Section 4 Special Population

### **Chapter 6** Pediatric Ulcerative Colitis

*Rayna Shentova-Eneva and Ivan Yankov*

#### **Abstract**

Inflammatory bowel disease (IBD) is a collective term that includes a group of disorders with unknown etiology characterized by chronic inflammation of the gastrointestinal tract and relapsing and remitting course. Ulcerative colitis (UC) is a type of IBD that affects the large intestine, causing irritation, inflammation, and ulcers in its lining. Approximately 25% of patients with IBD are diagnosed before the age of 18 years. Children and adolescents with UC are more likely to have more severe disease course with more extended intestinal involvement at diagnosis and faster disease progression than adults. Atypical presentation is also common in pediatric age. Treatment recommendations for children and adolescents are different than those for adults and offer many unique challenges for the healthcare professionals.

**Keywords:** typical ulcerative colitis, atypical ulcerative colitis, severe ulcerative colitis, diagnostic approach, management of pediatric ulcerative colitis

#### **1. Introduction**

Inflammatory bowel disease (IBD) represents a group of chronic disorders of the digestive tract with a relapsing and remitting clinical course and a debilitating character. IBD may occur at any age [1]. Approximately 25% of incident cases of inflammatory bowel disease occur during childhood [2–4]. The majority of newly diagnosed pediatric patients are teenagers, but the disease may have an earlier manifestation [5, 6]. According to the Montreal classification of IBD the pediatric IBD (PIBD) is defined as having an age of occurrence younger than 17 years [7]. Later the Paris classification defined A1a group for those children with less than 10 years of age IBD onset and A1b for children with onset of symptoms between 10 and <17 years of age [8]. The latest modification of the IBD classification defines disease onset under the age of 17 as PIBD and this is further classified into early onset IBD (EOIBD) when it occurs under 10 years of age, very early onset IBD (VEOIBD) with less than 6 years of age IBD onset, infantile (and toddler) onset of IBD (less than 2 years of onset) and neonatal IBD (disease onset within first 28 days of age) [9].

Evidence over the last several years have shown that VEOIBD is a separate disease entity with specific clinical features and outcomes that are different from those of adolescent-onset IBD [9, 10]. In most cases VEOIBD is associated with underlying primary immunodeficiencies or has an underlying monogenic etiology. It is characterized by a severe and often treatment-refractory course of disease [11]. Not

surprisingly VEOIBD is accepted currently as a unique disease that requires a specific diagnostic approach and specific treatment. A recent position paper summarized the diagnostic algorithm by suspected VEOIBD and described some of the potential treatments [12].

The classically group of IBDs in childhood includes three nosological entities: Crohn's disease (CD), IBD-unclassified (IBDU) and ulcerative colitis (UC) and [13].

CD is a type of IBD whose predilection site for development is the terminal ileum, but it may affect any part of the gastrointestinal tract, from the mouth to the anus [14]. The changes are usually segmental, the diseased sections alternating with healthy ones—the so-called skip lesions. The inflammation in CD is transmural and may affect the entire bowel wall. Initially, infiltrates are localized around the intestinal crypts, but with the disease progression, deeper layers are involved, and specific histological structures are formed—non-caseating epithelioid granulomas [13–16]. The transmural inflammation predetermines the disease-specific complications: wall thickening and narrowing of the lumen of the intestine, intestinal obstruction, fistulation, and abscess formation [16].

IBDU is the rarest of the IBD subgroups. It is more common in the pediatric population than in adults and is a diagnosis which is made in patients with IBD in whom the inflammation is confined to the colon and the disease has characteristics which do not allow to determine definitively whether it is UC or CD despite all necessary tests [7, 13, 16–18].

In UC, the inflammatory changes are usually localized in the colonic mucosa. The inflammation is ulcerative and purulent. It is continuous, usually starting from the rectum and gradually extending to the more proximal parts of the bowel. Histological findings include chronic inflammation of the mucosa with infiltration of polymorphonuclear neutrophils, accumulation of polymorphonuclear neutrophils in the crypts of the large intestine, formation of crypt abscesses, and disruption of the structure of the mucous glands. In more severe cases, inflammatory pseudopolyps are formed. The wall of the intestine becomes thick and rigid, without haustration [5, 6, 11, 13, 14, 16].

