Examining the relationship between bioavailable vitamin D and IVF outcomes

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Content 1

Title:
Examining the Relationship between Bioavailable Vitamin D and IVF Outcomes

Author:
Semara Thomas

Conferring Major/Program:
Department of Preventative Medicine, Keck School of Medicine

Degree:
MS in Clinical, Biomedical, and Translational Investigations
Track: Epidemiology and Disease Etiology
School: University of Southern California
Degree Date: May 2019

2

Table of Contents

Abstract _______________________________________________ 3-4

Introduction _______________________________________________ 5-6

Methods _______________________________________________ 6-8

Results _______________________________________________ 8-11

Discussion/Conclusion _______________________________________________ 11-13

References _______________________________________________ 14-16

3

Abstract

Purpose:
Total 25-hydroxyvitamin D [(25 (OH)D] is currently the most common measure of vitamin D
status. However, both bioavailable and free vitamin D have been proposed as more accurate
measurements. The influence of bioavailable vitamin D (BAVD), calculated from polyclonal
assays, on pregnancy outcomes has not been studied. This study aimed to assess whether low
levels of BAVD are associated with poor pregnancy outcomes in IVF among Asian and white
women.
Methods:
This is a retrospective cohort study of 242 patients (88 Asian, 154 non-Hispanic white) who
underwent IVF between January of 2008 and December of 2011 at an academic medical center
in southern California. Stored serum samples were used to assay total 25(OH)D, albumin and
vitamin D binding protein (VDBP). VDBP was assayed using a polyclonal antibody (ALPCO),
and BAVD was calculated using race-specific affinity coefficients. BAVD was categorized into
three groups (<-1 SD, -1 SD to +1 SD, >1 SD). Mean serum levels were compared using
Student’s t test. Clinical pregnancy rates were compared by logistic regression models.
Statistical analyses were performed using Stata 14.2 (StataCorp, College Station TX).
Results:
Non-Hispanic whites had higher mean levels of total 25(OH)D than Asians (34 ± 12.0 vs 30.4 ±
11.1 ng/mL, P = 0.02). Calculated BAVD was higher, on average, in non-Hispanic whites than
in Asians (1.90 ± 0.93 vs 1.77 ± 0.91 ng/mL, P = 0.002). Among Asian women, increasing levels
4

of BAVD were associated with decreasing odds of clinical pregnancy (p for trend = .03). An
opposite (positive) association between BAVD levels and clinical pregnancy rate was seen
among non-Hispanic white women, but the trend was not statistically significant (p for trend =
0.22), Table 1. The trends differed significantly by race (p for interaction = 0.01).
Conclusions:
This study reveals that the relationship between BAVD levels and IVF outcomes differs by race.
Increasing BAVD levels predict poorer IVF outcomes in Asian women but not in White women.

5

Introduction:
Vitamin D has been shown to be a critical factor in regulating cellular growth, and the
immune system
1-3
. Many studies have demonstrated that vitamin D plays an important role in the
reproductive system. Vitamin D receptors have been identified in various female reproductive
tissue including the ovaries, endometrium, fallopian tubes and placenta
4-5
. It has been shown to
be a modulator in embryo implantation and placentation
6-8
. Furthermore, poor obstetric and
reproductive outcomes have been linked to those that are vitamin D deficient
9-11
. A recent meta-
analysis examining the role of vitamin D and ART (assisted reproductive technology) concluded
that successful ART outcomes such as clinical pregnancy rate are associated with a vitamin D
replete status
12
.
Given its suspected role in poor reproductive outcomes, many healthcare providers
recommend vitamin D supplementation for those that are deficient. It has been estimated that
approximately 36% of reproductive-aged adults are vitamin D deficient
13
. Currently, the standard
for diagnosing vitamin D deficiency is through the measurement of the total concentration of
serum 25(OH) vitamin D (25(OH)D). The Endocrine Society Clinical Practice Guideline, defines
vitamin D “deficiency” as a 25(OH)D measurement below 20 ng/ml, and “insufficiency” as a
25(OH)D measurement of 21–29 ng/ml
14
. However, vitamin D bioavailability and function in
cells may be better characterized by the portion of 25(OH)D that is not bound to serum proteins,
known as bioavailable and/or free vitamin D
15-16
. Bioavailable vitamin D (BAVD), is either free
or bound to albumin, whilst free vitamin D, is completely unassociated with any carrier
proteins
17
. BAVD and free vitamin D can be calculated from serum measurements of total
25(OH)D, albumin, and VDBP (the predominant transporter of vitamin D in the serum)
18-21
.

