GUIDELINES FOR AUTHORS

Guidelines for Authors

June 2021 • Volume XLV, Issue 6

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Practical Gastroenterology publishes articles for the primary care physician, and your article should therefore have a nuts-and-bolts slant. We urge you to keep the nonspecialist in mind as you write your article. We cannot stress strongly enough the importance of focusing your article on information that will be useful and instructive to the primary care physician. In this regard, it would be helpful for you to emphasize prevention and cost (of tests, drugs, surgery, hospital stay, procedures, techniques, etc.) whenever and wherever possible.

We offer the following list to help you conform to our mechanical requirements:

  1. Please submit one copy of your manuscript as a Microsoft Word file, typed on 8½″ × 11″ pages with 1″ margins, double-spaced throughout, including references, tables and figure legends. Ideally, the length of the manuscript should be 2000–2500 words (10–13 pages). Manuscripts should be submitted via e-mail to: PracticalGastro@aol.com
  2. Manuscripts must be submitted as Microsoft Word files without automatic footnoting and as final format documents (without indications of markup).
  3. Tables should be submitted with titles. If the table has been previously published, identify the source and provide all information that would be included in a standard reference list (see below), along with indication that permission to republish has been obtained. It is your responsibility to obtain permission.
  4. Figures and illustrations (photographs, drawings, charts) help explain the text, add to the visual appeal of the published article, and are very welcome. Each table should have a title, and each figure should have an accompanying legend. If figures and illustrations have been previously published, you should identify the source and provide all information that would be included in a standard reference list (see below), along with indication that permission to republish has been obtained. It is your responsibility to obtain permission. All figures and illustrations must be supplied in JPEG format and must be identified as Figure 1, Figure 2, etc. When e-mailing figures and illustrations, do not embed them into a text document. Each JPEG should be sent as a separate document attached to the e-mail. Tables, figures and Illustrations should not be submitted as Excel spreadsheets or in Power Point.
  5. The title page should include the names, addresses, phone numbers, complete titles and affiliations of all authors.
  6. A color head-shot photograph of each author should accompany the manuscript. These will be published with your article. These must be submitted as JPEG files.
  7. An abstract of 125–150 words should also accompany your paper. This will be published at the beginning of your article. Please do not exceed the 150-word limit.
  8. References should be used sparingly and cited in the body of the paper using consecutive superscript (raised) numbers. The references section should be numbered consecutively in the order in which the references are cited in the text. References should follow AMA style, and journal names should be abbreviated according to Index Medicus practice. Inclusive page ranges should be indicated. The following references illustrate AMA style:
  1. Jacobson IM, McHutchison JG, Dusheiko GM, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416.
  2. Bernatsky S, Clarke AE, Suissa S. Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis. Arch Intern Med. 2008;168:378-81.
  1. Articles will be copyrighted upon publication by Practical Gastroenterology Publishing, Inc. The manuscript must not have been published previously. Each article we publish is subject to review by members of our Editorial Board. Articles are also subject to final editing.

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A SPECIAL ARTICLE

Benign Rectal Strictures: A Review Article

June 2021 • Volume XLV, Issue 6
Ammar Ahmad,Padmini Krishnamurthy

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The aim of this review article is to assess the various etiologies and different management techniques for benign rectal strictures. A systematic review was performed using PubMed central using the keywords that included ‘benign’, ‘stricture or strictures’, and ‘rectum, rectal, or anorectal’. Retrospective studies, prospective studies, case series, and case reports describing etiology or management of benign rectal strictures were included in this review article. A total of 730 cases of benign rectal strictures were identified in 79 articles. Anastomotic stricture was the most common cause of benign rectal strictures. Different techniques were used to manage benign rectal strictures including Hegar dilation, balloon dilation, stent placement, microsurgery, or other surgical techniques. The initial technique used for management was dependent on the provider as there are no clear guidelines for management of benign rectal strictures.

INTRODUCTION

Benign rectal strictures can be iatrogenic after a major colorectal surgery or spontaneous due to medical conditions. The most common cause of benign rectal strictures are anastomotic strictures. Rectal strictures behave differently from colonic strictures due to rectum’s anatomical relation with the anal canal, proximity to pelvic organs, and unique blood supply. Different management techniques such as surgical repair, endoscopic balloon dilation, rectal stent placement, medical treatment alone, or a combination of treatments have been used to treat benign rectal strictures. In this article, we describe the etiologies and management of benign rectal strictures.

Methods

A PubMed Central search was carried out, using the search term (benign) AND (stricture or strictures) AND (rectum or rectal or anorectal). Only articles that described strictures known to be benign at the time of diagnosis were included. Retrospective studies, prospective studies, case series, and case reports were included. Content from references found in the articles were included if deemed relevant. In total, 79 articles are included in this review article.

Clinical Presentation

Rectal strictures can present with minor symptoms to progressive constipation and on occasion, obstipation. Symptoms include left lower quadrant abdominal pain, increased frequency of bowel movements, difficulty in defecation, feeling of inadequate evacuation, pencil-thin stools, anal pain, and fecal urgency. Stenosis is often defined as inability to pass a 12mm diameter sigmoidoscope1 or narrowing to less than one-finger breadth by digital rectal examination.2

Etiology of Rectal Strictures

Anastomotic strictures are the most common cause of benign rectal strictures. Non-operative etiologies of rectal strictures include inflammatory bowel disease, rectal ischemia, sexually transmitted disease, radiation, endometriosis, pelvic actinomycosis, chronic suppository usage, and solitary rectal ulcer.3–17 Few cases of strictures have been reported after submucosal endoscopic dissection.18

Anastomotic Rectal Strictures

Post-operative anastomotic strictures develop in 3 to 30% of patients undergoing colorectal resection.3,19-22 Anastomotic rectal strictures are predominantly seen following resection of rectal cancer with colorectal or coloanal anastomosis (with residual rectal cuff). Other surgeries that can lead to anastomotic rectal strictures include hemorrhoidectomy and colorectal resection for extensive diverticular disease.1,22 Rectal strictures are more likely to form after stapled anastomosis compared to hand-sewn anastomosis.22–27 Ischemia, post-operative anastomotic leakage, and postoperative radiation are major risk factors for development of anastomotic strictures.2,19,22,28,29 Other contributing factors include obesity, incomplete “doughnut” construction, low-lying anastomosis, and post-operative infection.19,30 Temporary diverting ileostomy or colostomy may contribute to anastomotic strictures due to absence of dilation of anastomosis by fecal stream.31–33

Inflammatory Bowel Disease (IBD)

Anorectal strictures are more commonly seen in Crohn’s disease but can also be seen in ulcerative colitis. They are frequently present with fistulizing disease and proctitis.8,34 Rectal stricture in ulcerative colitis may portend development of cancer. The pathophysiology remains speculative since both inflammatory and fibrotic components frequently occur in anorectal strictures in patients with inflammatory bowel disease. The presence of anorectal strictures in Crohn’s disease is a predictor of poor outcomes.9

Miscellaneous Etiologies of Rectal Strictures

Radiation Induced Rectal Strictures

Rectal stricture is a rare complication of pelvic irradiation. Chronic radiation proctitis has been reported in up to 20% of patients receiving radiation of the pelvis, and rectal stricture occurs in about 1 to 15% of these cases.35 Radiation causes histologic alterations such as obliterative endarteritis, tissue ischemia and necrosis leading to submucosal collagen deposition. These changes result in transmural fibrosis and formation of rectal strictures.2

Infectious Rectal Strictures

Sexually transmitted infections (STIs) due to anal intercourse have been reported to cause rectal strictures in both HIV and non-HIV patients. Lymphogranuloma venereum caused by chlamydia trachomatis is the most frequently reported sexually transmitted infection to cause rectal strictures.5 A case report implicating HSV-2 as the cause of benign rectal stricture has been reported.4 These strictures can occur in HIV patients even with CD4 counts > 200 x 106/L. Biopsies with histological evaluation using special stains and serology is used to confirm diagnosis.5 Rare cases of rectal strictures due to actinomycosis infection have also been reported due to contiguous spread from intrauterine devices.10,17

Foreign Body Strictures

Benign rectal strictures can develop due to reactive inflammation and fibrosis around a foreign body.6 Strictures can develop following rectal administration of cation binding resins such as sodium polystyrene sulfonate or calcium polystyrene sulfonate and are usually diagnosed by presence of characteristic crystals on histology.36 Chronic suppository usage is also noted to cause anorectal stenosis and strictures due to chronic reactive inflammation.11,12

Endometriosis

Endometriosis should be suspected in women presenting with rectal stricture at a young age without any other explanation for the stricture. These patients generally have menstrual irregularity and cyclic abdominal pain that worsens during menstruation. The presence of ectopic endometrial tissue in the muscularis propria and subserosa or mesentery is thought to be the cause of the stricture.7

Solitary Rectal Ulcer Syndrome

Solitary rectal ulcer Syndrome is a benign disease that is often missed as a cause of rectal bleeding. It is thought to occur due to chronic hypoperfusion leading to ischemic injury to the rectal mucosa. Rarely, it can lead to stenosis or stricture of the rectum. Symptoms generally include chronic constipation, abdominal pain, rectal bleeding, and mucosal discharge.14,37

Ischemic Rectal Stricture

Ischemic proctitis is rare because the rectum has abundant blood supply and rich collaterals. A stricture due to ischemic proctitis develops due to acute compromise in blood flow usually in the setting of hypovolemic shock in patients with inadequate collateral circulation around the rectum.38

