J Clin Gastroenterol
and collaboration laboratory.
Volume 49, Number 3, March 2015
with a genetic
Mei-Chuan Chen, MBBS*w Chen-Jung Chang, MD*wz Yung-Hsiu Lu, PhDy8 Dau-Ming Niu, MDy8 Horng-Yuan Lou, MD*w Chun-Chao Chang, MD*w *Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University wDepartment of Internal Medicine, Division of Gastroenterology and Hepatology Taipei Medical University Hospital zFaculty of Medicine, School of Medicine National Yang Ming University yDepartment of Pediatrics, Taipei Veterans General Hospital 8Institute of Clinical Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan
REFERENCES 1. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439–450. 2. Ramdall RB, Cunha L, Astrin KH, et al. Acute intermittent porphyria: novel missense mutations in the human hydroxymethylbilane synthase gene. Genet Med. 2000;2:290–295. 3. Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2012;2012:19–27. 4. Mustajoki P. Normal erythrocyte uroporphyrinogen I synthase in a kindred with acute intermittent porphyria. Ann Intern Med. 1981;95:162–166. 5. Marsden JT, Peters TJ. Rhabdomyolysis in a patient with acute intermittent porphyria. Ann Clin Biochem. 2004;41(pt 4):341–343. 6. Garcia-Martul M, Santana-Cabrera L, Santos-Moyano Z, et al. Rhabdomyolysis after correction of severe hyponatremia due to an attack of acute intermittent porphyria. Nefrologia. 2008;28:563–564. 7. Yrjonen A, Pischik E, Mehtala S, et al. A novel 19-bp deletion of exon 15 in the HMBS gene causing acute intermittent porphyria associating with rhabdomyolysis during an acute attack. Clin Genet. 2008;74:396–398. 8. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: Pathophysiology and diagnosis. Eur J Intern Med. 2007;18:90–100. 9. Suarez JI, Cohen ML, Larkin J, et al. Acute intermittent porphyria: clinicopathologic correlation. Report of a case and review of the literature. Neurology. 1997;48:1678–1683. 10. Anyaegbu E, Goodman M, Ahn SY, et al. Acute intermittent porphyria: a
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r
diagnostic challenge. J Child Neurol. 2012;27:917–921. 11. Trimarchi H, Gonzalez J, Olivero J. Hyponatremia-associated rhabdomyolysis. Nephron. 1999;82:274–277.
The Management of Severe Ulcerative Colitis During the Third Trimester of Pregnancy To the Editor: Inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) have a peak incidence during child-bearing years. The management of IBD during pregnancy can provoke a great deal of anxiety in patients and physicians alike. Compared with age-matched controls, pregnant women with IBD are more likely to have spontaneous abortions, preterm deliveries, and low fetal birth weights. These risks and worsening of the IBD are increased by active disease at the time of conception and during pregnancy.1,2 Mounting evidence has demonstrated the relative safety of immunosuppressives and biologics in the treatment of IBD.3–5 However, the recognition of placental transfer of biologicals during the final months of gestation has raised concern regarding neonatal development.6,7 IBD gastroenterologists consider terminating the biologics in the first or second trimester so as to minimize placental transfer in the third.2,6,7 An important issue that has not been addressed is how to manage recurrence of IBD activity in the third trimester. The potential severity of UC and the need for urgent colectomy during late pregnancy has been well documented.8 We present the scenario of a 33year-old woman with a history of UC admitted to Lenox Hill Hospital 30 weeks into her second pregnancy complaining of bloody diarrhea and abdominal pain. She was diagnosed 3 years before with mild left-sided UC that responded well to mesalamine enemas. An exacerbation had also occurred during her first pregnancy. The UC was Project is in part supported by the New York Crohn’s Foundation. The authors declare that they have nothing to disclose.
