From conception to delivery: Managing the pregnant inflammatory bowel disease patient

Inflammatory bowel disease(IBD)typically affects patients during their adolescent and young adult years.As these are the reproductive years,patients and physicians often have concerns regarding the interaction between IBD,medications and surgery used to treat IBD,and reproduction,pregnancy outcomes,and neonatal outcomes.Studies have shown a lack of knowledge among both patients and physicians regarding reproductive issues in IBD.As the literature is constantly expanding regarding these very issues,with this review,we provide a comprehensive,updated overview of the literature on the management of the IBD patient from conception to delivery,and provide action tips to help guide the clinician in the management of the IBD patient during pregnancy.     

Pregnancy related issues in inflammatory bowel disease: evidence base and patients' perspective

Inflammatory bowel disease (IBD) affects women of childbearing age and can influence fertility, pregnancy and decisions regarding breastfeeding. Women with IBD need to consider the possible course of disease during pregnancy, the benefits and risks associated with medications required for disease management during pregnancy and breastfeeding and the effects of mode of delivery on their disease. When indicated, aminosalicylates and thiopurines can be safely used during pregnancy. Infliximab and Adalimumab are considered probably safe during the first two trimesters. During the third trimester the placenta can be crossed and caution should be applied. Methotrexate is associated with severe teratogenicity due to its folate antagonism and is strictly contraindicated. Women with IBD tend to deliver earlier than healthy women, but can have a vaginal delivery in most cases. Caesarean sections are generally recommended for women with active perianal disease or after ileo-anal pouch surgery.While the impact of disease activity and medication has been addressed in several studies, there are minimal studies evaluating patients' perspective on these issues. Women's attitudes may influence their decision to have children and can positively or negatively influence the chance of conceiving, and their beliefs regarding therapies may impact on the course of their disease during pregnancy and/or breastfeeding. This review article outlines the impact of IBD and its treatment on pregnancy, and examines the available data on patients' views on this subject.     

Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease

Introduction

Limited data suggest the absence of infliximab in breast milk, thereby implying the safety of this drug during breast-feeding. We aimed to re-evaluate the presence of infliximab in breast milk of nursing IBD patients.

Methods

Serum and breast milk were obtained post-partum from 3 breast-feeding patients with Crohn's disease before and after re-initiation of infliximab. ELISA assay was employed to measure infliximab level in maternal serum and in breast milk. The level of infliximab was also measured in breast milk of a control group of 8 nursing healthy mothers.

Results

Infliximab was undetectable in breast milk prior to the first infusion and was also not measurable in 8 lactating women not exposed to infliximab. Infliximab levels in breast milk rose up to 101 ng/ml within 2–3 days of the infusion. These levels of infliximab in breast milk were roughly 1/200th of the level in blood.

Conclusions

In contrast with prior reports, infliximab can be detected in the breast milk of nursing mothers. The miniscule amounts of infliximab transferred in breast milk are unlikely to result in systemic immune-suppression of the infant. Nonetheless, local effects of this exposure on the neonates' intestine and potential immune sensitization or tolerization towards the drug can not be excluded and merit further investigations.     

Inflammatory bowel diseases and human reproduction: A comprehensive evidence-based review

