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

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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

REFERENCES

• 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 More than 16 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.

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

This list is automatically updated

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VitaminDWiki - Pregnancy category contains

915 items in Pregnancy category

 - see also

• Overview Pregnancy and vitamin D
• Number of articles in both categories of Pregnancy and:Dark Skin 29;   Depression 21;   Diabetes 44;   Obesity 17;  Hypertension 44;   Breathing 35;  Omega-3 44;  Vitamin D Receptor 24 Click here for details
• All items in category Infant/Child 846 items
• Pregnancy needs at least 40 ng of vitamin D, achieved by at least 4,000 IU – Hollis Aug 2017
• 38+ papers with Breastfed etc, in the title
• Call to action – more Vitamin D for pregnancies, loading doses are OK – Holick Aug 2019
• 53+ preeclampsia studies
• 94+ studies with PRETERM in the title
• Fertility problem (PCOS) reduced by vitamin D: many studies 15+
• 94+ Gestational Diabetes
• Caesarean birth much more likely if low Vitamin D - many studies 15+ studies
• Post-partum depression and low Vitamin D - many studies 15+ studies
• Stillbirth reduced by Vitamin D, Zinc, Omega-3 - several studies 5+ studies
• Search VitaminDWiki for "Assisted reproduction" 33 items as of Aug 2022
• Fertility and Sperm category listing has 141 items along with related searches
• (Stunting OR “low birth weight” OR LBW) 1180 items as of June 2020
• Less labor pain if higher level of vitamin D – August 2021
• Healthy pregnancies need lots of vitamin D
• Ensure a healthy pregnancy and baby - take Vitamin D before conception
  

VitaminDWiki - Healthy pregnancies need lots of vitamin D contains

Most were taking 2,000 to 7,000 IU daily for >50% of pregnancy
   Click on hyperlinks for details

Problem	Vit. D Reduces	Evidence
0. Chance of not conceiving	3.4 times	Observe
1. Miscarriage	2.5 times	Observe
2. Pre-eclampsia	3.6 times	RCT
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 times	Observe
Stillbirth - OMEGA-3	4 times	RCT - 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		RCT
10. Childhood Wheezing	1.3 times	RCT
11. Additional child is Autistic	4 times	Intervention
12.Young adult Multiple Sclerosis	1.9 times	Observe
13. Preeclampsia in young adult	3.5 times	RCT
14. Good motor skills @ age 3	1.4 times	Observe
15. Childhood Mite allergy	5 times	RCT
16. Childhood Respiratory Tract visits	2.5 times	RCT

RCT = Randomized Controlled Trial

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Important conutrient for Pregnancy: Magnesium (55 studies)

This list is automatically updated

Important conutrient for Pregnancy: Omega-3 (11 studies)

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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 ng	Sleep *
60 ng	Breast Cancer death reduced 60% Preeclampsia RCT
50 ng	COVID-19 Fertility Psoriasis Infections Review Infection after surgery
40 ng	Breast Cancer 65% lower risk Depression ACL recovery Hypertension Asthma?
30 ng	Rickets

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

• Click here for more information

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

This list is automatcially updated

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VitaminDWiki - More than 16 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
   • Example: Breast Cancer
   • Vitamin D Receptor is associated in over 58 autoimmune studies
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
   • The amount needed varies: 20 ng ==> 150 ng
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

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VitaminDWiki - Vitamin D greatly improves Fertility

• Vitamin D is needed for human fertility – goal is 50 ng – Sept 2018
• In-vitro Fertilization costs at least 10,000 dollars, Vitamin D costs 5 dollars
• Infertile patients 1.7X more-likely to become pregnant if take Vitamin D – meta-analysis Feb 2023
• Live birth 1.7 X more likely after IVF if good level of vitamin D – meta-analysis Aug 2020
• If diagnosed infertile, more likely to have live birth if Vitamin D fortification – Feb 2020
• Preconception vitamin D is great - every extra 10 ng associated with 10 percent more likely to have live birth – Aug 2018
• Women with more than minimum vitamin D were 3.4 X more likely to achieve pregnancy and 1.6 X more likely to have live births – June 2017
• Assisted Reproduction – 5 studies concluded vitamin D repletion helps – Review March 2015
• Pregnancy success increased 30 percent if sunny (or vitamin D) one month earlier – June 2015
• IVF 4X more successful for white women with lots of vitamin D – many studies

Increased male Vitamin D increases fertility

• Birth rates doubled with Vitamin D - 300,000 for infertile men – RCT Nov 2017
• Higher vitamin D results in 22% fewer abnormal sperm (Mendelian analysis) – May 2024
• Conception was 3.7X more likely if the male had a good level of Vitamin D – July 2022
• Far better sperm in fertility clinic if more than 30 ng of Vitamin D - June 2022
• Fertility (sperm) associated with vitamin D – meta-analysis Sept 2019
• Infertility - 71 percent of the time of BOTH partners had less than 20 ng of Vitamin D – Aug 2017
• Male fertility 4 X higher if high Vitamin D – Nov 2015
• Vitamin D somewhat assists reproduction – both the mother and the father – May 2014

Decreased Fertility if decreased Vitamin D Receptor

• Unexplained infertility 4X more likely if poor vitamin D receptor – Dec 2020
• Male Infertility is associated with poor Vitamin D Receptor – July 2021

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This editorial was also reviewed by Grassrootshealth