[78] Gerasimidis K, Bertz M, Hanske L, Junick J, Biskou O, Aguilera M, et al. Decline in presumptively protective gut bacterial species and metabolites are paradoxically associated with disease improvement in pediatric Crohn's disease during enteral nutrition. Inflammatory Bowel Diseases. 2014;**20**:861-871. DOI: 10.1097/MIB.0000000000000023 [79] Quince C, Ijaz UZ, Loman N, Eren AM, Saulnier D, Russell J, et al. Extensive modulation of the fecal metagenome in children with Crohn's disease during exclusive enteral nutrition. The American Journal of Gastroenterology. 2015;**110**:1718-1729. DOI: 10.1038/ajg.2015.357

Nutrition. 2005;**29**:S173-S178. DOI: 10.1177/01486071050290S4S173

Alimentary Pharmacology & Therapeutics. 2008;**28**:724-733

disease. Journal of Pediatric Gastroenterology and Nutrition. 2000;**30**:78-84

253. DOI: 10.1002/ibd.21690

88 New Concepts in Inflammatory Bowel Disease

DOI: 10.1002/ibd.21017

2486. DOI: 10.3945/jn.108.099127

2012;**47**:872-882. DOI: 10.1007/s00535-012-0617-9

[92] Verma S, Holdsworth CD, Giaffer MH. Does adjuvant nutritional support diminish steroid dependency in Crohn disease? Scandinavian Journal of Gastroenterology. 2001;**36**:383-388

**Section 5**

**Pregnancy and Inflammatory Bowel Disease**

**Pregnancy and Inflammatory Bowel Disease**

[92] Verma S, Holdsworth CD, Giaffer MH. Does adjuvant nutritional support diminish steroid dependency in Crohn disease? Scandinavian Journal of Gastroenterology.

[93] Nakahigashi M, Yamamoto T, Sacco R, Hanai H, Kobayashi F. Enteral nutrition for maintaining remission in patients with quiescent Crohn's disease: Current status and future perspectives. International Journal of Colorectal Disease 2016;**31**:1-7. DOI: 10.1007/

[94] El-Matary W, Otley A, Critch J, Abou-Setta AM. Enteral feeding therapy for maintaining remission in Crohn's disease: A systematic review. Journal of Parenteral and Enteral

[95] Johnson T, Macdonald S, Hill SM, Thomas A, Murphy MS. Treatment of active Crohn's disease in children using partial enteral nutrition with liquid formula: A randomised

[96] Sigall-Boneh R, Pfeffer-Gik T, Segal I, Zangen T, Boaz M, Levine A. Partial enteral nutrition with a Crohn's disease exclusion diet is effective for induction of remission in children and young adults with Crohn's disease. Inflammatory Bowel Diseases.

[97] Pfeffer-Gik T, Levine A. Dietary clues to the pathogenesis of Crohn's disease. Digestive

Nutrition. 2017;**41**:550-561. DOI: 10.1177/0148607115621051

2014;**20**:1353-1360. DOI: 10.1097/MIB.0000000000000110

Diseases. 2014;**32**:389-394. DOI: 10.1159/000358143

controlled trial. Gut. 2006;**55**:356-361. DOI: 10.1136/gut.2004.062554

2001;**36**:383-388

90 New Concepts in Inflammatory Bowel Disease

s00384-015-2348-x

**Chapter 6**

**Provisional chapter**

**Pregnancy and Delivery of Women with IBD**

**Pregnancy and Delivery of Women with IBD**

DOI: 10.5772/intechopen.72827

We provide a basic overview of inheritance, fertility and influence of IBD and pregnancy, therapy in pregnancy and childbirth options. A crucial factor for good results is the degree of inflammation at the time of conception and during pregnancy. If the disease is inactive, there is no decrease in fertility and no greater risk of deterioration of disease in pregnancy and pregnancy does not differ from the normal population. The opposite situation occurs if there is a pregnancy at the time of disease activity. Then, in up to 75% of pregnancy courses with big problems, fertility declines, inflammation also worsens and the risk of exacerbations increases during pregnancy. This aggravates the course of pregnancy and childbirth and has a negative effect on the fetus. Therefore, it is necessary to plan for a longer period of disease stabilization and continue chronic medication and not discontinue drugs for the fear of negative impact of medications on fetal development. Commonly used drugs such as aminosalicylates, corticosteroids, immunosuppressants and biological therapy appear to be safe and well tolerated during pregnancy. The method of delivery is different for each individual and depends on the form and location

**Keywords:** inflammatory bowel disease, Crohn's disease, ulcerative colitis, pregnancy,

Inflammatory bowel disease (IBD) is a chronic bowel inflammation of unknown origin, which includes Crohn's disease (CD) and ulcerative colitis (UC). The incidence in our population has increased, the incidence of UC is 10.4/100,000 and the incidence of CD is 5.6/100,000. IBD affects young adults in their fertile age, 50% of patients are diagnosed under the age of 35 and

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

Additional information is available at the end of the chapter

of the inflammation and the preceding operations.

childbirth, breastfeeding

**1. Introduction**

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72827

Kateřina Hokerová

**Abstract**

Kateřina Hokerová

#### **Pregnancy and Delivery of Women with IBD Pregnancy and Delivery of Women with IBD**

DOI: 10.5772/intechopen.72827

Kateřina Hokerová Kateřina Hokerová

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72827

#### **Abstract**

We provide a basic overview of inheritance, fertility and influence of IBD and pregnancy, therapy in pregnancy and childbirth options. A crucial factor for good results is the degree of inflammation at the time of conception and during pregnancy. If the disease is inactive, there is no decrease in fertility and no greater risk of deterioration of disease in pregnancy and pregnancy does not differ from the normal population. The opposite situation occurs if there is a pregnancy at the time of disease activity. Then, in up to 75% of pregnancy courses with big problems, fertility declines, inflammation also worsens and the risk of exacerbations increases during pregnancy. This aggravates the course of pregnancy and childbirth and has a negative effect on the fetus. Therefore, it is necessary to plan for a longer period of disease stabilization and continue chronic medication and not discontinue drugs for the fear of negative impact of medications on fetal development. Commonly used drugs such as aminosalicylates, corticosteroids, immunosuppressants and biological therapy appear to be safe and well tolerated during pregnancy. The method of delivery is different for each individual and depends on the form and location of the inflammation and the preceding operations.

