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Vitamin D deficiency is the most common nutritional deficiency in the world – July 2022

The title of this page is derived from the first line of the following editorial

Time to implement vitamin D assessment and supplementation into routine obstetric practice?

REFLECTIONS| VOLUME 118, ISSUE 1, P123-124, JULY 01, 2022 https://doi.org/10.1016/j.fertnstert.2022.04.031
Paolo Ivo Cavoretto, M.D., Ph.D., Paola Viganò, D.Sc., Ph.D.

Vitamin D deficiency (25-hydroxyvitamin D concentration < 20 ng/mL) is the most common nutritional deficiency in the world, although vitamin D is one of the most well-understood compounds. Vitamin D is known to reduce the risks of many adverse health outcomes through both genetic and nongenetic mechanisms and it is readily available from supplements that are safe and inexpensive. However, the beneficial effects of vitamin D for patients with nonskeletal disorders have received widespread attention from researchers since 2000 (1).

Tamblyn et al. (2) conducted a systematic review and meta-analysis with the aim of investigating whether adequate vitamin D status protects from pregnancy loss. The study included 6 observational studies and 4 randomized controlled trials (RCTs). The rationale for this aim has strong biological plausibility because low vitamin D levels have been associated with several reproductive disorders, including endometriosis; polycystic ovary syndrome; uterine fibroids; and adverse obstetrics outcomes, such as preeclampsia, gestational diabetes mellitus, and preterm birth (2).

The study showed that vitamin D deficiency or insufficiency during pregnancy is associated with a higher miscarriage rate. The magnitude of risk progression in pregnancies with vitamin D deficiency or insufficiency ranged on average between 60% and 90% as compared to those with vitamin D repletion, showing a biological gradient with higher effect (risk of miscarriage) associated with greater depletion. Although the planned subgroup meta-analysis for preconception vitamin D assessment and the risk of recurrent miscarriage failed (because only 1 eligible study could be identified), the study established additional robust evidence for major effects of vitamin D in early human pregnancy and raised a call for future investigation in this area.

However, the study is not devoid of limitations, as correctly disclosed by the investigators (2). The inclusion of miscarriage cases with likely different etiologies, such as those occurring in the first trimester (mostly due to chromosomal defects) or second trimester (due to cervical insufficiency or other factors) as well as recurrent pregnancy losses (often due to combinations of parental chronic conditions), increased the heterogeneity of the outcomes. Therefore, the “dilution” of the real effect of vitamin D on the risk of miscarriage may be expected, with consequent minimization of statistical significance. Moreover, further sources of heterogeneity can be recognized based on diverse classification of vitamin D deficiency and at different timings of assessment, as the investigators correctly admitted. These limitations represent reasons for caution, but they do not diminish the biological and clinical importance of these findings. Instead, as mentioned above, they may support the hypothesis that the association between low vitamin D levels and miscarriage risk demonstrated by Tamblyn et al. (2) would be smaller than that expected after the exclusion of cases because of etiologies unrelated to the biological action of vitamin D (e.g., chromosomal defects). The occurrence of chromosomal defects as a consequence of vitamin D deficiency has not been proven and is biologically questionable. Therefore, cases with a genetic basis should be excluded from future studies assessing the risk of miscarriage based upon vitamin D levels or attempting its prevention by supplementation. Conversely, the recognized effects of vitamin D on the developing receptive endometrium, the immune system, thrombosis or hemostasis phenomenon, cardiovascular health, and placental function are all potentially critical to the risk of miscarriage (1). Finally, given the association between vitamin D deficiency or insufficiency and preterm birth, a potential mechanism involved in early cervical insufficiency underlying pregnancy loss cannot be excluded (3). This observation was enough to support pooling data derived from first and second trimester miscarriages, but we would like to recommend subgroup analyses as soon as information is available from future well-designed trials on this topic.

Notably, in studies evaluating the role of vitamin D in human health, some aspects need to be considered. Although observational studies can suggest that better provision of vitamin D is strongly associated with reductions in several health risks, RCTs frequently fail to provide supportive evidence for the expected health benefits of supplementation (4). In the field of reproduction, an example is represented by studies assessing the impact of vitamin D on the success rates of assisted reproductive technology procedures. Although observational, prospective, and retrospective studies were in strong support of a beneficial role of the vitamin, the RCT with the largest sample size and using high-dose supplementation was not able to confirm these findings (5).
There are various reasons for these difficulties in conducting well-designed RCTs to demonstrate treatment effects.

