Study: Vitamin D in miscarriage prevention

reference

Samimi M, Foroozanfard F, Amini F, et al. Effect of vitamin D supplementation on unexplained recurrent spontaneous abortion: a double-blind, randomized control trial.Glob J Health Sci. 2017;9(3):95-102.

Study objective

Investigating the Effects of Vitamin D Supplementation on Unexplained Recurrent Spontaneous Abortion (URSA)

design

Double-blind, randomized control trial

Participant

Investigators recruited 80 women aged 18 to 35 years who were referred for prenatal care at an obstetrics and gynecology clinic in Iran. All participants had experienced at least 2 consecutive or 3 nonconsecutive spontaneous miscarriages of unknown cause and pregnancy by the same partner in all past and present pregnancies. Participants had no other contributing factors, including uterine abnormalities, thrombophilia, genetic diseases, endocrine disorders, workplace chemical exposures, or sensitivity/allergy to progesterone or vitamin D3.

Study parameters assessed

Patients had serum vitamin D and interleukin (IL)-23 levels measured at baseline and again at study completion. Pregnancy loss was considered spontaneous abortion at any time point from the start of the study to 20 weeks of gestation.

Primary outcome measures

The incidence of spontaneous miscarriage at any time between the start of the study and 20 weeks of gestation was examined, as were serum levels of IL-23 at the start of pregnancy and again at the time of spontaneous miscarriage or 20 weeks of gestation.

intervention

The intervention group (n=40) received 400 IU of vitamin D3 in tablet form daily. The control group (n=40) received an identical placebo without D3. Both groups received 400 mg of vaginal progesterone per day. Patients also received folic acid and iron supplements at least 1 month before pregnancy.

Key insights

Before the start of the study, serum vitamin D levels were 11.65 ± 3.76 ng/ml in the intervention group and 11.53 ± 2.39 ng/ml in the control group (P=0.86). At the end of the study, the values ​​had changed to 13.21 ± 3.47 ng/ml and 11.08 ± 2.76 ng/ml, respectively (P=0.004). Before the start of the study, IL-23 levels were 20.69 ± 3.01 pg/ml in the intervention group and 21.52 ± 4.37 pg/ml in the control group (P=0.33) and at the end of the study they were 18.4±3.78 pg/ml and 23.16±4.74 pg/ml (P<0.001). There was an inverse relationship between vitamin D and IL-23 levels (P=0.004). The number of spontaneous abortions during the study period was 5 (12.8%) and 13 (34.2%) in the intervention and control groups, respectively (OR: 3.53; 95% confidence interval [CI]: 1.12-11.2;P=0.03).

Taking into account confounding factors such as age, pregnancy, number of abortions and IL-23 levels, vitamin D3 levels were not statistically significant (OR: 3.53; 95% CI: 1.12–11.2;P=0.03). However, serum IL-23 levels and the incidence of abortion were statistically significant (odds ratio [OR]: 1.63; 95% CI: 1.26–2.11;P<0.001). Based on their analysis, the researchers concluded that vitamin D3 reduces the frequency of abortions through the causal pathway with IL-23. They also point out that other biological confounders should be taken into account.

Practice implications

This study adds to the growing body of research supporting the role of vitamin D3 in infertility and recurrent miscarriage. This study specifically examined the relationship between serum vitamin D3 levels and IL-23 levels and the rate of unexplained recurrent spontaneous abortion (URSA).

URSA is a complex disease affecting 2% to 4% of women worldwide and is defined by the American Society of Reproductive Medicine as 2 or more consecutive spontaneous miscarriages before 20 weeks of gestation.¹Modifiable risk factors contributing to miscarriage have been identified as advanced maternal age, abnormally low or high body mass index (BMI), alcohol consumption, heavy lifting, and night shift work.²In the case of URSA, several contributing factors have been recognized, including uterine abnormalities, endocrine disorders, genetic disorders, coagulation disorders, and environmental factors, although the cause of most cases of URSA remains unknown.¹

According to the American Pregnancy Association, 40% to 60% of North Americans, including pregnant women, are vitamin D deficient.