**Keywords:** inflammatory bowel disease, Crohn's disease, ulcerative colitis, pregnancy, childbirth, breastfeeding

## **1. Introduction**

Inflammatory bowel disease (IBD) is a chronic bowel inflammation of unknown origin, which includes Crohn's disease (CD) and ulcerative colitis (UC). The incidence in our population has increased, the incidence of UC is 10.4/100,000 and the incidence of CD is 5.6/100,000. IBD affects young adults in their fertile age, 50% of patients are diagnosed under the age of 35 and

and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons © 2018 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

a quarter of patients get pregnant after they have been diagnosed with IBD. Young women are often concerned about the effect of IBD on their fertility, development of the fetus and as well about the effect of the pregnancy on their disease. They are interested in the effect of the chronic medication used during the pregnancy, management of the birth and possibility of breastfeeding. In the past, patients have been advised not to get pregnant, existing strategies of treating IBD makes the pregnancy possible and safe for the mother and the child.

the patient has an intestinal resection before the pregnancy. The length of the resected tissue and activity of the disease are proportional to a higher risk of miscarriage [6]. The percentage of preterm deliveries (<g.h. 37) is around 8% in the Czech Republic in the normal population, studies describe higher risk of preterm deliveries in the group of people with IBD, the risk is 1.87 times higher, which is 11.5–16% [6]. The risk of low fetal weight (<2500 g) is two times higher, which is explained by undernourishment of the mother in the time of relapse, especially if there are repeated exacerbations in the course of the pregnancy. This occurs more often in diseased with the CD than the UC, Although some studies have found a connection between congenital malformations (especially a cleft palate and malformations of the urinary tract) and the mother's UC, this suspicion was not confirmed in extensive studies. Most of the studies show that IBD is not connected with a risk of congenital malformations. The rate of malformations ranges between 1 and 4.8% of newborns, which is the same range as in the normal population. More serious malformations were more often found in a group with a severe course of the disease during the pregnancy compared to the ones in relapse. After considering the grade of disease, no study was able to prove that any medication used (corticoids,

Pregnancy and Delivery of Women with IBD http://dx.doi.org/10.5772/intechopen.72827 95

There is no proof to suggest that pregnancy worsens the disease; therefore, there is no reason to end the pregnancy. On the contrary, there are studies that have demonstrated positive effects and long-term improvement of IBD (impact of the pregnancy on the immune system) shown decrease of relapses in the following 3 years [2]. Development of IBD during the pregnancy is correlated with the activity of disease at the time of conception. If the disease is inactive at the time of conception, then the pregnancy goes without bigger problems in the majority of the diseased, only around one-third of patients have a relapse during the pregnancy, which is the same number as in a group of nonpregnant women in the course of 9 months. In two-thirds of the patients, the disease stays in inactive state during the whole pregnancy [1, 4, 6, 8]. On the other hand, if the IBD is active at the time of conception, two-thirds of the patients have a persistent disease and even an aggravation of the disease. Therapy plays an important role in pregnancy by keeping the disease in remission; therefore, it is recommended that the therapy should not be stopped due to the fear of side effects to

The majority of the drugs used for the treatment of IBD are considered to be safe during the pregnancy and breastfeeding [3]. Analysis of 19 retrospective studies has shown that the medication commonly used for therapy of IBD (aminosalicylates—ASA, corticoids, immunosuppressants and immunotherapy) does not significantly increase the incidence of stillborn, ectopic pregnancy, hypotrophy of the fetus or miscarriage. While using these drugs, the congenital

azathioprine and mesalazine) affects the result of pregnancy [5].

**5. The effect of pregnancy on IBD**

pregnancy.

**6. Therapy in pregnancy**

## **2. Genetics and IBD**

IBD is multifactorially determined. The risk for a child with a parent with an IBD is 2–13 times higher than the risk in the normal population [1]. A child of a parent with IBD has a 5% risk for CD and a 1.6% for UC. If both parents have IBD, the risk increases up to 37% [2, 3].

## **3. Fertility and IBD**

Infertility of women with IBD ranges between 7 and 12%, which is in line with the normal population [4–7]. The fertility can decrease with the following conditions:

## **4. The effects of IBD on pregnancy**

Multiple studies on the effects of IBD on pregnancy, development and growth of the fetus, have come to a conflicting conclusions most likely due to disparate conditions of the individual studies. All the studies agree that the key factor for a successful pregnancy is a function of whether the disease is active at the time of conception. Patients with an inactive IBD (minimum 12 months without clinical, laboratory and endoscopic signs of an active inflammatory process) are not in a higher risk of bad perinatological results. On the other hand, if the disease is active, up to 75% of pregnancies are connected with a high number of problems and relatively high risk of abortion, preterm birth or hypotrophy of the fetus. Therefore, it is necessary to plan the pregnancy while the disease is in remission [1, 4–6, 8]. The activity of the disease at the time of conception leads to a higher risk of fetal loss and preterm deliveries. Also, activity of the disease during the pregnancy is associated with lower fetal weight and as well with a preterm delivery [1, 3, 8, 9, 10]. Pregnancy loss affects 12.2% of patients with IBD as compared to 9.9% in the normal population. Miscarriages are more common in cases where the patient has an intestinal resection before the pregnancy. The length of the resected tissue and activity of the disease are proportional to a higher risk of miscarriage [6]. The percentage of preterm deliveries (<g.h. 37) is around 8% in the Czech Republic in the normal population, studies describe higher risk of preterm deliveries in the group of people with IBD, the risk is 1.87 times higher, which is 11.5–16% [6]. The risk of low fetal weight (<2500 g) is two times higher, which is explained by undernourishment of the mother in the time of relapse, especially if there are repeated exacerbations in the course of the pregnancy. This occurs more often in diseased with the CD than the UC, Although some studies have found a connection between congenital malformations (especially a cleft palate and malformations of the urinary tract) and the mother's UC, this suspicion was not confirmed in extensive studies. Most of the studies show that IBD is not connected with a risk of congenital malformations. The rate of malformations ranges between 1 and 4.8% of newborns, which is the same range as in the normal population. More serious malformations were more often found in a group with a severe course of the disease during the pregnancy compared to the ones in relapse. After considering the grade of disease, no study was able to prove that any medication used (corticoids, azathioprine and mesalazine) affects the result of pregnancy [5].