2014 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editor
in clinical remission until 6 weeks before presentation, and she was treated with oral mesalamine and steroids and then with IV and rectal steroids. However, she continued to have bloody diarrhea and required the transfusion of 4 units of packed red blood cells. Upon transfer to Lenox Hill, she was passing 10 to 15 bloody bowel movements per day with crampy, leftlower quadrant abdominal pain and tenesmus. A gravid abdomen was noted on examination with left-lower quadrant tenderness. Her Hb was 10.2, and the Creactive protein was elevated at 4.6.
MANAGEMENT OPTIONS Ideally, management of a pregnant UC patient should begin months before conception with an open dialog between the physician and patient. The increased risk of poor pregnancy outcomes needs to be reviewed and the risks and benefits of medical therapy weighed. Management of active disease is paramount as the greatest risk to the mother and fetus is from uncontrolled disease.1 The diagnostic evaluation of an exacerbation of bloody diarrhea should begin with laboratory and stool studies to rule out coincident gastrointestinal infections. Caution should be taken when interpreting laboratory values in the pregnant women. For example, hemoglobin levels vary during normal pregnancy and C-reactive protein may be elevated as early as the fourth week of gestation even in patients without UC. Imaging may be necessary to rule out complications such as obstruction or toxic megacolon. Radiation, however, should be avoided during pregnancy if possible. Ultrasound and magnetic resonance imaging without gadolinium are safe modalities when needed to evaluate the gravid abdomen. Endoscopy is preferably avoided, particularly during the first trimester of pregnancy but refractory disease or clinically significant bleeding may require otherwise. In these cases, flexible sigmoidoscopy is usually adequate to assess the colitis but not always. Minimal or no sedation should be used to reduce risk of fetal hypoxia. Surgery can and should be considered for severe refractory disease during pregnancy just as in other cases. Late in pregnancy surgery and simultaneous delivery can be considered. For CD, elective cesarean section should be considered with active perirectal abscess or fistulas. For UC a subtotal colectomy should be www.jcge.com |
257
J Clin Gastroenterol
Letters to the Editor
favored in anticipation of later creating an ileoanal pouch anastomosis with preservation of the anal sphincter. Most medications commonly used for IBD can be continued safely during pregnancy. Aminosalicylates (pregnancy class B) are considered low risk but are insufficient for the current situation. Rare cases of diarrhea in infants during breastfeeding have been reported but not significant enough to recommend against its use. Patients on sulfasalazine should take folic acid supplementation to reduce the risk of neural tube defects. Antibiotics should be avoided if possible, especially quinolones which have been associated with arthropathy in children and metronidazole which has been associated with cleft palate when used in the first trimester. Corticosteroids (class C) also pose a slight risk of cleft palate when given during the first trimester. Methotrexate falls in pregnancy category X and must be discontinued at least 6 months before conception. The immunosuppressive drugs azathioprine (AZA) and 6-mercatopurine (6-MP), are classified as category D because of teratogenicity in animal studies. However, extensive experience with these drugs and the transplant, rheumatologic, and IBD literature has not supported this association.9,10 Therefore, the continuation of these medications in patients who are in remission is not contraindicated.3,4,9,10 However, taking AZA/6-MP for the first time during pregnancy is not recommended because of the risk of pancreatitis or leukopenia which can jeopardize the fetus. Therefore, consideration can be given to stopping the immunosuppressives in patients who are in remission on combination therapy. AZA/6-MP are minimally transferred into breast milk and thought to be safe for breastfeeding.6,7 The biologicals most commonly used in the treatment of IBD are the anti-TNFs infliximab, adalimumab, and certolizumab. These drugs are pregnancy category B and mounting data support their safety in pregnancy.2,3,10 However, questions remain as to the effect on the long-term development of the newborn. Infliximab and adalimumab are IgG1 antibodies which undergo efficient placental transfer during the second and third trimesters. Infliximab levels have been detected in the infants as late as 7 months after birth. Exposure to live vaccines is contraindicated for the mother and the child as well.
