( PDF ) Rev Osteoporos Metab Miner. 2017; 9 (1) Supplement: 24-27

DOI: http://dx.doi.org/10.4321/S1889-836X2017000200005

Cancelo Hidalgo MJ
Hospital Universitario de Guadalajara – Universidad de Alcalá (España)

 

Introduction
There is increasing interest to learn how vitamin D acts. Both its established or classic functions such as bone metabolism, as well as the emerging areas of study into the different stages of women’s lives. In this review, we will pay special attention to the latter even as we recognize the limited amount of quality information currently available.

 

Childhood and adolescence
Child and adolescent nutrition is undoubtedly one of the major health concerns in developed countries. Regarding vitamin D, a high prevalence of deficiency has been reported among school-age children and adolescents. In some series, 40% of adolescents present values below 25 ng/ml, with low levels more frequent among girls. Thus, adequate nutrition or supplementation are recommended in case of deficiency or insufficiency1.
Children and adolescents require adequate levels of vitamin D to achieve proper mineralization and bone growth. When vitamin D levels are low, there is a reduction in intestinal absorption of calcium and phosphate. Also bone resorption increases and this may lead to alterations in the integrity and strength of the bone as in the case of rickets, a problem that is increasingly prevalent in countries such as the United Kingdom2.
In sunny areas, this need has also been shown, however, especially among dark-skinned and obese adolescents. In contrast, adolescents with higher serum vitamin D levels have more physical activity, better cardiovascular health and something of great importance at present, less depressive tendencies3.
Serum levels of 25-OH-D are directly related to bone mineral density, with the highest bone gain when they are at 40 ng/ml or more4.
In children, the recommended daily dose is estimated at 600 IU.
A meta-analysis of 6 clinical trials suggests that there is a lack of information to support the recommendation to supplement the diets of children and adolescents with normal serum vitamin D levels as no specific benefits have been documented. However, supplementation in children and adolescents with deficient serum levels produces significant increases in the level of 25-OH-D and this would have clinical implications such as improvement in bone mineral content, especially in the lumbar spine5.
Universal screening in children and adolescents is not recommended, but it would be in groups at high risk of deficiency such as malabsorption, gastric bypass, liver disease, nephrotic syndrome or treatments with drugs that affect the metabolism of vitamin D .

 

Fertile time
During the fertile time of the woman, several situations of high prevalence in the field of gynecology have some type of relation with vitamin D serum levels.

 

Hormonal contraceptives
A different response to vitamin D supplements has been reported among hormonal contraceptive users, compared to non-users, with the former having higher baseline levels and achieving a better response at the end of the period, compared to non-user.
Previous studies have indicated that, at baseline, 25-OH-D levels are 20% higher in users of combined hormonal contraception compared to non-users of this method. This effect may be attributed to the increased synthesis of the vitamin D binding protein (DBP), and the modification in the hepatic metabolism of vitamin D. All this has a clinical implication which is that when determining 25-OH-D serum levels, it should be taken into account whether the woman is taking or has recently taken combined hormonal contraceptives as, in this case, they may be higher.

 

Reproduction
The relationship of vitamin D to reproductive capacity and to the success of assisted reproduction techniques and in particular with in vitro fertilization (IVF) has been studied.
Women with normal pregnancies have been shown to present higher vitamin D serum levels than those ending with early spontaneous abortion7. The investigation of correlations between serum levels and levels in follicular fluid, or whether vitamin D would influence the ovule or the embryo, have concluded that the beneficial effect described is established through action on endometrial tissue8.
Women who have raised 25-OH-D serum levels are four times more likely to be successful in the IVF technique compared to those with low levels9.
Therefore, in reproductive studies and especially when assisted reproduction techniques are applied, it is considered appropriate to evaluate the serum levels of vitamin D and taking into account the high safety of the measurement, supplementary or treat the deficiency if necessary.