## **5. The effect of pregnancy on IBD**

a quarter of patients get pregnant after they have been diagnosed with IBD. Young women are often concerned about the effect of IBD on their fertility, development of the fetus and as well about the effect of the pregnancy on their disease. They are interested in the effect of the chronic medication used during the pregnancy, management of the birth and possibility of breastfeeding. In the past, patients have been advised not to get pregnant, existing strategies

IBD is multifactorially determined. The risk for a child with a parent with an IBD is 2–13 times higher than the risk in the normal population [1]. A child of a parent with IBD has a 5% risk for CD and a 1.6% for UC. If both parents have IBD, the risk increases up to 37% [2, 3].

Infertility of women with IBD ranges between 7 and 12%, which is in line with the normal

• An active inflammation (can affect the Fallopian tubes and the ovaries, in the perianal area

• Surgery before the pregnancy (IPAA—ileo pouch anal anastomosis—is connected with

Multiple studies on the effects of IBD on pregnancy, development and growth of the fetus, have come to a conflicting conclusions most likely due to disparate conditions of the individual studies. All the studies agree that the key factor for a successful pregnancy is a function of whether the disease is active at the time of conception. Patients with an inactive IBD (minimum 12 months without clinical, laboratory and endoscopic signs of an active inflammatory process) are not in a higher risk of bad perinatological results. On the other hand, if the disease is active, up to 75% of pregnancies are connected with a high number of problems and relatively high risk of abortion, preterm birth or hypotrophy of the fetus. Therefore, it is necessary to plan the pregnancy while the disease is in remission [1, 4–6, 8]. The activity of the disease at the time of conception leads to a higher risk of fetal loss and preterm deliveries. Also, activity of the disease during the pregnancy is associated with lower fetal weight and as well with a preterm delivery [1, 3, 8, 9, 10]. Pregnancy loss affects 12.2% of patients with IBD as compared to 9.9% in the normal population. Miscarriages are more common in cases where

• Medication that affects men's fertility such as methotrexate, sulfasalazine [1, 9, 10]

population [4–7]. The fertility can decrease with the following conditions:

lower fertility because of scarring in the area around the adnexae)

of treating IBD makes the pregnancy possible and safe for the mother and the child.

**2. Genetics and IBD**

94 New Concepts in Inflammatory Bowel Disease

**3. Fertility and IBD**

it can cause dyspareunia)

**4. The effects of IBD on pregnancy**

There is no proof to suggest that pregnancy worsens the disease; therefore, there is no reason to end the pregnancy. On the contrary, there are studies that have demonstrated positive effects and long-term improvement of IBD (impact of the pregnancy on the immune system) shown decrease of relapses in the following 3 years [2]. Development of IBD during the pregnancy is correlated with the activity of disease at the time of conception. If the disease is inactive at the time of conception, then the pregnancy goes without bigger problems in the majority of the diseased, only around one-third of patients have a relapse during the pregnancy, which is the same number as in a group of nonpregnant women in the course of 9 months. In two-thirds of the patients, the disease stays in inactive state during the whole pregnancy [1, 4, 6, 8]. On the other hand, if the IBD is active at the time of conception, two-thirds of the patients have a persistent disease and even an aggravation of the disease. Therapy plays an important role in pregnancy by keeping the disease in remission; therefore, it is recommended that the therapy should not be stopped due to the fear of side effects to pregnancy.

## **6. Therapy in pregnancy**

The majority of the drugs used for the treatment of IBD are considered to be safe during the pregnancy and breastfeeding [3]. Analysis of 19 retrospective studies has shown that the medication commonly used for therapy of IBD (aminosalicylates—ASA, corticoids, immunosuppressants and immunotherapy) does not significantly increase the incidence of stillborn, ectopic pregnancy, hypotrophy of the fetus or miscarriage. While using these drugs, the congenital anomalies were more often seen, which is probably connected to the activity of the disease and not to the therapy. Both methotrexate and thalidomide are clearly contraindicated [1].

damage. Vaginal birth is also possible in the patients with colostomy or ileostomy and it is not

Pregnancy and Delivery of Women with IBD http://dx.doi.org/10.5772/intechopen.72827 97

IBD affects women in the fertile age with consequences to their fertility, pregnancy and breastfeeding. The disease and the pregnancy affect each other, and the development of the disease and the pregnancy is determined by the activity of inflammation at the time of conception. Patients who are in remission at the time of conception will most likely stay in the remission during the pregnancy. On the other hand, 70% of the patients with an active inflammation at the time of conception will stay in that shape or even get worse during the pregnancy. Women with an active IBD are at a higher risk of adverse results of the pregnancy, whereas the women with inactive disease can expect normal course and good results of the pregnancy. That is why it is crucial to plan their pregnancy during remission, and not to cut out the antiinflammatory and immunosuppressant therapy put in place before the pregnancy. Most of the medication used in treatment of IBD is considered to be safe at the time of pregnancy and breastfeeding, but more studies are needed. Patients with IBD can have vaginal delivery, whereas patients with the perianal lesions, patients with affected rectum and patients after

associated with a higher risk of the complications with the stomies [1, 6].

the reconstructive surgery with IPAA should deliver by the Cesarean section.