Complication of Submucosal Dissection

Endoscopic submucosal dissection is widely used as a minimally invasive treatment for colorectal neoplasms. It can help avoid surgical treatments that can result in anal dysfunction and the need for permanent colostomy. Although rare, endoscopic submucosal dissection can result in the formation of a stricture when the lesion being resected is large and extends into the lower rectum.18

Medical Management of Strictures

Management of benign rectal stricture depends on the etiology and often requires endoscopic or surgical intervention. Infectious strictures due to chlamydia or actinomycoses heal well with antibiotic treatment.4,5 Rectal strictures due to inflammatory bowel disease have a healing rate of 59% with anti-tumor necrosis factor- agents with or without immunomodulators.9 It is important to biopsy strictures occurring after surgical resection of colorectal cancer and strictures related to IBD to rule out cancer.9 Stool softeners and laxatives are often needed, with high fiber diet even after resolution of stricture.22

Specific Management of Strictures

Treatment of benign rectal strictures can be difficult and usually requires multiple modalities. These include dilation with Hegar or bougie dilators, endoscopic interventions (balloon dilation, stent placement), or surgical treatment. Case reports, small case series, and retrospective studies comprise most of the published literature.Consequently, novel methods may have to be used keeping in mind maximum benefit and safety of the patient. Mechanical dilation or endoscopic methods are attempted first, as surgical treatment is difficult and has high risk of end-colostomy.

Dilation by Hegar Dilators

Hegar dilators, often used by surgeons in the initial management of benign rectal strictures, are least invasive and most cost-effective mode of treatment. Dilation is usually started with 14-20 French dilators and is gradually increase up to a maximum of 60 French dilators.29,39 Based on our review of literature, Hegar dilators were effective in 56.1% of the cases (Table 2).

Endoscopic Balloon Dilation

For a majority of the cases, endoscopic balloon dilation is considered the first line of treatment. It can be performed using through the scope hydrostatic or combined endoscopic-fluoroscopic pneumatic balloon dilators.22,24,40,41 Dilation under fluoroscopic guidance allows for better visualization and control over the process and ability to increase the balloon diameter as needed.40 Based on our review, balloon dilation has an overall success rate of 77.5% (Table 2). Dilation is considered successful when a 13mm colonoscope can be passed easily through the stricture with resolution of symptoms.24 Recurrence of symptoms occurred in 60% of cases after one dilation session. Consequently, on average two to three dilation sessions are required to achieve successful results.42–47 More dilation sessions are generally required for low lying rectal strictures.18 If successful results are not achieved in five or more dilation sessions, alternative methods should be pursued.48 There are no guidelines for time intervals between dilation sessions and is typically four weeks or more.40 In high-grade strictures, with a lumen < 7 mm, argon plasma coagulation or laser can be used to make a small incision that allows the endoscope to pass through the stricture for balloon dilation.22,49 Endoscopic balloon dilation is especially effective for shorter strictures, usually < 2 cm in length with low complication rates.50–52 Perforation is reported in about 1.1% of cases and abscess is reported in 0.2% of cases.53

Stent Placement for Rectal Strictures

Stent placement is usually the next option for treatment of rectal strictures that do not resolve with endoscopic balloon dilation. They are usually used for strictures longer than 2 cm.55,56 Most of the published literature on stents are case reports and case series. Three different types of stents have been used for rectal strictures: fully covered selfexpanding metal stents, uncovered metal stents, and biodegradable stents.4,56–60 Uncovered metal stents are rarely used due to risk of mucosal hyperplasia leading to re-occlusion. Additionally, uncovered stents cannot be removed via endoscopic method, resulting in the need for surgery.55

Fully covered self-expanding metal stents are most frequently used due to low tissue ingrowth and ease of removal.61 Based on our review, the success rate of fully covered self-expanding metal stents was 68.5% (Table 2). Migration of the stent was the most common complication and was reported in 31% of the cases. In some cases, migration occurs after stricture has sufficiently dilated.62 In a case series of four patients, migration was avoided with “upside-down” deployment of fully covered self-expanding metal stents.61 Rare complications such as stent fracture, coloenteric fistula, and perforation have been reported.56,62,63 Less serious complications of rectal stent placement include abdominal pain, rectal pain, and tenesmus.60,61 It is unclear as to how long metal stents should be left in place, and removal has been reported as early as four weeks to as late as 30 months.57,62

Biodegradable stents have been predominantly used for esophageal strictures.56,64,65 They are more flexible, do not have to be removed as they usually self-disintegrate, and have a mean patency of 4 months.56,66 Since they tend to be wider and longer, they are poorly tolerated in strictures closer to the anus. Based on our review, the success rate of biodegradable stents was 66.7% (Table 2). Migration was the most common complication, occurring in 27% of cases. Acute intestinal obstruction due to stent migration occurred in one case and required emergent surgical intervention.55

Surgery for Rectal Strictures

Surgery is the last resort for treatment of benign rectal strictures since there is a high risk of endcolostomy and creation of permanent stoma. About 28% of patients have refractory strictures requiring surgical correction.68 Several minimally invasive surgical options have been reported for refractory benign rectal strictures, especially involving the lower rectum. These include transanal minimally invasive surgery (TAMIS), transanal endoscopic microsurgery (TEM), laparoscopic stricturoplasty using transanal radial linear cutter, and transanal stapler resection of stricture.69–78 Resection with re-anastomosis is more successful in upper rectal strictures (>10 cm from anal verge), although coloanal anastomosis for mid and lower rectal strictures (within 10 cm of anal verge) have also shown satisfactory long-term functional results.68,79 Some recalcitrant rectal strictures in Crohn’s disease may need proctectomy and creation of a stoma.8

CONCLUSION

Benign rectal strictures are a common complication of rectal anastomotic surgeries but can also be caused by other etiologies such as Crohn’s disease, ischemia, infection, complication of endoscopic submucosal dissection, endometriosis, and chronic suppository usage. Management of rectal strictures is based on underlying etiology and may include both endoscopic and/or surgical interventions. This article provides guidance for the treatment of benign rectal strictures in different clinical scenarios.

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  1. Testoni PA, Fanti L, Antonucci E, Dabizzi E. Inverted “upsidedown” esophageal fully-covered self-expanding metal stent is effective for temporary treatment of colorectal strictures: a pilot case series. Endosc Int Open. 2019;7(6):E818-E823.
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  8. Schlegel RD, Dehni N, Parc R, Caplin S, Tiret E. Results of reoperations in colorectal anastomotic strictures. Dis Colon Rectum. 2001;44(10):1464-1468.
  9. Valdés-Hernández J, Del Rio FJ, Gómez-Rosado JC, et al. TAMIS repair of a rectal stenosis not treatable by endoscopy. Tech Coloproctol. 2018;22(11):891.
  10. Baatrup G, Svensen R, Ellensen VS. Benign rectal strictures managed with transanal resection–a novel application for transanal endoscopic microsurgery. Colorectal Dis. 2010;12(2):144-146.
  11. Pabst M, Giger U, Senn M, Gauer JM, Boldog B, Schweizer W. Transanal treatment of strictured rectal anastomosis with a circular stapler device: simple and safe. Dig Surg. 2007;24(1):12- 14.
  12. Anvari M. Endoscopic transanal rectal stricturoplasty. Surg Laparosc Endosc. 1998;8(3):193-196.
  13. Kato K, Saito T, Matsuda M, Imai M, Kasai S, Mito M. Successful treatment of a rectal anastomotic stenosis by transanal endoscopic microsurgery (TEM) using the contact Nd:YAG laser. Surg Endosc. 1997;11(5):485-487.
  14. Gomes da Silva R, Hanan B, Fonseca LM. Treatment of Anastomotic Stricture of a Handsewn Coloanal Anastomosis With Transanal Approach. Dis Colon Rectum. 2017;60(7):755.
  15. Bong JW, Lim SB. Transanal minimally invasive surgery as a treatment option for a completely occluded anastomosis after low anterior resection: A new approach to severe anastomotic stenosis. Asian J Endosc Surg. 2019;12(2):175-177.
  16. Kawaguti FS, Martins BC, Nahas CS, et al. Endoscopic radial incision and cutting procedure for a colorectal anastomotic stricture. Gastrointest Endosc. 2015;82(2):408-409.
  17. Araki Y, Kishimoto Y, Sato Y, et al. Transanal dilation using circular stapling for benign rectal stenosis: report of a case. Kurume Med J. 2002;49(3):149-151.
  18. Kawak S, Turaihi H, Bjordahl P. Transanal stricturoplasty: a minimally-invasive approach to a challenging problem. J Surg Case Rep. 2019;2019(3):rjz087. Published 2019 Mar 29.
  19. Yi BQ, Wang ZJ, Zhao B, et al. Zhonghua Wai Ke Za Zhi. 2013;51(7):577-581.

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NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #210

Vitamin D Replacement in Adults: Current Strategies in Clinical Management

May 2021 • Volume XLV, Issue 5
Ronak M. Patel,Lindsay Bazydlo,Sue A. Brown,Alan C. Dalkin

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Vitamin D, a prohormone, is needed for proper calcium homeostasis and potentially a host of additional physiologic functions. With changes in diet and an age-related decline in dermal production of vitamin D, practitioners often encounter patients with varying degrees of vitamin D insufficiency or deficiency. It is imperative to recognize and treat vitamin D deficiency before it manifests with detrimental effects on the body. This review will provide background on the physiology of vitamin D, common causes of hypovitaminosis D and conclude by providing a practical guide to vitamin D replacement and monitoring in common clinical scenarios.

