Characterizing the Influence of Vitamin D Levels on IVF Outcomes

B. Rudick; S. Ingles; K. Chung; F. Stanczyk; R. Paulson; K. Bendikson


Hum Reprod. 2012;27(11):3321-3327. 

In This Article


In this ethnically diverse population, we were able to confirm that vitamin D status is related to IVF success in non-Hispanic white patients; pregnancy rates declined with progressively lower levels of vitamin D. The odds of pregnancy were four times higher in vitamin D replete compared with deficient patients, substantiating the findings of Ozkan et al. (2010) in a larger study population. However, among Asians the beneficial effect of sufficient levels of vitamin D was not observed and in fact, vitamin D status was inversely related to IVF success. The influence of race on the relationship between vitamin D and clinical pregnancy was statistically significant.

We believe that our diverse study population is representative of a typical IVF population; we observed the expected associations between typical predictors of successful IVF outcomes and pregnancy rates. Our observed prevalence of vitamin D insufficiency (37%) and deficiency (21%) is similar to the prevalence in Ozkan's study (36 and 27% respectively), but is slightly lower than in national studies in women of childbearing age (Holick, 2009). This may be due to IVF population demographics, which tends to be older, mostly Caucasian, higher in socioeconomic status and education level (Chandra, et al. 2005; Ginde et al., 2010), and more likely to be taking prenatal vitamin supplementation. These demographics are associated with higher vitamin D status in population-based US surveys among reproductive aged women (Holick, 2009).

It is unclear why we saw an inverse relationship between 25(OH)D levels and clinical pregnancy rates among Asians. It is possible that though statistically significant, this is a chance finding. The number of Asians in the study was relatively small (n= 49). We could not identify any clinically important racial differences in patient characteristics or cycle parameters (including embryo quality) contributing to their lower pregnancy rates. It is possible that the influence of vitamin D status on pregnancy outcomes was overshadowed by other factors that contribute to the lower pregnancy rate observed among Asian patients (35% in Asians, 43% in non-Asians). Previous studies have demonstrated significantly lower live birth rates after IVF in Asian ethnicities compared with Caucasians (Hammoud et al., 2009), despite a younger age among Asian subjects and similar embryo quality (Hammoud et al., 2009; Butts and Seifer, 2010). Others have found a higher prevalence of diminished ovarian function in Asian-Chinese versus Caucasian oocyte donors, suggesting that oocyte factors may be involved in the lower IVF success rates in Asian populations (Gleicher et al., 2007; Shaine et al., 2009). Ideally, vitamin D levels in the recipients of donor IVF cycles could be studied to further eliminate confounding due to oocyte quality.

Finally, numerous studies have shown racial differences in the metabolism of vitamin D. In particular, southern Asians have been reported to have increased activity of the enzyme responsible for deactivating both 25(OH)D and calcitriol (Awumey et al., 1998). There are also ethnic differences in VDR gene polymorphisms that may confound or modify the relationship between vitamin D levels and reproductive outcomes (Ingles et al., 1997; Ingles, 2007). Our finding of significant heterogeneity by Asian ancestry suggests that the relationship between vitamin D and reproduction should be considered within the context of ethnicity.

Although vitamin D status was not associated with ovarian stimulation parameters or with markers of embryo quality, vitamin D levels were correlated with pregnancy outcomes in our non-Hispanic white population. It is possible that vitamin D may have an impact on embryo quality not captured using the current methods available to assess embryo viability. However, more plausible, is that vitamin D may exert an effect on IVF cycle outcomes via the endometrium. The VDR is expressed in the endometrium and plays a vital role in activating the innate immune response (Evans et al., 2004; Vigano et al., 2006). Additionally, vitamin D may play an important autocrine role through its regulation of the transcription of genes such as HOXA10, critical for embryo implantation and placentation (Evans et al., 2006).

Recent studies demonstrate that vitamin D is important throughout gestation as well, not just at the time of implantation. There are varying levels of vitamin D metabolites and HOXA10 expression throughout pregnancy in the endometrium, decidua and placenta (Evans et al., 2006). In cultured syncytiotrophoblasts, calcitriol regulates hCG expression and secretion, and it stimulates estradiol and progesterone secretion from trophoblasts in a dose-dependent manner (Barrera et al., 2007; Barrera et al., 2008). Clinical studies demonstrate an association between lower vitamin D levels and increased risk of pre-eclampsia and gestational diabetes. Thus, vitamin D may have an important role in maintaining a healthy pregnancy (Bodnar et al., 2007).

These data add clinical support to the growing body of evidence that vitamin D may play an important role in IVF success as well, possibly via localized effects in the endometrium. Research is needed to further elucidate the mechanism by which vitamin D acts, the ethnic heterogeneity in vitamin D metabolism and its subsequent effects on IVF success. The prevalence of vitamin D deficiency and insufficiency is alarmingly high in infertile patients. A role for vitamin D supplementation may exist as a means of improving one's natural fertility both among the fertile and the infertile. Regardless of potential fertility benefits, patients can be counseled regarding appropriate vitamin D supplementation for overall health benefits, pregnancy health and chronic disease risk reduction.