[1] Van der Woude CJ. ECCO Guidelines/Consensus Paper. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. Journal of Crohn's and Colitis. 2015;**9**(2):107-124. Available from: https://www. ecco-ibd.eu/images/6\_Publication/6\_3\_ECCO%20Guidelines/FINAL\_MASTER\_JCC\_

[2] Kment M. Idiopatické střevní záněty v graviditě. Interní medicína pro praxi. 2008;**10**(7a8):

[3] Kwan LY, Mahadevan U. Inflammatory bowel disease and pregnancy: An update. Expert

Online\_PulishedVersion\_PregnancyGuidelines\_2015\_Doi101093\_jju006.pdf

Address all correspondence to<EMAIL_ADDRESS>
Review of Clinical Immunology. 2010;**6**(4):643-657

Nemocnice Hořovice, Hořovice, Czech Republic

**8. Conclusion**

**Author details**

Kateřina Hokerová

**References**

333-335

If the therapy is able to keep the disease inactive, it is recommended not to stop and continue the therapy during the whole pregnancy because the benefits outweigh the risks of the conservative therapy and the danger of relapse after completing the therapy.

## **7. The mode of delivery**

The percentage (44%) of the Cesarean section is higher in the group of patients with IBD than in normal population [3]. Recent population studies from Sweden have shown that women with the UC without any surgery in the past had two times higher risk of elective Cesarean section, even though vaginal birth is the safest way for the mother and the child. Additional studies have also shown that the Cesarean sections are mostly performed on the basis of patient's or the doctor's preference, but not from a real indication. Even though some doctors think that all the patients with IBD should have a Cesarean section, it seems reasonable to make the vaginal birth possible for the women with inactive or in the moderate stage of the disease. The decision about the mode of the delivery should be strictly individual and it should be an agreement among the mother, the obstetrician, the gastroenterologist and the surgeon [6].

Cesarean section is definitely indicated when there is an active perianal disease with abscesses and fistulas or active rectal disease (proctitis in UC and CD) with consideration of the protection of the anal sphincter. IPAA or ileorectal anastomosis is considered as a relative indication for the Cesarean section, the guidelines about the mode of delivery after IPAA are not uniform, and both ways are described. With a consideration of a protection of the anal sphincter and keeping the pouch continence, the Cesarean section is preferred. Patients with the IPAA have, due to the surgery, a border continence of stool and that is closely related to an intact sphincter and the function of the pelvic floor. The function of the pouch is affected already in the third trimester and it goes back to the original shape during 6 months after the delivery. In the vaginal birth, the pudendal nerves can be affected due to the pressure in the second stage of labor or in the forceps delivery, which can lead to more frequent stools. In the long-term observation (5 years), it is observed that after the vaginal birth, the function of the pouch worsens faster especially in the births with the higher risks of obstetric injuries (instrumental labor, episiotomy, the fetal weight above 4000 g, emergent Cesarean section, second stage of labor longer than 2 h) In the majority of the patients, the primary Cesarean section is chosen. Other reason for that is as well the emergency Cesarean section from the obstetrics indication can be very risky because of abdominal adhesions after previous surgeries [1, 3, 9, 10]. Vaginal birth should be allowed only to women without the signs of rectal and perianal forms of the disease [6]. Traumatic changes of the perianal area can be a cause of long-term festering complications or fistulas, preforming of episiotomy can induce the perianal lesions in the future course of the disease in 20% [5]. If the woman with IBD has a vaginal birth, it is appropriate to avoid episiotomy; however, it is better to perform an episiotomy than a spontaneous uncontrollable damage. Vaginal birth is also possible in the patients with colostomy or ileostomy and it is not associated with a higher risk of the complications with the stomies [1, 6].

## **8. Conclusion**

anomalies were more often seen, which is probably connected to the activity of the disease and

If the therapy is able to keep the disease inactive, it is recommended not to stop and continue the therapy during the whole pregnancy because the benefits outweigh the risks of the con-

The percentage (44%) of the Cesarean section is higher in the group of patients with IBD than in normal population [3]. Recent population studies from Sweden have shown that women with the UC without any surgery in the past had two times higher risk of elective Cesarean section, even though vaginal birth is the safest way for the mother and the child. Additional studies have also shown that the Cesarean sections are mostly performed on the basis of patient's or the doctor's preference, but not from a real indication. Even though some doctors think that all the patients with IBD should have a Cesarean section, it seems reasonable to make the vaginal birth possible for the women with inactive or in the moderate stage of the disease. The decision about the mode of the delivery should be strictly individual and it should be an agreement among the mother, the obstetrician, the gastroenterologist and the

Cesarean section is definitely indicated when there is an active perianal disease with abscesses and fistulas or active rectal disease (proctitis in UC and CD) with consideration of the protection of the anal sphincter. IPAA or ileorectal anastomosis is considered as a relative indication for the Cesarean section, the guidelines about the mode of delivery after IPAA are not uniform, and both ways are described. With a consideration of a protection of the anal sphincter and keeping the pouch continence, the Cesarean section is preferred. Patients with the IPAA have, due to the surgery, a border continence of stool and that is closely related to an intact sphincter and the function of the pelvic floor. The function of the pouch is affected already in the third trimester and it goes back to the original shape during 6 months after the delivery. In the vaginal birth, the pudendal nerves can be affected due to the pressure in the second stage of labor or in the forceps delivery, which can lead to more frequent stools. In the long-term observation (5 years), it is observed that after the vaginal birth, the function of the pouch worsens faster especially in the births with the higher risks of obstetric injuries (instrumental labor, episiotomy, the fetal weight above 4000 g, emergent Cesarean section, second stage of labor longer than 2 h) In the majority of the patients, the primary Cesarean section is chosen. Other reason for that is as well the emergency Cesarean section from the obstetrics indication can be very risky because of abdominal adhesions after previous surgeries [1, 3, 9, 10]. Vaginal birth should be allowed only to women without the signs of rectal and perianal forms of the disease [6]. Traumatic changes of the perianal area can be a cause of long-term festering complications or fistulas, preforming of episiotomy can induce the perianal lesions in the future course of the disease in 20% [5]. If the woman with IBD has a vaginal birth, it is appropriate to avoid episiotomy; however, it is better to perform an episiotomy than a spontaneous uncontrollable

