A. Vitamin D metabolism and action. Osteoporos Int. 1998;8(2 Suppl):S13–9.
Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am J Clin Nutr. 2008;88(2):491S–9S.
Mitchell DM, Henao MP, Finkelstein JS, Burnett-Bowie SA. Prevalence and predictors of vitamin D deficiency in healthy adults. Endocr Pract. 2012;18(6):914–23.
Looker AC, Johnson CL, Lacher DA, Pfeiffer CM, Schleicher RL, Sempos CT. Vitamin D status: United States, 2001–2006. NCHS Data Brief. 2011;59:1–8.
Forrest KYZ, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011;31(1):48–54.
Kennel KA, Drake MT, Hurley DL. Vitamin D deficiency in adults: when to test and how to treat. Mayo Clin Proc. 2010;85(8):752–8.
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–30.
Institute of Medicine, Food and Nutrition Board. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academy Press; 2010.
American College of Obstetricians and Gynecologists. Vitamin D: screening and supplementation during pregnancy. Committee opinion no. 495. Obstet Gynecol. 2011;118:197–8.
Kwiecinski GG, Petrie GI, Deluca HF. Vitamin D is necessary for reproductive functions of the male rat. J Nutr. 1989;119(5):741–4.
Jensen MB, Nielsen JE, Jorgensen A, Meyts ER-D, Kristensen DM, Jorgensen N, et al. Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract. Hum Reprod. 2010;25(5):1303–11.
Johnson JA, Grande JP, Roche PC, Kumar R. Immunohistochemical detection and distribution of the 1,25-dihydroxyvitamin D-3 receptor in rat reproductive tissues. Histochem Cell Biol. 1996;105(1):7–15.
Schleicher G, Privette TH, Stumpf WE. Distribuition of soltriol [1,25(OH)2-vitamin-D3] binding sites in male sex organs of the mouse: an autoradiographic study. J Histochem Cytochem. 1989;37(7):1083–6.
Corbett ST, Hill O, Nangia AK. Vitamin D receptor found in human sperm. Urology. 2006;68(6):1345–9.
Aquila S, Guido C, Perrotta I, Tripepi S, Nastro A, Ando S. Human sperm anatomy: ultrastructural localization of 1 alpha,25-dihydroxyvitamin D(3) receptor and its possible role in the human male gamete. J Anat. 2008;213(5):555–64.
Jensen MB, Bjerrum PJ, Jessen TE, Nielsen JE, Joensen UN, Olesen IA, et al. Vitamin D is positively associated with sperm motility and increases intracellular calcium in human spermatozoa. Obstet Gynecol Surv. 2011;66(9):556–8.
Blomberg Jensen M, Jorgensen A, Nielsen JE, Bjerrum PJ, Skalkam M, Petersen JH, et al. Expression of the vitamin D metabolizing enzyme CYP24A1 at the annulus of human spermatozoa may serve as a novel marker of semen quality. Int J Androl. 2012;35(4):499–510.
Ramlau-Hansen CH, Moeller UK, Bonde JP, Olsen J, Thulstrup AM. Are serum levels of vitamin D associated with semen quality? Results from a cross-sectional study in young healthy men. Fertil Steril. 2011;95(3):1000–4.
Hammoud AO, Meikle AW, Peterson CM, Stanford J, Gibson M, Carrell DT. Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters. Asian J Androl. 2012;14(6):855–9.
Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab. 2008;4(2):80–90.
Ota K, Dambaeva S, Han AR, Beaman K, Gilman-Sachs A, Kwak-Kim J. Vitamin D deficiency may be a risk factor for recurrent pregnancy losses by increasing cellular immunity and autoimmunity. Hum Reprod. 2014;29(2):208–19.
Andreoli L, Piantoni S, Dall’Ara F, Allegri F, Meroni PL, Tincani A. Vitamin D and antiphospholipid syndrome. Lupus. 2012;21(7):736–40.
Tavakoli M, Jeddi-Tehrani M, Salek-Moghaddam A, Rajaei S, Mohammadzadeh A, Sheikhhasani S, et al. Effects of 1,25(OH)2 vitamin D3 on cytokine production by endometrial cells of women with recurrent spontaneous abortion. Fertil Steril. 2011;96(3):751–7.
Gysler SM, Mulla MJ, Stuhlman M, Sfakianaki AK, Paidas MJ, Stanwood NL, et al. Vitamin D reverses aPL-induced inflammation and LMWH-induced sFlt-1 release by human trophoblast. Am J Reprod Immunol. 2014.
Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007;92(9):3517–22.
Bodnar LM, Catov JM, Zmuda JM, Cooper ME, Parrott MS, Roberts JM, et al. Maternal serum 25-hydroxyvitamin D concentrations are associated with small-for-gestational age births in white women. J Nutr. 2010;140(5):999–1006.
Mannion CA, Gray-Donald K, Koski KG. Association of low intake of milk and vitamin D during pregnancy with decreased birth weight. CMAJ. 2006;174(9):1273–7.
Brooke OG, Brown IRF, Bone CDM, Carter ND, Cleeve HJW, Maxwell JD, et al. Vitamin-D supplements in pregnant Asian women: effects on calcium status and fetal growth. BMJ. 1980;280(6216):751–4.
Morley R, Carlin JB, Pasco JA, Wark JD. Maternal 25-hydroxyvitamin D and parathyroid hormone concentrations and offspring birth size. J Clin Endocrinol Metab. 2006;91(3):906–12.
Merewood A, Mehta SD, Chen TC, Bauchner H, Holick MF. Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab. 2009;94(3):940–5.
Poel YHM, Hummel P, Lips P, Stam F, van der Ploeg T, Simsek S. Vitamin D and gestational diabetes: a systematic review and meta-analysis. Eur J Intern Med. 2012;23(5):465–9.
Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril. 2001;75(1):1–10.
Agic A, Xu H, Altgassen C, Noack F, Wolfler MM, Diedrich K, et al. Relative expression of 1,25-dihydroxyvitamin D3 receptor, vitamin D 1 alpha-hydroxylase, vitamin D 24-hydroxylase, and vitamin D 25-hydroxylase in endometriosis and gynecologic cancers. Reprod Sci. 2007;14(5):486–97.
Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72(3):690–3.
Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011;7(4):219–31.
Girgis CM, Clifton-Bligh RJ, Hamrick MW, Holick MF, Gunton JE. The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev. 2013;34(1):33–83.
Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr. 2011;65(9):1005–15.
Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79(5):820–5.
Tai K, Need AG, Horowitz M, Chapman IM. Vitamin D, glucose, insulin, and insulin sensitivity. Nutrition. 2008;24(3):279–85.
Chiu KC, Chuang LM, Lee NP, Ryu JM, McGullam JL, Tsai GP, et al. Insulin sensitivity is inversely correlated with plasma intact parathyroid hormone level. Metabolism. 2000;49:1501–5.
McCarty MF, Thomas CA. PTH excess may promote weight gain by impeding catecholamine-induced lipolysis-implications for the impact of calcium, vitamin D, and alcohol on body weight. Med Hypotheses. 2003;61:535–42.
Reis JP, von Muhlen D, Kritz-Silverstein D, Wingard DL, Barrett-Connor E. Vitamin D, parathyroid hormone levels, and the prevalence of metabolic syndrome in community-dwelling older adults. Diabetes Care. 2007;30:1549–55.
Maestro B, Campion J, Davila N, Calle C. Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J. 2000;47:383–91.
Maestro B, Davila N, Carranza MC, Calle C. Identification of a Vitamin D response element in the human insulin receptor gene promoter. J Steroid Biochem Mol Biol. 2003;84:223–30.
Kim JJ, Choi YM, Chae SJ, Hwang KR, Yoon SH, Kim MJ, et al. Vitamin D deficiency in women with polycystic ovary syndrome. Clin Exp Reprod Med. 2014;41(2):80–5.
Wehr E, Trummer O, Giuliani A, Gruber HJ, Pieber TR, Obermayer-Pietsch B. Vitamin D-associated polymorphisms are related to insulin resistance and vitamin D deficiency in polycystic ovary syndrome. Eur J Endocrinol. 2011;164:741–9.
Mazloomi S, Sharifi F, Hajihosseini R, Kalantari S, Mazloomzadeh S. Association between hypoadiponectinemia and low serum concentrations of calcium and vitamin D in women with polycystic ovary syndrome. ISRN Endocrinol. 2012;2012:949427.
Li HW, Brereton RE, Anderson RA, Wallace AM, Ho CK. Vitamin D deficiency is common and associated with metabolic risk factors in patients with polycystic ovary syndrome. Metabolism. 2011;60(10):1475–81.
