Meta-analysis fails to find association of vitamin D with ART outcome

Published 19 November 2020

Despite some earlier evidence to the contrary and ongoing debate, a new meta-analysis has concluded that serum vitamin D levels have no influence on ART outcomes in terms of pregnancy, live birth and miscarriage rates. But the debate goes on.

Vitamin D is back in the news (had it ever gone away?). Long recognised for its role in bone and muscle strength, the sunshine vitamin has now been described as ‘a key micronutrient’ in resistance to viral infections, including COVID-19.(1) The coronavirus advice suggests that recommended – and not excessive – levels should be maintained, especially among those deprived of sunlight; around 80% of vitamin D production is said to be derived from skin.

Vitamin D deficiency has also been implicated in infertility. A single-centre study published in 2009 found that IVF patients with replete stores of vitamin D in follicular fluid were significantly more likely to achieve pregnancy than those with lower levels.(2) Their results, said the investigators, suggested a role for vitamin D supplementation in women having IVF. Similarly, a systematic review from 2014 found a downturn in ART outcomes in patients with vitamin D deficiency, while a more recent review described vitamin D deficiency as an ‘important’ condition to treat in women considering ART.(3,4) But other studies have not been so clear, with many unable to find any association.

These inconsistent results have now been addressed once more in a new meta-analysis of all studies investigating the impact of serum vitamin D on IVF outcomes - live birth rate, ongoing and clinical pregnancy rate and miscarriage rate.(5) After excluding many studies and reviews, the authors were left with just 14 eligible studies for their analysis, which included more than 4000 subjects.

The analysis itself was complicated, resting on three measures of vitamin D (and its metabolite 25(OH)D) - deficient (<20 ng/ml), insufficient (20-30 ng/ml), and replete (>30 ng/ml) – whose associations were compared with the primary outcomes. Primary analysis showed that women with a replete level of vitamin D did indeed have somewhat higher pregnancy and live birth rates than those defined as deficient or insufficient. However, a sensitivity analysis for bias and other confounders led to non-significant differences between the three vitamin D levels. Moreover, no statistically significant difference was found for miscarriage.

The authors thus conclude that serum vitamin D levels do not influence IVF outcomes in terms of pregnancy and live birth rates, or miscarriage. However, they do not write off the possibility of association, or even of causation. They describe the debate over vitamin D in reproduction as ‘ongoing’, acknowledging evidence of the role of vitamin D in folliculogenesis, oogenesis and endometrial receptivity. Moreover, noting that ‘most of the favorable IVF treatment outcomes are associated with 25(OH)D thresholds >30 ng/ml’, they recognise that vitamin D ‘could be involved in the mechanisms of conception’. A definite maybe more than a definite no?

A token nod to the possibility was largely how an accompanying editorial concluded. ‘Despite the lack of clear and convincing evidence to date,’ wrote the author, ‘I will continue to test my couples with infertility for vitamin D deficiency, prescribe supplementation where needed, and monitor serum levels to ensure repletion.’(6) This was, he added, good medicine anyway. But he did not hide his disappointment in these latest results – ‘because it defies our wishes for a nicely logical explanation of the relationship between vitamin D and IVF success that allows for a seemingly simple solution’. However, as with so many supplements promoted for improved ART results, such ‘simple solutions’ as vitamin D may yet need the weight of a strong randomised trial, which may not be too far away.(7)

1. Lanham-New SA, Webb AR, Cashman KD, et al. Vitamin D and SARS-CoV-2 virus/ COVID-19 disease. BMJ Nutrition, Prevention & Health 2020; doi:10.1136/ bmjnph-2020-000089.
2. Ozkan S, Jindal S, Greenseid K, et al. Replete vitamin D stores predict reproductive success following in vitro fertilization. Fertil Steril 2010; 94: 1314–1319.
3. Pacis MM, Fortin CN, Zarek SM, 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 2015; 32: 323–335.
4. Chu J, Gallos I, Tobias A, et al. Vitamin D and assisted reproductive treatment outcome: a systematic review and meta-analysis. Hum Reprod 2018; 33: 65-80.
5. Cozzolino M, Busnelli A, Pellegrini L, et al. How vitamin D level influences in vitro fertilization outcomes: results of a systematic review and
meta-analysis. Fertil Steril 2020; 114: 1014-1024.
6. McGovern PG. Is Vitamin D important for in
vitro fertilization success? Fertil Steril 2020; 114: 962.
7. Paffoni A, Somigliana E, Sarais V, et al. Effect of vitamin D supplementation on assisted reproduction technology (ART) outcomes and underlying biological mechanisms: protocol of a randomized clinical controlled trial. The "supplementation of vitamin D and reproductive outcome" (SUNDRO) study. BMC Pregnancy Childbirth 2019; 19: 395. doi: 10.1186/s12884-019-2538-6

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