not to the therapy. Both methotrexate and thalidomide are clearly contraindicated [1].

servative therapy and the danger of relapse after completing the therapy.

**7. The mode of delivery**

96 New Concepts in Inflammatory Bowel Disease

surgeon [6].

IBD affects women in the fertile age with consequences to their fertility, pregnancy and breastfeeding. The disease and the pregnancy affect each other, and the development of the disease and the pregnancy is determined by the activity of inflammation at the time of conception. Patients who are in remission at the time of conception will most likely stay in the remission during the pregnancy. On the other hand, 70% of the patients with an active inflammation at the time of conception will stay in that shape or even get worse during the pregnancy. Women with an active IBD are at a higher risk of adverse results of the pregnancy, whereas the women with inactive disease can expect normal course and good results of the pregnancy. That is why it is crucial to plan their pregnancy during remission, and not to cut out the antiinflammatory and immunosuppressant therapy put in place before the pregnancy. Most of the medication used in treatment of IBD is considered to be safe at the time of pregnancy and breastfeeding, but more studies are needed. Patients with IBD can have vaginal delivery, whereas patients with the perianal lesions, patients with affected rectum and patients after the reconstructive surgery with IPAA should deliver by the Cesarean section.

## **Author details**

Kateřina Hokerová

Address all correspondence to<EMAIL_ADDRESS>
Nemocnice Hořovice, Hořovice, Czech Republic

## **References**

[4] Alstead EM, Nelson-Piercy C. Inflammatory bowel disease in pregnancy. 2013. Available

[6] Lukáš K, Pařízek A. Idiopatické střevní záněty a těhotenství. Časopis lékařů českých.

[7] Pintérová Kolesárová M, Pintér M. Vliv idiopatického střevního zánětu na interval

[8] Ferguson ChB. Inflammatory bowel disease in pregnancy. British Medical Journal. 2008;**337**(a427). Available from: http://dx.doi.org/10.1136/bmj.39566.681458.BE (Published

[9] Peppercon MA, Mahadevan U. Fertility, pregnancy and nursing in inflammatory bowel disease. 2017. Available from: http://www.uptodate.com/contents/fertility-pregnancy

[10] Peppercon MA, Mahadevan U. Patient information: Inflammatory bowel disease and pregnancy. 2017. Available from: http://www.uptodate.com/contents/inflammatory-

from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774968/

2010;**149**:163-172

98 New Concepts in Inflammatory Bowel Disease

[5] Kment M. Choroby gastrointestinálního traktu v graviditě. Triton. 2003:43-61

potřebný pro početí pacientek. Česká Gynekologie 2008;**732**:109-112

July 2008); http://www.bmj.com/content/337/bmj.39566.681458.BE

and-nursing-in-inflammatory-bowel-disease

boweldisease-and-pregnancy-beyond-the-basics

## *Edited by Batool Mutar Mahdi*

Inflammatory bowel disease is a chronic immune-mediated inflammation of the gastrointestinal tract of unknown origin, which includes Crohn's disease, ulcerative colitis, and inflammatory bowel disease of unclassified type. It is associated with different intestinal and extraintestinal manifestations like different neurological and psychiatric disorders. Histology is an important tool in the diagnosis and prognosis of inflammatory bowel disease and has an increasing part in patients' management. The objective of treatment is to make and keep long-lasting remission by immunosuppressive treatment like corticosteroids, thiopurines, and monoclonal antibodies directed against tumor necrosis factor alpha. Therapeutic drug monitoring of thiopurines by measuring levels of their metabolites has been proposed as a potentially effective tool in optimizing therapy in inflammatory bowel disease. Diets and their components influence microbiota of the intestine, function of the epithelial barrier, immune response, and other factors that have an important role in development and treatment of inflammation in the gut mucosa.

New Concepts in Inflammatory Bowel Disease

New Concepts in

Inflammatory Bowel Disease

*Edited by Batool Mutar Mahdi*

Photo by Ugreen / iStock


**1. Introduction**

22 Crosstalk and Integration of Membrane Trafficking Pathways

Zaal, K.J.M.; Smith, C.L.; Polishchuk, R.S.; Altan, N.; Cole, N.B.; Ellenberg, J.; Hirschberg, K.;

99, pp. 589–601.

Presley, J.F.; Roberts, T.H.; Siggia, E.;Phair, A,D. & Lippincott-Schwartz, J. (1999). Golgi membranes are absorbed into and reemerge from the ER during mitosis. *Cell.*

> The identities of many intracellular organelles and of specific domains of the cell surface rely on the delivery of proteins and lipids through biosynthetic or/and endocytic pathways to the sites of their specific activities. The Golgi complex serves as a central station in the biosynthetic pathway, from where proteins are sorted towards their different destinations, such as various domains of the cell surface or the endosomal-lysosomal system. To be delivered from the Golgi complex to their target compartments, cargo proteins are incorporated into dynamic membrane-bound organelles that are generally known as 'post-Golgi carriers'. Given that these post-Golgi carriers have such an important role in the process of intracellular transport their morphology, living dynamics and molecular composition became the subjects of significant interest over the last decade.