#### **2. Specific features of pediatric ulcerative colitis**

Pediatric ulcerative colitis is a different disease entity from adult-onset UC. It has a particular etiopathogenesis, unique clinical characteristics, specific disease course and outcome.

#### **2.1 Etiopathogenesis**

The etiopathogenesis of IBD is complex and multifactorial. It is suggested that a dysregulation of mucosal immune system leads to excessive inflammatory response to the contents of the intestinal lumen (microflora, infectious agents, nutrients, etc.). This abnormal immune response results in chronic inflammation and damaging of body's own structures [20]. Different genetic and environmental factors may contribute to the development of the immune dysregulation and the abnormal immune response [21]. Typical for the pathogenesis of pediatric IBD is that the role of the genetic factors is stronger than in adults, while environmental factors are of major importance in later clinical manifestation [22–24].

Childhood-onset UC is often associated with a consanguinity and a positive family history of IBD which provides an additional clue to an underlying genetic predisposition [25].

Currently, over genetic 160 loci have been associated with IBD. Most of the variants lead to aberrations in several mechanisms altering the intestinal immune homeostasis and contribute to both CD and UC risk. However, some polymorphisms are unique to UC- or early-onset UC-specific risk [26–28]. Furthermore, some types of infantile IBD or VEOIBD that manifest phenotypically with UC are thought to be monogenic diseases having a Mendelian inheritance [9, 12].

#### **2.2 Clinical manifestation**

The most common symptoms of pediatric UC include abdominal pain, chronic diarrhea with or without blood, weight loss, fatigue, fever, and rectorrhagia [6]. Generally, the clinical manifestation of the disease is associated with its location and the degree of inflammation [29]. Children with UC have more extended disease compared to adults with UC [30]. They are likely to present with pancolitis, whereas in adults the disease is predominantly confined to the rectum or left side of the colon [16]. The differences in disease location result in different clinical presentation in comparison with adult patients with UC. The majority of children with UC report of abdominal pain and bloody diarrhea, whereas adults tend to present most often with rectal bleeding [14, 16]. Furthermore, pediatric patients with UC have more often extraintestinal manifestations, impaired nutritional status or are at impaired general condition compared to adults with UC [30–32].

#### **2.3 Endoscopic findings**

The typical endoscopic findings of UC are continuous mucosal inflammation that starts from the rectum, extends proximally, and ends at transition zone anywhere in the colon or involves the whole colon [13]. Sometimes, in case of severe pancolitis the ileocecal valve and the most distal part of the terminal ileum may also be affected. This extension of the inflammatory process is termed "backwash ileitis" [14]. The typical macroscopic features of UC include erythema, granularity, friability, purulent exudates and ulcers which usually appear as superficial small ulcers. The typical histologic findings of UC include chronic inflammation in the mucosa accompanied by cryptitis or crypt abscesses. The inflammation is most severe distally and is getting milder proximally [13].

Pediatric-onset UC may present also with atypical endoscopic findings. Recognized and described are the following 5 phenotypes [13, 19]:


Based on the specific endoscopic manifestations of pediatric UC in 2013 was introduced the term "atypical UC": a new child-specific IBD category consisting of 5 atypical disease phenotypes. Nowadays the pediatric UC is divided into typical UC and atypical UC [13].

#### **2.4 Evolution and outcome**

In contrast to adult-onset presentations, children with UC have extended disease and are likely to present with pancolitis [26, 33]. This more extended disease is consistently associated with a more severe and aggressive disease course. According to the literature, within 5 years from diagnosis a significantly higher percentage of patients with childhood-onset UC are admitted to emergency units for acute severe colitis, compared to adult-onset disease [33]. Furthermore, children with UC are more likely to receive corticosteroids, be initiated on immunomodulators, and require surgery in the first year after diagnosis than adults with UC [26, 33].