INTRODUCTION

Vitamin D plays a critical role in human health. Well recognized is the importance of vitamin D in the absorption of calcium and phosphate mineral and the subsequent actions on bone mineralization, bone strength, and fracture protection.1 In recent years, increasing preclinical evidence supports a role for vitamin D in a multitude of extra-skeletal physiological functions while low vitamin D levels have been linked in observational studies to immune dysfunction, malignancies (e.g. breast, colon, prostate), skeletal muscle strength, cardiovascular, and glycemic regulation.2,3 Despite these associations, randomized controlled trials are either lacking or do not consistently find that vitamin D supplementation alters most of these non-skeletal outcomes.4-7 However, it is generally agreed that perturbations in vitamin D metabolism can have an important impact on human health and hence screening for, and adequately treating, vitamin D deficiency is important for general health purposes.8

There exist two primary sources of vitamin D in humans: dermal production of vitamin D3 (cholecalciferol) and nutritional supplementation with either vitamin D3 or vitamin D2 (ergocalciferol). Shortfalls in dietary intake, reduction in ultraviolet light exposure needed for dermal biosynthesis of vitamin D, age-related decline in dermal production of vitamin D, disorders altering the gastrointestinal absorption of fats, and conditions that accelerate the metabolism of vitamin D stores can all predispose an individual to vitamin D deficiency. It is not surprising that hypovitaminosis D can be present in a wide array of clinical scenarios.

Conversely, while wide-spread supplementation of milk, juices, cereal, and daily multivitamins and calcium preparations with vitamin D is part of a general health approach to prevent vitamin D deficiency, over-replacement with vitamin D can have adverse consequences. Excess absorption of calcium and phosphate can predispose to hypercalciuria and nephrolithiasis and much less commonly, calcium mineral deposition of soft tissues and organs such as the kidney, thereby adversely altering function. It is the purpose of this article to:

  1. briefly review the physiology and regulation of vitamin D activity
  2. identify common clinical conditions in adults in which an evaluation of vitamin D status is indicated
  3. review commercially available assays for vitamin D with their specific advantages and limitations,
  4. propose a practical therapeutic plan for adults that includes monitoring and treatment goals that are generally acceptable for most patients with vitamin D deficiency

Physiology of Calcium Homeostasis and the Role of Vitamin D

The central player in the regulation of calcium is parathyroid hormone (PTH). PTH synthesis and secretion are directly regulated by the extracellular calcium concentration via the Calcium-sensing receptor (CaSR) through an inhibitory mechanism. Activation of the CaSR results in a reduction in PTH. Conversely, hypocalcemia increases PTH. Target organs for PTH action include the bone and kidney. PTH increases bone turnover and osteoclast action to release calcium and phosphorus into the circulation. In terms of renal actions, PTH enhances resorption of filtered calcium thereby limiting renal losses of calcium. In addition, and relevant to this review, PTH drives conversion of stored 25-hydroxyvitamin D (calcidiol) into the active metabolite 1,25-dihydroxyvitamin D (calcitriol) via the actions of 1-alpha hydroxylase (CYP27B1). Calcitriol, in turn, enhances gastrointestinal absorption of calcium and phosphorus in the small bowel, though there may be a small contribution of calcidiol in this regard. In addition, and to a more modest degree, calcitriol favors bone mineralization and the deposition of calcium mineral into newly formed bone (osteoid). The increase in circulating calcium then feeds back at the level of the parathyroid gland to inhibit further PTH secretion

Stored vitamin D, i.e. calcidiol, is the product of 25-hydroxylation by the hepatocytes. Both vitamin D2 and D3 , regardless of their source, are fully and rapidly converted to calcidiol such that measurement of cholecalciferol or ergocalciferol is not practical. Calcidiol circulates attached to a vitamin D binding protein (high affinity, low capacity) and albumin (low affinity, high capacity), both products of hepatic biosynthesis. While the capacity to synthesize calcidiol from the parent compounds is generally well in excess of normal physiologic needs, severe hepatic dysfunction and end-stage liver disease can be associated with vitamin D deficiency due to a decline in calcidiol production.

Due to the feedback regulation described above, vitamin D toxicity due to excess ingestion of calcidiol is unlikely. If calcidiol levels rise above the normal range, calcium feedback to the parathyroid glands inhibits parathyroid hormone release, via activation of the CaSR, which in turn reduces the conversion of calcidiol to calcitriol. In effect, thereby preventing further enhancement in calcium absorption. None-the-less, excess levels of vitamin D (> 80 ng/mL) can increase circulating calcium levels which results in hypercalcemia and hypercalciuria and a long-term risk of nephrolithiasis.

Clinical Presentation of Vitamin D Deficiency, Differential Diagnosis and Laboratory Testing in Adults

The majority of patients with vitamin D deficiency have few, if any signs or symptoms related to the condition. Over the long term, reductions in vitamin D can lead to a reduction in circulating calcium, secondary hyperparathyroidism, increased bone remodeling and mobilization of calcium from bone. Severe vitamin D deficiency can result in osteomalacia that is often asymptomatic, but in some can be associated with diffuse bone pain. In addition, enhanced bone fragility can present with fracture from a ground level fall. The associated laboratory studies include a reduced 25-hydroxyvitamin D, normal or lownormal calcium levels, elevated PTH and alkaline phosphatase levels and a reduced 24-hour urinary calcium excretion rate.

There remains some discussion on the proper diagnostic nomenclature for patients with hypovitaminosis D. The Endocrine Society’s practice guidelines9 detail three categories:
1. Vitamin D sufficiency: 25-hydroxyvitamin D of > 30 ng/mL (75 nmol/L)
2. Vitamin D insufficiency: 25-hydroxyvitamin D between 21-29 ng/mL (51-74 nmol/L)
3. Vitamin D deficiency: 25-hydroxyvitamin D of < 20 ng/mL (<50 nmol/L)

It is important to note that the biologic contributions of either vitamin D2 or vitamin D3 are similar and hence differentiation between the two forms is not important for diagnostic purposes. Of greater import, measurement of 1,25-dihydroxyvitamin D (calcitriol) is not included in the identification of vitamin D deficient patients. Calcitriol levels are maintained in the normal range even in the presence of severe calcidiol deficiency and will not reflect many patients’ vitamin D balance.

A full discussion of the causes of vitamin D insufficiency and deficiency is beyond the scope of this manuscript. In overview, malabsorptive conditions predispose to deficiencies of all fatsoluble vitamins. Infectious etiologies (e.g. C. Difficile), inflammatory (e.g. ulcerative colitis) and iatrogenic (e.g. bariatric surgery) all can result in substantial reductions in vitamin D stores. In addition, with aging, dermal production of cholecalciferol declines and hence even reasonable UV light exposure may not be sufficient to maintain normal 25-hydroxyvitamin D levels.

It is also important to mention that there are acute causes of vitamin D deficiency. In patients receiving care in an intensive care unit for severe illness, there is some data suggesting that 25-hydroxyvitamin D levels may abruptly drop below the reference range.10,11 That said, data supporting a benefit for urgent restoration of vitamin D levels is lacking. Hence, we neither check vitamin D levels, nor add vitamin D replacement in this patient population.

Measurement of Vitamin D

An immunoassay can use a variety of detection techniques and 2 methods for the measurement of 25-hydroxyvitamin D are chemiluminescence and radioactivity. Chemiluminescent immunoassays can be automated and allow for a faster turn-around time, with the downside being that it is unable to distinguish between 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 and is reported only as a total 25-hydroxyvitamin D level. Radioactivity as a detection method is becoming less common but radioimmunoassays (RIA) are still available. In general, immunoassays tend to underestimate the concentration of 25-hydroxyvitamin D2 due to a lower affinity of the antibody for this analyte compared to 25-hydroxyvitamin D3. Liquid chromatography tandem mass spectrometry is a popular choice for measuring 25-hydroxyvitamin D, as it separates and measures 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 individually and has been established as the gold standard to which chemiluminescent and RIA assays are compared.

A study comparing measurements from different laboratories using either highperformance liquid chromatography (HPLC), RIA, or automated chemiluminescent assays for measurements of serum 25-hydroxyvitamin D demonstrated that the degree of variability of the results between methods and between laboratories, even when using the same method, confounded the diagnosis of vitamin D insufficiency.12 Specifically, some chemiluminescent and RIA assays were found to underestimate the contribution of 25-hydroxyvitamin D2 to total circulating 25-hydroxyvitamin D levels. Since ergocalciferol (vitamin D2) is often used for treatment of hypovitaminosis D, the inability to measure 25-hydroxyvitamin D2 could result in apparent laboratory failures in assessing therapeutic responses and/or lead to a misdiagnosis of vitamin D insufficiency or deficiency. Increases in unmeasured vitamin D could potentially result in dose escalation and subsequent dangerous consequences such as hypervitaminosis D. As a result, we suggest ascertaining the specific assay for 25-hydroxyvitamin D used by your own laboratory, not only during diagnosis (although measurement of only 25-hydroxyvitamin D3 in that setting would be of little harm), but also when monitoring response to treatment.