> Post-Golgi carriers (PGCs) were originally discovered and described as a result of the development of green fluorescent protein (GFP) technology and live-cell imaging (Lippincott-Schwartz et al., 2000). The first few fluorescently tagged cargo proteins observed in living cells revealed a new world of highly dynamic structures traveling from the Golgi complex to the plasma membrane (Hirschberg et al., 1998; Nakata et al., 1998). With time, the list of molecules that could be visualized *in vivo* expanded greatly, to expose the unexpected complexity of the post-Golgi transport pathways. However, in mammalian cells, most of PGSs have several common features that are independent of the pathway(s) to which they belong.

> PGCs form from membrane domains of the Golgi complex that lack resident Golgi enzymes, and there are known as 'PGC precursors' (Hirschberg et al., 1998; Keller et al., 2001; Polishchuk et al., 2003; Puertollano et al., 2003). The shapes and sizes of PGCs that can even carry the same cargo vary across a relatively wide range. Most that were seen under light microscopy were clearly larger that plasma membrane (PM)-associated clathrin vesicles and 100-nm-diameter fluorescent beads (Lippincott-Schwartz et al., 2000). Indeed, while the smaller PGSs can usually have an extension of 300 nm to 400 nm, some large carriers can reach dozens of microns in length. Video microscopy has revealed that many of these

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Morphogenesis and Dynamics of Post-Golgi Transport Carriers 25

The first step of PGC formation coincides with the segregation of the cargo proteins from the Golgi-resident enzymes. This appears to be a common process for proteins that exit the Golgi complex to head towards different post-Golgi compartments, such as the basolateral PM (Hirschberg et al., 1998; Polishchuk et al., 2003), the apical PM (Keller et al., 2001), and the endosomal-lysosomal system (Puertollano et al., 2003). These enzyme-free Golgi domains usually exhibit a tubular structure and contain *bona-fide* TGN markers (Polishchuk et al., 2003; Puertollano et al., 2003). At the EM level, this segregation of the cargo proteins from the Golgiresident enzymes corresponds to the transition of the cargo-containing compartments from

This thus raises the question of the mechanism by which the originally flat Golgi membranes are converted into highly bent, tubular-reticular TGN structures. A long time ago, Rambourg and Clermont (Rambourg and Clermont, 1990) noted that the cisternae in the middle of a Golgi stack appear quite 'solid' and contain just a few small fenestrae (Fig. 2A). During progression toward the *trans* face of the Golgi complex, both the number and size of these fenestrae increase (Rambourg and Clermont, 1990). Thus the *trans*-most Golgi cisternae generally look like flat tubular webs (Fig. 2A, B), which frequently 'peel off' from the Golgi stack (Rambourg and Clermont, 1990) (Fig. 2C, D), and these can then be easily transformed into TGN membranes by a few fission events (see Fig. 2B). A similar conversion of the Golgi compartments was seen to

The mechanisms behind this transformation are not yet completely clear. The cisterna-like morphology of the Golgi compartments can be stabilized through the formation of large polymers formed by the Golgi enzymes (Nilsson et al., 1996). Indeed, truncation of the protein domains responsible for enzyme oligomerization results in a loss of the regular Golgi morphology (Nilsson et al., 1996). Thus, a gradual reduction in Golgi enzyme polymers in the *trans*-Golgi compartments would favor transformation of cargo-containing cisternae into networks of tubular membranes. This process can be further assisted by changes in the lipid composition of the *trans*-Golgi membranes, which include the input of material from the endocytic system (Pavelka et al., 1998) and the local activities of TGNspecific lipid-modifying enzymes or lipid-transfer proteins (De Matteis and Luini, 2008). Therefore, the membranes become thicker in the TGN and they thus fail to provide a favorable environment for the short transmembrane domains of the Golgi enzymes (Munro, 1995). As a result, the Golgi enzymes get pushed out of the tubular TGN back towards the

The bending of the flat cisternae membranes into TGN tubules might be also facilitated by the action of specific proteins. Various roles of structural proteins in membrane deformation/ tubulation have been widely recognized (McMahon and Gallop, 2005). These proteins act either by forcing membrane curvature or by sensing and stabilizing it. As an example of the former, coat proteins (such as clathrin) polymerize into curved structures that can bend membrane domains (Antonny, 2006). Alternatively, such TGN proteins as the FAPPs can insert their amphipathic helices into the outer leaflet of a lipid bilayer, thereby increasing the positive membrane curvature (Lenoir et al., 2010). Other rigid curved proteins, or protein modules (such as the BAR domain), can bind to curved membranes and stabilize them by electrostatic interactions (Cullen, 2008; McMahon and Gallop, 2005).

**2.1 Morphogenesis of PGC precursors at the TGN**

cisterna-like into a tubular network morphology (Polishchuk et al., 2003).

occur along the Golgi stack in the yeast *Pichia pastoris* (Mogelsvang et al., 2003).

core Golgi regions that are composed of the stacked cisternae.

carriers are globular in appearance, although they are frequently stretched into tubular shapes during their translocation through the cytosol. Thus, PGCs have been frequently referred to as 'pleiomorphic' structures. PGCs use microtubules to move towards particular locations within the cell. Although carriers can form and support post-Golgi transport without association with microtubules, the correct targeting of cargo proteins is usually compromised under such conditions (Kreitzer et al., 2003; Rindler et al., 1987)

The life cycle of a PGC consists of three stages: (i) formation; (ii) transition through the cytosol; and (iii) docking and fusion with the target membrane (Fig. 1) (Polishchuk et al., 2000). In this chapter we take you on a journey with newly born PGCs, to follow them through all of the stages of their life cycle.