To evaluate the effects of inflammatory bowel diseases (IBDs) on human reproduction, we reviewed the current literature using a systematic search for published studies (articles and/or abstracts) without limits for English language. We searched on Medline (through PubMed), the Institute for Scientific Information, the Web of Science and the websites for the registration of controlled trials (http://controlled-trials.com/). Bibliographies of retrieved articles, books, expert opinion review articles and reviewed bibliographies from subject experts were manually searched. Titles and abstracts were screened initially, and potential relevant articles were identified and reviewed. Whenever possible, data were analyzed by comparing IBD patients vs healthy controls, and patients with active IBDs vs those with disease in remission. The effects of IBDs on female fertility, fertility in infertile couples, pregnancy and male infertility were examined separately. Patients with IBDs in remission have normal fertility. At the moment, there is no established guideline for the preservation of fertility in women with IBD undergoing surgery. Further data are needed regarding guidelines for the management of these patients. Data regarding IBDs and infertility are currently completely lacking. Considering the prevalence of intestinal pathology in young adults of childbearing age, this field is of great scientific and clinical interest, opening up important future perspectives. Another important and as yet unexplored point is the response to treatments for infertility in patients with IBDs. In particular, the question is whether the reproductive outcomes (clinical and biological) can be influenced by the IBD of one of the partners. The goals for successful reproductive outcomes in IBD population are correct counseling and disease remission. IBDs significantly affect several reproductive aspects of human (female, male, couple) reproduction. Further data are needed to develop guidelines for the clinical management of subjects of reproductive age with IBDs.     

Epidemiology and inflammatory bowel diseases

The role of alcohol in causing or aggravating the pathogenesis of inflammatory bowel disease is unclear.For finding a conclusive answer for this valuable question we conducted this review.Only two studies were identified that successfully fulfilled our inclusive criteria.Usual consumption of alcohol reduced the risk compared with less frequent use(odds ratio = 0.57,95%CI:0.37-0.86).Light alcoholic drinking has protective effects against development of ulcerative colitis.But this inverse association disappeared when smoking was included.     

Patterns of airway involvement in inflammatory bowel diseases

Extraintestinal manifestations occur commonly in inflammatory bowel diseases(IBD). Pulmonary manifestations(PM) of IBD may be divided in airway disorders, interstitial lung disorders, serositis, pulmonary vasculitis, necrobiotic nodules, drug-induced lung disease, thromboembolic lung disease and enteropulmonary fistulas. Pulmonary involvement may often be asymptomatic and detected solely on the basis of abnormal screening tests. The common embryonic origin of the intestine and the lungs from the primitive foregut, the co-existence of mucosa associated lymphoid tissue in both organs, autoimmunity, smoking and bacterial translocation from the colon to the lungs may all be involved in the pathogenesis of PM in IBD. PM are mainly detected by pulmonary function tests and highresolution computed tomography. This review will focus on the involvement of the airways in the context of IBD, especially stenoses of the large airways, tracheo-bronchitis, bronchiectasis, bronchitis, mucoid impaction, bronchial granulomas, bronchiolitis, bronchiolitis obliterans syndrome and the co-existence of IBD with asthma, chronic obstructive pulmonary disease, sarcoidosis and a1-antitrypsin deficiency.     

Treatment of pregnant women with a diagnosis of inflammatory bowel disease

The frequency of diagnosis of inflammatory bowel disease(IBD) has increased in younger populations.For this reason,pregnancy in patients with IBD is a topic of interest,warranting additional focus on disease management during this period.The main objective of this article is to summarize the latest findings and guidelines on the management of potential problems from pregnancy to the breastfeeding stage.Fertility is decreased in patients with active IBD.Disease remission prior to conception will likely decrease the rate of pregnancy-related complications.Most of the drugs used for IBD treatment are safe during both pregnancy and breastfeeding.Two exceptions are methotrexate and thalidomide,which are contraindicated in pregnancy.Antitumor necrosis factor agents are not advised during the third trimester as they exhibit increased transplacental transmission and potentially cause immunosuppression in the fetus.Radiological and endoscopic examinations and surgical interventions should be performed only when absolutely necessary.Surgery increases the fetal mortality rate.The delivery method should be determined with consideration of the disease site and presence of progression or flare up.Treatment planning should be a collaborative effort among the gastroenterologist,obstetrician,colorectal surgeon and patient.     

Medical management of inflammatory bowel disease among Canadian gastroenterologists

BACKGROUND:

Little is known about physician perceptions of and practices in using infliximab – a biological agent that was approved in Canada for the treatment of Crohn’s disease in 2001, and for ulcerative colitis in 2006.