Strategies for Vitamin D Replacement

While many preparations of vitamin D and its metabolites are available to restore normal circulating levels of vitamin D, cholecalciferol and ergocalciferol are used more frequently as they are less expensive and, in particular, cholecalciferol is readily available to most patients in overthe-counter formulations (Table 1). While the biological activities of the two forms of vitamin D are comparable, in our practice cholecalciferol is generally the preferred formulation for vitamin D supplementation as there is data to suggest that it is more effective than ergocalciferol at increasing total 25-hydroxyvitamin D levels.13-15 This observation may be due to a predictable decrease in vitamin D3 level seen in patients treated with ergocalciferol.16 We do not utilize calcitriol in most instances unless the patient manifests clinical signs of hypocalcemia, have hypoparathyroidism (and the associated deficit in renal 1-hydroxylation) or if they would be more likely to absorb calcitriol (e.g. following bariatric surgery).

In adult patients without malabsorption, but with vitamin D deficiency (25-hydroxyvitamin D of < 20 ng/mL (<50 nmol/L)), we initially treat with 2,000-6,000 international units (IU) cholecalciferol daily or 50,000 IU of ergocalciferol (or cholecalciferol) weekly for 6-8 weeks.9 Once the course of therapy is complete, we repeat testing including a 25-hydroxyvitamin D level along with a measurement of serum calcium. In addition, in patients with secondary hyperparathyroidism prior to treatment, normalization of PTH levels can confirm adequacy of replacement, though we elect to do this infrequently to reduce cost and recognizing that changes in PTH levels can lag behind changes in vitamin D levels. Once replete, the vitamin D dose is reduced to a maintenance regimen generally of 2,000 IU/day cholecalciferol, or 50,000 IU of ergocalciferol (or cholecalciferol), every 14-30 days, and levels are again repeated in 2-3 months. We feel the majority of these patients are at a relatively high risk of repeat vitamin D deficiency in the future, and they are counseled that this is life-long therapy. Of note, in obese individuals, steady state levels may take a longer time to reach and hence we often delay repeat measurement for an additional 1-3 months.

Patients who have vitamin D insufficiency (25-hydroxyvitamin D between 21-29 ng/mL (51-74 nmol/L)) may be replaced with 400-2,000 IU cholecalciferol per day to achieve normal 25-hydroxyvitamin D levels. In general, we do not recommend high dose vitamin D without documentation of vitamin D deficiency as there are emerging data to suggest routine use of this type of supplementation in vitamin D replete individuals may not be beneficial.17

In patients with malabsorptive states, higher doses of vitamin D may be needed, even as high as 6,000 IU-10,000 IU daily of cholecalciferol or 50,000 IU twice weekly of ergocalciferol(or cholecalciferol) for short-term use.9 Once replete,these patients usually continue on slightly reduced or in some cases the same dose of vitamin D long term to avoid recurrence of vitamin D deficiency. We often follow vitamin D and calcium levels every 3-6 months going forward to ensure adequate replacement and less often once stable.

In addition, there are special patient populations that may benefit from treatment with metabolites of vitamin D. Patients with liver disease may have impairment of 25-hydroxylation of vitamin D and these patients may benefit from calcidiol (25-hydroxyvitamin D).18,19 Similarly, patients with severe renal disease or end-stage renal disease (ESRD, beyond stage 3) may have impairment in 1-hydroxylation of 25-hydroxyvitamin D and may benefit from calcitriol (1,25-dihydroxyvitamin D).20 Vitamin D analogs are often used in the ESRD patient population to reduce the sequelae of severe secondary hyperparathyroidism and the decision whether to treat a low 25-hydroxyvitamin D level is complex. Indeed, in many instances, we do replace these patients with cholecalciferol or ergocalciferol, to potentially reduce the effects of secondary hyperparathyroidism, even while recognizing that calcium balance is not significantly altered as a result.

Summary

Vitamin D has an important role in many physiological functions, most prominent and well established are its roles in calcium homeostasis and bone health and deficiency may be asymptomatic. Screening patients for vitamin D deficiency should be performed in individuals presenting with low bone mineral density. Cholecalciferol (D3 ) is the preferred replacement supplement, inexpensive, and readily available over-the-counter. Monitoring the success of vitamin D replacement is key and needs to be tailored to the patient in light of the vitamin D preparation to ensure sufficiency and avoid toxicity. The treatment plans outlined within this manuscript should provide practitioners with safe and effective means to restore vitamin D levels to the normal range.

References

  1. Dawson-Hughes B, Harris SS, Krall EA et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997;337:670-6.
  2. Pilz S, Gaksch M, Kienreich K, et al. Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial. Hypertension 2015;65:1195-1201.
  3. Mitri J, Dawson-Hughes B, Hu FB, et al. Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr 2011;94:486-94.
  4. Bischoff-Ferrari HA, Vellas B, Rizzoli R, et al; DO-HEALTH Research Group. Effect of Vitamin D Supplementation, Omega-3 Fatty Acid Supplementation, or a Strength-Training Exercise Program on Clinical Outcomes in Older Adults: The DO-HEALTH Randomized Clinical Trial. JAMA 2020;324:1855-1868.
  5. Pittas AG, Dawson-Hughes B, Sheehan P, et al; D2d Research Group. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med 2019;381:520-530.
  6. Shea MK, Fielding RA, Dawson-Hughes B. The effect of vitamin D supplementation on lower-extremity power and function in older adults: a randomized controlled trial. Am J Clin Nutr 2019;109:369- 379.
  7. Giustina A, Adler RA, Binkley N, et al. Consensus statement from 2nd International Conference on Controversies in Vitamin D. Rev Endocr Metab Disord 2020;21:89-116.
  8. Lips P, Bilezikian JP, Bouillon R. Vitamin D: Giveth to Those Who Needeth. J Bone Min Res Plus 2019;4:e10232.
  9. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011;96:1911–1930
  10. Czarnik T, Czarnik A, Gawda R, et al. Vitamin D kinetics in the acute phase of critical illness: A prospective observational study. J Crit Care. 2018;43:294-299.
  11. Waldron JL, Ashby HL, Cornes MP, et al. Vitamin D: a negative acute phase reactant. J Clin Pathol. 2013;66(7):620-2.
  12. Binkley N, Krueger D, Cogwill CS, et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab, 2004; 89:3152-3157.
  13. Tripkovic L, Lambert H, Hart K, et al. Comparison of vitamin D2 and vitamin D3 supplementation in raising serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. Am J Clin Nutr 2012;95:1357-64.
  14. Heaney RP, Recker RR, Grote J, et al. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab 2011; 96:E447-52.
  15. Trang HM, Cole DE, Rubin LA, et al. Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2. Am J Clin Nutr 1998;68:854-858.
  16. Lehmann U, Hirche F, Stangl GI, et al, Bioavailability of Vitamin D2 and D3 in Healthy Volunteers, a Randomized Placebo-Controlled Trial. J Clin Endocrinol Metab 2013;98,4339–4345,
  17. Burt LA, Billington EO, Rose MS, et al. Effect of High-Dose Vitamin D Supplementation on Volumetric Bone Density and Bone Strength: A Randomized Clinical Trial. JAMA 2019;322:736-745. Erratum in: JAMA 2019;322:1925.
  18. Cianferotti, L, Cricelli, C, Kanis, JA et al. The clinical use of vitamin D metabolites and their potential developments: a position statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF). Endocrine 2015;50:2–26.
  19. Brandi ML, Minisola S. Calcidiol [25(OH)D3]: from diagnostic marker to therapeutical agent. Curr Med Res Opin 2013;29:1565-72.
  20. Zand L; Kumar R. The Use of Vitamin D Metabolites and Analogues in the Treatment of Chronic Kidney Disease. Endocrinology & Metabolism Clinics of North America. 46(4):983-1007, 2017

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LETTER TO THE EDITOR

Re: Nutrition Issues in Gastroenterology, Series #205 Enhanced Recovery After Surgery and Immunonutrition: An Evidence-Based Approach

May 2021 • Volume XLV, Issue 5

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Dear Carol Rees Parrish MS, RDN:

We read with great interest the article titled, “Enhanced Recovery After Surgery (ERAS) and Immunonutrition (IMN): An EvidenceBased Approach” by Friedman & Thiele in your December 2020 issue.1 We appreciate the importance of this area of on-going research and the work that went into putting such an article together. However, after our review, we believe this article contains some important omissions and interpretation inaccuracies of the literature (particularly those in Table 2) that could skew the overall interpretation of the benefits of IMN to the reader.

In Table 2, Friedman & Thiele inaccurately report the study design and results of Thornblade et al., 2017.2 First, this was not a randomized controlled trial (as the title of Table 2 and inclusion criteria would suggest) but rather a prospective cohort study. Secondly, Thornblade et al. states “Although differences in serious adverse events were non-significant (RR = 0.76, 95% CI: 0.49- 1.16), prolonged length of stay (RR = 0.77, 95% CI: 0.58-1.01 p = 0.05) was lower in those receiving IMN.” Friedman & Thiele report in Table 2 that the “IMN group had increased LOS”.

Table 2 also references a study by HamiltonReeves et al. published in 2016.3 HamiltonReeves et al. published two manuscripts from their pilot study; one in 2016 and one in 2018.3,4 The data in Table 2 are the findings from the 2018 article, not the 2016 article as indicated. In 2016, Hamilton-Reeves et al. reported, “Participants receiving specialized IMN had a 33% reduction in postoperative complication rate (95% CI: 1-64; p = 0.060) and a 39% reduction in infection rate (95% CI: 8-70; p = 0.027) during late-phase recovery.”3 These positive findings were omitted in Friedman & Thiele’s review.