**A.** An example of PGCs dynamics, as taken in the area (dashed box) of a living cell expressing VSVG-GFP upon release of this chimeric protein from the Golgi complex. **B.** Representative images extracted from a time-lapse sequence (corresponding to the area outlined by the dashed box in panel A) show the dynamics of PGC formation from the Golgi complex (arrows). **C.** Transition of the same newly formed PGC through the cytoplasm (arrows). **D.** Fusion of the same PGC (panels B, C) with the target membrane, as shown in these three subsequent time-lapse images by arrows.

Fig. 1. The life cycle of a PGC.


**1. Introduction**

Software-Defined Networking (SDN) is an intelligent architecture in networking. It decouples the control and data plane which helps to improve the network performance and make it scalable, secure, and programmable. Internet of Things (IoT) network embedded with sensors nodes, RFID tags, smart cards, low resource devices which can communicate and share huge data to provide services to the clients. It is too difficult to provide security to the IoT system in heterogeneous and large networks. To combine SDN and IoT in a single architecture as SDN-IoT, it can make the infrastructure plane controllable, smart, reliable, and scalable [1]. IoT has many applications in different areas such as smart cities, smart vehicular networks, and security surveillance. To make these secure, SDN plays a huge part since it controls

the whole network from its control plane. IoT devices capture and store sensitive information which is a great concern to make the network and physical devices secure from the eavesdroppers. 5G is the latest communication technology that is famous for low latency, massive connectivity, high throughput, and heterogeneous nature. By making SDN-IoT architecture in 5G, it can be flexible, dynamic and helps to improve the bad scalability due to hardware differences in heterogeneous environments. To make these happen there are many security challenges that need to be taken care of. One of the major necessities of 5G is low latency which is a real challenge with a huge growing market. Many cryptographic algorithms exist, but due to their high time and space complexity requirements, it will be a good choice to avoid these in a fast communication system like 5G. Recently, a lightweight cryptographic algorithm (LWCA) is a new area of cryptography applied in 5G [2]. These algorithms do not require much space, and the time complexity is also low which makes this technique applicable in IoT networks where limited battery life and strict physical constraints both need to be considered. Currently, many researchers tend to shift their focus from cryptographic aspects of security to lightweight security algorithms [3]. This helps the system to become less complex, provide high performance and also lower the cost. Traditional cryptographic techniques have high complexity as well as it is difficult to implement. In this chapter, we discuss different lightweight cryptographic algorithms and their applications in the SDN-5G network. There are three vulnerable areas in SDN-IoT architecture: Control Plane, Data Plane, and the Interfaces between Control and Data Plane due to their programmable nature and open access architecture.

LCAs are divided into four types: 1. Block cipher, 2. Stream cipher, 3. Hash functions, 4. Elliptic curve cryptography. Each of the techniques has its own strength and weaknesses. Based on the application's requirements, it can be used in different layers of SDN-IoT architecture. Block ciphers are AES, DES, DESL, DESX, DESLX, Piccolo, TEA, XTEA, mCRYPTON, PRESENT, TWINE, LBlock whereas SNOW-V and Espresso are the stream cipher presented in this chapter maintaining the strict requirements of LWCA. Apart from the above-mentioned algorithms also, GRAIN works as a stream cipher and can use as one of the LWC algorithms in the SDN-IoT network. It uses very few gates with high security and less power consumption. When it comes to security perspectives, HIGHT, ICEBERG, CLEFIA are good choices. Hummingbird holds both of the properties of block and stream cipher and can implement in both hardware as well software. This flexibility of implementation and maintaining the lightweight properties can use this technique in both the infrastructure and control layers of the SDN-IoT network in 5G. SHA-1, SHA-2, SHA-3, BLAKE2 are the algorithms used as Hash function techniques. We will discuss each of them and their applications in the SDN-IoT network later in this chapter. There are some application areas of cryptography where we work with such devices that operate on battery power and need cryptographic algorithms which consume less power, such devices are medical implant devices or environment-measuring devices. Although very few works have been done in this direction and many exposures are open for future research work in this subarea of cryptography which we mention here as lightweight cryptography (LWC). Most of the LWC algorithms can resist linear and differential attacks which are the basic criteria of any general cryptographic algorithm. It is important to measure the performance of LWC algorithms before using them in any application. One of the key criteria of the LWC algorithm is low latency. For that, some of the automobile sectors which require immediate response use LWC techniques for security purposes. IoT devices that require less CPU cost and memory

consumption such as smart TV, tablet PCs are the application area of LWCAs. Also, medical sensors, smart agriculture sensors, RFID tag applications, electrical home appliances, automobile industry are the different applications of LWCAs.


*2.1. Design Iteration Code*

The design process is described in Figure 1. In a first step, assumptions about the propulsion system, the wing configuration, the fuselage shape and the empennage were applied in the pre-design (red box). With these assumptions, preliminary values were defined for the range, passenger and luggage weight, runway take-off length, cruise and landing speed and wingspan. Having these pre-design values, as well as the initial values (blue box) set, the sizing process (green box) began with the weight estimation according to Roskam [14].

In the next step, the sizing diagram was used to identify the design point and, thus, the power and wing area. This calculated wing area was used to size the wing, resulting in the required aerodynamic lift coefficients *CA*,*Land* and *CA*,*To*. Further, the lift coefficient was used to obtain the drag-polar and, thus, the lift-to-drag ratio. This ratio was, in turn, used to derive the weight of the aircraft components and, thus, the center of gravity. With the calculated maximum takeoff mass, the payload-range diagram was created, which then led to the required fuel mass. Bringing the iteration to an end and moving on to the analysis (yellow box), a CAD model was adjusted, and the three-side view was drawn, bringing the mechanical concept to a final freeze.

**Figure 1.** Schematic representation of the sizing code with the pre-design in red, the initial values in blue, the sizing process in green and the results and analysis in yellow.