  • First, vitamin D is a nutrient and not a drug, and the corresponding physiologic response has a sigmoid curve. This means that at low intake, a little response is generated; the effect increases fairly rapidly for a particular amount of intake or exposure range, and then at higher intake, the response reaches a plateau. Therefore, in RCTs in which identical doses are administered to all subjects in the treatment arm, the doses will be too small to normalize the levels of the vitamin in many patients with deficiency and will be unable to induce a detectable response in those who with repletion (4). The possibility to measure relevant health benefits in the treatment arm is obviously reduced in patients with these conditions.
  • Another potential problem related to RCTs refers to the vitamin D threshold effect. Although the currently used serum threshold for bone health is well established, nonskeletal health may benefit from higher levels. The threshold required to limit the risk of spontaneous abortion is completely unknown, and the failure to ensure and maintain the adequate level for the outcome of interest during RCTs represents a confounder.
  • Other potential reasons for the failure of RCTs include poor attention to conutrient status, which is often important in studies of nutrient efficacy; the role of genetic polymorphisms contributing to the modulation of the action of vitamin D in target tissues; and the adjustment of the doses and timings to ensure a planned status in relation to population characteristics (4).

Tamblyn et al. (2) were not able to pool data from selected RCTs focused on vitamin D treatment. The 4 studies were characterized by great disparity among the regimens used by reporting the bias and other problems preventing a direct comparative analysis. A preconception intervention was foreseen only in 2 of the studies. Notably, in line with the aforementioned observations, none of the studies was able to observe a significant effect of vitamin D supplementation on the reduction of the miscarriage rate. An RCT by Samimi et al. (included in the meta-analysis object of this commentary) indeed found a significant reduction in the miscarriage rate after vitamin D supplementation in a population of women with unexplained recurrent spontaneous abortion. However, after correcting for confounding factors in the logistic regression analysis, the effect of vitamin D on the incidence of abortion was no more statistically significant.

Is it time to implement vitamin D assessment and supplementation into routine obstetric practice? We believe that there is probably enough evidence for promoting the measurement of vitamin D levels before conception or in the first trimester of pregnancy (if this was not done earlier) as a prognostic biomarker for miscarriage. On the other hand, it is not yet proven that correcting the vitamin D levels may reduce miscarriage risk. The difficulties in ensuring that RCTs with appropriate designs are conducted do not, however, justify the acceptance of deficiency.

Well-designed RCTs on intervention with vitamin D should identify outcomes a priori excluding those linked to unrelated etiologies, assess preconception nutritional status and vitamin D levels, define appropriate dosages minimizing threshold effects, and check very carefully the issue of power because the nutrient effect tends to be small. It is intuitive that the results of null-effect studies affected by flaws may reduce confidence with regard to the nonskeletal health benefits of vitamin D, for which deficiency is avoidable through simple measures.
DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/35196
 Download the PDF from VitaminDWiki

  • 1. Schröder-Heurich B, Springer CJ, von Versen-Höynck F. Vitamin D effects on the immune system from periconception through pregnancy. Nutrients 2020; 12:1432.
  • 2. Tamblyn JA, Pilarski Nicole NS, Markland AD, Marson EJ, Devall A, et al. Vitamin D and miscarriage: a systematic review and meta-analysis. Fertil Steril 2022;118:111-22.
  • 3. Bodnar LM, Platt RW, Simhan HN. Early-pregnancy vitamin D deficiency and risk of preterm birth subtypes. Obstet Gynecol 2015;125:439^7.
  • 4. Boucher BJ. Why do so many trials of vitamin D supplementation fail? Endocr Connect 2020;9:R195-206.
    See in VitaminDWiki The many reasons why Vitamin D trials fail – Oct 2020
    Summary by VitaminDWiki lists 15 reasons
  • 5. Somigliana E, Sarais V, Reschini M, Ferrari S, Makieva S, Cermisoni GC, et al. Single oral dose of vitamin D3 supplementation prior to in vitro fertilization and embryo transfer in normal weight women: the SUNDRO randomized controlled trial. Am J Obstet Gynecol 2021;225:283.e1-10.