BAVD and free vitamin D are similar measurements of what is thought to be the more
6

“biologically active” form of vitamin D in the body, thus representing an alternative manner to
determine vitamin D status than traditional total 25 (OH)D.
Using both 25 (OH)D and bioavailable/free vitamin D, studies have shown that ethnic
minorities have higher rates of vitamin D deficiency than their white counterparts
22
.
Additionally, ethnic minorities are more likely to have lower clinical pregnancy and live birth
rates after IVF (in-vitro fertilization), compared to white women
23
. Given the association
between vitamin D status, and reproductive/obstetric outcomes, it is possible that vitamin
deficiency may explain differences in ART success between ethnic groups. The influence of
bioavailable vitamin D (BAVD) on ethnic differences in pregnancy outcomes after IVF has not
been studied. This study aimed to assess whether low levels of BAVD are associated with poor
pregnancy outcomes in IVF among Asian and white women.
Methods:
Participants
This was a retrospective cohort study, approved by the Institutional Review Board at the
University of Southern California. Subjects who identified as either non-Hispanic White or
Asian, who underwent their first cycle of IVF at USC Fertility between January of 2008 and
December of 2011 were eligible for inclusion in the study. Participants were excluded if they had
undergone previous IVF cycles at USC Fertility or were undergoing oocyte donation.
Participants were also excluded if their ethnicity was unknown or categorized as any race other
than Asian or non-Hispanic White. Ethnicity was categorized according to self-identified
ethnicity on their intake patient questionnaire. Asian race included patients whose origins were
from Southeast Asia as well as the Indian subcontinent. All patients underwent ovarian
7

stimulation using standardized regimens for controlled ovarian stimulation and pituitary down-
regulation. The specific protocol was selected based upon their prognosis determined by
diagnosis, predicted ovarian reserve, and age.
Study procedures
Serum samples were collected at the time of down-regulation just prior to ovarian
stimulation and were stored at -20°C until assayed. Circulating levels of total 25(OH)D were
measured in frozen, never previously thawed serum samples using radioimmunoassay (RIA;
DiaSorin, Stillwater, MN, USA). Serum 25(OH)D was categorized according to clinically
accepted ranges with deficiency at (<20 ng/mL), insufficiency (20-30 ng/mL), and replete (>30
ng/mL) (Holick, 2007). VDBP and albumin (normal range 3.5 – 5.3 g/dL) were measured on the
identical samples. VDBP was measured with polyclonal immunoassay (ELISA; ALPCO, USA).
Albumin was measured using a calorimetric method. Once measurements were completed then
using the affinity constants of 25(OH)D for VDBP (Ka = 7 x 108 M
-1
) and albumin (Ka = 6 x
105 M
-1
), free 25(OH)D and BAVD were able to be calculated. BAVD is equal to the
combination of albumin bound 25(OH)D and free 25(OH)D. Clinical pregnancy was defined as
an intra-uterine pregnancy seen on transvaginal ultrasound with evidence of a gestational sac,
yolk sac and fetal cardiac motion.
Data Analysis
Continuous data was summarized with means ± SD. If data was highly skewed, then
median with 25
th
and 75
th
quartiles was used. All categorical data was summarized as
percentages (%). Analysis was then performed with student’s t-test for continuous outcomes and
chi-square or Fisher’s exact test for categorical outcomes. BAVD was categorized into three
groups (<-1 SD, -1 SD to +1 SD, >1 SD). For 80% power and alpha of 0.05, we required 154
8

non-Hispanic White and 55 Asian patients. All P values are two sided and statistical
significance was established as P < 0.05. All analyses were conducted using Stata 11.0 (Stata
Corp 2014, College Station TX).

Results:
Demographics
A total of 249 eligible patients with serum available for testing were identified for the
study. Of the 249 patients, 161 identified as non-Hispanic White and 88 identified as Asian.
Participant characteristics by ethnicity are described in Table 1. No significant differences
between Asians and non-Hispanic Whites were noted in BMI, age, or infertility diagnosis.
Table 1. Participant Characteristics

Age & BMI: mean (SD), p value from t test; Others: N (%), p value from Fisher’s Exact test (RPL) or
Chi-Square test (all others)
DOR: Diminished ovarian reserve. RPL: Recurrent pregnancy loss. BMI: Body mass index
(kg/meter squared).
9

Vitamin D and Vitamin D Binding Protein Levels
The Asian participants had lower mean levels of total 25(OH)D than non-Hispanic
Whites (30.4 ± 11.1 vs 34 ± 12.0 ng/mL, P = 0.02). Similarly, bioavailable vitamin D levels,
were, on average, lower in Asians than non-Hispanic whites (1.52 ± 0.09 vs 1.90 ± 0.07 ng/mL,
p = 0.002), Figure 1. A similar pattern was seen for calculated free vitamin D. Free vitamin D
was highly correlated with bioavailable vitamin D (R=0.97). Total 25(OH) vitamin D was only
modestly correlated with bioavailable vitamin D and free vitamin D (R=0.59 and R=0.62,
respectively) Figure 2. VDBP levels were similar in Asian and non-Hispanic White participants
(634 ± 252 vs 643 ± 250, p = 0.80).