Friedman and Thiele also omitted positive results from Uno et al., 2016.5 In addition to reporting a significant decrease in postoperative infectious complications and serum IL-6, Uno et al., also reported that length of stay was significantly shorter, and severity of complications was significantly lower in the IMN group compared to control.5 These inaccuracies and omissions of positive findings may mislead the reader about the results reported by recent trials of IMN. Additionally, the publications listed in Table 2 are not included in the reference list making it difficult for readers to identify the primary source of these findings.

Friedman & Thiele raise the concern that, “there is some data that IMN can be harmful in certain populations” yet, mortality outcomes of recently published trials were not reported by Friedman & Thiele. Mortality rates were monitored in 9 of the 12 studies listed in Table 2.2,5-12 Of these nine studies, seven reported no difference in mortality between groups.2,5-10 The remaining two studies reported higher mortality in the control groups.11-12 Specifically, Lewis et al., stated that “death within 30 days postoperative was twice as high for those in the standard nutrition group versus the IMN group, with no deaths in the perprotocol analysis for those in the IMN group” and Klek et al. reported significantly increased mortality with standard nutrition compared to IMN at three months (16.7% versus 0.0%, p = 0.004).11-12 We echo Friedman & Thiele’s concerns about small sample sizes in these recently published trials, however, given the importance of this outcome, we believe it is an unfortunate omission of this review.

Friedman and Thiele highlight three societies which recommend or have favorable guidance on IMN use including the European Society for Clinical Nutrition and Metabolism (ESPEN), the American College of Surgeons Strong for Surgery Campaign and the American Society for Enhanced Recovery. Unfortunately, they omit that other societies also have recent guidelines which support the use of IMN. For example, the 2016 guidelines from the American Society for Parenteral and Enteral Nutrition and Society of Critical Care Medicine suggest the routine use of an immune-modulating formula (containing both arginine and fish oil) in the surgical ICU and the 2018 ERAS Guidelines for Colorectal Surgery state that perioperative IMN is beneficial with a strong recommendation grade.13,14

Finally, regarding the “Oxepa® experience,” mentioned by Friedman & Thiele, it is worth clarifying that the subsequent RCT performed by Rice et al., did not use Oxepa® as their intervention.13 Instead, this intervention consisted of bolus feedings of omega-3 fatty acids, g-linolenic acid, and antioxidants provided twice per day. Importantly, the control formula was isocaloric, but not isonitrogenous to the intervention.15 In fact, Rice et al., reported that the control formula contained five times more protein than the intervention formula (20g protein/240ml versus 3.8g protein/240ml, respectively). Given these prominent differences in study design, the results of Rice et al. do not necessarily negate the findings reported by Pontes-Arruda, et al. as is implied by Friedman & Thiele.16

Although we highlight these concerns, we agree with Friedman & Thiele that all research should adhere to the scientific method and be challenged by peer-review regarding scientific design, analysis, and interpretation and add that this caution should be practiced regardless of funding source. We also agree that further health economics and outcomes research will prove meaningful moving forward. It is essential to critically review healthcare practices to ensure that patients are provided the best possible care within the context of growing cost constraints. We truly appreciate the opportunity to discuss our concerns in order that your readers have the most accurate data when making decisions with their patients regarding immunonutrition.

Katie N. Robinson, PhD, MPH, RD

Medical Science Liaison
Scientific and Medical Affairs
Abbott Nutrition, Columbus, OH, USA

Beth Besecker, MD, MBA

Director of Medical Affairs
Adult Nutrition, U.S.
Abbott Nutrition, Columbus, OH, USA

References

References

  1. Thiele R, Friedman J. Enhanced Recovery After Surgery (ERAS) and Immunonutrition: An Evidence-Based Approach. Practical Gastroenterology. 2020:27.
  2. Thornblade LW, Varghese Jr TK, Shi X, et al. Preoperative immunonutrition and elective colorectal resection outcomes. Dis Colon Rectum. 2017;60(1):68.
  3. Hamilton-Reeves JM, Bechtel MD, Hand LK, et al. Effects of immunonutrition for cystectomy on immune response and infection rates: a pilot randomized controlled clinical trial. Eur Urol. 2016;69(3):389-92.
  4. Hamilton-Reeves JM, Stanley A, Bechtel MD, et al. Perioperative immunonutrition modulates inflammatory response after radical cystectomy: results of a pilot randomized controlled clinical trial. J Urol. 2018;200(2):292-301.
  5. Uno H, Furukawa K, Suzuki D, et al. Immunonutrition suppresses acute inflammatory responses through modulation of resolvin E1 in patients undergoing major hepatobiliary resection. Surgery. 2016;160(1):228-36.
  6. Mudge LA, Watson DI, Smithers BM, et al. Multicentre factorial randomized clinical trial of perioperative immunonutrition versus standard nutrition for patients undergoing surgical resection of oesophageal cancer. Br J Surg. 2018;105(10):1262-72.
  7. Hogan S, Solomon M, Rangan A, et al. The Impact of Preoperative Immunonutrition and Standard Polymeric Supplements on Patient Outcomes After Pelvic Exenteration Surgery, Taking Compliance Into Consideration: A Randomized Controlled Trial. JPEN J Parenter Enteral Nutr. 2020;44(5):806-14.
  8. Gade J, Levring T, Hillingsø J, et al. The effect of preoperative oral immunonutrition on complications and length of hospital stay after elective surgery for pancreatic cancer–a randomized controlled trial. Nutr. Cancer. 2016;68(2):225-33.
  9. Kanekiyo S, Takeda S, Iida M, et al. Efficacy of perioperative immunonutrition in esophageal cancer patients undergoing esophagectomy. Nutrition. 2019;59:96-102.
  10. Martin II RC, Agle S, Schlegel M, et al. Efficacy of preoperative immunonutrition in locally advanced pancreatic cancer undergoing irreversible electroporation (IRE). Eur J Surg Oncol. 2017;43(4):772-9.
  11. Lewis S, Pugsley M, Schneider C, et al. The Effect of Immunonutrition on Veterans Undergoing Major Surgery for Gastrointestinal Cancer. Fed Pract. 2018;35(Suppl 4):S49.
  12. Klek S, Scislo L, Walewska E, et al. Enriched enteral nutrition may improve short-term survival in stage IV gastric cancer patients: A randomized, controlled trial. Nutrition. 2017;36:46- 53.
  13. McClave SA, Taylor BE, Martindale R, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.
  14. Gustafsson UO, Scott MJ, Hubner M, et al. Guidelines for perioperative care in elective colorectal surgery: Enhanced Recovery After Surgery (ERAS®) society recommendations: 2018. World J Surg. 2019;43(3):659-95.
  15. Rice TW, Wheeler AP, Thompson BT, et al. Enteral omega-3 fatty acid, γ-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306(14):1574-81.
  16. Pontes-Arruda A, DeMichele S, Seth A, et al. The use of an inflammatio-modulating diet in patients with acute lung injury or acute respiratory distress syndrome: a meta-analysis of outcome data. JPEN J Parenter Enteral Nutr. 2008;32(6):596-605

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DISPATCHES FROM THE GUILD CONFERENCE, SERIES #36

Inflammatory Bowel Disease Therapies and Pregnancy and Neonatal Outcomes: Results from the PIANO Registry

May 2021 • Volume XLV, Issue 5
Florence-Damilola Odufalu,Uma Mahadevan

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Pregnant women with inflammatory bowel disease (IBD) are at higher risk for adverse pregnancy outcomes, and disease activity is a major determinant of these adverse outcomes. Controlling disease activity prior to conception and through the postpartum period is critical to improve health outcomes for both mother and child. However, due to misconceptions and a lack of robust safety data, discontinuation of IBD therapies during pregnancy can occur. Effective management of pregnant IBD patients is complex and requires a multidisciplinary approach. This update reviews the results from the prospective, 13 year Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry addressing common questions and concerns regarding IBD pregnancy and therapeutics, and maternal and fetal outcomes with respect to disease activity, infections, and infant growth and development.

Introduction

The peak age of onset of inflammatory bowel disease (IBD) is during the third decade of life, overlapping with reproductive years. Women with IBD are more likely to have adverse pregnancy complications, further exacerbated by active maternal disease.1 Although most patients with IBD have uncomplicated prenatal and postpartum courses, active disease complicates approximately 30% of pregnancies.2 Therefore, controlling maternal disease activity throughout pregnancy with stable pharmacologic therapy is a high priority. However, there remains concern about the safety of IBD therapies with respect to both mother and child. Medication non-adherence remains high in the pregnant IBD population and has the potential to worsen outcomes.3 This update highlights maternal and neonatal outcomes from the large multicenter prospective cohort, Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO).4

The recent publication of the PIANO registry data in Gastroenterology is a product of over a decade of research and 1500 pregnancies among women with IBD followed prospectively throughout pregnancy and the first four years of the infant’s life. Patients were enrolled across the U.S. through the Crohn’s Colitis Foundation Clinical Research Alliance. The primary objective of the PIANO registry is to address whether exposure to thiopurines, biologics and combination therapy (monoclonal antibodies and thiopurines) in pregnant women with IBD leads to an increase in specific adverse outcomes.