 

Polycystic ovarian syndrome
This affects 5-10% of reproductive age women. A significant association has been documented between this syndrome and vitamin D deficiency, indicating that in some series, 73% of women with polycystic ovary syndrome (PCOS) are <30 ng/mL10.
In a 30-year meta-analysis, the relationship between serum vitamin D levels and metabolic and endocrine abnormalities in women with PCOS is analyzed by determining the effects of vitamin D supplementation. The results indicate that vitamin D deficiency is common among women with PCOS and may be associated with endocrine and metabolic disorders of PCOS. Women with lower levels of vitamin D had more frequent alterations in carbohydrate metabolism, increased fasting glucose, and increased insulin resistance than women with normal values. However, vitamin D supplementation was not found to correct these alterations11.

 

Pregnancy
There is currently a notable interest in the knowledge of the effect of vitamin D on various aspects related to fetal development and the end result of gestation.
During pregnancy, the maternal intestine increases the calcium absorption capacity, which allows, even in situations of calcium deficiency or vitamin D deficiency, fetal levels to be adequate to allow fetal skeletal development. However, when the maternal supply is discontinued after delivery, the newborn may develop hypocalcemia.
Vitamin D deficiency is considered to be three times more frequent in winter and spring than in summer and fall, and this is related to the time of pregnancy. A study in Germany in pregnant women indicated that 25-OH-D levels in winter were below 50 ng/ml in 98% of mothers and in 94% of cord blood tests. This indicates the need to improve serum levels in this population, especially in winter. Thus, the authors suggest that since many pregnant women plan pregnancy and take prenatal micronutrient supplements, they should provide 800 IU/day of vitamin D, especially in winter12.
Racial differences in serum vitamin D levels have also been identified during gestation, and in a population study of women recruited at 27 weeks of pregnancy and living in London, levels <25 ng/ml were found among Asian women 47%, 64% in the Eastern countries, 58% in the black and 13% in the Caucasian13.
Another relevant factor to consider in the pregnant woman is obesity, having described that in those women with BMI ≥30, 61% had vitamin D deficiency, compared to those with a BMI of 25 or less, where the deficiency appeared in 36%14.
A relevant question is the clinical implication that for the health of the mother or the fetus would have the deficiency of vitamin D. Several actions have been postulated:

– Preeclampsia
Analysis of the studies carried out with this aim indicates conflicting results and some find a direct relationship between serum vitamin D levels and the presence of hypertension or preeclampsia, while others do not.
It has been reported that mothers with serum levels below 50 ng/ml have a five-fold increased risk of severe preeclampsia15. In one study, women who developed severe preeclampsia before 34 weeks had serum levels of vitamin D lower than the control group. Low levels in the first half of gestation were associated with increased risk of preeclampsia and double risk in neonates being deficient <37.5 ng/m16. It has also been noted that in cases of early onset of severe preeclampsia and small children for gestational age (PEG), vitamin D levels were significantly lower than those with severe preeclampsia early onset, but without PEG17.
However, other studies have failed to demonstrate these associations, although two meta-analyzes have concluded that vitamin D insufficiency is associated with preeclampsia and low birth weight infants for gestational age18,19.
Vitamin D deficiency has been associated with low birth weight20. An Australian study reports that children born to mothers with vitamin D deficiency had a mean weight lower than 200 g compared to children of mothers with normal serum levels21.
Analysis of the association with the risk of developing diabetes during gestation shows controversial results since it has shown a positive association in several cohort studies22,23, and in others it has not been demonstrated, although relevant confounding factors such as Pre-gestational weight or ethnicity24.
A 31-year meta-analysis has shown that vitamin D insufficiency is associated with a higher risk of developing gestational diabetes25.
Regarding the perinatal results, it has been reported that vitamin D deficiency is associated with four times greater risk of cesarean delivery than controls26 and a higher presence of bacterial vaginosis in pregnant women27.
Therefore, a debate in development at the moment is The desirability of performing universal screening and/or supplementation of all pregnant women in order to improve maternal and infant outcomes.
If there is greater agreement in the identification of the pregnant women of greater risk (obese, of dark skin, total clothes, limited mobility) and to propose strategies of supplementation, at least in them. On the other hand, supplementation has proven to be safe in pregnancy.
Some agencies recommend information and supplementation to pregnant women and infants with 400 IU/day, especially in women at higher risk, with three levels of recommendation being established, although the optimal dose of vitamin D in pregnancy is not fully established28 (Table 1).