The colectomy rate is significantly higher in children compared to adult UC populations [33]. Based on the literature the colectomy rate within 10 years from diagnosis is over 40% in pediatric-onset UC compared to less than 20% in adult-onset UC [34]. However, other studies show lower colectomy rates of 25% in 6 years and 15% in 10 years [35, 36].

Another specific feature of childhood-onset UC is the possible change in the diagnosis from onset to long-term follow-up [6]. A recent study of the natural history of pediatric-onset IBD showed an increased disease reclassification over time from UC diagnosis to CD diagnosis [37]. Patients initially diagnosed as UC (a correct initial diagnosis) developed findings that led to a diagnostic change to CD [38].

#### **3. Classification of pediatric ulcerative colitis**

In May 2009 an international group of experts in pediatric IBD met in Paris and created a classification which reflects the specific phenotypic characteristics of pediatric IBD—the so-called Paris classification (**Table 1**). It represents a pediatric modification of the adult Montreal Classification of IBD. The classification of pediatric UC disease according to the Paris classification. With respect to disease extent it is divided into four categories: ulcerative proctitis (E1), left-sided UC (E2), extensive UC (E3) and pancolitis (E4). Disease severity is categorized as never severe (S0) and ever severe (S1) [8].

#### **Table 1.**

*Paris classifications for pediatric ulcerative colitis (adapted from Levine et al. [8]).*

For measuring disease activity and evaluation of disease severity is used a validated, multi-item, scoring system—the so-called Pediatric Ulcerative Colitis Activity Index (PUCAI) (**Table 2**). The PUCAI is a score comprised of six parameters, including the assessment of abdominal pain, rectal bleeding, stool consistency, number of stools per 24 h, nocturnal stools, and activity level. Each item is assigned a value contributing to a combined total PUCAI score ranging from 0 to 85. Categories of UC disease activity are defined by the following total PUCAI scores: 0–9 (no activity), 10–34 (mild activity), 35–64 (moderate activity), and 65–85 (severe activity) [39]. The items that are included in the PUCAI score and their corresponding points are presented.


#### **Table 2.**

*Pediatric ulcerative colitis activity index (adapted from Turner et al. [39]).*

### **4. Diagnosis of pediatric ulcerative colitis**

The diagnosis of pediatric UC is based on standard consensus-based criteria for diagnosing IBD in pediatric patients, the so-called Porto criteria. They were prepared and issued in 2005 by the IBD Working Group of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition [16]. In 2013 the initial criteria were revised and updated [13]. According to the Porto criteria the diagnosis of pediatric UC involves history taking, physical and laboratory examination, esophagogastroduodenoscopy and ileocolonoscopy with histology, and imaging of the small bowel [11, 13, 16]:


of choice in children IBD at diagnosis with high diagnostic accuracy. Alternatively, **wireless capsule endoscopy** can be used to identify small bowel mucosal lesions in children in whom magnetic resonance enterography cannot be performed. **Abdominal ultrasound** is also a useful imaging modality that accurately detects and characterizes inflammation of the bowel wall, but it is more valuable in CD diagnosis and usually should be complemented by more sensitive imaging method.

**10. Genetic tests and immunological investigations:** They are recommended for all patients with suspected VEOIBD, presenting with UC phenotype.

#### **Figure 1.**

*Diagnostic algorithm for pediatric ulcerative colitis. IBD: inflammatory bowel disease; VEOIBD: very early onset inflammatory bowel disease; EIM: extraintestinal manifestation; UC: ulcerative colitis; MRI: magnetic resonance imaging; WCE: wireless capsule endoscopy; CD: Crohn's disease; IBDU: Inflammatory bowel disease unclassified.*

A summary of the diagnostic algorithm for suspected pediatric UC is presented at **Figure 1**.

#### **5. Therapy of pediatric ulcerative colitis**

The management of pediatric UC is based on therapeutic guidelines produced by the European Crohn's and Colitis Organization (ECCO) and European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) [40, 41]. Generally, the treatment strategy should be guided by the endoscopic extent of inflammation and disease severity. However, in children with UC the therapy depends mainly on disease severity, assessed by the corresponding disease activity index: Pediatric Ulcerative Colitis Activity Index (PUCAI) [39, 40]. The treatment goal is induction and maintenance of steroid-free complete remission [40].

