Pre-Conception Health Special Interest Group

THE FERTILITY SOCIETY OF AUSTRALIA - Pre-Conception Health Special Interest Group

Micronutrient (folic acid, iodine and vitamin D) supplements pre-conception and during pregnancy.
The evidence relating to the use of folic acid, iodine and vitamin D supplementation to improve reproductive outcomes is reviewed.

EVIDENCE REVIEW:
Folic acid
- Women
There is good quality evidence from meta-analysis of several large multicentre
randomised controlled trials (RCTs) that daily supplementation with folic
acid, taken alone or as part of a multivitamin preparation during the
periconception period reduces the risk of neural tube defects (NTD) in
the babies [1]. Folic acid doses between 0.36 mg (360 mcg) and 4 mg
(4000mcg) appear to be safe. Precipitation of vitamin B12 deficiency has
been reported with high dose folic acid supplements but is rare. Folic acid
doses of 2mg and 4 mg showed evidence of benefit in trials investigating the
prevention of recurrent NTD [1]. Folic acid with multivitamins versus folic
acid alone has not been compared in sufficiently large populations so neither
can be recommended over the other in primary prevention of NTD. There
is insufficient evidence that periconceptual folic acid reduces other birth
defects such as cleft lip/palate, congenital heart disease, or miscarriage.
Obese women (BMI > 29k/m2) were more likely to have a baby affected
with a NTD than women of lower BMI despite similar usage of vitamins
and folic acid in the periconception period and this risk increased in obese
women who were smokers [2]. Obese women taking folic acid supplementation
are more likely to have low serum folate levels than normal weight women
[3]. The RCOG, on the basis of these studies, has recommended that women
with a BMI >30 kg/m2 should take high dose folic acid when planning a
pregnancy. This has provoked controversy as maternal hyperglycemia may
be a confounding factor in the findings. Women with genetically abnormal
metabolism of folic acid may theoretically benefit from the administration
of 5 methyl-tetrahydrofolate (5MTHF) but there have been no RCTs to
confirm the benefit of this. Furthermore, there have been no RCTs with
NTD and birth defects as outcomes of interest comparing weekly and daily
folic acid supplementation.
- Men
One small RCT compared the effect of folic acid and placebo on seminal
parameters and found no difference in fertile and infertile men [4]. The
same study showed that folic acid in combination with zinc was associated
with improved total sperm count. Folic acid in combination with other
agents in men undergoing ART for male factor subfertility improved embryo
morphology but not live birth rate [5]. Another study found that folic acid in
combination with zinc only improved seminal parameters in men who were
wild type for the C677T methylenetetrahydrofolatereductase polymorphism
[6]. There is insufficient evidence to justify widespread use of folic acid
supplementation to augment seminal parameters and fertility in men.

Iodine
- Women
Severe maternal iodine deficiency is associated with stillbirth, miscarriage,
congenital abnormalities including but not limited to the clinical picture of
“cretinism” which is characterised by intellectual impairment, diplegia and
deafness [7-8]. Lesser degrees of maternal iodine deficiency have been
associated lower IQ scores in the offspring in several population based studies
and this appears to be corrected with maternal iodine supplementation [9-10].
In 2009 a committee of NHMRC recommended that pregnant and breast
feeding women take 150mcg iodine supplementation per day regardless
of the fact that some areas in Australia, as determined by epidemiological
studies, are iodine replete [11]. There are no data of the effects of iodine
supplementation in iodine replete populations such as Western Australia
and Queensland. It is suggested that cross sectional research over time in
school-age children in both iodine deficient and iodine replete areas be
conducted following implementation of NHMRC guidelines.
A committee of the WHO published guidelines for supplementation of
iodine for women and recommended that women of childbearing age
should take 150 mcg of iodine per day and women who are pregnant or
lactating should take 250 mcg of iodine per day [11].
- Men
There are no data on the role of iodine supplementation in men with
infertility. The association between abnormal thyroid function and male
infertility is uncertain.