Treatment of women with vitamin D deficiency and vitamin D supplementation is safe during gestation and may represent short- and long-term benefits.
An issue that has been raised with regard to supplementation or treatment is whether the administered dose would be added to that ingested by the diet and this could lead to exceeding the safe limits. In this sense, the analysis of the average intake with a pregnant woman’s diet is estimated at about 1.8 µg (72 IU) of vitamin D per day, which is far from a possible toxicity.
A Cochrane review of 2016 concluded that pregnant women receiving vitamin D supplements at a single or continuous dose have an increase in serum 25-OH-D at term and a possible reduction in the risk of preeclampsia, low birth weight And premature delivery. However, when vitamin D and calcium are combined, the risk of preterm birth increases. The clinical significance of increased serum 25-OH-D concentrations is still unclear. Due to the above, these results should be interpreted with caution. A relevant fact is that no study of those analyzed reported adverse effects29.
At the moment, we are working in the Spanish Society of Gynecology and Obstetrics (SEGO) to establish recommendations appropriate to the characteristics of pregnant women in our environment

 

Post menopause
In post menopause, the estrogen production deficit is the main pathophysiological factor of osteoporosis where vitamin D plays a relevant role. Decreased intake, absorption, and vitamin D synthesis that occurs with aging are associated with reduced plasma calcium levels and a consequent secondary hyperparathyroidism which, together with decreased estrogen, lead to increased resorption and decreased mass bone fractures, factors that determine the risk of fractures. This section is developed in detail in another section of this same review.

 

Other considerations

 

Blood pressure
Minor blood pressure values have been identified in women with vitamin D supplements. Sun exposure is the major source of vitamin D formation and lower numbers of AT have been associated with sun exposure30.
In an intervention study in 148 elderly women with vitamin D deficiency, supplementation with 800 IU of vitamin D and 1200 mg of calcium showed a 9% reduction in systolic BP compared to those supplemented with calcium alone31.

 

Oncological processes
Based on epidemiological studies that have reported a different prevalence of cancer among countries with different latitudes and therefore exposure to ultraviolet radiation, the hypothesis has been raised of the preventive role that vitamin D could have in at least some types of cancer of high prevalence in women such as colon and breast. A 50% reduction in the risk of cancer has been reported when serum vitamin D levels exceed 32 ng/ml32. Specifically, this beneficial association has been reported in relation to breast cancer33. In vitro studies in breast cancer cell lines have revealed mechanisms of action of vitamin D by which it modifies the cell growth of the tumor lines, increasing the cellular apoptosis and diminishing the angio-genesis.
The relationship of serum vitamin D levels to tumor prognosis has recently been reported in women with breast cancer, with the lowest levels of vitamin D being found in women with advanced tumors and in premenopausal women with triple-negative tumors. Vitamin D levels are also related to tumor progression, recurrence and death from this cause34.
Although there are no specific recommendations on these aspects, and the safety of supplementation, if necessary, it is reasonable to consider the need to reach recommended daily doses to achieve adequate serum vitamin D levels.
In general, daily doses of 600-800 IU/day are recommended to achieve serum levels of 25-OH-D> 30ng/ml. It can be administered in daily, weekly, monthly or annual guidelines.

