Immune Mediators and Vitamin D Status in the Development of Comorbidities of Pregnancy

Immune Mediators and Vitamin D Status in the Development of Comorbidities of Pregnancy - Description

Rebecca . Moore, . MD. Funded by:. W.K. Kellogg Foundation. NIH Grant UL1TR0000062. Jennifer Mulligan, PhD. : . Dept. of Otolaryngology . Howell Harmon. : . Dept. of Otolaryngology . Judith . Shary. ID: 652271 Download Presentation

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Immune Mediators and Vitamin D Status in the Development of Comorbidities of Pregnancy

Rebecca . Moore, . MD. Funded by:. W.K. Kellogg Foundation. NIH Grant UL1TR0000062. Jennifer Mulligan, PhD. : . Dept. of Otolaryngology . Howell Harmon. : . Dept. of Otolaryngology . Judith . Shary.

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Immune Mediators and Vitamin D Status in the Development of Comorbidities of Pregnancy




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Slide1

Immune Mediators and Vitamin D Status in the Development of Comorbidities of PregnancyRebecca Moore, MD

Funded by:W.K. Kellogg FoundationNIH Grant UL1TR0000062

Jennifer Mulligan, PhD

:

Dept

of Otolaryngology

Howell Harmon

:

Dept

of Otolaryngology

Judith

Shary

:

Dept

of Pediatrics

Myla

Ebeling

:

Dept

of Pediatrics

Carol Wagner, MD

:

Dept

of Pediatrics, Division of Neonatology

Slide2

Disclosure Statement Rebecca Moore, MD Has no financial relationships to disclose or conflicts of interest to resolve.

Slide3

Pregnancy and Maternal Immunity

During pregnancy, the maternal immune system undergoes remarkable changes:

Transitions from pro-inflammatory to anti-inflammatory pathways

1

Continues to protect the fetus from immune destruction

Guards the mother and child from infectious pathogens

2

1

Chaouat

G, et al.

Am J Reprod Immunol 1996. 2Somerset DA, et al. Immunology. 2004.

Slide4

Importance of Maternal ImmunityDisruption of this delicate balance:Places mother and child at greater risk for infection, including chorioamnionitisIncreases likelihood of pregnancy complications, such as pregnancy loss, preeclampsia, gestational diabetes and preterm labor & birth

Somerset DA, et al. Immunology. 2004.

Slide5

2016 Premature Birth Report Card

www.marchofdimes.org

Slide6

Role of Vitamin D in Immune Function1Liu PT, et al. Science 2006. 2Chun RF, et al. Expert Rev Clin Pharmacol. 2011.

Vitamin D is a known immune modulator of both the innate and adaptive immune

systems:

Induces antibacterial responses via toll-like

receptors

1

Expression

of the vitamin D receptor is associated with activated human T and B

lymphocytes 2

Slide7

1Chambers ES, et al. Curr Allergy Asthma Rep. 2011. 2Cantorna MT, et al. Mol Aspects Med. 2008.

Vitamin D

has the ability to control T-cell phenotypes:

Regulatory T cells

1

T-helper 1 vs T-helper 2 cells

2

Vitamin D actions

Role of Vitamin D in Immune Function

Slide8

Vitamin D in Pregnancy1Roberts JM, et al. J Nutrition. 2007. 2Wagner C, et al. Am J Obstet Gynecol. 2013.

Increased risk of vitamin D insufficiency (serum 25(OH)D levels <32ng/mL)

at delivery:

1

83%

African American

47%

Caucasian

Total circulating vitamin D level (25(OH)D) definitions:

2

Deficiency: <50 nmol/L (20 ng/mL) Insufficiency: 50 nmol/L to 79 nmol/L (≥ 20 to <32 ng/mL)

Sufficiency

: 80

nmol

/L or greater (≥32 ng/mL)

Optimized sufficiency

: 100

nmol

/L or greater (

40 ng/mL)

Slide9

Risk of Insufficiency Associations between low maternal 25(OH)D levels and pregnancy complications have been established.1Our previous NICHD trial yielded evidence to support a dose-dependent trend toward reduced premature labor & birth, as well as infection.2,3

Interim analysis showed an inverse association of serum circulating 25(OH)D and comorbidities of pregnancy.

1Robinson, et al. Am J Perinatol. 2013.

2

Hollis

BW, Wagner CL.

Calcified tissue international

. 2012.

3Wagner CL, et al. Am J Obstet Gynecol. 2013.

Slide10

Specific AimTo further investigate maternal vitamin D levels in relation to immune mediator changes during pregnancy and the development of comorbidities of pregnancy (COP): Preterm labor & birth Preeclampsia Chorioamnionitis

Slide11

Hypothesis

Higher levels of maternal vitamin D during pregnancy are associated with decreased COP

Increased TGF-β and IL-10

Decreased L-2, IL-6 and TNF-α

Slide12

Study Design Using the existing cohort of now 270 mothers: Case-control study Hematologic samples from current RCT25(OH)D & immune mediator concentrations Comorbidities of PregnancyPreterm labor & birth, Preeclampsia, Chorioamnionitis

Kellogg Foundation Vitamin D in Pregnancy Project RCT enrolled subjects: 18-45 years of age 8-14 weeks gestation Singleton pregnancy Subjects were randomized into one of two

treatment regimens: Control group: 400 IU/day vitamin D

3

Study

group: 4,400 IU/day vitamin D

3

Slide13

Study DesignHematologic samples from pregnant women enrolled in an existing RCT were analyzed from each trimester, correlating with study visit 1, visit 4 and visit 7.