Vitamin D
Vitamin D facilitates the transfer of calcium to the fetus, particularly
during the third trimester of pregnancy. Vitamin D deficiency in neonates
can result in hypocalcemic tetany and reduced bone growth including rickets.
There are reports of rickets in neonates born to women with vitamin D
deficiency in Australia [13, 14]. A systematic review of observational studies
of women with vitamin D deficiency ( associated with increased risk of adverse obstetric outcome such as
preeclampsia, gestational diabetes mellitus, preterm birth and being small
for gestational age [15]. An observational study suggested respiratory
disease in the baby was reduced when the cord levels of vitamin D level
were higher [16].
Vitamin D is obtained from two sources: the major source is through the
action of ultraviolet radiation on the skin (D3 or cholecalciferol) and the
lesser source is from food (D2 or erogocalciferol). The recommended daily
intake is the same for pregnant and non-pregnant women (5 mcg per day).
There is lack of agreement on the definition of vitamin D deficiency both
in pregnancy and in non-pregnant women and defining the upper limit of
the reference range has been particularly controversial [17-19]. In Australia
a position statement issued by a Working Group in 2005 defined severe
deficiency as deficiency as 25.1-50nmol/l [20]. The Working Group did not specifically
address the issues of vitamin D in pregnant women but provided good
advice on skin exposure applicable to Australia and New Zealand and the
best oral supplements to use. Risk factors for vitamin D deficiency are:
having dark skin, being veiled, suffering malabsorption syndromes, taking
anticonvulsants and using sunscreen. Winter exacerbates the risk of vitamin
D deficiency [21].
Routine screening of pregnant women for vitamin D deficiency has been
recommended [22]. However, results of RCTs of the effect of maternal
antenatal vitamin D supplementation on neonatal outcomes are conflicting
and inconclusive. A Cochrane review found only four trials involving only
623 women comparing Vitamin D supplements to placebo during
pregnancy [23]. The review concluded that there was insufficient evidence
of adequate quality to recommend vitamin D supplementation in pregnancy.
Furthermore, another comprehensive review concluded that only severe
deficiency should be treated during pregnancy [24].
The role of vitamin D in infertility is uncertain. One study conducted in
Turkey measured vitamin D levels in follicular fluid at IVF and found
that higher levels were associated with an increased chance of IVF success
[25]. However the study was small and did not control for a number of
confounders including race.
There is need for further research into the role of vitamin D deficiency
preconceptually and in infertility in both women and men.

SUMMARY:
There is evidence that folic acid, iodine and vitamin D are important
for reproductive outcomes. Folic acid and iodine supplementation is
recommended for women planning to conceive and in pregnancy.
Vitamin D supplementation is recommended only for women with
vitamin D deficiency.
There is insufficient evidence to justify recommending the use of folic
acid, iodine and vitamin D to improve reproductive outcomes for fertile
and infertile men and further research should be conducted in this area.

RECOMMENDATIONS:
Folic acid
The recommended dose of folic acid for women without special
considerations planning to conceive is 400-500 mcg.
The recommended dose of folic acid for women with special
considerations is 2-5 mg per day. The special considerations requiring the
higher dose of folic acid are:
1. Personal history (self or past pregnancy) of neural tube defect (NTD)
2. A first degree relative with a pregnancy with a NTD
3. Use of sodium valproate
4. Body mass index greater than 30 kg/m2
5. Diabetes mellitus (type 1 or type 2)

Iodine
Women planning a pregnancy, including those with thyroid disease,
should take iodine supplements in the dose of 150 mcg per day prior
to and during pregnancy.

Vitamin D
There is insufficient evidence to justify routine supplementation of
vitamin D for all women who are pregnant or planning a pregnancy.
However, it is prudent to recommend measurement of vitamin D levels
in women planning a pregnancy who are at risk of vitamin D deficiency
including those who are veiled, have dark skin, have a malabsorption
syndrome, take anticonvulsants, or regularly use sunscreen or avoid
exposure to sunlight. The optimal level of vitamin D during pregnancy
is uncertain but it would seem reasonable to offer supplementation for
severe ( prevent neonatal rickets. Mild deficiency (26 -50nmol/l) can be
adequately treated with increased sun exposure. There is insufficient
evidence to allow extrapolation of the clinical use of the high doses of
vitamin D prescribed for treatment of osteoporosis and osteopenia to
women in the preconceptual period and during pregnancy.