258 | www.jcge.com
The limited data available suggest that stopping biologics in the second trimester may increase the risk of poor pregnancy outcomes without any clinical benefit. We would recommend against stopping biologicals during the pregnancy when patients are well controlled on their current regimen.
MANAGEMENT OF PRESENTED CASE A decision was made to perform a flexible sigmoidoscopy; check for Clostridium difficile, hepatitis B, and tuberculosis; and to start Infliximab when this workup was negative. The examination showed severely friable ulcerated mucosa contiguous from the rectum to the hepatic flexure. An infusion of Infliximab was then initiated at 5 mg/kg. The very next day, the patient reported improvement in her symptoms including a decrease in pain, stool frequency, and tenesmus. She was observed in the hospital for 5 more days as her symptoms progressively improved. On the day of discharge she was passing semiformed stool without any gross blood. She delivered a healthy 7 lb 13 oz baby at 38 weeks via C-section without any complication and was advised to avoid giving the child the rotavirus vaccine for 6 months after birth because it is a live vaccine. The child was breast fed for 1 month without complication. Both mother and the baby are currently healthy and the UC continues to be in endoscopic remission. The patient is maintained on infliximab every 8 weeks.
CONCLUSIONS Biologic agents are safe during pregnancy in IBD patients. In a patient whose disease is in remission, the timing of the last dose of biologics should be determined in conjunction with the patient after weighing the proven risks of disease activity against the theoretical risks of placental transfer of biologics to the newborn. In contrast, disease activity during the third trimester is clearly an imminent threat to the mother and fetus and must be controlled quickly. In such a scenario, the initiation of a biological is not contraindicated and probably the treatment of choice. Anish Mammen, MD Burton I. Korelitz, MD, MACG Department of Gastroenterology Lenox Hill Hospital, New York, NY
Copyright
r
Volume 49, Number 3, March 2015
REFERENCES 1. Baiocco PJ, Korelitz BI. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol. 1984;6: 211–216. 2. Mahadevan U, Sandborn WJ, Li DK, et al. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology. 2007;133:1106–1112. 3. Casanova MJ, Chaparro M, Domenech E, et al. Safety of thiopurines and antiTNF-a drugs during pregnancy in patients with inflammatory bowel disease. Am J Gastroenterol. 2013;18: 433–440. 4. Nielson OH, Loftus EV Jr, Jess T. Safety of TNF-a inhibitors during IBD pregnancy: a systematic review. BMC Med. 2013;11:174–187. 5. Francella A, Dyan A, Bodian C, et al. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology. 2003;124:9–17. 6. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor factor agents in pregnant patients with inflammatory bowel disease. Clin Gastro Hepatol. 2013;11:286–292. 7. Zelinkova Z, Van Der Ent C, Brun KF, et al. Effects of discontinuing anti-tumor necrosis factor therapy during pregnancy on the course of inflammatory bowel disease and neonatal exposure. Clin Gastro Hepatol. 2013;11:318–321. 8. Anderson JB, Turner GM, Williamson RCN. Fulminant ulcerative colitis in later pregnancy and the puerperium. J R S Med. 1987;80:492–494. 9. Korelitz BI. Continuing immunomodulators and biologic medications in pregnant IBD patients. Inflamm Bowel Dis. 2007;13:1441–1442. 10. Gisbert JP. Safety of immunomodulators and biologics for the treatment of inflammatory bowel disease during pregnancy and breast-feeding. Inflamm Bowel Dis. 2010;16:881–894.
Refractory Acute Upper Gastrointestinal Nonvariceal Bleeding Should Arterial Embolization be the Rule? To the Editor: We read with great interest the article by Sildiroglu et al1 recently The author declares that there is nothing to disclose.
2014 Wolters Kluwer Health, Inc. All rights reserved.
and collaboration laboratory.