Pregnancy Outcomes

The investigators from the PIANO registry studied adverse outcomes during the prenatal and postpartum period. The study enrolled 1712 pregnant women with IBD, including Crohn’s Disease (CD), Ulcerative Colitis (UC) and IBD indeterminate. Of those, 1490 completed pregnancy with 1431 live births. The cohort had a higher number of patients (62%) with Crohn’s Disease. This is in comparison to the prevalence of 37 to 246 cases per 100,000 persons for ulcerative colitis and from 26 to 199 cases per 100,000 persons for Crohn’s Disease.5 The median disease duration was 8.3 years. The cohort included women with exposure to infliximab, adalimumab, certolizumab pegol, golimumab, natalizumab, vedolizumab, ustekinumab, mercaptopurine, azathioprine, or combination therapy.

Pregnancy outcomes examined included spontaneous abortion (SAB), preterm birth (<37 weeks), stillbirth, intrauterine growth restriction (IUGR), small for gestational age (SGA), low birth weight (LBW) (<2500 g), abruptio placenta, eclampsia/preeclampsia, cesarean delivery, Neonatal Intensive Care Unit (NICU) stay at birth and congenital malformations. Adverse pregnancy outcomes are outlined in Table 1. Overall, there were no differences in rates of pregnancy complications comparing those exposed to biologics and thiopurines and those not exposed to these medications. Similar findings were observed even when comparing pregnancies in mothers with IBD without any IBD medication exposure, biologic exposure excluding the 3rd trimester, and biologic exposure throughout pregnancy and through birth. This highlights that sustained IBD therapy throughout the duration of pregnancy does not increase maternal or infant complications.

There has been a rapid increase in Cesarean delivery since 1996, with rates in the general population as high as 33%.6 When active perianal disease is present (usually in CD), there is up to a 10-fold increased risk for fourth-degree laceration and elective Cesarean delivery is recommended.7 In the PIANO cohort, Cesarean delivery was observed in 43% of enrolled participants. Women on biologics or on combination therapy had higher rates of Cesarean delivery compared to the unexposed population. Active or severe IBD was the most common indication for Cesarean delivery for women with and without biologic or thiopurine exposure. However, in women on combination therapy, perianal disease was the most common indication for Cesarean delivery.

Disease Activity

The PIANO registry explored the impact of disease activity on both maternal and infant outcomes. UC mothers had significantly lower rates of remission per trimester and higher rates of flares compared to CD mothers. This finding is consistent across several studies as discussed in a meta-analysis of 14 studies, which found a significantly higher risk ratio of active disease during pregnancy in patients with UC who commenced pregnancy with active disease (55%) compared with those whose disease was in remission at conception (36%) (risk ratio, 2.0; 95% confidence interval, 1.5–3; P < .001).8 The higher rates of increased disease activity during pregnancy in UC compared to CD is interesting and may point to a mechanistic difference in response to the pregnancy state or may suggest the mothers with UC are undertreated compared to CD.

Results from PIANO also determined that the first trimester represents the period with the highest rate of flare. This was more pronounced in women with IBD not on therapy. Prior studies also correlate with these findings, demonstrating that discontinuation of anti-TNF before week 24 increases the risk of disease flare.9,10 In the PIANO cohort, higher rates of disease activity was associated with risk of spontaneous abortion (HR 3.41, 95% CI 1.51-7.69). These findings highlight that priority should be given to treating active disease in pregnancy and the critical role of preconception planning and a stable therapeutic regimen for improved pregnancy outcomes.

Infections

Pregnancy represents a unique immunologic state and dysregulation of immunological mechanisms is increasingly implicated in the pathogenesis of preterm birth, infections and other pregnancy related complications.11 Consequently, pregnancy presents many challenges for making decisions on how to approach and prevent infectious diseases. In pregnant women with IBD, there is a lack of data regarding rates of infections for mother and child with exposure to immunosuppressive therapies.

Birth, and the first few months of life, represent a critical time where children have vulnerable immune systems and are more susceptible to infection. In this critical time, part of the infant immunity is reliant on maternal antibodies that cross the placenta, and most of this transfer occurs during the third trimester. With the exception of certolizumab, biologics (monoclonal antibodies) actively cross the placenta.12,13 The effect of biologics presence in the neonate and the effect on the developing immune system raises several concerns about infection risk. Results from the TEDDY study suggested exposure to anti-TNFα drugs in utero does not increase the risk of severe infections in children born to mothers with IBD.9 Outcomes from the PIANO cohort confirmed that there was no increase in serious, non-serious or any infection in the first year of life in infants with thiopurine, biologic or combination therapy exposure (Figure 1). The majority of infections were non-serious, consisting primarily of otitis media and upper respiratory infections. Serious infections were rare, consisting of febrile illnesses requiring antibiotics, sepsis or hospitalization. Preterm birth was the only independent risk factor for infection (OR 1.73, 95% CI 1.19-2.51). Infection rates did not differ by individual biologic agent.

In nursing mothers receiving biologic therapy, very low levels of drug are detected in breastmilk.14,15 When compared to infants that were not breastfed, breastfed infants in PIANO with biologic exposure did not have higher rates of infection or reduction in achievement of developmental milestones.15

Daycare attendance among the general population is associated with an increased risk of serious and non-serious respiratory and gastrointestinal infections in the first years of life. Through the PIANO cohort, longitudinal information was examined in mother-child pairs. Overall, as expected, children in daycare had a higher rate of any infection. However, there was no difference in serious infections compared to those not in daycare. Biologic use was not associated with increase in infection in children attending daycare.16

It is well established that IBD patients on immunosuppression, particularly on combination therapy, are at risk for reduced or inadequate vaccine response.17 Data from the PIANO cohort has shed light on the long-term outcomes of vaccine response in infants with in utero exposure to biologics (monoclonal antibodies), thiopurines and combination therapy. In a study by Beaulieu, Ananthakrishnan et. al, data from infants born in the PIANO cohort demonstrate that the rates of adequate serologic response to Haemophilus influenzae B (HiB) and tetanus vaccines were similar among infants born to women on biologic therapy compared to those who were not exposed during pregnancy.18 There was also no association between cord blood or infant serum concentrations of biologics and adequacy of vaccine titers.18

Subgroup analysis of the TREAT registry demonstrated that anti-TNFa may be associated with increased maternal complications including infection.19 The rate of serious infections among those who had received infliximab was significantly higher than those who were not treated with infliximab (1.37 per 100 patient-years vs .65; RR [95% CI], 2.15[1.442–3.210]; P < .001), however this was confounded by disease activity as patients in the infliximab-treated group were more likely to be receiving prednisone, immunomodulators, and narcotic analgesics.19 In the PIANO cohort, maternal postpartum infections were rare. The incidence of perineal trauma and poor wound healing is not significantly different in the IBD patient population compared to the general population.20

Infant Growth and Development

Epidemiological studies have shown that infants exposed to stress in the womb are at higher risk of impaired cognitive development and growth restriction. A recent study by Stoye et al. examined the impact of maternal stress and found that chronic maternal stress state in pregnancy is associated with microstructure and structural connectivity of the newborn amygdala, a region of functional importance for early social development and emotion regulation.21

Studies in childhood growth and development are often difficult to ascertain causality, as there are several host factors and socioeconomic factors that contribute to growth and development. The PIANO study examined differences in infant growth and developmental milestones at 12 months of age by drug exposure. Overall, there were no differences in height or weight outcomes by drug exposure, or in odds of being very low for length or weight, controlling for preterm birth and maternal disease activity. There were also no differences in developmental milestones in the first year of life by exposure status within the cohort or compared to validated Ages & Stages Questionnaire norms. However, scores of biologic and/or thiopurine exposed infants were slightly higher than the general population in some categories.22

Congenital Malformation

The risk of congenital malformations related to biologic and thiopurine exposure were addressed in the PIANO cohort. Of the 1431 live births observed, 133 (9%) infants had congenital malformations. No pattern of congenital malformations was suggested based on IBD and medication exposure. The observed rate of congenital malformations was higher than reported in national observation estimates of congenital malformation prevalence data, but not different by drug of exposure. This increased rate is likely secondary to the close monitoring of each participant over one year and strict inclusion and classification of congenital malformations.23

Summary

Pregnant women with IBD are at higher risk for adverse complications of labor and delivery. This risk is heightened by active disease, emphasizing the importance of controlling disease activity prior to conception and through delivery. However, there remains concern about the safety and approach for managing IBD therapies during pregnancy, as well as the impact on the developing fetus and long-term outcomes. The PIANO registry clarified this risk to provide IBD patients and providers important safety information and guidance. The PIANO registry provides clear long-term safety data on mother and child demonstrating that biologic, thiopurine or combination during pregnancy is not associated with increased adverse maternal or fetal outcomes at birth or within the first year of life, and likely the first four years of life as well. With this collection of safety data, providers can advise that women with IBD on biologics, thiopurines or combination therapy should continue this regimen throughout pregnancy and the post-partum period to maintain remission for the health of the mother and the child. Future studies in PIANO will use the existing infrastructure to look at new therapies for IBD and will continue to follow children out to 18 years of age.