VitaminDWiki pages with MISCARRIAGE in title (31 as of June 2022)

This list is automatically updated

Items found: 32
Title Modified
Miscarriage 2.5X more likely if second-hand smoke and low vitamin D – Sept 2022 06 Sep, 2022
Miscarriage 1.6 X more likely if low vitamin D – meta-analysis May 2022 09 Jun, 2022
Recurrent Miscarriage 4X more likely if low vitamin D – meta-analysis June 2022 07 Jun, 2022
Recurrent pregnancy loss (miscarriage) risk should be reduced by vitamin D, vitamin B12 – March 2021 24 Dec, 2021
Researchers found flu vaccine increased miscarriage risk by 7X -Sept 2017 24 Dec, 2021
Miscarriage – study found all 4 of the reasons to be related to vitamin D – Dec 2021 24 Dec, 2021
Recurrent miscarriage associated with low Vitamin D – Nov 2013 24 Dec, 2021
Recurrent pregnancy loss (miscarriage) is associated with low vitamin D in 6 ways – March 2021 25 Mar, 2021
Recurrent miscarriage occurs 2.2 more often if poor Vitamin D Receptor – Aug 2019 26 Feb, 2021
Spontaneous Miscarriage strongly associated with 2 vitamin D genes – March 2020 15 Feb, 2020
Preterm birth 9 X more likely if fetus had a poor Vitamin D Receptor and previous miscarriage – Aug 2017 12 Nov, 2019
Miscarriage 32 percent more likely if work night shift (probably low Vitamin D) – April 2019 05 Apr, 2019
Miscarriage 2 times more likely if low vitamin D – meta-analysis May 2017 05 Apr, 2019
Miscarriage 10 percent more likely for each 10 ng less vitamin D at preconception – May 2018 01 Aug, 2018
Miscarriages strongly associated with poor placental, decidua gene which locally activates Vitamin D – Dec 2016 28 Jul, 2018
Second miscarriage associated with low vitamin D – review June 2018 20 Jun, 2018
Pregnancies with more than 40 ng of vitamin D are great - miscarriage, LBW, SGA, preterm – Feb 2018 14 Feb, 2018
Pregnancies with more than 40 ng of vitamin D are great - miscarriage, LBW, SGA, preterm – Feb 2018 14 Feb, 2018
Cesarean (associated with low Vitamin D) increased asthma, obesity, miscarriage and stillbirth – meta-analysis Jan 2018 26 Jan, 2018
Early menarche, miscarriage and stillbirth are associated with heart disease (all are associated with low Vitamin D) – Jan 2018 18 Jan, 2018
Preterm birth far more likely if previous miscarriage and poor Vitamin D receptor – Aug 2017 20 Nov, 2017
APS (associated with miscarriage, stillbirth. preterm delivery and stroke) is 3X more likely if low vitamin D – meta-analysis Oct 2017 13 Oct, 2017
Frequent miscarriage associated with both lower vitamin D and poor Vitamin D receptor – Sept 2017 14 Sep, 2017
Miscarriage in first trimester 2.5X more likely if less than 20 ng of vitamin D – July 2015 07 Jul, 2017
Miscarriage 70 percent more likely if low vitamin D (see also data on CYP27B1) – May 2016 07 Jul, 2017
Just 400 IU of daily Vitamin D reduced miscarriage (recurrent) by 3.5 times – RCT July 2016 07 Jul, 2017
Preterm birth 2X more likely if poor Vitamin D Receptor, 9 X if also had previous miscarriage – June 2017 15 Jun, 2017
Infants have low levels of vitamin D – associations with phototherapy and miscarriage – Dec 2016 01 Jan, 2017
Infants have low vitamin D levels in infants – association with phototherapy and miscarriage – Dec 2016 01 Jan, 2017
Recurrent miscarriage associated with half as much vitamin D getting to fetus – Sept 2016 07 Aug, 2016
Miscarriage 3X more often if very low vitamin D – Jan 2016 12 Jun, 2016
Miscarriage in 2nd trimester associated with low vitamin D – July 2012 07 Sep, 2015

