SUPPLEMENTS

Vitamin D and other dietary supplements in pursuit of fertility

Published 06 April 2020

Vitamin D deficiency is widespread (up to 50%) among all women of reproductive age - and presently in the news again. For those with low levels of this ‘sunshine vitamin’, studies have long suggested an association with infertility-related factors such as endometriosis, whereas higher levels of vitamin D in serum have been linked to a greater chance of pregnancy and live birth. However, little is known specifically about vitamin D supplements and if their role really does improve the odds of conception and having a baby. Now, a new study understood to be the first of its kind does indeed suggest a positive benefit from increased intake of vitamin D through dietary supplementation.(1)

This large nationwide cohort study took advantage of what the authors describe as a ‘unique social experiment’ – a mandatory programme in Denmark between 1962 and 1985 to fortify margarine with vitamin D – to examine the link between supplementation and live birth rates in more than 16,000 infertile women. And its findings give some credence to the proposition that infertile women with sufficient vitamin D levels ‘have an increased chance’ of becoming mothers. The overall odds of a live birth 12 months after infertility diagnosis increased significantly (OR 1.87, 95% CI 1.68-2.08) in those patients who discovered they were infertile during the margarine fortification programme. For women diagnosed in the period immediately after the programme ended, the chance was 52% higher. This latter rate compares with those diagnosed more than a year after the programme ended and therefore not exposed to extra vitamin D.

The study cohort was linked to the Danish Medical Birth Registry using each patient’s unique personal identification number, with all analyses adjusted for the woman’s age at primary infertility diagnosis. The termination of the fortification programme on 31 May 1985 gave the authors a fixed cut-off point to separate the study population into three diagnostic groups (June 1980 to May 1985; June 1985 to August 1986; and September 1986 to August 1991). The proportion (15%) of women in the first group – that is, those exposed to the fortified margarine programme – who had a live birth was higher than for those in the second (12%) and third 'non-exposed' groups (9%).

The calendar period of conception did not markedly affect the association between vitamin D exposure and live birth. This is evidenced by a consistently higher proportion of live births among women who conceived during Autumn and Winter (October to March) when very limited vitamin D synthesis occurs in Denmark.

Despite the reported benefit, the study had several acknowledged limitations, not least that the authors had no knowledge of how many women received fertility treatment after the vitamin D study period; the specific cause of infertility was not registered for the vast majority of women; the margarine was fortified with vitamins A and E in addition to vitamin D; the data did not include confounders such as BMI and smoking; and no information was available on whether participants were supplementing their diets independently with vitamin D, in addition to the fortified margarine.

So what does the evidence suggest from studies relating to this and other dietary supplements and their association with live birth rates? Much of the data is from trials relating to male infertility, including a report published this year on antioxidants.(2) This multicentre study found no improvement in live birth rates or natural pregnancy from treating men with supplements such as vitamins C and E, l-carnitine, zinc and selenium. A Cochrane review of antioxidants for male subfertility found current evidence ‘inconclusive’.(3) The results from a randomised controlled trial in more than 2000 male patients with planned fertility treatment also make negative reading.(4) The study did not support the use of folic acid and zinc supplements after showing no improvement in live birth rates.

In comparison, however, the results with vitamin D at least appear to offer some promise for infertile couples. On this basis, should women be offered vitamin D supplements if tests show their levels are low? Not surprisingly, the authors of this latest study say further work is needed - including into the potential mechanisms linking the vitamin to any increased chance of success, into the type of individuals who could benefit and the optimal dose for supplementation.

This echoes the conclusion of investigators behind the most recent meta-analysis on vitamin D levels and ART outcomes.(5) Although they found a strong link between low vitamin D levels and lower live birth rates, the researchers also cautioned that this does not mean supplementation necessarily improves chances of having a baby after fertility treatment. Their message was instead that randomised controlled trials are needed to test the theory further that correcting a vitamin D deficiency could benefit infertile couples.


1. Jensen A, Nielsen M, Guleria S, et al. Chances of live birth after exposure to vitamin D–fortified margarine in women with fertility problems: results from a Danish population-based cohort study. Fertil Steril 2020;
doi: 10.1093/j.fertnstert.2019.09.017
2. Steiner AZ, Hansen KR, Barnhart KT, et al. The effect of antioxidants on male factor infertility: the Males, Antioxidants, and Infertility (MOXI) randomized clinical trial. Fertil Steril 2020;
doi: 10.1016/j.fertnstert.2019.11.008
3. Showell MG, Mackenzie-Proctor R, Brown J, et al. Antioxidants for male subfertility. Cochrane Database Syst Rev 2019;
doi: 10.1002/14651858
4. Schisterman EF, Sjaarda LA, Clemons T, et al. Effect of folic acid and zinc supplementation in men on semen quality and live birth among couples undergoing infertility treatment: A randomized clinical trial. JAMA 2020;
doi: 10.1001/jama.2019.18714
5. Chu J, Gallos I, Tobias A. et al. Vitamin D and assisted reproductive treatment outcome: a systematic review and meta-analysis. Hum Reprod 2018;
doi.org/10.1093/humrep/dex326

INFERTILITY

History of infertility associated with risk of developing obesity-related reproductive cancers

INFERTILITY PREVALENCE

Prevalence of infertility judged higher than previous estimates, though studies vary greatly