Figure 1. Mean Total, Bioavailable and Free Vitamin D. Calculated from polyclonal VDBP
and race-specific affinity constants.

10

Figure 2. Pearson Correlation of Vitamin D Tests. Calculated from polyclonal VDBP and
race-specific affinity constants.

Pregnancy Outcomes
Among Asian women, increasing levels of BAVD were associated with decreasing odds
of clinical pregnancy (p for trend = .03). An opposite (positive) association between BAVD
levels and clinical pregnancy rate was seen among non-Hispanic white women, but the trend was
not statistically significant (p for trend = 0.22), Table 2. The trends differed significantly by race
(p for interaction = 0.01 An inverse relationship in Asian participants was seen with analysis
according to free vitamin D levels as well (data not shown).

11

Table 2. Clinical Pregnancy Rates and BAVD levels

Discussion:
In this study, we found that Asian women, in comparison to non-Hispanic White women,
had significantly lower vitamin D levels, and were more likely to be vitamin D deficient, as
measured by total 25(OH)D and by BAVD. Although the prevalence of vitamin D deficiency in
ethnic minorities is well known, debate exists as to the relationship between vitamin D
deficiency and reproductive outcomes
9-10, 24-27
. Furthermore, there is limited data on ethnic
differences in vitamin D status and the association with ART outcomes. In our study, we
examined this relationship and how it relates to ART outcomes in the Asian ethnic population.
We found that as Asian women exceeded the normal range of serum vitamin D (as measured by
BAVD), pregnancy rates were reduced. Similar to prior studies, overall clinical pregnancy and
Standardized Bioavailable Vitamin D (ng/ml) P for
trend

< 0.70 0.70- 2.51 > 2.51

Asian (N=85)

Unadjusted CPR (%) 70% (7/10) 31% (20/64) 27% (3/11) 0.05
Adjusted* (95% CI) 0.78 (0.54,
1.00)
0.32 (0.2,
0.43)
0.28 (0.02,
0.55)
0.03
Non-Hispanic White
(N=157)

Unadjusted CPR (%) 43% (3/7) 48% (57/118) 56% (18/32) 0.68
Adjusted* (95% CI) .041 (0.06,
0.76)
0.48 (0.4,
0.57)
0.60 (0.43,
0.77)
0.22
* Adjusted for number of embryos transferred, embryo quality, previous failed cycle and
obesity.
12

live births rates were significantly lower in Asian women, when compared to white women
24
.
Interestingly, white race and elevated vitamin D levels were not associated with decreased odds
of pregnancy.
Consistent with our observations, previous studies have demonstrated that BAVD, when
measured using the polyclonal assay, accurately reflects vitamin D status
28
. BAVD and free
vitamin D were strongly correlated with each other (R=0.99, monoclonal; R=0.97, polyclonal),
confirming that these are similar measures of the unbound “biologically active” form of vitamin
D in circulation. The use of a polyclonal VDBP assay to measure BAVD is a critical part of our
study design because it correctly detects the VDBP genotypes that are more common in non-
white populations, as opposed to the monoclonal assay
29-30.
Few studies have utilized BAVD as a
measure of vitamin D status when examining ART outcomes. Fabris et al., showed that clinical
pregnancy was not impacted by circulating levels of total 25 (OH)D or bioavailable vitamin D
27
.
However, this study was limited to recipients of donated oocytes and to women of a southern
European descent. In our study, all patients who identified as either white or Asian, and
underwent their first cycle of IVF were included. Although both white and Asian subjects did not
have worse reproductive outcomes at the lowest levels of vitamin D, Asian women paradoxically
had poorer pregnancy rates as the vitamin D repletion exceeded the normal range.
This inverse relationship of vitamin D and pregnancy rates in Asian women, but not
white women, was demonstrated previously by Rudick et al
9
. There is evidence to suggest a
biological mechanism for the poor reproductive outcomes associated with elevated levels of
vitamin D. Elevated levels of vitamin D can have an antagonistic effect on sex steroid hormone
receptors in the endometrium
31-33
. It is unclear why this adverse effect is demonstrated in only
one ethnic group. The white women in our study had increasing odds of clinical pregnancy as
13

