Vitamin D and Miscarriage New Study

Posted By Braverman IVF & Reproductive Immunology || 04-June-2018

A recent study published in the Lancet Diabetes and Endocrinology journal, showed that sufficient and adequate Vitamin D levels may reduce the risk for another miscarriage in patients having suffered previous losses.

At Braverman Reproductive Immunology, we have been diagnosing and treating Vitamin D deficiency for years that appears to be prevalent in our patients with Recurrent Pregnancy Loss. Deficiency of Vitamin D also appears to play a significant role in the propagation of autoimmune and inflammatory disorders also seen commonly on our patient population.

In this blog, we will give you a clear insight of what is known about miscarriage risk, autoimmunity (including endometriosis) and obstetrical complication in relation to Vitamin D.

1. Vitamin D: synthesis and functions

a. What is vitamin D?

Vitamin D is a fat-soluble vitamin belonging to the steroid hormone family. Two main forms are essentials:

  • Vitamin D2 (ergocalciferol) that you can get through your diet.
  • Vitamin D3 (cholecalciferol) that you synthetize after sun exposure and represent 95% of your vitamin D production (1).

    As shown in the Figure 1 below, these precursors bind to a binding protein (VDBP) to transit in the blood and reach the liver where they are modified into calcidiol (25-OH cholecalciferol) then metabolized a second time by the kidney to generate calcitriol (or 1, 25 dihydroxycholecalciferol), the active form of vitamin D.

    Figure 1: Vitamin D metabolic pathway

    b. Role of vitamin D

    By binding to its receptor (VDR), calcitriol (active form of vitamin D) regulates over 900 genes in human including several actions in reproductive tissues besides playing a key role in:

  • Calcium homeostasis
  • Regulation of cellular growth
  • Regulation of cellular differentiation
  • Regulation of immune response
  • Regulation of apoptosis (cell death) Vitamin D and its receptor are present in the ovaries (2) where they stimulate the production of the steroid hormones estrogen and progesterone (3). The endometrium (uterus) itself can synthesize the active form of Vitamin D (4) and express the vitamin D receptor VDR as well (2).

    2. Vitamin D deficiency and its consequences on pregnancy outcome Vitamin D deficiency is associated with higher risk for miscarriage

    In the recent study from the Lancet journal, included N=1200 women with one or two prior miscarriages, they followed them for up to six menstrual cycles while attempting pregnancy and throughout pregnancy if they conceived. Their Vitamin D levels were measured at baseline (preconception) and at 8 weeks of pregnancy (if they have conceived). The results showed that women with sufficient preconception vitamin D were more likely to achieve clinical pregnancy and livebirth as compared to women with insufficient Vitamin D concentrations. Among women who achieved pregnancy, sufficient preconception vitamin D (>30 ng. mL-1) was associated with reduced risk of pregnancy loss.

    This study is very important as it shows that a sufficient preconception vitamin D level is associated with better chances for a pregnancy (+10%) and a livebirth (+15%) and a reduced risk for another pregnancy loss.

    Low levels of vitamin D are common in pregnant women and has been shown in several epidemiological studies worldwide.  Vitamin D deficiency is associated with an increased risk of infection (5), bacterial vaginosis (6), pre-eclampsia (7) and low serum vitamin D levels in the newborn (8). Many evidences support the beneficial role of vitamin D in promoting women reproductive health and fertility. Studies in animal (9) and in human (10) have shown that Vitamin D is a potent regulator of a process named decidualization that corresponds to the preparation of your uterus (with modification of endometrial cells) for the establishment of a pregnancy. Therefore, a vitamin D deficiency may negatively impact your uterine lining. A condition we commonly see in our own patient population. Vitamin D is a main regulator of a gene named HOXA10, essential for the regulation of the endometrial development and receptivity during the window of implantation (11). Lower expression of HOXA10 was found in the endometrium of ENDO patients (12) and could be due to lower vitamin D levels thus playing a role in ENDO patient’s infertility. A reason why our treatments likely treat the defects found in tests such as the ERA (Endometrial Receptivity Assay). urther, vitamin D regulates genes involved in trophoblast invasion and angiogenesis, key mechanism in embryo implantation and placenta function, thus supporting fetal growth and development (13-15).