Volume 49, Number 3, March 2015
with a genetic
Mei-Chuan Chen, MBBS*w Chen-Jung Chang, MD*wz Yung-Hsiu Lu, PhDy8 Dau-Ming Niu, MDy8 Horng-Yuan Lou, MD*w Chun-Chao Chang, MD*w *Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University wDepartment of Internal Medicine, Division of Gastroenterology and Hepatology Taipei Medical University Hospital zFaculty of Medicine, School of Medicine National Yang Ming University yDepartment of Pediatrics, Taipei Veterans General Hospital 8Institute of Clinical Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan
REFERENCES 1. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439–450. 2. Ramdall RB, Cunha L, Astrin KH, et al. Acute intermittent porphyria: novel missense mutations in the human hydroxymethylbilane synthase gene. Genet Med. 2000;2:290–295. 3. Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2012;2012:19–27. 4. Mustajoki P. Normal erythrocyte uroporphyrinogen I synthase in a kindred with acute intermittent porphyria. Ann Intern Med. 1981;95:162–166. 5. Marsden JT, Peters TJ. Rhabdomyolysis in a patient with acute intermittent porphyria. Ann Clin Biochem. 2004;41(pt 4):341–343. 6. Garcia-Martul M, Santana-Cabrera L, Santos-Moyano Z, et al. Rhabdomyolysis after correction of severe hyponatremia due to an attack of acute intermittent porphyria. Nefrologia. 2008;28:563–564. 7. Yrjonen A, Pischik E, Mehtala S, et al. A novel 19-bp deletion of exon 15 in the HMBS gene causing acute intermittent porphyria associating with rhabdomyolysis during an acute attack. Clin Genet. 2008;74:396–398. 8. Giannoglou GD, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: Pathophysiology and diagnosis. Eur J Intern Med. 2007;18:90–100. 9. Suarez JI, Cohen ML, Larkin J, et al. Acute intermittent porphyria: clinicopathologic correlation. Report of a case and review of the literature. Neurology. 1997;48:1678–1683. 10. Anyaegbu E, Goodman M, Ahn SY, et al. Acute intermittent porphyria: a
Copyright
r
diagnostic challenge. J Child Neurol. 2012;27:917–921. 11. Trimarchi H, Gonzalez J, Olivero J. Hyponatremia-associated rhabdomyolysis. Nephron. 1999;82:274–277.
The Management of Severe Ulcerative Colitis During the Third Trimester of Pregnancy To the Editor: Inflammatory bowel disease (IBD), Crohn’s disease (CD), and ulcerative colitis (UC) have a peak incidence during child-bearing years. The management of IBD during pregnancy can provoke a great deal of anxiety in patients and physicians alike. Compared with age-matched controls, pregnant women with IBD are more likely to have spontaneous abortions, preterm deliveries, and low fetal birth weights. These risks and worsening of the IBD are increased by active disease at the time of conception and during pregnancy.1,2 Mounting evidence has demonstrated the relative safety of immunosuppressives and biologics in the treatment of IBD.3–5 However, the recognition of placental transfer of biologicals during the final months of gestation has raised concern regarding neonatal development.6,7 IBD gastroenterologists consider terminating the biologics in the first or second trimester so as to minimize placental transfer in the third.2,6,7 An important issue that has not been addressed is how to manage recurrence of IBD activity in the third trimester. The potential severity of UC and the need for urgent colectomy during late pregnancy has been well documented.8 We present the scenario of a 33year-old woman with a history of UC admitted to Lenox Hill Hospital 30 weeks into her second pregnancy complaining of bloody diarrhea and abdominal pain. She was diagnosed 3 years before with mild left-sided UC that responded well to mesalamine enemas. An exacerbation had also occurred during her first pregnancy. The UC was Project is in part supported by the New York Crohn’s Foundation. The authors declare that they have nothing to disclose.