vitamin D levels increased beyond repletion, although this did not reach statistical significance.
More studies are needed to further evaluate the effect of excess circulating vitamin D on
reproductive outcomes.
Limitations of this study include biases inherent to the retrospective study design.
Additionally, this cohort was limited to patients undergoing their first cycle of IVF and the
results of our study may not be applicable to all IVF patients. Although this cohort contained a
mixture of vitamin D supplemented and non-supplemented patients, there is no evidence to
suggest that vitamin D supplementation impacts the accuracy of the assay. Lastly, the
bioavailable and free vitamin D levels were not measured directly, but rather calculated from
VDBP levels, thus introducing error into the results. It is possible to measure unbound vitamin D
directly, but it is expensive and can be cost prohibitive. There is limited information on the
accepted ranges for bioavailable vitamin D and free vitamin D as they relate to a person’s
vitamin D status. Thus, we cannot conclude that the BAVD and free levels calculated truly
represent as “deficient” values in the cohort.
The significance of our study’s results is that it underlies the importance of accurate
measurements and comparisons of vitamin D levels in a multi-ethnic cohort of patients. Both
polyclonal VDBP assays to measure BAVD and total 25 (OH)D accurately reflect vitamin D
status in both patient groups. However, measuring the more “biologically active” form of
vitamin D levels revealed that excess levels are associated with worse reproductive outcomes in
Asian women. Physicians should use caution in aggressively treating vitamin D deficiency in
Asian women before pregnancy. Our study did not directly address the mechanism of how
vitamin D status, defined BAVD, led to poor reproductive outcomes in Asian women. It remains
an important clinical and research question that warrants further exploration.
14

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Asset Metadata

Creator Thomas, Semara Ari (author)

Core Title Examining the relationship between bioavailable vitamin D and IVF outcomes

Contributor Electronically uploaded by the author (provenance)

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Publication Date 04/24/2019

Defense Date 04/23/2019

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag IVF,OAI-PMH Harvest,Pregnancy,Race,vitamin D

Format application/pdf (imt)

Language English

Advisor Bendikson, Kristin (committee chair), McGinnis, Lynda (committee member), Paulson, Richard (committee member)

Creator Email semara.thomas@gmail.com,semarath@usc.edu

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Abstract (if available)

Abstract Purpose: Total 25-hydroxyvitamin D [(25 (OH)D] is currently the most common measure of vitamin D status. However, both bioavailable and free vitamin D have been proposed as more accurate measurements. The influence of bioavailable vitamin D (BAVD), calculated from polyclonal assays, on pregnancy outcomes has not been studied. This study aimed to assess whether low levels of BAVD are associated with poor pregnancy outcomes in IVF among Asian and white women. ❧ Methods: This is a retrospective cohort study of 242 patients (88 Asian, 154 non-Hispanic white) who underwent IVF between January of 2008 and December of 2011 at an academic medical center in southern California. Stored serum samples were used to assay total 25(OH)D, albumin and vitamin D binding protein (VDBP). VDBP was assayed using a polyclonal antibody (ALPCO), and BAVD was calculated using race-specific affinity coefficients. BAVD was categorized into three groups (<-1 SD, -1 SD to +1 SD, >1 SD). Mean serum levels were compared using Student’s t test. Clinical pregnancy rates were compared by logistic regression models. Statistical analyses were performed using Stata 14.2 (StataCorp, College Station TX). ❧ Results: Non-Hispanic whites had higher mean levels of total 25(OH)D than Asians (34 ± 12.0 vs 30.4 ± 11.1 ng/mL, P = 0.02). Calculated BAVD was higher, on average, in non-Hispanic whites than in Asians (1.90 ± 0.93 vs 1.77 ± 0.91 ng/mL, P = 0.002). Among Asian women, increasing levels of BAVD were associated with decreasing odds of clinical pregnancy (p for trend = .03). An opposite (positive) association between BAVD levels and clinical pregnancy rate was seen among non-Hispanic white women, but the trend was not statistically significant (p for trend = 0.22), Table 1. The trends differed significantly by race (p for interaction = 0.01). ❧ Conclusions: This study reveals that the relationship between BAVD levels and IVF outcomes differs by race. Increasing BAVD levels predict poorer IVF outcomes in Asian women but not in White women.