References

  1. Mahadevan U, Sandborn WJ, Li DK, Hakimian S, Kane S, Corley DA. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology. 2007;133(4):1106-1112.
  2. Caprilli R, Gassull MA, Escher JC, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: special situations. Gut. 2006;55 Suppl 1:i36-58.
  3. Mountifield RE, Prosser R, Bampton P, Muller K, Andrews JM. Pregnancy and IBD treatment: this challenging interplay from a patients’ perspective. J Crohns Colitis. 2010;4(2):176-182.
  4. Mahadevan U, Long MD, Kane SV, et al. Pregnancy and Neonatal Outcomes after Fetal Exposure To Biologics and Thiopurines among Women with Inflammatory Bowel Disease. Gastroenterology. 2020.
  5. Loftus EV, Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology. 2004;126(6):1504-1517.
  6. Martin JA, Hamilton BE, Osterman MJK. Births in the United States, 2019. NCHS Data Brief. 2020(387):1-8.
  7. Hatch Q, Champagne BJ, Maykel JA, et al. Crohn’s disease and pregnancy: the impact of perianal disease on delivery methods and complications. Dis Colon Rectum. 2014;57(2):174-178.
  8. Abhyankar A, Ham M, Moss AC. Meta-analysis: the impact of disease activity at conception on disease activity during pregnancy in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2013;38(5):460-466.
  9. Chaparro M, Verreth A, Lobaton T, et al. Long-Term Safety of In Utero Exposure to Anti-TNFalpha Drugs for the Treatment of Inflammatory Bowel Disease: Results from the Multicenter European TEDDY Study. Am J Gastroenterol. 2018;113(3):396-403.
  10. Truta B, Leeds IL, Canner JK, et al. Early Discontinuation of Infliximab in Pregnant Women With Inflammatory Bowel Disease. Inflamm Bowel Dis. 2020;26(7):1110-1117.
  11. PrabhuDas M, Bonney E, Caron K, et al. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol. 2015;16(4):328-334.
  12. Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of Adalimumab and Infliximab in Mothers and Newborns, and Effects on Infection. Gastroenterology. 2016;151(1):110-119.
  13. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of antitumor necrosis factor agents in pregnant patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11(3):286-292; quiz e224.
  14. Lahat A, Shitrit AB, Naftali T, et al. Vedolizumab Levels in Breast Milk of Nursing Mothers With Inflammatory Bowel Disease. J Crohns Colitis. 2018;12(1):120-123.
  15. Matro R, Martin CF, Wolf D, Shah SA, Mahadevan U. Exposure Concentrations of Infants Breastfed by Women Receiving Biologic Therapies for Inflammatory Bowel Diseases and Effects of Breastfeeding on Infections and Development. Gastroenterology. 2018;155(3):696-704.
  16. Long MD, Siegel CA, Abraham BP, Chiorean M, Mahadevan U. Day Care Attendance and Infectious Complications in Children Born to Mothers with Inflammatory Bowel Disease. Clin Gastroenterol Hepatol. 2021.
  17. Mamula P, Markowitz JE, Piccoli DA, Klimov A, Cohen L, Baldassano RN. Immune response to influenza vaccine in pediatric patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2007;5(7):851-856.
  18. Beaulieu DB, Ananthakrishnan AN, Martin C, Cohen RD, Kane SV, Mahadevan U. Use of Biologic Therapy by Pregnant Women With Inflammatory Bowel Disease Does Not Affect Infant Response to Vaccines. Clin Gastroenterol Hepatol. 2018;16(1):99-105.
  19. Lichtenstein GR, Feagan BG, Mahadevan U, et al. Pregnancy Outcomes Reported During the 13-Year TREAT Registry: A Descriptive Report. Am J Gastroenterol. 2018;113(11):1678-1688.
  20. Lewin SM, Martin C, Scherl E, Stein DJ, Ganguly EK, Mahadevan U. 161 – Risk Factors for Poor Wound Healing after Episiotomy and Perineal Laceration: Results from the Piano Registry. Gastroenterology. 2018;154(6, Supplement 1):S-45.
  21. Stoye DQ, Blesa M, Sullivan G, et al. Maternal cortisol is associated with neonatal amygdala microstructure and connectivity in a sexually dimorphic manner. Elife. 2020;9.
  22. Mahadevan U, Martin CF, Chambers C, et al. 1 Achievement of Developmental Milestones Among Offspring of Women With Inflammatory Bowel Disease: The PIANO Registry. Gastroenterology. 2014;146(5, Supplement 1):S-1.
  23. Mai CT, Isenburg JL, Canfield MA, et al. National population-based estimates for major birth defects, 2010-2014. Birth Defects Res. 2019;111(18):1420-1435.

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FROM THE PEDIATRIC LITERATURE

Radiation Exposure during Pediatric ERCP

May 2021 • Volume XLV, Issue 5

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Endoscopic retrograde cholangiopancreatography (ERCP) is increasing as a pediatric gastrointestinal diagnostic and therapeutic modality. However, ERCP is associated with ionizing radiation exposure, and in adult gastroenterology literature, radiation exposure is reduced if procedures are performed by high-volume endoscopists. It is unknown if this same finding occurs with pediatric gastroenterologists who perform ERCP.

The authors of this study performed a retrospective review of all pediatric ERCPs completed at a single, large children’s hospital over a 15-year period (2002-2017). ERCPs in this setting were performed by both adult and pediatric gastroenterologists, and a “highvolume gastroenterologist” was defined as one who performed greater than 100 adult and pediatric ERCPs per year while a “low-volume gastroenterologist” was defined as one who performed less than 100 such procedures. Each gastroenterologist had ERCP data reviewed including obtaining information about each pediatric patient (age, sex, diagnosis, and ERCP intervention). Fluoroscopy time during ERCP was compared between high-volume and low-volume gastroenterologists.

A total of 385 ERCPs were performed on 321 patients by 8 gastroenterologists (5 adult; 3 pediatric). Three adult gastroenterologists and one pediatric gastroenterologist were high-volume providers while the rest were low volume. A separation into high- versus low-volume providers demonstrated that 175 ERCPs were performed by low-volume gastroenterologists and 210 were performed by high-volume gastroenterologists. The average patient age was 13.4 years with 51% of patients being Caucasian. All patient variables did not differ significantly between low-volume and high-volume gastroenterologists. Throughout the study, the proportion of therapeutic ERCPs increased significantly over time. Median fluoroscopy time per procedure was 4.85 (± 2.68) minutes. High-volume gastroenterologists had a median fluoroscopy time of 2.04 minutes which was significantly lower than low-volume gastroenterologists who had a median fluoroscopy time of 5.21 minutes. Univariate and multi-variate analyses also demonstrated significantly increased fluoroscopy time for patients who needed an ERCP for a pancreas disorder, for patients with any type of ductal stricture, and for any patient less than 4 years of age or greater than 16 years of age. Significantly decreased fluoroscopy time was associated with patients who had undergone prior ERCP. The ASGE Procedure Complexity Scale for patient procedures did not predict fluoroscopy time although the Stanford Fluoroscopy Complexity Scale did show a significant correlation between total fluoroscopy time and increasingly complex pediatric procedures. Finally, ERCPs with fluoroscopy controlled by a radiology technician or radiologist had significantly higher fluoroscopy time compared to endoscopist-controlled fluoroscopy, and C-arm use was associated with significantly more fluoroscopy time compared to use of a fixed fluoroscopy unit.

This study demonstrates that high-volume endoscopists who perform ERCP utilize less fluoroscopy time comparted to low-volume endoscopists. Also, the person controlling the fluoroscopy and type of machine providing imaging appears to effect exposure time. Multicenter as well as prospective studies are needed to confirm these important findings This study demonstrates that high-volume endoscopists who perform ERCP utilize less fluoroscopy time comparted to low-volume endoscopists. Also, the person controlling the fluoroscopy and type of machine providing imaging appears to effect exposure time. Multicenter as well as prospective studies are needed to confirm these important findings

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The Risk of Cancer in Children with Inflammatory Bowel Disease

May 2021 • Volume XLV, Issue 5

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Inflammatory bowel disease (IBD) in children is associated with chronic inflammation, and such inflammation increases the risk of cancer development. Since IBD incidence is increasing in children, the authors of this study performed a meta-analysis regarding the potential cancer risk in children with IBD using PRISMA guidelines. Potential articles and abstracts evaluating the risk of cancer in pediatric patients with IBD (defined as occurring under 25 years of age) were obtained from PubMed, Google Scholar, Scopus, Cochrane Central Register of Controlled Trials as well as from major cancer and gastroenterology meetings. IBD terms such as “Crohn’s disease”, “ulcerative colitis”, and “inflammatory bowel disease” combined with various potential cancer terms including “childhood”, “cancer”, “malignancy”, as well as several types of malignancy were searched via these databases. Each potential data source was reviewed by 2 authors, and the Jadad score and the Cochrane Risk of Bias Assessment Instrument were used to determine randomized controlled trial quality. The NewcastleOttawa Scale was used to assess observational study quality. GRADE criteria (Grading of Recommendations, Assessment, Development and Evaluation) were used to determine risk of bias. The primary outcome was to determine the risk of cancer noted in studies using standardized incidence ratios. Secondary outcomes included the pooled incidence rates of all cancers as well as site-specific cancers. Meta-regression analysis was performed to determine if medication type influenced cancer development.