2014 Wolters Kluwer Health, Inc. All rights reserved.
Letters to the Editor
in clinical remission until 6 weeks before presentation, and she was treated with oral mesalamine and steroids and then with IV and rectal steroids. However, she continued to have bloody diarrhea and required the transfusion of 4 units of packed red blood cells. Upon transfer to Lenox Hill, she was passing 10 to 15 bloody bowel movements per day with crampy, leftlower quadrant abdominal pain and tenesmus. A gravid abdomen was noted on examination with left-lower quadrant tenderness. Her Hb was 10.2, and the Creactive protein was elevated at 4.6.
MANAGEMENT OPTIONS Ideally, management of a pregnant UC patient should begin months before conception with an open dialog between the physician and patient. The increased risk of poor pregnancy outcomes needs to be reviewed and the risks and benefits of medical therapy weighed. Management of active disease is paramount as the greatest risk to the mother and fetus is from uncontrolled disease.1 The diagnostic evaluation of an exacerbation of bloody diarrhea should begin with laboratory and stool studies to rule out coincident gastrointestinal infections. Caution should be taken when interpreting laboratory values in the pregnant women. For example, hemoglobin levels vary during normal pregnancy and C-reactive protein may be elevated as early as the fourth week of gestation even in patients without UC. Imaging may be necessary to rule out complications such as obstruction or toxic megacolon. Radiation, however, should be avoided during pregnancy if possible. Ultrasound and magnetic resonance imaging without gadolinium are safe modalities when needed to evaluate the gravid abdomen. Endoscopy is preferably avoided, particularly during the first trimester of pregnancy but refractory disease or clinically significant bleeding may require otherwise. In these cases, flexible sigmoidoscopy is usually adequate to assess the colitis but not always. Minimal or no sedation should be used to reduce risk of fetal hypoxia. Surgery can and should be considered for severe refractory disease during pregnancy just as in other cases. Late in pregnancy surgery and simultaneous delivery can be considered. For CD, elective cesarean section should be considered with active perirectal abscess or fistulas. For UC a subtotal colectomy should be www.jcge.com |
257
J Clin Gastroenterol
Letters to the Editor
favored in anticipation of later creating an ileoanal pouch anastomosis with preservation of the anal sphincter. Most medications commonly used for IBD can be continued safely during pregnancy. Aminosalicylates (pregnancy class B) are considered low risk but are insufficient for the current situation. Rare cases of diarrhea in infants during breastfeeding have been reported but not significant enough to recommend against its use. Patients on sulfasalazine should take folic acid supplementation to reduce the risk of neural tube defects. Antibiotics should be avoided if possible, especially quinolones which have been associated with arthropathy in children and metronidazole which has been associated with cleft palate when used in the first trimester. Corticosteroids (class C) also pose a slight risk of cleft palate when given during the first trimester. Methotrexate falls in pregnancy category X and must be discontinued at least 6 months before conception. The immunosuppressive drugs azathioprine (AZA) and 6-mercatopurine (6-MP), are classified as category D because of teratogenicity in animal studies. However, extensive experience with these drugs and the transplant, rheumatologic, and IBD literature has not supported this association.9,10 Therefore, the continuation of these medications in patients who are in remission is not contraindicated.3,4,9,10 However, taking AZA/6-MP for the first time during pregnancy is not recommended because of the risk of pancreatitis or leukopenia which can jeopardize the fetus. Therefore, consideration can be given to stopping the immunosuppressives in patients who are in remission on combination therapy. AZA/6-MP are minimally transferred into breast milk and thought to be safe for breastfeeding.6,7 The biologicals most commonly used in the treatment of IBD are the anti-TNFs infliximab, adalimumab, and certolizumab. These drugs are pregnancy category B and mounting data support their safety in pregnancy.2,3,10 However, questions remain as to the effect on the long-term development of the newborn. Infliximab and adalimumab are IgG1 antibodies which undergo efficient placental transfer during the second and third trimesters. Infliximab levels have been detected in the infants as late as 7 months after birth. Exposure to live vaccines is contraindicated for the mother and the child as well.
