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Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study

BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1161 (Published 03 April 2019) Cite this as: BMJ 2019;365:l1161

Linked editorial

The remarkable impact of bivalent HPV vaccine in Scotland

Linked opinion

Bivalent HPV vaccine in Scotland is having a considerable and sustained effect

Scotland's public health campaigns to improve vitamin D nutriture occurred within the same timeframe as HPV vaccination

(Word count without footnotes and citations: 934)
In April 2019, Palmer et al [1] published a retrospective population study crediting vaccination against human papilloma virus (HPV) with reduction in HPV prevalence in Scotland, and the authors attributed a reduction in HPV prevalence among unvaccinated women with “herd protection.” However the authors did not mention Scotland’s population-wide public health campaigns to address endemic vitamin D deficiency. The Scottish Government recognized the high prevalence of vitamin D deficiency in its population and began recommending vitamin D supplementation not later than 2006. Vitamin D deficiency results in impaired mucosal and immune defenses and correlates in a dose-dependent manner with increased cervicovaginal HPV infection [2]. By 2009, coincident with the start of the HPV vaccination campaign in 2008, numerous vitamin D supplementation (and sun exposure) campaigns were being implemented throughout Scotland to combat the documented population-wide problem of vitamin D deficiency.

Our views of vitamin D experienced a paradigm shift in the early part of this century with landmark publications such as Vieth’s authoritative documentation of safety in 1999 [3], Zittermann’s “Vitamin D in preventive medicine” in British Journal of Nutrition in 2003 [4], and Vasquez’s “Clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers” in 2004 [5] followed by an important partial summary of vitamin D usage guidelines in British Medical Journal in 2005 [6]. These and similarly themed articles have contributed to increased awareness of vitamin D’s safety and roles in preventive medicine and public health, including reducing the burden of infectious diseases such as viral infections and various types of cancer. Consistent with this evidence of safety and benefit, along with evidence that the human daily requirement is an order of magnitude greater than previously believed [7], use of vitamin D supplementation began to increase slowly and then exponentially in the United States [8] and other countries, especially English-speaking societies, most notably the United Kingdom. Indeed, according to the Scottish Health Survey 2003 [9], use of dietary supplements such as vitamins (including vitamin D), fish oils (a source of vitamin D) and minerals (magnesium supplementation improves vitamin D status and is necessary for vitamin D activation, binding, transport, metabolism, and gene expression [10]) had already begun to increase between 1998 and 2003. Certainly not later than 2006, the Scottish Government was already recommending widespread use of vitamin D supplements to combat the high prevalence of vitamin D deficiency in Scotland [11].

Widespread vitamin D deficiency in Scotland was followed by widespread recommendations for vitamin D supplementation starting in 2006 and 2009. In 2006, Burleigh and Potter published in Scottish Medical Journal [12] stating that, “The prevalence of vitamin D deficiency is high in older outpatients in this geographical area.” In 2007, Hyppönen and Power [13] showed that among British adults “Prevalence of hypovitaminosis D in the general population was alarmingly high during the winter and spring, which warrants action at a population level rather than at a risk group level.” In 2008, Rhein [14] further specified that “Vitamin D deficiency is widespread in Scotland.” In 2009, the Scottish Government acknowledged the need to educate its population about the importance of vitamin D3 supplementation [15]. From that time until the present, the Scottish Government, United Kingdom National Health Services, and various advocacy groups and programs (e.g., ScotsNeedVitaminD.com[16], Healthy Start, which provides vitamin D supplements to all children and pregnant women in Scotland [17]) continue assertive public health campaigns recommending vitamin D supplementation and increased vitamin D production via sun exposure via the “Shine on Scotland” program initiated in 2009 [18] for all of its citizens [19-23].