OBJECTIVES:

To describe Canadian gastroenterologists’ use and perceptions of infliximab in the treatment of refractory inflammatory bowel disease (IBD), and to identify factors that may influence a gastroenterologist’s decision to initiate infliximab therapy.

METHODS:

A postal questionnaire was distributed to all practicing clinicians captured in the 2007 membership of the Canadian Association of Gastroenterology. Each physician was contacted up to a maximum of three times.

RESULTS:

Of 466 questionnaires mailed out, responses were received from 336 (72%), with 292 respondents (63%) returning fully completed surveys. For 80% of respondents, IBD patients comprised less than 30% of their clinical practice. Most prescribed infliximab at an initial dose of 5 mg/kg (97%), prescribed loading doses at 0, 2 and 6 weeks (88%), premedicated with corticosteroids (74%), administered maintenance infusions at eight-week intervals (89%), co-administered immunosuppressive agents (81%) and continued infliximab ‘indefinitely’ as long as it was effective and well tolerated (76%). Most gastroenterologists (>70%) identified lack of drug insurance coverage and provincial funding criteria as important barriers to prescribing infliximab.

CONCLUSIONS:

Most Canadian gastroenterologists exhibited similar practice patterns with respect to the use of infliximab for induction and maintenance therapy of IBD. Common barriers to the initiation of infliximab therapy were identified.     

Inflammatory bowel disease and pregnancy: Evidence, uncertainty and patient decision-making

Inflammatory bowel disease (IBD) often affects women during their child-bearing years. Management of a pregnant IBD patient, or a patient contemplating pregnancy, poses unique challenges and can be quite daunting. Knowledge of the basic interplay among disease, normal host physiology and pregnancy is vital to managing these patients. One of the most important advances in the management of IBD over the past decade has been the finding that normal pregnancy outcomes can be achieved when a woman enters the pregnancy in remission. New insights into the safety of a wider spectrum of drugs in these patients has allowed for increased success in IBD management. The evidence supporting medical interventions including biological therapy such as antibodies to tumour necrosis factor agents is reviewed. Once the treating physician understands this complex relationship, management of the pregnant IBD patient can often become a rewarding experience.     

Characteristics of inflammatory bowel diseases in patients with concurrent immune-mediated inflammatory diseases

Patients with inflammatory bowel disease (IBD) are more likely to have concurrent immune-mediated inflammatory diseases (IMIDs) than those without IBD. IMIDs have been observed to alter the phenotype and outcomes of IBD in recent studies. Several studies have found that IBD patients with concurrent IMIDs may have more extensive or severe disease phenotypes, and are considered to be at increased risk of requiring biologics and IBD-related surgeries, suggesting that having multiple IMIDs is a poor prognostic factor for IBD. Furthermore, IBD patients with primary sclerosing cholangitis and Takayasu arteritis are reported to have unique endoscopic phenotypes, suggesting concurrent IMIDs can influence IBD phenotype with specific intestinal inflammatory distributions. In this review, we discuss the pathogenesis, disease phenotypes, and clinical outcomes in IBD patients with concomitant IMIDs.     

Crohnology： A tale of time and times and inflammatory bowel diseases

Time, times and timing are key words in inflammatory bowel diseases （IBD）. The leifmotif of this issue or World Journal of Gastroenterology is time. We have asked experts to review on the epidemiology of these diseases over time, the changes in innate immunity that could be present in the first time, and then the timing of key treatments. The correct time of using azathioprine, mercaptopurine, infliximab, cyclosporine and surgery are reviewed. We have chosen experts with not only great clinical expertise but also personal interest in clinical and basic investigation. Our goal in this monograph is to get an idea not only of the present but of the immediate future in some of the key management issues in IBD. To this end, we think that the authors are the most adequate.     

