Intended for healthcare professionals

Rapid response to:


Treatment of unexplained infertility

BMJ 2008; 337 doi: (Published 07 August 2008) Cite this as: BMJ 2008;337:a772

Rapid Response:

Nutritional factors in unexplained infertility

We were interested in the commentary on the paper by El-Toukhy and
Khalaf on the paper by Bhattacharya et al (1) in the same edition of BMJ,
which showed very little benefit from either clomifene or IUI. This does
not surprise us as we have been researching this area. Although you have
cited cervical, uterine, ovulatory, peritoneal, immunological, or
fertilisation defects as possible explanations for unexplained
infertility, there is no mention of the factors we have been researching.

Trace element deficiencies have long been recognised as causing
infertility in veterinary practice (2) and oxidative stress has been
suggested as a cause of blighted ovum (3) . Oxidative stress has been
shown to cause very early pregnancy loss (4) and antioxidant minerals and
vitamins have been shown to improve the outcome of pregnancy. For
instance, in a randomised controlled trial in 60 women at risk of
preeclampsia, Rumiris et al showed that a mineral and vitamin combination
(Vitamins A 300 mg, B6 2.2 mg, B12 2.2 g, C 200 mg, E 267 mg,
folic acid 400 g, N-acetyl cysteine 200 mg, copper 2 mg, zinc 15
mg, manganese 0.5 mg, iron 30 mg, calcium 800 mg and selenium 200
g) reduced very early pregnancy loss by 29% compared to
supplementation with folic acid 400 µg and iron 30 mg daily (n=31/29) in
patients at risk of preeclampsia (5). A small survey (n=87) on nutritional
status and failed IVF has shown an associated with higher levels of the
anti-nutrients cadmium and lead and lower levels of zinc and selenium (6).

A beneficial effect from over-the-counter antioxidant multivitamins on the
success rate for IVF might be expected: one research team found that
measurements of antioxidant status of follicular fluid were improved in
supplemented subjects whose pregnancy rate was 45.8% compared with 22.9%
in unsupplemented subjects (7) (n=215). In our own research comparing a
small group of subjects with unexplained infertility with age-matched
normal fertile controls we found a correlation between infertility and the
selenium:cadmium ratio with infertile subjects having low serum selenium
and raised whole blood cadmium, which was statistically significant
despite the small size of our sample (8). In our survey of pre-
conceptional supplementation (n=130) 50% of a sub-sample (n=42) who were
preparing for IVF were taking only folic acid 400 µg daily but 14.2% were
taking a mineral and vitamin supplement that was very similar to the
Rumiris et al mineral and vitamin supplement detailed above. We compared
our data for total nutrient intake (dietary + supplemental) with the
recommended daily intake for early pregnancy and found that intakes were
suboptimal in 50% of the subjects for selenium, zinc, magnesium and iodine
and borderline deficient in 50% of subjects for vitamins B12, C and E,
β-carotene, iron, folate + folic acid and essential fatty acids (8).

Indeed, borderline low iodine and selenium deficiency are known to have an
adverse effect on ovulatory performance (2,9). While we recognise that
nutritional status is only part of the explanation for “unexplained
infertility”, it would seem wise to take steps to optimise that status
when veterinary and animal evidence for its importance is so strong.

Yours sincerely,

(1) El-Toucky, Khalaf Y (2008). Treatmant of unexplained infertility
– should he tailored to the patient’sexpectetions, centre’s experience and
available resources. BMJ;337(7666):362-363.

(2) Hostetler CE, Kincaid RL, Mirando MA (2003). The role of
essential trace elements in embryonic and fetal development in livestock.
The Veterinary Journal;166,(2): 125-139.

(3) Jauniaux E, Watson AL, Hempstock J, Bao Y-P, Skepper JN, Burton
GJ, (2000). Onset of maternal arterial blood flow and placental oxidative
stress: A possible factor in human early pregnancy failure. American
Journal of Pathology;157(6):2111-2122.

(4) Guerin P, El Mouatassim S, Menezo Y (2006). Oxidative stress and
protection against
reactive oxygen species in the pre-implantation embryo and its
surroundings. Human Reproduction Update 2001;7(2):175-189.

(5) Rumiris D, Purwosunu Y, Wibowo N, Farina A, Sekizawa (2006). A Lower
rate of preeclampsia after antioxidant supplementation in pregnant women
with low antioxidant status. Hypertension in Pregnancy;25(3):241–253.

(6) Stovell A, Matar R, Winston R Eyani L, Ward N (2000). Human
infertility and environmental heavy metals: lead cadmium and zinc.
Proceedings of the fifth international conference on environmental
pollution, Ed A Anagnostopolousmith; Publised by Korakidis, Thessaloniki:

(7) Matthews S, White KL, Sutcliffe AE, Parsons WJ, Rutherford AJ, Sharma
V, Picton HM, Hay AWM (2001) . Multivitamin supplements are associated
with an increase in follicular fluid antioxidant levels and appear to
improve outcome in assisted reproduction. Human Reproducrion;16(S1):151

(8) Nichols JAA, Curtis EPP, Rayman MP, Taylor A (2008). A survey to
estimate total nutrient intake at conception — Dietary and supplementary.
Journal of Nutritional & Environmental Medicine; 17(1): 12–43.

(9) Wynn M, Wynn A (1998). Human Reproduction and Iodine Deficiency:
Is It a Problem in the UK? Journal of Nutritional & Environmental
Medicine;8(1):53 – 64

Competing interests:
None declared

Competing interests: No competing interests

04 September 2008
Dr John A A Nichols
GP Researcher
Professor Margaret P Rayman, Dr Andrew Taylor
University of Surrey