Vitamin D supplementation has been the subject of many clinical trials documenting anti-inflammatory, antiviral, and anticancer benefits. Correction of vitamin D deficiency has significant anti-inflammatory [24] and immunomodulatory [25] benefits. Vitamin D and its direct metabolites promote production of antimicrobial peptides which have antibacterial and antiviral properties, while also reducing viral replication by inhibiting the NF-kappaB pathway. Consistent with these immunomodulatory and antiviral mechanisms, data from several placebo-controlled trials shows that vitamin D provides benefit in a variety of infectious conditions including human immunodeficiency virus (HIV) [26], hepatitis C virus [27-29] and upper respiratory infections [30-31]. Vitamin D administration displays impressive clinical effectiveness against dermal HPV as shown in case reports, clinical series, and placebo-controlled trials, with remarkable safety, high efficacy, and a consistent trend toward complete resolution of lesions [32-36]. In 2014, Schulte-Uebbing et al [37] published “Chronical cervical infections and dysplasia (cervical intraepithelial neoplasia [CIN] 1-2): vaginal vitamin D treatment” showing that among 200 women with cervical dysplasia, vitamin D vaginal suppositories (12,500 IU, 3 nights per week, for 6 weeks) provided “very good anti-inflammatory effects” and “good antidysplastic effects” in women with CIN 1. In 2017, Vahedpoor and colleagues [38] published a double-blind placebo-controlled trial of vitamin D in women with HPV, in which they found that vitamin D3 administration for 6 months among women with CIN1 resulted in its regression and had beneficial effects on markers of insulin metabolism and antioxidant status. In 2018, Vahedpoor and colleagues [39] published a double-blind placebo-controlled trial of vitamin D in women with HPV, in which they observed, “The recurrence rate of CIN1/2/3 was 18.5 and 48.1% in the vitamin D and placebo groups respectively”, thereby clearly favoring treatment with vitamin D over placebo.

In Scotland, programs advocating HPV vaccination (started in 2008) and vitamin D supplementation (started not later than 2006 and again in 2009) occurred in close chronologic proximity. Crediting the reduction in HPV-related disease solely to vaccination via retrospective population study is potentially invalid and misleading, especially when the authors make no account whatsoever of the national program for vitamin D supplementation which started in the same timeframe. Numerous studies have shown that vitamin D provides immunomodulatory, anti-inflammatory, microbiome-modifying, antiviral and anti-HPV benefits with high safety, good efficacy, low cost, wide availability, and clinically important collateral benefits.