#### **5.1 Medical therapy**

#### *5.1.1 5-Aminosalicylates (5-ASA)*

5-ASA are the preferred first-line therapy for induction and maintenance of remission for patients with mild (PUCAI 10–34) and some patients with moderate disease (PUCAI 35–64) [40]. The preparations are available as forms for local administration (suppositories and enemas) and forms for systemic administration (tablets and granules). Topical 5-ASA are effective in mild-to-moderate distal UC, but usually they are combined with oral 5-ASA, as the combination therapy is more effective than either treatment alone [40, 42]. Rectal 5-ASA are superior to rectal steroids for induction and maintenance of remission in distal UC [43]. Oral 5-ASA preparations are generally preferred to sulfasalazine due to a superior side effect profile combined with similar efficacy. However, sulfasalazine is cheaper and available in liquid formulation [40, 42]. The recommended dosing for oral mesalamine is 60–80 mg/kg/day (maximum 4.8 g daily) and for oral sulfasalazine 40–70 mg/kg/day (maximum 4 g daily). Both are usually given in divided doses, but according to the studies once daily dosing of 5-ASA may be as effective as twice daily dosing [44]. The recommended dosing for rectal mesalamine is 25 mg/kg up to 1 g daily (1 g daily is as effective as higher doses) [40]. Lack of meaningful response to 5-ASA within 2–3 weeks of therapy is an indication for treatment modification and initiation of steroids [40, 42].

#### *5.1.2 Steroids*

Treatment with steroids is recommended for induction of remission in children with moderate and severe UC. It is not recommended for maintenance of remission [40]. Available are forms for oral, intravenous, and local administration. Steroid dependency is defined as response or remission with corticosteroid treatment, but recurrence of symptoms when the dose is lowered or within 3 months following complete taper [40]. Steroid refractory UC is defined as lack of clinical response to oral prednisolone at doses 0.75–1 mg/kg/day (max. 40 mg/day) within 4 weeks or lack of clinical response to intravenous prednisolone at doses 0.75–1 mg/kg/day (max. 60 mg/day) within 1 week [40, 41].

Oral steroids should be used as second-line therapy for mild or moderate UC not responding to 5-ASA (oral ± rectal) and may be considered as first line in more severe moderate disease. The recommended daily dose for oral prednisolone/prednisone is 1 mg/kg/day up to 40 mg/day administered once daily (in the morning) for 2–3 weeks followed by a tapering period of up to 8–10 weeks [40]. Second-generation oral steroids with lower systemic effect such as beclomethasone dipropionate and budesonide-MMX may be considered in patients with mild disease refractory to 5-ASA before oral prednisolone. The recommended dosing schedule for beclomethasone dipropionate is 5 mg once daily for 4 weeks and for budesonide-MMX 9 mg for 8 weeks. The recommendations are for patients with weight > 30 kg. Dosing for children <30 kg has not been established [40].

Intravenous steroids should be used as first-line therapy in patients with severe UC (PUCAI ≥ 65) (See section Acute severe ulcerative colitis) [40, 41].

Rectal steroid preparations are useful for patients who are 5-ASA intolerant and in selected patients refractory to 5-ASA before starting oral prednisolone [40].