Safety of anti-tumor necrosis factor therapy in inflammatory bowel disease

Inflammatory bowel disease （IBD）, in particular Crohn＇s disease refractory to conventional therapy, fistulizing Crohn＇s disease and chronic active ulcerative colitis,generally respond well to anti-tumor necrosis factor（TNF） therapy. However, serious side effects do occur,necessitating careful monitoring of therapy. Potentialside effects of anti-TNF therapy include opportunistic infections, which show a higher incidence whenconcomitant immunosuppression is used. Furthermore,antibody formation against anti-TNF is associated with decreased efficacy and an increased frequency of infusion reactions. The hypothesis of a slightlyincreased risk of lymphomas in IBD patients treated with anti TNF-therapy is debatable, since most studieslack the specific design to properly address this issue.Alarmingly, the occurrence of hepatosplenic T-cell lymphomas coincides with combined immunosuppressive therapy. Despite the potential serious side effects, anti-TNF therapy is an effective and relatively safe treatment option for refractory IBD. Future research is needed to answer important questions, such as the long-term risk of malignancies, safety during pregnancy, when to discontinue and when to switch anti-TNF therapy, as well as to determine the balance between therapeutic and toxic effects.     

Autoimmune liver diseases and inflammatory bowel diseases in children: current issues and future perspectives

Inflammatory bowel diseases (IBDs) represent a group of intestinal disorders with a chronic and relapsing inflammation of the gut, and with a potential risk of systemic involvement of other organs and systems. Over the pediatric age, an incidence higher than 20% of developing extraintestinal manifestation during follow-up has been reported. The liver and the biliary system are frequently involved, and primary sclerosing cholangitis (PSC) is the most predominant entity with an incidence rate of 6.4–7.8% in children. PSC recognizes a multifactorial pathogenesis, and so far a not fully known mechanism for this association. The peculiar phenotype and the distinct clinical course of patients with IBD and PSC-associated make this ‘linkage’ an attractive study model to better understand mechanisms underlying these diseases. Approaching to these patients is complex and multidisciplinary, and a unique therapeutic strategy has not been standardized yet. New medications are being studied; however, further studies are needed to fully understand the pathogenesis and to improve the care of these patients. The aim of this paper is to review the recent literature regarding hepatobiliary involvement in IBD patients, with particular attention to PSC, and to provide the latest information for a correct diagnosis and appropriate management.     

Endothelial dysfunction in inflammatory bowel diseases: Pathogenesis,assessment and implications

Endothelial dysfunction is considered one of the etiological factors of inflammatory bowel disease(IBD). An inflammatory process leads to functional and structural changes in the vascular endothelium. An increase of leukocyte adhesiveness and leukocyte diapedesis, as well as an increased vascular smooth muscle tone and procoagulant activity is observed. Structural changes of the vascular endothelium comprise as well capillary and venule remodeling and proliferation of endothelial cells. Hypoxia in the inflammatory area stimulates angiogenesis by upregulation of vascular endothelial growth factor, fibroblast growth factor and tumor necrosis factor-α. Inflammatory mediators also alter the lymphatic vessel function and impair lymph flow, exacerbating tissue edema and accumulation of dead cells and bacteria. The endothelial dysfunction might be diagnosed by the use of two main methods: physical and biochemical. Physical methods are based on the assessment of large arteries vasodilatation in response to an increased flow and receptors stimulation. Flowmediated vasodilatation(FMD) is the method that is the most widely used; however, it is less sensitive in detecting early changes of the endothelium function. Most of the studies demonstrated a decrease of FMD in IBD patients but no changes in the carotic intima-media thickness. Biochemical methods of detecting the endothelial dysfunction are based on the assessment of the synthesis of compounds produced both by the normal and damaged endothelium. The endothelial dysfunction is considered an initial step in the pathogenesis of atherosclerosis in the general population. In IBD patients, the risk of cardiovascular diseases is controversial. Large, prospective studies are needed to establish the role of particular medications or dietary elements in the endothelial dysfunction as well to determine the real risk of cardiovascular diseases.     