[1] Palmer T, Wallace L, Pollock KG, Cuschieri K, Robertson C, Kavanagh K, Cruickshank M. Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12-13 in Scotland: retrospective population study. BMJ. 2019 Apr 3;365:l1161. doi: 10.1136/bmj.l1161
[2] Shim J, Pérez A, Symanski E, Nyitray AG. Association Between Serum 25-Hydroxyvitamin D Level and Human Papillomavirus Cervicovaginal Infection in Women in the United States. J Infect Dis. 2016 Jun 15;213(12):1886-92. doi: 10.1093/infdis/jiw065
[3] Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999 May;69(5):842-56
[4] Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003 May;89(5):552-72
[5] Vasquez A, Manso G, Cannell J. The clinical importance of vitamin D (cholecalciferol): a paradigm shift with implications for all healthcare providers. Altern Ther Health Med. 2004 Sep-Oct;10(5):28-36 https://www.ncbi.nlm.nih.gov/pubmed/15478784
[6] Vasquez A, Cannell J. Calcium and vitamin D in preventing fractures: data are not sufficient to show inefficacy. BMJ. 2005 Jul 9;331(7508):108-9 https://doi.org/10.1136/bmj.331.7508.108-b and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC558659/
[7] Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr. 2003 Jan;77(1):204-10
[8] Rooney MR, Harnack L, Michos ED, Ogilvie RP, Sempos CT, Lutsey PL. Trends in Use of High-Dose Vitamin D Supplements Exceeding 1000 or 4000 International Units Daily, 1999-2014. JAMA. 2017 Jun 20;317(23):2448-2450. doi: 10.1001/jama.2017.4392
[9] "The proportion of adults who report taking dietary supplements (such as vitamins, fish oils, minerals etc) has increased slightly since 1998 (there was no change between 1995 and 1998). In 1998, 15% of men and 16% of women aged 16-64 took some form of dietary supplement, which increased to 20% and 26%, respectively, in 2003." The Scottish Health Survey 2003. Chapter 3 Fruit and Vegetable Consumption and Eating Habits. https://www.webarchive.org.uk/wayback/archive/20180602183443/http://www.... Accessed April 2019
[10] Reddy P, Edwards LR. Magnesium Supplementation in Vitamin D Deficiency. Am J Ther. 2019 Jan/Feb;26(1):e124-e132. doi: 10.1097/MJT.0000000000000538
[11] "Therefore, routine vitamin D supplementation is recommended for all children over 1 year of age and should be continued until 5 years unless the diet is diverse and plentiful." Scottish Government. Nutritional Guidance for Early Years: food choices for children aged 1-5 years in early education and childcare settings. Published: 23 Jan 2006. https://www.gov.scot/publications/nutritional-guidance-early-years-food-... Accessed April 2019
[12] Burleigh E, Potter J. Vitamin D deficiency in outpatients: a Scottish perspective. Scott Med J. 2006 May;51(2):27-31
[13] Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007 Mar;85(3):860-8
[14] Rhein HM. Vitamin D deficiency is widespread in Scotland. BMJ. 2008 Jun 28;336(7659):1451. doi: 10.1136/bmj.39619.479155.3A
[15] Boy wins NHS backing in vitamin D campaign. The Scotsman 2009 December https://www.scotsman.com/news/boy-wins-nhs-backing-in-vitamin-d-campaign... Accessed April 2019
[16] “At scotsneedvitamind.com, we believe the people of Scotland would see health improvements by taking a regular Vitamin D supplement. We think there is enough evidence currently available to make all of us take action, from health care professionals to parents and teachers.” https://scotsneedvitamind.com/about-us/ Accessed April 2019
[17] "The United Kingdom National Health Services created a program called Healthy Start, which offers vouchers for free vitamin D supplements to qualifying pregnant women, women with a baby under one year old and children under the age of five years located in Scotland, Northern Ireland, England and Wales. In April of 2017, the Scottish government partnered with the Healthy Start program to offer free vitamin D supplements to all Scottish pregnant women, regardless of whether they qualify for vouchers. This joint effort was created to decrease the risk of rickets and other health complications caused by vitamin D deficiency. Scotland offers free vitamin D supplements for all pregnant residents. Posted on: November 28, 2017 by Missy Sturges and John Cannell, MD. https://www.vitamindcouncil.org/scotland-offers-free-vitamin-d-supplemen.... See also: National Health Services Scotland. Vitamin D. https://www2.gov.scot/resource/0038/00386784.pdf Accessed April 2019
[18] Scottish warning over vitamin D levels. 19 September 2010 https://www.bbc.com/news/uk-scotland-11355810 Accessed April 2019
[19] "Following recommendations from the Scientific Advisory Committee on Nutrition (SACN), Scottish Government advice on vitamin D for all age groups has been updated as follows: Everyone age 5 years and above should consider taking a daily supplement of 10 micrograms vitamin D, particularly during the winter months (October – March)." Scottish Government. Vitamin D. https://www2.gov.scot/Topics/Health/Healthy-Living/Food-Health/vitaminD Accessed April 2019