#### *5.1.3 Immunomodulators*

Thiopurines are recommended for maintaining remission in children with UC. They should be used as second-line therapy for maintaining remission in children with mild or moderate UC after 5-ASA failed and as first-line therapy for maintaining remission in children with severe UC and in 5-ASA intolerant patients. Although thiopurines have been shown to be more effective than 5-ASA they should generally be reserved as second-line therapy, considering their safety profile [40]. Before starting therapy with thiopurines it is recommended the determination of thiopurines methyltransferase (TPMT) genotype or phenotype to identify patients at greater risk of early profound myelosuppression or other thiopurine associated toxicity. Dose should be reduced in heterozygous patients or in those with low activity. Thiopurines should not be used in children homozygous mutants for TPMT or those with very low TPMT activity. Concomitant use of allopurinol 50 mg once daily in patients <30 kg and 100 mg once daily in patients ≥30 kg (maximum 5 mg/ kg) with reduced dose of azathioprine (to approximately 25–30% of initial dose) is a valid therapeutic option in cases of hyperactive TPMT resulting in high 6-MMP and low 6-TGN. The recommended dosing in patients with normal TPMT is 2–2.5 mg/ kg/day for azathioprine and 1–1.5 mg/kg/day for mercaptopurine, in a single daily dose [40]. The therapeutic effect of thiopurines may take up to 10–14 weeks after the start of treatment. Measurement of thiopurine metabolites, 6-methyl mercaptopurine and 6-thioguanine is helpful to assess compliance, adjust therapy and avoid adverse events [40, 42].

Methotrexate may be considered as alternative therapeutic option for maintaining remission in selected children with UC. Generally, there is no evidence supporting its routine use for maintenance of remission in UC, therefore it should be used only when other alternatives are not possible or available [40, 45].

Tacrolimus is a potent immunomodulator which administration is reserved for special occasions. Oral tacrolimus may be considered in selected outpatient UC children as another option to steroids for bridging to thiopurines or vedolizumab. The target trough level should be 10–15 ng/mL when initiating the treatment, and 5–10 ng/mL during the follow up period. Rectal tacrolimus may be considered as third-line therapy in patients with ulcerative proctitis who are either refractory or intolerant to mesalamine and steroids topical therapies. The recommended dose is 0.07 mg/kg/day, maximum 3 mg/day [40].

#### *5.1.4 Biologics*

Treatment with biologics is recommended as second- or third-line therapy for children with moderate or severe UC. Currently approved for pediatric use are three tumor necrosis factor (TNF)-alpha inhibitors: *infliximab*, *adalimumab*, *golimumab*; and one anti-integrin drug: *vedolizumab*. However, the mainstay of pediatric UC management is the therapy with *infliximab*. It is used for induction and maintenance of remission in children and adolescents who have had an inadequate response to conventional therapy including corticosteroids and thiopurines or who are intolerant to or have medical contraindications for such therapies. The recommended dose is 5 mg/kg per dose at weeks 0, 2, and 6, then 5 mg/kg every 8 weeks thereafter. Higher dosing should be considered in children with low body weight (<30 kg) or high BMI, and in the presence of higher inflammatory burden and hypoalbuminemia. A combination therapy with immunomodulator is preferred to reduce the likelihood of developing drug-antibodies and to enhance the effectiveness [40]. Target trough levels during induction are ≥15 μg/ mL and post induction at the start of maintenance (week 14) ≥5 μg/mL [46–48].

*Adalimumab* or *golimumab* may be considered as therapeutic option in children with moderate to severe UC who are intolerant to *infliximab* or initially respond but then lose response to *infliximab* (secondary loss of response). The recommended dosing for *adalimumab* is 160 mg at week 0, followed by 80 mg after 2 weeks and then 40 mg every other week in adolescents with weight ≥ 40 kg. In children with weight < 40 kg the recommended dosing is 92 mg/m2 at week 0, followed by 46 mg/m2 after 2 weeks and then 23 mg/m<sup>2</sup> every other week. *Adalimumab* target levels should be ≥13 μg/mL during the induction phase and ≥7.5 μg/mL during the maintenance phase [47, 49]. The recommended dosing for *golimumab* is 200 mg at week 0 followed by 100 mg at week 2 and every 4 weeks thereafter in adolescents with weight ≥ 45 kg. In children with weight < 45 kg the recommended dosing is 115 mg/m2 at week 0, followed by 60 mg/m2 at week 2 and every 4 weeks thereafter. Recommended target trough levels during maintenance are >2 mg/mL [40].