Mahmoudi T, Gourabi H, Ashrafi M, Yazdi RS, Ezabadi Z. Calciotropic hormones, insulin resistance, and the polycystic ovary syndrome. Fertil Steril. 2010;93(4):1208–14.
Panidis D, Balaris C, Farmakiotis D, Rousso D, Kourtis A, Balaris V, et al. Serum parathyroid hormone concentrations are increased in women with polycystic ovary syndrome. Clin Chem. 2005;51(9):1691–7.
Hahn S, Haselhorst U, Tan S, Quadbeck B, Schmidt M, Roesler S, et al. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2006;114(10):577–83.
Yildizhan R, Kurdoglu M, Adali E, Kolusari A, Yildizhan B, Sahin HG, et al. Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet. 2009;280(4):559–63.
Lagunova Z, Porojnicu AC, Lindberg F, Hexeberg S, Moan J. The dependency of vitamin D status on body mass index, gender, age and season. Anticancer Res. 2009;29(9):3713–20.
Merhi Z. Advanced glycation end products and their relevance in female reproduction. Hum Reprod. 2014;29(1):135–45.
Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001;44(2):129–46.
Vazzana N, Guagnano MT, Cuccurullo C, Ferrante E, Lattanzio S, Liani R, et al. Endogenous secretory RAGE in obese women: association with platelet activation and oxidative stress. J Clin Endocrinol Metab. 2012;97(9):E1726–30.
Unoki H, Yamagishi S. Advanced glycation end products and insulin resistance. Curr Pharm Des. 2008;14(10):987–9.
Diamanti-Kandarakis E, Piperi C, Kalofoutis A, Creatsas G. Increased levels of serum advanced glycation end-products in women with polycystic ovary syndrome. Clin Endocrinol (Oxf). 2005;62(1):37–43.
Diamanti-Kandarakis E, Piperi C, Patsouris E, Korkolopoulou P, Panidis D, Pawelczyk L, et al. Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol. 2007;127(6):581–9.
Jia X, Chang T, Wilson TW, Wu L. Methylglyoxal mediates adipocyte proliferation by increasing phosphorylation of Akt1. PLoS One. 2012;7(5):e36610.
Diamanti-Kandarakis E, Piperi C, Livadas S, Kandaraki E, Papageorgiou E, Koutsilieris M. Interference of AGE-RAGE signaling with steroidogenic enzyme action in human ovarian cells. San Francisco: Endocrine Society; 2013.
Yoshizawa T, Handa Y, Uematsu Y, Takeda S, Sekine K, Yoshihara Y, et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet. 1997;16(4):391–6.
Kinuta K, Tanaka H, Moriwake T, Aya K, Kato S, Seino Y. Vitamin D is an important factor in estrogen biosynthesis of both female and male gonads. Endocrinology. 2000;141(4):1317–24.
Halloran BP, Deluca HF. Effect of vitamin D deficiency on fertility and reproductive capacity in the female rat. J Nutr. 1980;110(8):1573–80.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.
Firouzabadi RD, Aflatoonian A, Modarresi S, Sekhavat L, MohammadTaheri S. Therapeutic effects of calcium & vitamin D supplementation in women with PCOS. Complement Ther Clin Pract. 2012;18(2):85–8.
Aleyasin A, Hosseini MA, Mahdavi A, Safdarian L, Fallahi P, Mohajeri MR, et al. Predictive value of the level of vitamin D in follicular fluid on the outcome of assisted reproductive technology. Eur J Obstet Gynecol Reprod Biol. 2011;159(1):132–7.
Anifandis GM, Dafopoulos K, Messini CI, Chalvatzas N, Liakos N, Pournaras S, et al. Prognostic value of follicular fluid 25-OH vitamin D and glucose levels in the IVF outcome. Reprod Bio Endocrinol. 2010;8:91.
Ozkan S, Jindal S, Greenseid K, Shu J, Zeitlian G, Hickmon C, et al. Replete vitamin D stores predict reproductive success following in vitro fertilization. Fertil Steril. 2010;94(4):1314–9.
Rudick B, Ingles S, Chung K, Stanczyk F, Paulson R, Bendikson K. Characterizing the influence of vitamin D levels on IVF outcomes. Hum Reprod. 2012;27(11):3321–7.
Rudick BJIS, Chung K, Stanczyk FZ, Paulson RJ, Bendikson KA. Influence of vitamin D levels on in vitro fertilization outcomes in donor-recipient cycles. Fertil Steril. 2014;101(2):447–52.