 

Summary
The evidence provides information on the relevant role of vitamin D in various areas of women’s health. Knowing that the prevalence of insufficient or clearly deficient levels is high at any stage of life, including pregnancy, it seems reasonable to be alert to the identification of those women who may benefit from supplementation or treatment to achieve adequate levels.

Conflict of interest: The author declares that she has no conflict of interest.

 

Bibliografía

1. Andıran N, Çelik N, Akça H, Doğan G. Vitamin D deficiency in children and adolescents. J Clin Res Pediatr Endocrinol. 2012;4(1):25-9. doi: 10.4274/jcrpe.574.
2. Ahmed SF, Franey C, McDewitt H, et al. Recent trends and clinical features of childhood vitamin D deficiency presenting to a children’s hospital in Glasgow. Arch Dis Child. 2011;96:694-6.
3. Zhu H, Bhagatwala J, Huang Y, Pollock NK, Parikh S, Raed A, et al. Race/Ethnicity-Specific Association of Vitamin D and Global DNA Methylation: Cross-Sectional and Interventional Findings. PLoS One. 2016;11(9):e0162582. doi: 10.1371/journal.pone.0162582.
4. Holick MF. Resurrection of vitamin D deficiency and rickets. J Clin Invest. 2006;116:2062-72.
5. Winzenberg T, Powell S, Shaw KA, Jones G. Effects of vitamin D supplementation on bone density in healthy children: Systematic review and metaanalysis. BMJ. 2011;342:c7254.
6. Pilz S, Hahn A, Schön C, Wilhelm M, Obeid R. Effect of Two Different Multimicronutrient Supplements on Vitamin D Status in Women of Childbearing Age: A Randomized Trial. Nutrients. 2017;9(1). pii: E30. doi: 10.3390/nu9010030.
7. Rudick B, Ingles S, Chung K, Stanczyk F, Paulson R, Bendikson K. Characterizing the influence of vitamin D levels on IVF outcomes. Hum Reprod. 2012;27(11): 3321-7. doi: 10.1093/humrep/des280.
8. Rudick BJ, Ingles SA, Chung K, Stanczyk FZ, Paulson RJ, Bendikson KA. Influence of vitamin D levels on in vitro fertilization outcomes in donor-recipient cycles. Fertil Steril. 2014;101(2):447-52. doi: 10.1016/j.fertnstert.2013.10.008.
9. Mousa A, Abell S, Scragg R, de Courten B. Vitamin D in Reproductive Health and Pregnancy. Semin Reprod Med. 2016;34(2):e1-13. doi: 10.1055/s-0036-1583529.
10. Wehr E, Trummer O, Giuliani A, Gruber HJ, Pieber TR, Obermayer-Pietsch B. Vitamin D-associated polymorphisms are related to insulin resistance and vitamin D deficiency in polycystic ovary syndrome. Eur J Endocrinol. 2011;164(5):741-9. doi: 10.1530/EJE-11-0134.
11. He C, Lin Z, Robb SW, Ezeamama AE. Serum Vitamin D Levels and Polycystic Ovary syndrome: A Systematic Review and Meta-Analysis. Nutrients. 2015;7(6):4555-77. doi: 10.3390/nu7064555.
12. Pilz S, Hahn A, Schön C, Wilhelm M, Obeid R. Effect of Two Different Multimicronutrient Supplements on Vitamin D Status in Women of Childbearing Age: A Randomized Trial. Nutrients. 2017;9(1). pii: E30. doi: 10.3390/nu9010030.
13. Yu CK, Sykes L, Sethi M, Teoh TG, Robinson S. Vitamin D deficiency and supplementation during pregnancy. Clin Endocrinol (Oxf). 2009;70:685-90.
14. Bodnar LM, Catov JM, Roberts JM, Simhan HN. Prepregnancy obesity predicts poor vitamin D status in mothers and their neonates. J Nutr. 2007;137:2437-42.
