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Recurrent spontaneous abortions associated with low vitamin D levels – Nov 2013

Vitamin D deficiency may be a risk factor for recurrent pregnancy losses by increasing cellular immunity and autoimmunity

Medicine Human Reproduction Volume 29, Issue 2Pp. 208-219.
Kuniaki Ota 1,2, Svetlana Dambaeva 2, Ae-Ra Han 1, Kenneth Beaman 2, Alice Gilman-Sachs 2 and Joanne Kwak-Kim 1,2,*
1Reproductive Medicine, Department of Obstetrics and Gynecology, Chicago Medical School at Rosalind Franklin University of Medicine and Science, Vernon Hills, IL 60061, USA
2Department of Microbiology and Immunology, Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
↵*Correspondence address: Department of Obstetrics and Gynecology, Department of Microbiology and Immunology, Reproductive Medicine, Chicago Medical School at Rosalind Franklin University of Medicine and Science, 830 West End Court, Suite 400, Vernon Hills, IL 60061, USA. Tel: +1-847-247-6904; Fax: +1-847-247-6951; E-mail: joanne.kwakkim at rosalindfranklin.edu
Received July 21, 2013. Revision received September 30, 2013. Accepted October 29, 2013.

STUDY QUESTION Do women with recurrent pregnancy losses (RPL) and low vitamin D have increased prevalence of auto- and cellular immune abnormalities when compared with women with RPL who have normal vitamin D, and does vitamin D have any effect on cellular immunity in vitro?

SUMMARY ANSWER A high proportion of women with RPL have vitamin D deficiency and the risk of auto- and cellular immune abnormalities is increased in women with RPL and vitamin D deficiency.

WHAT IS KNOWN ALREADY Vitamin D deficiency in pregnant women is associated with increased risk of obstetrical complications such as pre-eclampsia, bacterial vaginosis associated preterm delivery, gestational diabetes mellitus and small-for-gestational age births.

STUDY DESIGN, SIZE, DURATION A retrospective cross-sectional study of 133 women with RPL who were enrolled in a 2-year period, together with laboratory experiments.

PARTICIPANTS/MATERIALS, SETTING, METHODS Women with three or more consecutive spontaneous abortions prior to 20 weeks of gestation who were enrolled at the University clinic. Serum vitamin D level, cellular activity and autoimmune parameters in vivo and in vitro were measured.

MAIN RESULTS AND THE ROLE OF CHANCE Sixty-three out of 133 women (47.4%) had low vitamin D (<30 ng/ml). The prevalence of antiphospholipid antibody (APA) was significantly higher in low vitamin D group (VDlow) (39.7%) than in the normal vitamin D group (VDnl) (22.9%) (P< 0.05) and the adjusted odds ratio (OR) for APA in VDlow was 2.22 with the 95% confidence interval (CI) of 1.0–4.7. The prevalence of antinuclear antigen antibody (VDlow versus VDnl; 23.8% versus 10.0%, OR 2.81, 95% CI 1.1–7.4), anti-ssDNA (19.0% versus 5.7%, OR 3.76, 95% CI 1.1–12.4) and thyroperoxidase antibody (33.3% versus 15.7%, OR 2.68, 95% CI 1.2–6.1) was significantly higher in VDlow than those of VDnl (P < 0.05 each). Peripheral blood CD19+ B and CD56+ NK cell levels and NK cytotoxicity at effector to target cell (E:T) ratio of 25:1 were significantly higher in VDlow when compared with those of VDnl (P < 0.05 each). Reduction (%) of NK cytotoxicity (at E:T ratio of 50:1 and 25:1) by IgG (12.5 mg/dl) was significantly lower in VDlow than those of VDnl (P < 0.05, P < 0.01, respectively). There were no differences in Th1/Th2 ratios between VDlow and VDnl. When vitamin D3 was added in NK cytotoxicity assay in vitro, NK cytotoxicity at E:T ratio of 50:1 was significantly suppressed with 10 nMol/L (nM) (11.9 ± 3.3%) and 100 nM (10.9 ± 3.7%) of vitamin D3 when compared with controls (15.3 ± 4.7%) (P < 0.01 each). TNF-α/IL-10 expressing CD3+/4+ cell ratios were significantly decreased with 100 nM of vitamin D3 (31.3 ± 9.4, P < 0.05) when compared with controls (40.4 ± 11.3) in vitro. Additionally, INF-γ/IL-10 expressing CD3+/4+ cell ratio was significantly decreased with 100 nM of vitamin D3 (12.1 ± 4.0, P < 0.05) when compared with controls (14.8 ± 4.6). 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 and granulocyte colony stimulating factor levels were significantly increased (P < 0.01 each) with vitamin D3 100 nM when compared with those of controls.

LIMITATIONS, REASONS FOR CAUTION The prevalence of vitamin D deficiency in women with RPL in this study is open to a possible type I error since women with vitamin D supplementation were excluded from this study.

WIDER IMPLICATIONS OF THE FINDINGS Assessment of vitamin D level is recommended in women with RPL. Vitamin D supplementation should be explored further as a possible therapeutic option for RPL.

STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the intramural funding from Department of Microbiology and Immunology, Chicago Medical School at Rosalind Franklin University of Medicine and Science. None of the authors has any conflict of interest to declare.


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IU Cumulative Benefit Blood level CofactorsCalcium $*/month
200 Better bones for mom
with 600 mg of Calcium
6 ng/ml increase Not needed No effect $0.10
400 Less Rickets (but not zero with 400 IU)
3X less adolescent Schizophrenia
Fewer child seizures
20-30 ng/ml Not needed No effect $0.20
2000 2X More likely to get pregnant naturally/IVF
2X Fewer dental problems with pregnancy
8X less diabetes
4X fewer C-sections (>37 ng)
4X less preeclampsia (40 ng vs 10 ng)
5X less child asthma
2X fewer language problems age 5
42 ng/ml Desirable < 750 mg $1
4000 2X fewer pregnancy complications
2X fewer pre-term births
49 ng/ml Should have
cofactors
< 750 mg $3
6000 Probable: larger benefits for above items
Just enough D for breastfed infant
More maternal and infant weight
Should have
cofactors
< 750 mg $4

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