Benefits of Vitamin D for Cancer and Pregnancy/Birth Outcomes. William B. Grant, PhD Sunlight, Nutrition and Health Research Center, San Francisco

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1 Benefits of Vitamin D for Cancer and Pregnancy/Birth Outcomes William B. Grant, PhD Sunlight, Nutrition and Health Research Center, San Francisco

2 Disclosure I receive funding from Bio Tech Pharmacal, Inc. (Fayetteville, AR) I serve on the board of directors of VitaminDCouncil.org (San Luis Obispo, CA) I am a scientific advisor to GrassrootsHealth.net (Encinitas, CA)

3 Outline Vitamin D pathways Cancer: UVB exposure and vitamin D Geographical ecological studies Observational studies Studies of mechanisms Clinical trials Pregnancy/birth outcomes and vitamin D Beneficial outcomes found Observational studies Clinical trial demonstrating beneficial effect

4 Vitamin D Pathways Hollis and Wagner, Bone Research, 2017

5 Colon Cancer Mortality Rates, White Males Garland et al., Am J Public Health The brothers Cedric and Frank Garland published their seminal paper in 1980

6 High doses in SW due to thinner stratospheric ozone layer and higher surface elevation. Data from the NASA Total Ozone Mapping Spectrometer (TOMS)

7 Higher mortality rates along coast due to fog and clouds

8 Breast Cancer Mortality Rates, White Females, Less pronounced geographical variation with respect to solar UVB doses due to less time in the sun, use of sunscreen, increased risk from other factors such as obesity, and improved survival rates.

9 All less Lung Cancer vs. UVB Index by Occupation in Nordic Countries 28% higher incidence rate for most indoor vs. most outdoor work. For men, the UVB index (lip cancer less lung cancer) was significantly inversely correlated with 14 types of internal cancer. Grant WB. Role of solar UV irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol. 2012;4(2):

10 16 UVB/Vitamin D Sensitive Cancers from Ecological Studies Vitamin D sensitive cancers with strong support from ecological studies in six mid latitude plus Nordic countries after accounting for other factors: Gastrointestinal: colon, esophageal, gallbladder, gastric, intestinal, rectal Urinary tract: bladder, kidney Female: breast, cervical, endometrial, ovarian, vulvar Blood: non Hodgkin s lymphoma Miscellaneous: laryngeal, lung

11 Graph of odds ratio for breast cancer incidence vs. 25(OH)D concentration from 11 case control studies. Grant WB, Boucher BJ (2017) PLOS ONE 12(5): e

12 All Cancer Mortality Rate vs. Serum 25(OH)D Concentration HR HR HR - low HR - high The cancer mortality rate for 8 ng/ml is 36% (95% CI, 6%, 74%) higher than for 50 ng/ml. Gaksch M, et al. Vitamin D and mortality: Individual participant data meta analysis of standardized 25 hydroxyvitamin D in individuals from a European consortium. PLoS One Feb 16;12(2):e (OH)D (ng/ml)

13 All cause and Cancer Survival vs. Baseline 25(OH)D Norway Results of a 9 yr study. Significantly reduced cancer specific mortality rate for 25OHD trend for breast and lung cancer, and lymphoma. Tretli S, et al. Cancer Causes Control. 2012;23(2):

14 Mechanisms Mechanisms whereby vitamin D reduces risk are based on genetic actions of 1,25(OH) 2 D and include: Cellular effects on differentiation, proliferation and apoptosis Reduced inflammation Reduced angiogenesis around tumors Reduced metastasis

15 Creighton University Clinical Trial Trial with 2303 postmenopausal women in Nebraska with mean BMI = 30 kg/m 2, baseline 25(OH)D of 33 ng/ml, given 2000 IU/d vitamin D 3 plus 1.5 g/d calcium or placebo, and followed for 4 yrs. By intention to treat, HR = 0.70 (95% CI, 0.47, 1.02, P = 0.06). (one extra case in treatment arm) Lappe et al., Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women: A Randomized Clinical Trial. JAMA 2017

16 Creighton University Trial: Observational Results Significantly reduced risk for 25(OH)D >50 ng/ml

17 All Cause Mortality Rate vs. 25(OH)D Meta analysis Results from 32 studies were included. All cause mortality rate rose nearly linearly below 38 ng/ml. Garland et al., Am J Pub Health, 2014

18 Pregnancy and Birth Outcomes Maternal vitamin D deficiency is linked to increased risk of gestational diabetes, preeclampsia, primary C section, preterm birth. For the offspring, increased risk of asthma, autism, other neurological disorders, rickets.

19 Skin Pigmentation Skin pigmentation has adapted to where people live for many generations. The driving factors are vitamin D production, protection against DNA damage and folate production. Jablonski NG. Human skin pigmentation as an example of adaptive evolution. Proc Am Philos Soc Mar;156(1): Grant WB. The UVB vitamin D3 skin pigmentation is alive and well. Am J Phys Anthro Dec; 61(4):

20 Human Skin Color Distribution (Chaplin and Jablonski)

21 Women have lighter skin pigmentation due to vitamin D requirements during pregnancy and lactation.

22 Primary Cesarean Section Delivery Merewood A, et al. Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab Mar;94(3):940 5.

23 Development of Asthma/Recurrent Wheeze vs. Vitamin D Treatment Kaplan Meier survival estimates for the effect of vitamin D treatment during pregnancy on the development of asthma/ recurrent wheeze by age 3 year analyzed in an intent to treat format. Hollis & Wagner, 2017.

24 Reduced Risk of Preterm Birth Over 1000 women were enrolled and given free vitamin D supplements with the goal of achieving >40 ng/ml 25(OH)D. McDonnell SL, et al. Maternal 25(OH)D concentrations 40 ng/ml associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center. PLoS One Jul 24;12(7): e

25 Trial involving women in South Carolina given 400, 2000, or 4000 IU/d vitamin D 3 starting at 12 th week of pregnancy. Hollis BW, et al. Vitamin D supplementation during pregnancy: double blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res Oct; 26(10):

26 Conclusion Optimal serum 25(OH)D 3 concentration is 40 to 60 ng/ml (100 to 150 nmol/l). Solar UVB exposure is the most important source of vitamin D 3. In absence of UVB exposure, it takes IU/d ( micrograms/d) vitamin D 3 to reach optimal concentrations.

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