For more information about pre-conception health visit www.yourfertility.org.au

References
1. De-Regil LM, Fernandez-Gaxiola AC, Dowswell T, Pena-Rosas JP. 2010. “Effects and safety of periconceptional folate supplementation for preventing birth defects.”
Cochrane Database Syst Rev: CD007950.
2. Watkins ML, Scanlon KS, Mulinare J, Khoury MJ. 1996. “Is maternal obesity a risk factor for anencephaly and spina bifida?” Epidemiology 7: 507-12.
3. Mojtabai R. 2004. “Body mass index and serum folate in childbearing age women.” Eur J Epidemiol 19: 1029-1036.
4. Wong WY, Merkus HM, Thomas CM, Menkveld R, Zielhuis GA, Steegers-Theunissen RP. 2002. “Effects of folic acid and zinc sulfate on male factor subfertility: a
double-blind, randomized, placebo-controlled trial.” Fertil Steril 77: 491-8.
5. Tremellen K, Miari G, Froiland D, and Thompson J. (2007). “A randomised control trial examining the effect of an antioxidant (Menevit) on pregnancy
outcome during IVF-ICSI treatment.” Australian and New Zealand Journal of Obstetrics and Gynaecology, 47: 216–221.
6. Ebisch IM, van Heerde WL, Thomas CM, van der Put N, Wong WY, Steegers-Theunissen RP. 2003. “C677T methylenetetrahydrofolatereductase polymorphism
interferes with the effects of folic acid and zinc sulfate on sperm concentration.” Fertil Steril 80: 1190-4.
7. Pharoah PO, Ellis SM, Ekins RP, Williams ES. 1976. “Maternal thyroid function, iodine deficiency and fetal development.” Clin Endocrinol (Oxf) 5: 159-66.
8. Melse-Boonstra A, Jaiswal N. 2010. “Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development.” Best Pract Res Clin
Endocrinol Metab 24: 29-38.
9. Qian M, Wang D, Watkins WE, Gebski V, Yan YQ, et al. 2005. “The effects of iodine on intelligence in children: a meta-analysis of studies conducted in China.”
Asia Pac J ClinNutr 14: 32-42.
10. Velasco I, Carreira M, Santiago P, Muela JA, Garcia-Fuentes E, et al. 2009. “Effect of iodine prophylaxis during pregnancy on neurocognitive development of
children during the first two years of life.” J Clin Endocrinol Metab 94: 3234-41.
11. NHMRC Iodine Supplementation During Pregnancy and Lactation 2010 https://www.nhmrc.gov.au/sites/default/files/documents/attachments/publi...
new45-literature-review.pdf
12. Andersson M, de Benoist B, Delange F, Zupan J. 2007. “Prevention and control of iodine deficiency in pregnant and lactating women and in children less than
2-years-old: conclusions and recommendations of the Technical Consultation.” Public Health Nutr 10(12A): 1606-11.
13. Thomson K, Morley R, Grover SR, Zacharin MR. 2004. “Postnatal evaluation of vitamin D and bone health in women who were vitamin D-deficient in pregnancy,
and in their infants.” Med J Aust 181: 486-8.
14. Teale GR, Cunningham CE. 2010. “Vitamin D deficiency is common among pregnant women in rural Victoria.” Aust N Z J Obstet Gynaecol 50: 259-61.
15. Wei SQ, Qi HP, Luo ZC, Fraser WD. 2013. “Maternal vitamin D status and adverse pregnancy outcomes: a systematic review and meta-analysis.” J Matern Fetal
Neonatal Med doi 10.3109/14767058.2013.765849.
16. Camargo CA, Jr., Ingham T, Wickens K, Thadhani R, Silvers KM, et al. 2011. “Cord-blood 25-hydroxyvitamin D levels and risk of respiratory infection, wheezing,
and asthma.” Pediatrics 127: e180-7.
17. Nassar N, Halligan GH, Roberts CL, Morris JM, Ashton AW. 2011. “Systematic review of first-trimester vitamin D normative levels and outcomes of pregnancy.”
Am J Obstet Gynecol 205: 208 e1-7.
18. Reid IR, Avenell A. 2011. “Evidence-based policy on dietary calcium and vitamin D.” J Bone Miner Res 26: 452-4.
19. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, et al. 2011. “The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of
Medicine: what clinicians need to know.” J Clin Endocrinol Metab 96: 53-8.
20. Working Group of the Australian and New Zealand Bone and Mineral Society; Endocrine Society of Australia; Osteoporosis Australia 2005 Vitamin D and adult
bone health in Australia and New Zealand: a position statement. Med J Aust 182: 281-8.
21. NHMRC Nutrient Report 2011.
22. Ebeling PR. 2011. “Routine screening for vitamin D deficiency in early pregnancy: past its due date?” Med J Aust 194: 332-3.
23. De-Regil LM, Palacios C, Ansary A, Kulier R, Pena-Rosas JP. 2012. “Vitamin D supplementation for women during pregnancy.” Cochrane Database Syst Rev 2:
CD008873.
24. Specker B. 2004. “Vitamin D requirements during pregnancy.” Am J Clin Nutr 80: 1740S-7S.
25. Ozkan S, Jindal S, Greenseid K, Shu J, Zeitlian G, et al. 2010. “Replete vitamin D stores predict reproductive success following in vitro fertilization.” Fertil Steril
94: 1314-9.