Range Calculation for Hybrid-Electric Aircraft

Conventional fuel burning aircraft can be sized using the well-known Breguet equation, while battery electric aircraft can be sized using the modified Breguet Equation [15]. It is possible to simplify the mission segments as "equivalent stationary horizontal flight

phases" [16]; however, for this application, a more detailed incremental time step approach was chosen. This allows the split between the energy sources to vary from one moment to the next. With this approach, the normal flightpath of an aircraft can be simulated in small time increments, calculating the required energy for each time step, splitting that energy between battery and fuel and deriving the resulting mass change from it. This allows for a very refined energy management strategy between the primary and secondary energy source.

The input parameters for the incremental calculation are the basic aircraft characteristics regarding mass, aerodynamics, efficiencies and specific energy. The output is fuel and energy used per flight segment. This incremental approach will also be used in Section 3.1 to create the payload-range diagram for the aircraft.

#### *2.2. Design Process of the Aircraft*

To feed the design iteration code with information about new technologies, they must be thoroughly investigated. For each new component of the aircraft, a literature study was conducted to derive equations and reference values to apply to the design. The reference aircraft was used to calibrate the masses, empennage and sizing diagram.


**3.3. Toxic context**

The next challenge is to compare the tissue culture doses to the levels in the whales. Comparisons can be made to gain toxicological context; however, one must always bear in mind that cells grown on a dish are in a different environmental context than cells in a tissue and so the comparisons will not be precise. To contextualize the chromium toxicity data, we have converted our treatment concentrations to parts per million and converted the levels observed in the biopsies to molarity. This way we can determine if the levels we are using in the cell cultures are environmentally relevant concentrations.

Skin Biopsy Applications in Free Ranging Marine Mammals: A Case Study of Whale Skin Biopsies

*Right Whales (individual levels)*  **Whale ID Number Cr Tissue Level (ppm) Total Cr (uM)**  3646 4.9 94 2642 5.1 98 3301 6 115 1218 6.3 121 3351 8.1 156 1611 9 173 1607 10 192

Mean all right whales 7.1 135 *Sperm Whales (average by region)*

**Location Cr Tissue Level (ppm) Total Cr (uM)**

Sri Lanka 3.32 63 Canaries 3.69 70 Maldives 5.18 99 Mediterranean 5.21 100 Pacific Crossing 5.55 106 Papua New Guinea 5.72 109 Atlantic Ocean Crossing 6.28 120 Sea of Cortez 6.51 125 Indian Ocean Crossing 7.65 147

Chagos 7.95 152 Cocos 8.63 166 Australia 9.19 176 Mauritius 9.59 184 Galapagos 12.9 248 Seychelles 20.6 396 Kiribati 44.3 852 Bahamas 81.9 1575

Mean all sperm whales 9.3 179

Ocean pollution is emerging as a global priority. No longer can the world's oceans be considered an easy collective dumping site because even the most remote areas of the ocean are accumulating high levels of waste and pollutants. We now understand that any kind of pollution eventually ends up in the ocean. It may be carried by the wind, freshwater rivers

**Table 2.** Tissue Level Conversions

**4. Conclusions**

as a Valuable and Essential Tool for Studying Marine Mammal Toxicology and Conservation 119

Our sodium chromate treatments convert to a range of 0.052-1.3 ppm and our lead chromate treatments convert to a range of 0.34-6.8 ppm (Table 1). Considering that average tissue levels for sperm whales and right whales were 9.3 and 7.0 ppm, respectively, our treatment concentrations are well below the average levels measured in whale skin (Tables 1 and 2). In fact, if we were to treat the cell cultures with the lowest sperm whale regional average measured in Sri Lankan waters (63.8 uM) we would kill all of the cells because our highest treatment concentration of 25 uM was highly cytotoxic (Figure 2) as measured by our cytotoxicity assay. Even our lowest detectable level in the sperm whale, 0.9 ug/g, is equivalent to treating cells with 6.38 uM and would induce cytotoxicity in approximately 65% of North Atlantic right whale cells and 90% of sperm whale cells. This level of treatment would also induce DNA damage in approximately 20% of both sperm whale and right whale metaphases. Given that our experimental doses are so much lower than the levels found in whales; this outcome raises concern about the impact of chromium pollution on whales regardless of the difference in environmental context between cells in a dish and cells in a tissue.

**Table 1.** Chromate Treatment Conversions.

**Table 2.** Tissue Level Conversions


**3. Bypassing Models Using Data**

The main objective of control design based on the data-driven approach is enabling the possibility to synthesize controllers entirely from data of available measurements, which is a simplified route with respect to the classic system identification (modeling and parametric identification) plus a model-based control approach. This is illustrated in Figure 1.

**Figure 1.** Proposed data-driven control vs. traditional "system identification + model-based" approach.

Moreover, stability conditions and the desired performance must be completely comparable with a model-based scheme. This is also in sharp contrast with basic empiric gain-tuning rules for classic P, PI, and PID controllers, which do not require a model of the system, but cannot guarantee stability and performance in a deterministic way (see [22,23]). Our present conviction is to generate a controller purely from measurements that permits to omit the need for an explicit mathematical model without losing stability and general performance capabilities with respect to a model-based technique.

The process begins with the establishment of essential conditions to assure that the measured data are convenient for control design. In brief, we introduce a test that determines whether the information provided by the available data is sufficient to fully recuperate the system physical laws.


*2.8. Characterization of Dispersed SEDDS*

The dispersions of both Citrem and Standard SEDDS were characterized in terms of size and polydispersity index (PdI) by dynamic light scattering; zeta potential was measured by laser Doppler electrophoresis using Zetasizer Nano ZS (Malvern Instruments, Worcestershire, UK). The dispersions of blank and complex-loaded SEDDS were dispersed 1:100 (*w*/*w*) in DI water and 10-mM MES-HBSS buffer (pH 6.5) immediately before the experiment and evaluated at 37 ◦C. Data were collected in triplicate.