#### *5.1.5 Antibiotics*

Antibiotics should not be routinely used for induction or maintenance of remission of pediatric [40]. However, recent studies demonstrated that a combination of specific antibiotics—the so called wide-spectrum antibiotic cocktail could be used as therapeutic option for pediatric patients with severe UC resistant to other treatments [50, 51].

#### *5.1.6 Probiotics*

The use of specific probiotic agents (e.g., VSL#3 or *Escherichia coli* Nissle 917) may be considered as an adjuvant therapy in pediatric patients with mild UC or as first-line therapy in selected patients with mild UC intolerant to 5-ASA [40].

#### **5.2 Surgical therapy**

Despite advances in conventional therapy surgery remains an integral part of the management strategy in children with UC. It should be considered in patients with active, or steroid-dependent, UC despite optimized medical therapy, and in those with colon dysplasia [40]. The most common surgery that is carried out is a subtotal/total colectomy with a temporary stoma [42]. A minimally invasive laparoscopic approach is recommended for superior outcomes. Generally, the restorative proctocolectomy with ileal pouch-anal anastomosis and a covering loop ileostomy, performed as one- or two- or three-stage procedures is the recommended elective surgery for pediatric patients with UC [40].

#### **5.3 Acute severe ulcerative colitis**

Acute severe ulcerative colitis (ASC) is defined by a PUCAI score of at least 65 points [39]. According to the literature 11–23% of children with UC experience at least one severe exacerbation during the course of their disease [52–54]. ASC is an emergency which requires immediate management. Children with ASC should be treated in a hospital by a multidisciplinary team. They need close monitoring and frequent reevaluation [41].

Intravenous methylprednisolone is used as first-line treatment for ASC in children. It is preferred over hydrocortisone due to its minimal mineralocorticoid activity. The recommended dosage is 1–1.5 mg/kg/day (up to 60 mg/day) given in one or two divided daily doses. The majority of patients will respond to this treatment. However, sequential measurement of PUCAI scores is essential for identifying those patients requiring a step up in treatment with second-line (rescue) therapy [41, 42]. A PUCAI score of >45 on day 3 indicated a likelihood of steroid failure and should dictate planning for second-line therapy. In children with a PUCAI of 35–65 on day 5 intravenous steroids should be continued for an additional 2–5 days before a decision on secondline therapy is made. A PUCAI score of >65 on day 5 indicated the need for starting a rescue therapy [41].

The second-line therapy involves either *infliximab* or calcineurin inhibitors (*cyclosporin* or *tacrolimus*) [41]. Both are equally effective in inducing clinical remission in children with ASC [55]. Due to increased clearance of *infliximab* in ASC the recommended dosing for induction of remission is higher up to 10 mg/kg per dose and may be given more frequently than usual (e.g., weeks 0, 1, and 4–5). After achievement of remission target drug levels should be 5–10 μg/mL. The recommended dosage for *tacrolimus* is 0.1 mg/kg per dose orally twice daily with target drug levels during induction 10–15 ng/mL and 5–7 ng/mL once remission achieved. The recommended induction dosage for *cyclosporine* is 2 mg/kg/day administered as continuous intravenous infusion. Target drug levels should be 150–300 ng/mL during the induction phase and 100–200 ng/mL during the maintenance phase. Response to rescue therapy should be judged daily by PUCAI. If the rescue therapy fails, there is an option for a second-line rescue therapy in selected patients or it should be proceeded to a surgical management [41].

Many gastrointestinal infections have been associated with pediatric ASC. Exclusion of several specific pathogens, such as *Clostridium difficile* or Cytomegalovirus is crucial for the adequate management. In addition, for all patients on triple immunosuppressive therapy which includes *anti-TNF* or a calcineurin inhibitor plus *thiopurines* or *methotrexate* plus steroids should be considered a *Pneumocystis jiroveci* pneumonia prophylaxis with *trimethoprim-sulfamethoxazole*. The recommended trimethoprim-sulfamethoxazole dosing is 450 mg/m<sup>2</sup> twice daily (maximum 1.92 g daily) for 3 days each week, either consecutive or alternate day dosing [41].