[20] Scottish Government. Vitamin D information for health professionals in Scotland. November 2017 https://www.gov.scot/binaries/content/documents/govscot/publications/pub... Accessed April 2019
[21] "Scots should consider taking vitamin D supplements all-year round, but particularly in autumn and winter, according to new health advice." All Scots advised to take vitamin D says new health guidance. 21 July 2016. https://www.bbc.com/news/uk-scotland-36856176 Accessed April 2019
[22] "International experts are calling for food in Scotland to be fortified with vitamin D, in an attempt to cut the large numbers of people who develop multiple sclerosis at sunshine-deprived northern latitudes." Add vitamin D to Scotland's food – experts: Dosing whole population would help cut levels of multiple sclerosis, say scientists. 23 Dec 2011 https://www.theguardian.com/uk/2011/dec/23/vitamin-d-scotland-food-multi... Accessed April 2019
[23] All Scottish babies should have vitamin D supplement, CMO says. The Pharmaceutical Journal 2017 Nov 30. https://www.pharmaceutical-journal.com/news-and-analysis/news/all-scotti... Accessed April 2019
[24] Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM. 2002 Dec;95(12):787-96
[25] Sánchez-Armendáriz K, García-Gil A, Romero CA, Contreras-Ruiz J, Karam-Orante M, Balcazar-Antonio D, Domínguez-Cherit J. Oral vitamin D3 5000 IU/day as an adjuvant in the treatment of atopic dermatitis: a randomized control trial. Int J Dermatol. 2018 Dec;57(12):1516-1520. doi: 10.1111/ijd.14220
[26] Stallings VA, Schall JI, Hediger ML, Zemel BS, Tuluc F, Dougherty KA, Samuel JL, Rutstein RM. High-dose vitamin D3 supplementation in children and young adults with HIV: a randomized, placebo-controlled trial. Pediatr Infect Dis J. 2015 Feb;34(2):e32-40. doi: 10.1097/INF.0000000000000483
[27] Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol. 2011 Dec 21;17(47):5184-90. doi: 10.3748/wjg.v17.i47.5184
[28] Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients. World J Gastroenterol. 2012 Feb 28;18(8):800-5. doi: 10.3748/wjg.v18.i8.800
[29] Komolmit P, Kimtrakool S, Suksawatamnuay S, Thanapirom K, Chattrasophon K, Thaimai P, Chirathaworn C, Poovorawan Y. Vitamin D supplementation improves serum markers associated with hepatic fibrogenesis in chronic hepatitis C patients: A randomized, double-blind, placebo-controlled study. Sci Rep. 2017 Aug 21;7(1):8905. doi: 10.1038/s41598-017-09512-7
[30] Jung HC, Seo MW, Lee S, Kim SW, Song JK.Vitamin D3 Supplementation Reduces the Symptoms of Upper Respiratory Tract Infection during Winter Training in Vitamin D-Insufficient Taekwondo Athletes: A Randomized Controlled Trial. Int J Environ Res Public Health. 2018 Sep 14;15(9). pii: E2003. doi: 10.3390/ijerph15092003
[31] Lee MT, Kattan M, Fennoy I, Arpadi SM, Miller RL, Cremers S, McMahon DJ, Nieves JW, Brittenham GM. Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease. Blood Adv. 2018 May 8;2(9):969-978. doi: 10.1182/bloodadvances.2017013979
[32] Moscarelli L, Annunziata F, Mjeshtri A, Paudice N, Tsalouchos A, Zanazzi M, Bertoni E. Successful treatment of refractory wart with a topical activated vitamin d in a renal transplant recipient. Case Rep Transplant. 2011;2011:368623. doi: 10.1155/2011/368623. Epub 2012 Jan 3.
[33] Aktaş H, Ergin C, Demir B, Ekiz Ö. Intralesional Vitamin D Injection May Be an Effective Treatment Option for Warts. J Cutan Med Surg. 2016 Mar-Apr;20(2):118-22. doi: 10.1177/1203475415602841. Epub 2015 Aug 20
[34] Raghukumar S, Ravikumar BC, Vinay KN, Suresh MR, Aggarwal A, Yashovardhana DP. Intralesional Vitamin D3 Injection in the Treatment of Recalcitrant Warts: A Novel Proposition. J Cutan Med Surg. 2017 Jul/Aug;21(4):320-324. doi: 10.1177/1203475417704180. Epub 2017 Apr 6.
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[37] Schulte-Uebbing C, Schlett S, Craiut I, Antal L, Olah H. Chronical cervical infections and dysplasia (CIN I, CIN II): vaginal vitamin D (high dose) treatment. Dermatoendocrinol 2014 Oct; 6:e27791. doi:10.4161/derm.27791
[38] Vahedpoor Z, Jamilian M, Bahmani F, Aghadavod E, Karamali M, Kashanian M, Asemi Z. Effects of Long-Term Vitamin D Supplementation on Regression and Metabolic Status of Cervical Intraepithelial Neoplasia: a Randomized, Double-Blind, Placebo-Controlled Trial. Horm Cancer. 2017 Feb;8(1):58-67. doi: 10.1007/s12672-016-0278-x. Epub 2017 Jan 3
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Competing interests: Dr Alex Vasquez is a lecturer and author of numerous articles, letters, and books related to topics of nutrition, clinical medicine, neuroinflammation, and the human microbiome. Dr Vasquez has served as a consultant to Biotics Research Corporation.

13 April 2019
Alex Vasquez
Physician, author, lecturer, editor
Barcelona, Spain