Vitamin D levels have previously been shown to reduce the incidence of first trimester miscarriage; However, no association has been found between low vitamin D and second trimester miscarriage.³Women with URSA and low vitamin D levels are more likely to have antiphospholipid antibodies, antinuclear antibodies, thyroperoxidase antibodies, and elevated natural killer (NK) cells than women with normal vitamin D status.⁴suggesting an immunomodulatory role at the fetomaternal interface. The presence of vitamin D receptors and enzymes responsible for vitamin D hydroxylation and the identification of localized vitamin D3 synthesis in human placenta and decidua⁵further highlight the potential mechanism between vitamin D status and ongoing pregnancy.

Until recently, research on recurrent miscarriage focused on the T helper type 1 (Th1)/Th2 paradigm. In this paradigm, maternal tolerance to fetal alloantigens is explained by the predominant Th2 immunity during pregnancy, which overrides Th1 immunity and thereby protects the fetus from Th1 cell attack.⁶However, recent findings point to the paradigm of Th1/Th2/Th17 and regulatory T cells (Tregs).⁶There are now several studies indicating an increased Th17/Treg ratio in URSA, creating an inhospitable environment for fetal survival.⁷A study by Wang et al. revealed that both Th17 and IL-23 were higher in the serum and placenta of women with URSA compared to normal women in early pregnancy.⁸

Vitamin D3 has been extensively studied for its immunomodulatory effects, including its ability to suppress cytokine production by Th17. The presence of IL-23 secreted by activated type 1 macrophages and dendritic cells promotes the development of Th17 and resulting cytokines, including IL-17. Vitamin D reduces the differentiation of Th17/Treg intermediate cells into Th17 cells, possibly via their high concentration of vitamin D receptors.⁹This shift alters the expression of many genes, including the gene for IL-17, potentially reducing the Th17-induced inflammatory pathway associated with URSA.

Several studies focus on serum vitamin D3 levels at the time of miscarriage, but none to date have shown the effects of vitamin D supplementation on pregnancy outcome in URSA. The dosage used in the current study was 400 IU, which is below the therapeutic range in almost all regions of the world, with recommendations from different organizations varying widely from 600 IU to 4,000 IU for pregnant women.¹⁰Of note, serum vitamin D levels in both the intervention and control groups were still well below the minimum recommended level of 20 ng/ml at the end of the study, although there was a statistical decrease in IL-23 levels, which the authors attribute to vitamin D supplementation. The authors do not address the persistent vitamin D deficiency in the intervention group or indicate whether they would expect improved results if serum levels were increased to the normal range. Given the positive result of the study using a lower than therapeutic dosage of vitamin D3 coupled with the pre-existing vitamin D deficiency status of the test subjects, one could speculate that the use of therapeutic levels of vitamin D3 could result in serum levels being brought back into a sufficient range, providing an even further benefit to the incidence of URSA.

In a recent study, 300,000 IU of vitamin D3 was administered by injection in a single bolus dose following lymphocyte immunotherapy (LIT), a controversial treatment for URSA. The researchers demonstrated a reduction in the Th17/Treg ratio after vitamin D3 supplementation and demonstrated a promising trend toward better pregnancy outcome in the treatment group. The study was published before all women who achieved pregnancy had given birth, so data on miscarriage rates were not available.¹¹We can hope to see more studies in this area with therapeutic doses in the near future.

According to the American Pregnancy Association, 40% to 60% of North Americans, including pregnant women, are vitamin D deficient.¹²Considering that vitamin D3 is an inexpensive and easily accessible vitamin with a variety of health benefits, including overall health, fertility, and pregnancy outcome, it makes great sense to ensure patients' vitamin D status prior to conception to prevent not only miscarriage, but a wide range of preventable diseases and conditions.