Garbedian KBM, Moody J, Liu K. Effect of vitamin D status on clinical pregnancy rates following in vitro fertilization. CMAJ Open. 2013;1(2):E77–82.
Polyzos NP, Anckaert E, Guzman L, Schiettecatte J, Van Landuyt L, Camus M, et al. Vitamin D deficiency and pregnancy rates in women undergoing single embryo, blastocyst stage, transfer (SET) for IVF/ICSI. Hum Reprod. 2014.
Bureau of Labor Statistics. Consumer price index. Washington, DC: Bureau of Labor Statistics; 2014. Available from: http://www.bls.gov/schedule/archives/cpi_nr.htm.
Centers for Medicare and Medicaid Services. 2014 clinical laboratory fee schedule. Baltimore, MD: Centers for Medicare and Medicaid Services, 2014. Available from: http://www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/ClinicalLabFeeSched/clinlab.html.
Drug Price Search. https://www.rxpricequotes.com. Accessed 11 Aug 2014.
Chambers GM, Sullivan EA, Ishihara O, Chapman MG, Adamson GD. The economic impact of assisted reproductive technology: a review of selected developed countries. Fertil Steril. 2009;91(6):2281–94.
You JH, Chung TK. Expectant, medical or surgical treatment for spontaneous abortion in first trimester of pregnancy: a cost analysis. Hum Reprod. 2005;20(10):2873–8.
Bagot CN, Troy PJ, Taylor HS. Alteration of maternal Hoxa10 expression by in vivo gene transfection affects implantation. Gene Ther. 2000;7(16):1378–84.
Vanni VS, Vigano’ P, Somigliana E, Papaleo E, Paffoni A, Pagliardini L, et al. Vitamin D and assisted reproduction technologies: current concepts. Reprod Biol Endocrinol. 2014;12:47.
Purcell K, Schembri M, Frazier LM, Rall MJ, Shen SH, Croughan M, et al. Asian ethnicity is associated with reduced pregnancy outcomes after assisted reproductive technology. Fertil Steril. 2007;87(2):297–302.
Fujimoto VY, Luke B, Brown MB, Jain T, Armstrong A, Grainger DA, et al. Racial and ethnic disparities in assisted reproductive technology outcomes in the United States. Fertil Steril. 2010;93(2):382–90.
Gleicher N, Weghofer A, Li J, Barad D. Differences in ovarian function parameters between Chinese and Caucasian oocyte donors: do they offer an explanation for lower IVF pregnancy rates in Chinese women? Hum Reprod. 2007;22(11):2879–82.
Gleicher N, Kim A, Weghofer A, Barad DH. Differences in ovarian aging patterns between races are associated with ovarian genotypes and sub-genotypes of the FMR1 gene. Reprod Biol Endocrinol. 2012;10:77.
Karolinska University Hospital. Vitamin D during in vitro fertilisation (IVF)—a prospective randomized trial. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 Aug 17]. Available from: http://clinicaltrials.gov/show/NCT01019785 NLM Identifier: NCT01019785.
Acknowledgments
The authors thank Dr. Elizabeth E. Puscheck and Dr. Alan H. DeCherney for their generous support, as well as J.C. Sanchez for graphical design assistance.
Funding
This study was funded, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, and ZIA HD-008737 to JHS.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Capsule
Vitamin D has been shown to play important roles in reproduction and vitamin D deficiency is a prevalent condition. A systematic review of vitamin D and ART outcomes yielded five studies that reported ART outcomes improved after vitamin D repletion, two studies found no association, and one study reported a negative association. Currently, Level I evidence is insufficient and a recommendation for routine vitamin Dscreening and supplementation prior to ART cannot be supported. There is a pressing need for additional studies of vitamin D replacement in this clinical scenario.
Michelle M. Pacis and Chelsea N. Fortin Contributed equally to the manuscript.
Rights and permissions
About this article
Cite this article
Pacis, M.M., Fortin, C.N., Zarek, S.M. et al. Vitamin D and assisted reproduction: should vitamin D be routinely screened and repleted prior to ART? A systematic review. J Assist Reprod Genet 32, 323–335 (2015). https://doi.org/10.1007/s10815-014-0407-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-014-0407-9
Keywords
- Vitamin D
- Assisted reproductive technology
- ART
- In vitro fertilization
- IVF