The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice

BACKGROUND: Thiopurines are the most commonly used immunomodulatory drugs in inflammatory bowel diseases. AIM: To evaluate the use, the therapeutic and safety profiles of thiopurines in a large sample of IBD patients. METHODS: We reviewed 3641 case histories of IBD patients. Thiopurines were prescribed in 582 patients (16.0%); the analysis was performed on the 553 (267 ulcerative colitis, 286 Crohn's disease) with exhaustive clinical data. RESULTS: The main indications for treatment were steroid-dependence (328/553, 59.3%) and steroid-resistance (113/553, 20.7%). Thiopurines were started when CD were younger than UC patients (p<0.001) but earlier from diagnosis in UC than in CD patients (p=0.003). Efficacy was defined as optimal (258/553, 46.6%), partial (108/553, 19.5%), absent (85/553, 15.4%) and not assessable (102/553, 18.4%). Efficacy was independent of disease type, location/extension or duration and age at starting. Side effects were observed in 151/553 (27.3%) patients, leading to drug discontinuation in 101 (18.3%). 15 out of the 130 (11.5%) patients who took thiopurines for more than 4 years relapsed, more frequently in CD than in UC (OR=3.67 95% C.I. 0.98-13.69; p=0.053). CONCLUSIONS: Thiopurines confirm their clinical usefulness and acceptable safety profile in managing complicated IBD patients. The majority of patients treated for longer than 4 years maintain response. No clinical and demographic predictive factors for efficacy and side effects were identified.     

Hematological malignancies in chronic inflammatory bowel diseases: report of five cases and review of the literature

Several forms of primary and secondary hematological malignancies were rarely observed during the clinical course of inflammatory bowel diseases (IBD). Patients needing a prolonged treatment with immunosuppressants, such as azathioprine or methotrexate, with familiarity and genetic predisposition seem to be at a higher risk of leukemia. On the other hand, asthenia, thickness, and fever may be the symptoms of the onset of each kind of hematological malignancy. The finding of anemia, alteration of leukocyte count and large undetermined cells may suggest increased probability of abnormal proliferation of a single white blood cell line. In this report, the occurrence of hematological malignancies is described in five patients affected by IBD (three with ulcerative colitis and two with Crohn’s disease) attending our Gastroenterology Unit.     

Extraintestinal manifestations and complications in inflammatory bowel diseases

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBD) that often involve organs other than those of the gastrointestinal tract. These nonintestinal affections are termed extraintestinal symptoms. Differentiating the true extraintestinal manifestations of inflammatory bowel diseases from secondary extraintestinal complications, caused by malnutrition, chronic inflammation or side effects of therapy, may be difficult. This review concentrates on frequency, clinical presentation and therapeutic implications of extraintestinal symptoms in inflammatory bowel diseases. If possible, extraintestinal manifestations are differentiated from extraintestinal complications. Special attention is given to the more recently described sites of involvement; i.e. thromboembolic events, osteoporosis, pulmonary involvement and affection of the central nervous system.     

Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases

Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors(PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.     

Adenosine： An immune modulator of inflammatory bowel diseases

Inflammatory bowel disease （IBD） is a common and lifelong disabling gastrointestinal disease. Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response. Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models. High extracellular adenosine suppresses and resolves chronic inflammation in IBD models. High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis. Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation. Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells, respectively. Increased extracellular adenosine levels activate the A2a receptor, which would reduce cytokines responsible for chronic inflammation.     

Monitoring inflammatory bowel disease during pregnancy:Current literature and future challenges

Inflammatory bowel disease has a high prevalence in women of childbearing age and can have a significant impact on pregnancy, from conceiving to carrying the pregnancy. Active disease during pregnancy is known to have negative effects on pregnancy outcomes; therefore, careful monitoring during this period is an important but challenging aspect of care and is crucial as it affects important management decisions. Recent data seems to suggest that endoscopy is a relatively safe procedure during all trimesters of pregnancy. Serum biomarkers such as C-reactive protein and fecal calprotectin are helpful non-invasive markers, but have shown conflicting results for correlation with disease activity in some initial studies. Further work is necessary to establish standard of care monitoring during pregnancy.