ASC is associated with increased risk for venous thromboembolic events (VTE) [56–58]. However, thromboprophylaxis with subcutaneous low molecular weight heparin is recommended only for children or adolescents with an underlying

predisposition such as smoking, use of oral contraceptives, complete immobilization, obesity, concurrent significant infection, known prothrombotic disorder, previous VTE, family history of VTE, etc. [41].

Adequate nutrient intake and early treatment of the accompanying conditions such as anemia, infections, etc., are also an integral part of the successful management of ASC and should not be overlooked.

#### **5.4 Very early onset inflammatory bowel disease with colitis phenotype**

The colitis phenotype is the most common in the VEOIBD group [40]. The clinical manifestation could be very heterogeneous and requires a different treatment approach altogether [12]. A large percentage of children with VEOIBD presenting as colitis have a mild disease which can be easily managed with 5-ASA [59]. Others demonstrate an extended disease with severe and treatment refractory course. They require escalated dosing strategies and more intensive treatments: early introduction of biologics, combination therapies, higher dosage of immunomodulators or biologics, etc. [12]. Additionally, many of the patients with VEOIBD with colitis phenotype have an underlying monogenic disorder and benefit from specific targeted therapies [12, 40]. If the molecular defect is caused by a mutation affecting predominantly immunological cells (e.g., IL10 signaling defects, XIAP and chronic granulomatous disease), hematopoietic stem cell transplantation may be curative [40]. Therapies that inhibit the hyperactive T-cell signaling could be used successfully in patients with *CTLA4* or *LRBA* defects [60]. *Abatacept* and *rapamycin* could also be used in those patients and in patients with other defects that involve loss of Tregs or unchecked T-cell activation, such as *FOXP3* and *PIK3CD* mutations. Generally, targeted medical therapies can be used in a variety of monogenic diseases as a maintenance therapy, and in some cases, as a bridge to hematopoietic stem cell transplantation [12].

#### **6. Conclusions**

Pediatric UC is a disease with a heterogeneous phenotype which poses many unique challenges. The majority of children with UC present with pancolitis. Since disease extent is consistently associated with disease severity, it is not surprising that they have more aggressive disease course requiring more intensive therapies. Furthermore, children with UC have some unique age-related issues, such as delay of growth and pubertal development, nutrition disorders, psychological or emotional problems. Pediatric UC may present also atypically making the diagnosis difficult and demanding specific diagnostic tests and procedures. In addition, there is a group of patients with early-onset UC who needs a completely different diagnostic and treatment approach.

Pediatric UC is a disease with unique features and characteristics. Its correct diagnosis and successful management always require a hard teamwork and multidisciplinary approach.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Rayna Shentova-Eneva1,2\* and Ivan Yankov3,4

1 Department of Gastroenterology and Hepatology, University Children's Hospital "Prof. Ivan Mitev", Sofia, Bulgaria

2 Medical University of Sofia, Bulgaria

3 Department of Pediatrics and Medical Genetics, University Hospital "St. George", Plovdiv, Bulgaria

4 Medical University of Plovdiv, Bulgaria

\*Address all correspondence to: rshentova@yahoo.com

© 2022 The Author(s). Licensee IntechOpen. 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.

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#### **Chapter 7**

## Ulcerative Colitis and Pregnancy

*Athula Kaluarachchi, Nilesh Fernandopulle, Probhodana Ranaweera, Dinindu Kaluarachchi, Indumini Kaluarachchi and Sanupa Kumarasiri Jayawardena*

#### **Abstract**

Ulcerative colitis (UC) is characterized by relapsing and remitting episodes of inflammation limited to the mucosal layer of the colon. It commonly involves the rectum and may extend to involve other parts of the colon. The age of onset for females is during the reproductive years, and many are likely to get pregnant after the diagnosis of the disease. Women have comparable fertility to the general population when the disease is in remission. Fertility is likely to get affected in women with active disease and in women who had undergone ileal pouch-anal anastomosis (IPAA). Assisted reproduction has improved the chances of successful pregnancy in these women whose fertility is impaired following surgery. Affected females delay pregnancy due to active disease, fear of medications affecting the fetus, and fear of transmitting the disease to the newborn. Most drugs used in the management are safe in pregnancy except for drugs such as methotrexate and tofacitinib. Congenital abnormalities are not increased in pregnancies complicated with ulcerative colitis. Preconception counseling with the objective of planning the pregnancy during remission, reviewing drug therapy, and educating on the importance of continuing medication and its safety are important for better outcomes for the mother and the baby.