15. Baker AM, Haeri S, Camargo CA Jr, Espinola JA, Stuebe AM. A nested case-control study of midgestation vitamin D deficiency and risk of severe preeclampsia. J Clin Endocrinol Metab. 2010;95:5105-9.
16. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007;92:3517-22.
17. Robinson CJ, Alanis MC, Wagner CL, Hollis BW, Johnson DD. Plasma 25-hydroxyvitamin D levels in early-onset severe preeclampsia. Am J Obstet Gynecol. 2010;203:366.e1-6.
18. Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM. Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ. 2013;346:f1169.
19. Wei SQ, Qi HP, Luo ZC, Fraser WD. Maternal vitamin D status and adverse pregnancy outcomes: a systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2013;26:889-99.
20. Robinson CJ, Wagner CL, Hollis BW, Baatz JE, Johnson DD. Maternal vitamin D and fetal growth in early-onset severe preeclampsia. Am J Obstet Gynecol. 2011;204:556.e1-4.
21. Bowyer L, Catling-Paull C, Diamond T, Homer C, Davis G, Craig ME. Vitamin D, PTH and calcium levels in pregnant women and their neonates. Clin Endocrinol. (Oxf) 2009;70:372-7.
22. Clifton-Bligh RJ, McElduff P, McElduff A. Maternal vitamin D deficiency, ethnicity and gestational diabetes. Diabet Med. 2008;25:678-84.
23. Zhang C, Qiu C, Hu FB, David RM, van Dam RM, Bralley A, et al. Maternal plasma 25- hydroxyvitamin D concentrations and the risk for gestational diabetes mellitus. PLoS One. 2008;3:e3753.
24. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care. 2004;27:2813-8.
25. Aghajafari F, Nagulesapillai T, Ronksley PE, Tough SC, O’Beirne M, Rabi DM. Association between maternal serum 25-hydroxyvitamin D level and pregnancy and neonatal outcomes: systematic review and meta-analysis of observational studies. BMJ. 2013;346:f1169.
26. Shand AW, Nassar N, Von Dadelszen P, Innis SM, Green TJ. Maternal vitamin D status in pregnancy and adverse pregnancy outcomes in a group at high risk for pre-eclampsia. BJOG. 2010;117:1593-8.
27. Hensel KJ, Randis TM, Gelber SE, Ratner AJ. Pregnancy-specific association of vitamin D deficiency and bacterial vaginosis. Am J Obstet Gynecol. 2011;204:41.e1-9.
28. Royal College of Obstetricians & Gynaecologists. Vitamin D in pregnancy. Scientific Impact Paper No. 43 June 2014.
29. De-Regil LM, Palacios C, Lombardo LK, Peña-Rosas JP. Cochrane Database Syst Rev. Vitamin D supplementation for women during pregnancy. 2016;(1):CD008873. doi: 10.1002/14651858.CD008873.pub3.
30. Krause R, Buhring M, Hopfenmuller W, et al. Ultraviolet B and blood pressure. Lancet. 1998;352:709-10.
31. Pfeifer M, Begerow B, Minne HW, et al. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab. 2001;86:1633-7.
32. Lappe JM, Travers-Gustafason D, Davies KM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007;85:1586-91.
33. Welsh J, Wietzke JA, Zinser GM, Byrne B, Smith K, Narvaez CJ. Vitamin D-3 receptor as a target for breast cancer prevention. J Nutr. 2003;133(7 Suppl):2425S-2433S.
34. Yao S, Kwan ML, Ergas IJ, Roh JM, Cheng TD, Hong CC, McCann SE, Tang L, Davis W, Liu S, Quesenberry CP Jr, Lee MM, Ambrosone CB, Kushi LH. Association of Serum Level of Vitamin D at Diagnosis With Breast Cancer Survival: A Case-Cohort Analysis in the Pathways Study. JAMA Oncol. 2017 ;3(3):351-7. doi: 10.1001/jamaoncol.2016.4188.