    3. Vitamin D deficiency and its consequences on autoimmunity

    a- Vitamin D deficiency is associated with higher autoimmunity

    In a study (16), including women with RPL (with a minimum of 3 consecutive losses before 20 weeks), it was shown that half of the patients were deficient for vitamin D and more interestingly, these low vitamin D levels were associated with increased cellular immunity and autoimmunity as seen by:

  • higher prevalence of antiphospholipid antibodies (APA) that doubled in the low Vitamin D group as compared to the control group (RPL patient with normal Vitamin D levels)
  • higher prevalence of antinuclear antigen antibody (ANA) that tripled in the low Vitamin D RPL group
  • higher prevalence of anti-ssDNA that was 3.5 times higher in the low Vitamin D RPL group
  • higher prevalence of thyroperoxidase antibody (TPO) antibodies was 2.7 times higher in the low vitamin D group
  • higher prevalence in NK cytotoxicity activity in the low vitamin D group

    In addition, in vitro experiment on NK cells showed that IFN-γ and TNF-α secretion from NK cells were significantly decreased (P < 0.01 each), and IL-10, IL-1β, vascular endothelial growth factor (VEGF) and granulocyte colony stimulating factor (GCSF) levels were significantly increased (P < 0.01 each) with vitamin D when compared with those of controls. These are all changes that promote tolerance of the maternal immune system to the foreign genetics on the embryo.

    These data clearly show the great benefits of Vitamin D that decreases inflammation leading to a more tolerogenic environment and inducing angiogenesis to support embryo implantation.

    b- Vitamin D deficiency is associated with endometriosis

    A study comparing n=1385 cases of ENDO proven by laparoscopy to over 69 000 disease-free women (The Nurse Health Study) showed that women in the highest quintile for vitamin D have 24% lower risk of endometriosis than those in the lower quintile (17). These results, without proving any causality between vitamin D levels and endometriosis, showed a strong association between low levels of Vitamin D and the occurrence of endometriosis.

    To learn more about Vitamin D impact on endometriosis and how Vitamin D can help reduce endometriotic lesions, read our blog on the topic.

    4. Vitamin D deficiency and obstetrical complications

    Adequate intake of vitamin D during pregnancy is very important for both maternal and infant’s health.

    Maternal vitamin D is the only source of vitamin D to support the growing fetus during pregnancy. A recent study published in the journal JAMA Pediatrics, showed Vitamin D benefits on pregnancy and neonates’ health., which is a meta-analysis including 24 clinical trials for a total of N=5405 pregnant women, results showed that women supplemented with Vitamin D during pregnancy as compared to controls have:

  • Higher vitamin D concentrations
  • Had more neonates achieving vitamin D levels of 20 ng/mL
  • The neonates have higher birth weight and height and the difference is seen up to 12 months post-natal
  • The neonates were at reduced risk of being small for gestational age (SGA) with no risk for neonatal mortality or congenital abnormality

    5. How Vitamin D can help restore optimal environment suitable for a healthy pregnancy

    a- Vitamin D has a direct effect on immune regulation and oxidative stress:

    Vitamin D plays an important role in the modulation of the immune function (18) and oxidative stress (19) with dramatic impact on fertility ranging from poor oocyte quality, miscarriage to pregnancy complication including pre-eclampsia, preterm labor and stillbirth (16,18, 20).

    The activation of the vitamin D pathway has multiple beneficial effects on the immune function leading to less inflammation:

  • Inhibition of Th1 cells development (21)
  • Inhibition of Th-1 like cytokine secretion (22)
  • Dendritic cells and monocyte-macrophages become tolerogenic (differentiation of myeloid precursor to macrophages and inhibition of IFN-γ stimulated macrophages (23)
  • Inhibition of a master regulator of gene expression (NFB) which leads to the suppression of chemokine production by cells in the organ targeted for inflammation (24).

    A study led in pregnant women supplemented with vitamin D for 9 weeks (25) showed a positive impact on their metabolic status as seen by:

  • Decrease in serum CRP levels (marker of inflammation)
  • Decrease in plasma total antioxidant capacity and total glutathione concentrations (reflecting lower oxidative stress levels)

    Altogether, vitamin D may minimize the risk for obstetrical complications such as pre-eclampsia as recently suggested (26-27)

    b- Vitamin D significantly improve metabolic dysfunction in gestational diabetes (GDM)

    Early pregnancy vitamin D status is inversely associated with GDM risk (28) and benefit of its use have been shown in pregnant women with GDM (29-30). Vitamin D supplementation in pregnant women with diabetes had beneficial effects on glycemia and total and LDL-cholesterol concentrations with:

  • a significant decrease in concentrations of fasting plasma glucose 
  • a significant decrease in serum insulin
  • a significant decrease in cholesterol level
  • a significant decrease in total lipoprotein and low-density lipoprotein

    At Braverman Reproductive Immunology, we are constantly studying the latest discoveries in the field of reproductive immunology and promoting their use to offer you better diagnostic, monitoring and treatments. There is a high prevalence of vitamin D deficiency in our patient population suffering from reccurent pregnancy loss and this has to be corrected prior to conception. We are systematically determining your Vitamin D levels and if appropriate, we recommend supplementation to replenish your vitamin D reserve and optimize your chances of having a healthy pregnancy.


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