258 | www.jcge.com
The limited data available suggest that stopping biologics in the second trimester may increase the risk of poor pregnancy outcomes without any clinical benefit. We would recommend against stopping biologicals during the pregnancy when patients are well controlled on their current regimen.
MANAGEMENT OF PRESENTED CASE A decision was made to perform a flexible sigmoidoscopy; check for Clostridium difficile, hepatitis B, and tuberculosis; and to start Infliximab when this workup was negative. The examination showed severely friable ulcerated mucosa contiguous from the rectum to the hepatic flexure. An infusion of Infliximab was then initiated at 5 mg/kg. The very next day, the patient reported improvement in her symptoms including a decrease in pain, stool frequency, and tenesmus. She was observed in the hospital for 5 more days as her symptoms progressively improved. On the day of discharge she was passing semiformed stool without any gross blood. She delivered a healthy 7 lb 13 oz baby at 38 weeks via C-section without any complication and was advised to avoid giving the child the rotavirus vaccine for 6 months after birth because it is a live vaccine. The child was breast fed for 1 month without complication. Both mother and the baby are currently healthy and the UC continues to be in endoscopic remission. The patient is maintained on infliximab every 8 weeks.
CONCLUSIONS Biologic agents are safe during pregnancy in IBD patients. In a patient whose disease is in remission, the timing of the last dose of biologics should be determined in conjunction with the patient after weighing the proven risks of disease activity against the theoretical risks of placental transfer of biologics to the newborn. In contrast, disease activity during the third trimester is clearly an imminent threat to the mother and fetus and must be controlled quickly. In such a scenario, the initiation of a biological is not contraindicated and probably the treatment of choice. Anish Mammen, MD Burton I. Korelitz, MD, MACG Department of Gastroenterology Lenox Hill Hospital, New York, NY
Copyright
r
Volume 49, Number 3, March 2015
REFERENCES 1. Baiocco PJ, Korelitz BI. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol. 1984;6: 211–216. 2. Mahadevan U, Sandborn WJ, Li DK, et al. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology. 2007;133:1106–1112. 3. Casanova MJ, Chaparro M, Domenech E, et al. Safety of thiopurines and antiTNF-a drugs during pregnancy in patients with inflammatory bowel disease. Am J Gastroenterol. 2013;18: 433–440. 4. Nielson OH, Loftus EV Jr, Jess T. Safety of TNF-a inhibitors during IBD pregnancy: a systematic review. BMC Med. 2013;11:174–187. 5. Francella A, Dyan A, Bodian C, et al. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology. 2003;124:9–17. 6. Mahadevan U, Wolf DC, Dubinsky M, et al. Placental transfer of anti-tumor factor agents in pregnant patients with inflammatory bowel disease. Clin Gastro Hepatol. 2013;11:286–292. 7. Zelinkova Z, Van Der Ent C, Brun KF, et al. Effects of discontinuing anti-tumor necrosis factor therapy during pregnancy on the course of inflammatory bowel disease and neonatal exposure. Clin Gastro Hepatol. 2013;11:318–321. 8. Anderson JB, Turner GM, Williamson RCN. Fulminant ulcerative colitis in later pregnancy and the puerperium. J R S Med. 1987;80:492–494. 9. Korelitz BI. Continuing immunomodulators and biologic medications in pregnant IBD patients. Inflamm Bowel Dis. 2007;13:1441–1442. 10. Gisbert JP. Safety of immunomodulators and biologics for the treatment of inflammatory bowel disease during pregnancy and breast-feeding. Inflamm Bowel Dis. 2010;16:881–894.
Refractory Acute Upper Gastrointestinal Nonvariceal Bleeding Should Arterial Embolization be the Rule? To the Editor: We read with great interest the article by Sildiroglu et al1 recently The author declares that there is nothing to disclose.
2014 Wolters Kluwer Health, Inc. All rights reserved.