VitaminDWiki - Pregnancy category contains

860 items in Pregnancy category

 - see also

VitaminDWiki - Healthy pregnancies need lots of vitamin D contains

0. Chance of not conceiving3.4 times Observe
1. Miscarriage 2.5 times Observe
2. Pre-eclampsia 3.6 timesRCT
3. Gestational Diabetes 3 times RCT
4. Good 2nd trimester sleep quality 3.5 times Observe
5. Premature birth 2 times RCT
6. C-section - unplanned 1.6 timesObserve
     Stillbirth - OMEGA-3 4 timesRCT - Omega-3
7. Depression AFTER pregnancy 1.4 times RCT
8. Small for Gestational Age 1.6 times meta-analysis
9. Infant height, weight, head size
     within normal limits
10. Childhood Wheezing 1.3 times RCT
11. Additional child is Autistic 4 times Intervention
12.Young adult Multiple Sclerosis 1.9 timesObserve
13. Preeclampsia in young adult 3.5 timesRCT
14. Good motor skills @ age 31.4 times Observe
15. Childhood Mite allergy 5 times RCT
16. Childhood Respiratory Tract visits 2.5 times RCT

RCT = Randomized Controlled Trial

Important conutrient for Pregnancy: Magnesium (52 studies)

This list is automatically updated

Important conutrient for Pregnancy: Omega-3 (10 studies)

This list is automatically updated

Different Vitamin D thresholds are needed to treat different health problems

Vitamin D Treats
150 ng Multiple Sclerosis *
80 ng Cluster Headache *
Reduced office visits by 4X *
70 ngSleep *
60 ngBreast Cancer death reduced 60%
Preeclampsia RCT
50 ng COVID-19
Infections Review
Infection after surgery
40 ng Breast Cancer 65% lower risk
ACL recovery
30 ng Rickets

* Evolution of experiments with patients, often also need co-factors

VitaminDWiki pages with CALL TO ACTION in title (10 as of June 2022)

This list is automatcially updated

Items found: 11

VitaminDWiki - The many reasons why Vitamin D trials fail – Oct 2020 contains

  1. Trials mistakenly use a single size dose for everyone
    • However, much larger doses are needed by those who are:
      • Obese
      • Poor-responders (poor gut, poor liver, some poor genes, low Magnesium, etc .)
      • Elderly
        • Less vitamin D absorbed by the gut
        • Less Vitamin D processed by the liver (40% of the elderly have poor livers)
        • Less Vitamin D receptors in elderly ==> less to tissues
  2. Trials often not last long enough (typically just 8 weeks)
    • Takes months to achieve a new level, then months longer to use that new level
    • To make muscle, make bone, fight cancer, etc.
  3. Trials often are spread over several seasons
    • The same dose does not give the same response if given during Winter vs Summer
  4. Exercise is sometimes also needed (Vitamin D is not a magic bullet)
    • Build muscle or bone
  5. Cofactors are often needed to get Vitamin D to the tissues
    • Examples include Magnesium, Omega-3
  6. Some Health Problems actively block Vitamin D from getting to tissues
  7. Some environmental conditions actively reduce Vitamin D in the body
    • Examples: Smoking, DDT, Roundup. Lead
  8. 30 ng is not the amount needed by all diseases
  9. Compliance is typically < 90%
  10. Vitamin D used in the trial is oil-based - with 20% reduction in response
    • Even more of a reduction if oil-based Vitamin D is not taken with a fatty meal
  11. Participants are not told to take it with the largest meal of the day (typically dinner)
    • Which increases response by ~30%
  12. Participants talk to each other and determine who is getting the placebo (no response)
  13. Trial used D2 instead of D3
    • Much less of a problem after 2010, but some international trials have not gotten the word
  14. Trial gave vitamin D to everyone - independant of Vitamin D Level
    • Those who already have a good level of vitamin D will niot benefit by getting more
  15. Too long of time between dosing
    • Benefit starts to fall off at 17 days, and is vitually gone at 90 days.
  16. 4X range of responses to the same dose of vitamin D

VitaminDWiki - Vitamin D greatly improves Fertility

Increased male Vitamin D increases fertility

Decreased Fertility if decreased Vitamin D Receptor

This editorial was also reviewed by Grassrootshealth

Created by admin. Last Modification: Wednesday June 22, 2022 13:07:43 GMT-0000 by admin. (Version 18)

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