A large number of potential studies (total of 969,127) was initially identified; however, only 66 studies including 38,092 patients were included in the final analysis. A total of 44 studies evaluated patients with Crohn’s disease; 31 studies evaluated patients with ulcerative colitis; and 5 studies evaluated patients with IBD (no distinction given). Patients less than 18 years of age were included in 50 studies (75.76%) while the remainder of the studies included patients 18 to 24 years of age. A total of 14 of the 62 observational studies had a Newcastle-Ottawa score of 6 or higher. All randomized controlled trials had a Jadad score of 2 or 3. No inter-rater disagreement for data scoring was noted between the study authors.

A total of six retrospective observational studies including 17,450 patients evaluated the standardized incidence ratio of cancer occurrence. At least 125 patients developed a malignancy although the final number of patients with a malignancy was not clear. Four of these studies evaluated patients with Crohn’s disease and noted a 2.4-fold increased risk of cancer (pooled SIR 2.42, P < .0001, 95% CI 1.90-3.06; meta-analysis heterogeneity score (I2) = 0%) while five of these studies evaluated patients with ulcerative colitis and noted a 2.1-fold increased risk of cancers (pooled SIR 2.10, P < .0001, 95% CI 1.51-2.90; I2 = 41.54%). A pooled standardized risk ratio for all pediatric patients with IBD was 2.39 (P < .0001, 95% CI 2.00-2.86; I2 = 0%). The pooled incidence of overall pediatric cancers came from 9 prospective and 44 retrospective studies. The pooled incidence rate of overall cancers in patients with Crohn’s disease was 0.014 (95% CI 0.0087- 0.021; I2 = 78.90%) while the pooled incidence rate of overall cancers in patients with ulcerative colitis was 0.031(95% CI 0.018-0.052; I2 = 91.59%) and the pooled incidence rate of overall cancers in all of the included studies was 0.018 (95% CI 0.013-0.025; I2 = 89.10%). A metaregression analysis determined that follow-up study duration positively correlated with cancer development risk, and this finding was statistically significant. No such association was seen with various medications used to treat pediatric IBD including use of steroids, immunomodulators, and anti-tumor necrosis factor medications.

Regarding specific cancer development, not enough data was available to perform a metaanalysis for the development of colorectal cancer. However, the pooled incidence rate of colorectal cancer in CD was 0.0075 (95% CI 0.0049-0.011; I2 = 41.30%) while the pooled incidence rate of colorectal cancer in ulcerative colitis was 0.020 (95% CI 0.012-0.034; I2 = 87.95%) and the pooled incidence rate in all pediatric IBD patients was 0.010 (95% CI 0.0074-0.014; I2 = 81.30%). There appeared to be a statistically significant and positive correlation between male patients and the risk of colorectal cancer while a statistically significant and negative correlation was seen between age of IBD diagnosis / onset and risk of colorectal cancer with younger patients at time of diagnosis having an increased risk of colorectal cancer long term. Only one study provided standardized incidence ratio data on hematologic cancers in the setting of IBD. However, enough studies were present to determine the pooled incidence rate of pediatric patients with Crohn’s disease and ulcerative colitis. Patients with Crohn’s disease had a pooled incidence rate of 0.0061 (95% CI 0.0040-0.0090; I2 = 27.14%) while patients with ulcerative colitis having a pooled incidence rate of 0.0045 (95% CI 0.0040-0.0090; I2 = 31.66%).

The pooled incidence rate of all pediatric patients with IBD was 0.0054 (95% CI 0.0039-0.0075; I2 = 35.25%). Meta-regression analysis showed no risk of hematologic cancers in patients having received steroids, immunomodulators, or antitumor necrosis factor medications. Finally, cumulative meta-analyses showed that all cancer types had a decreasing incidence over time.

This study shows that pediatric patients with IBD do have an inherent cancer risk, but it is reassuring that the risk of cancer is not associated with standard IBD therapy. It also is helpful to know that the incidence of cancer in this study decreased over time suggesting pediatric patients with IBD may be maintaining good disease control over time. However, the range of heterogeneity of meta-analyses in this study suggests that better data is needed to answer this question more clearly.

Komaki Y, Komaki F, Yamada A, Micic D, Ido A, Sakuraba A. Risk of cancers in patients with pediatric inflammatory bowel diseases: a systemic review and meta-analysis. Journal of Pediatrics 2021; 229: 102-117.

FROM THE LITERATURE

Barrett’s Esophagus in Patients with Scleroderma

May 2021 • Volume XLV, Issue 5

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To assess the prevalence of Barrett’s esophagus (BE) in a large cohort of patients with systemic sclerosis or scleroderma (SSc), women referred from the Mayo Clinic Arizona Rheumatology Clinic who completed EGD between 2002 and 2020 were included. Demographic and highresolution manometry data were evaluated. The diagnosis of scleroderma was confirmed by an expert rheumatologist. The BE diagnosis was confirmed by an expert gastrointestinal pathologist.

A total of 235 women with SSc underwent EGD and high-resolution manometry (HRM) was completed in 172 patients. Women with SSc with BE were significantly more likely to have scleroderma esophagus (absent contractility with hypotensive lower esophageal sphincter), on HRM than women with SSc without BE.

There were 30 patients with SSc (12.8%), with histologically-proven BE. Dysplasia was found in 13 (43.3%), 4 with indefinite, 7 with low-grade and 2 with adenocarcinoma. The incidence of any dysplasia was 5.3% per year (0.9% per year for adenocarcinoma).

In this large study on prevalence of BE in patients with SSc, yielding a prevalence of 12.8%, women with SSc with BE were significantly more likely to have absent contractility with a hypotensive lower esophageal sphincter finding on HRM. The high prevalence and incidence of dysplasia found suggest that women with SSc should be included in the screening recommendations for BE.

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FROM THE LITERATURE

Safety and Efficacy of a New Sulfate-Based Tablet Preparation for Colonoscopy

May 2021 • Volume XLV, Issue 5

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This new-based bowel prep for colonoscopy contains poorly-absorbed sulfate salt, which acts to retain water within the intestinal lumen, resulting in a copious diarrhea in bowel cleansing. This study was carried out to evaluate the safety and efficacy of these oral sulfate tablets (OST), compared with a US FDA-approved bowel prep solution containing PEG3350, electrolytes, and ascorbate (PEG-EA).

A total of 515 patients with a mean age of 57 years were enrolled in a single-blind, multi-center, noninferiority study. Subjects were assigned either PEG-EA or OST administered in split-dose regimen starting the evening before colonoscopy. PEG EA was taken according to its approved labeling (1 L of prep solution with 16 oz. of additional water) in the evening and again in the morning. OST patients took a total of 24 tablets, 12 in the evening and the following morning, taken with 16 ounces of water with each dose of 12 tablets; then drinking an additional 32 ounces of water with each dose. Colonoscopies were performed by blinded investigators. Cleansing efficacy was evaluated globally and segmentally using a 4-point scale (Excellent-no more than small bits of feces/ fluid, which can be suctioned easily; achieves clear visualization of the entire mucosa); Good-feces/ fluid requiring washing and suctioning, but still achieving clear visualization of the entire colon mucosa; Fair–enough feces after washing and suctioning to prevent clear visualization of the entire colon mucosa; Poor–large amounts of fecal residue and additional bowel preparation required.

Scores of Good or Excellent were considered to be a success. Safety was assessed by spontaneously reported adverse events, solicited ratings of expected prep symptoms and laboratory testing.

A high rate of cleaning success was seen with OST (92%), which was noninferior to PEG-EA (89%). Only a small proportion of patients rated their expected gastrointestinal symptoms as severe (less than 5%). No clinically significant differences were seen between the preps for chemistry and hematology parameters. No serious adverse experiences were reported with OST.

This preparation of sulfate tablets achieved a high level of cleansing in the study, compared with US FDA-approved preps. OST was noninferior to PEG-EA in this study and achieved significantly more excellent preps overall and in the proximal colon. The OST prep was well tolerated with a similar rate of spontaneously reported adverse experiences to PEG-EA and a low rate of severe expected gastrointestinal symptoms.

Di Palma, J., Bhandari, R., Cleveland, M., et al. “A Safety and Efficacy Comparison of a New Sulfate-Based Tablet Bowel Preparation Versus a PEG and Ascorbate Comparator in Adult Subjects Undergoing Colonoscopy.” American Journal of Gastroenterology 2021; Vol. 116, pp. 319-328.

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FROM THE LITERATURE

IBD and the Risk of COVID-19

May 2021 • Volume XLV, Issue 5

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To determine whether patients with IBD have an increased risk of developing SARS-CoV-2 compared with patients without IBD, a nationwide, retrospective cohort study was carried out in the U.S. Veterans Affairs Healthcare System from January 2020 to June 30, 2020. Each patient with IBD was matched with 2 patients without IBD on age, sex, race, location, and comorbidities. The outcome of interest was development of SARSCoV-2.

A total of 38,378 patients with IBD and 67,433 patients without IBD, were evaluated; 87 (0.22%) and 132 (0.20%) patients developed incident CoVID-2 infection, respectively.

It was concluded that patients with IBD are not at significantly increased risk of developing SARS CoV-2 infection when compared with patients without IBD.

Khan, N., Patel, V., Xie, D., et al. “Are Patients with Inflammatory Bowel Disease at an Increased Risk of Developing SARS/CoVID-2 than Patients Without Inflammatory Bowel Disease? Results From a Nationwide Veterans’ Affairs Cohort Study.” American Journal of Gastroenterology 2021; Vol. 116, pp. 808-810.

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