1

st

Trimester

2

nd

Trimester

3

rd Trimester1st study visit (10-14 weeks gestation)4th study visit(24 weeks gestation)7th

study visit(36 weeks gestation)

Slide14

MethodsMaternal 25(OH)D concentrations assayed using RIA. TGF-β, TNF-α, IL-2, IL-6 and IL-10 concentrations measured by ELISA.Comorbidities of Pregnancy (COP):Preterm labor & birth <37 weeks gestationPreeclampsia Chorioamnionitis

Associations between maternal 25(OH)D and COP, and between immune mediator concentrations and COP, were analyzed using Wilcoxon rank-sum tests. Associations between maternal immune mediator concentrations and 25(OH)D levels were examined using a Spearman correlation analysis.

Slide15

Results: Maternal DemographicsCOP = Comorbidities of pregnancy

Preterm labor& birth (n=21) Preeclampsia (n=10)

Chorioamnionitis

(n=3

)

*6 subjects with preeclampsia & preterm labor & birth

No statistically significant

differences between groups.

Slide16

1

st

Trimester

:

3

rd

Trimester

:

COP = Comorbidities of pregnancy Preterm labor& birth (n=21) Preeclampsia (n=10)Chorioamnionitis (n=3

)

*6 subjects with preeclampsia & preterm labor & birth No statistically significant differences between groups.

Demographics and 25(OH)D levels

Slide17

No statistically significant differences between groups. (n=267)

(n=3)

25(OH)D levels and Chorioamnionitis

Slide18

25(OH)D levels and Preeclampsia

(n=10)(n=260)

No statistically significant differences between groups.

Slide19

25(OH)D levels and Preterm Labor & Birth

(n=21)(n=249)

No statistically significant differences between groups.

Slide20

25(OH)D levels and all COP

(n=28)

(n=242)

COP = Comorbidities of pregnancy

Preterm labor& birth (n=21)

Preeclampsia (n=10)

Chorioamnionitis (

n=3

)*6 subjects with preeclampsia & preterm labor & birth No statistically significant differences between groups.

Slide21

ResultsNo significant correlations between maternal immune mediator concentrations and 25(OH)D levels were found using a Spearman correlation analysis. No differences when comparing groups of 25(OH)D sufficient (≥32 ng/mL) vs insufficient and the development of preterm labor & birth, preeclampsia or chorioamnionitis.

Slide22

ResultsImmune Mediators and Comorbidities Of Pregnancy: No significant relationships were found in the preeclampsia (n=10) or chorioamnionitis (n=3) groups when compared to controlsSignificant alterations were found in preterm labor & birth group (n=21), compared to controls

Slide23

1st Trimester2

nd Trimesterp=0.017

p<0.0001

*

*

Decreased TGF-β in Preterm Labor & Birth

Slide24

p=0.005p=0.019

2nd Trimester

3

rd

Trimester

*

*

Increased TNF-α in Preterm Labor & Birth

Slide25

p=0.001p=0.016

2nd Trimester

3

rd

Trimester

*

*

Decreased IL-6 in Preterm Labor & Birth

Slide26

SummaryMothers in this study who developed preterm labor & birth were found to have decreased TGF-β and IL-6, in addition to increased TNF-α. No significant correlations between maternal immune mediator concentrations and 25(OH)D levels were found in this cohort.

Slide27

DiscussionLower than expected prevalence of chorioamnionitis, preeclampsia and preterm labor & birth lead to inadequate power to detect a relationship between 25(OH)D levels and the selected COP. Further analyses are underway to more accurately delineate the relationship between maternal immune mediator concentrations and preterm labor & birth.

Slide28

Questions?

Slide29

Slide30

Study DesignHematologic samples from pregnant women enrolled in an existing RCT were analyzed from each trimester, correlating with visit 1, visit 4 and visit 7.

1

st

Trimester

2

nd

Trimester

3

rd Trimester1st visit

(10-14 weeks gestation)

4th visit(24 weeks gestation)7

th

visit

(36 weeks gestation)

6

th

visit

Slide31

Future DirectionsMaternal hematologic samples collected nearer preterm birth/delivery will be analyzed and compared to age and race matched controls of the same gestation. This data will hopefully incite further investigation into maternal immune mediator concentration changes as a possible predictor of preterm labor/birth.

1

st

Trimester

2

nd

Trimester

3

rd Trimester1

st visit

(10-14 weeks gestation)4th visit(24 weeks gestation)

7

th

visit

(36 weeks gestation)

6

th

visit

Slide32

Future Directions Further analysis of maternal serum obtained at visit 6, which was just prior delivery for most women who developed COP, is underway. This forthcoming data will allow us to more accurately determine the immune mediator concentrations and 25(OH)D levels of women who delivered prior to visit 7. Placental samples from each group will be analyzed to determine the immunological landscape of women with COP vs those without, in relation to maternal 25(OH)D levels.

Slide33

Maternal Serum 25(OH)D and COPNo statistically significant differences between groups.

Slide34

1Chambers ES, Hawrylowicz CM. Curr Allergy Asthma Rep. 2011. 2Cantorna MT, Yu S, Bruce D. Mol Aspects Med. 2008.

Slide35

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