**Keywords:** ulcerative colitis, pregnancy, inflammatory bowel disease, fertility, fetus

#### **1. Introduction**

Ulcerative colitis (UC) is an inflammatory bowel disease, sometimes diagnosed during the reproductive years. The incidence and prevalence of ulcerative colitis vary not only according to geographical region but also to race and ethnicity. In an Australian study, the estimated crude prevalence of IBD was 653 per 100,000 patients, Crohn's disease was 306 per 100,000, and ulcerative colitis was 334 per 100,000. In this study, males had a lower risk of Crohn's disease and a higher risk of UC compared to females [1].

In a systematic review and meta-analysis of studies done in the Arab world, quantitative analysis revealed a pooled incidence of 2.33 (95% confidence interval [CI] 1.2–3.4) per 100,000 persons per year for UC and 1.46 (95% CI 1.03–1.89) per 100,000 persons per year for CD [2].

The incidence and prevalence of UC in Latin America were different between regions and studies, ranging from 0.04 to 8.00/100,000 and 0.23 to 76.1/100,000, respectively. An increasing trend was seen over the period from 1986 to 2015. Most patients with UC were females (53.6–72.6%) [3]. In the Asian region, the mean annual incidence of IBD was 1.5 per 100,000. India had the highest incidence of IBD and ulcerative colitis [4].

Approximately 25% of women are likely to get pregnant after the diagnosis of the disease [5]. Prepregnancy counseling and controlling the disease activity before pregnancy are important because active disease at the time of conception and during the pregnancy has shown to result in poor maternal and fetal outcomes [6–9]. Review of drug therapy is also important since some of the drugs such as Methotrexate and Tofacitinib used in the management could affect the fetus.

Active disease during pregnancy is associated with an increased risk of maternal and fetal complications; therefore, it is important to continue therapy and have the disease under control at the time of conception and during pregnancy [6, 7, 9, 10].

Almost 50% of women with IBD have been identified to have a poor knowledge of pregnancy-related issues [11]. Poor knowledge of specific issues related to reproductive health leads to patient concerns and noncompliance. Different educational activities, including eLearning, have shown to improve the patient's knowledge of pregnancy-related issues and reduce patient concerns, which in turn will improve compliance [12, 13]. Current knowledge of prepregnancy assessment of patients with UC, the management of pregnancy, safety and the effects of medication, management of delivery, and the postpartum period will be discussed in this chapter.

#### **2. Prepregnancy planning**

Women with UC have a higher risk of adverse pregnancy outcomes than women without the disease. The magnitude of this risk is related to the disease activity at the time of pregnancy. As such, a woman with inflammatory bowel disease needs interventions to manage the disease before pregnancy to minimize adverse outcomes [6, 7, 9, 10]. This is particularly important if the patients have undergone surgical management.

Ulcerative colitis (UC) can affect women during their childbearing years. Pregnancy presents a unique challenge, in the management of UC, where the physician needs to make sure the mother's health is optimally managed, while not compromising the health of the fetus. At most instances, pregnancy in a UC patient would have an uncomplicated course. A multi-disciplinary treatment approach is required when a UC patient becomes pregnant.

#### **2.1 Preconception counseling and education**

It is important that patients are advised to conceive during a period of remission of their disease. Prepregnancy planning and proper communication with the treating physician are paramount in this context. Fertility wishes must be discussed with any female with UC in their reproductive age during the consultation and appropriate advice should be given. There are several concerns regarding UC during pregnancy, its impact on pregnancy outcomes, and its effect on the disease. These should be discussed with the patients before pregnancy.

It has been shown that 30–35% of pregnancies are complicated by flares [14]. A meta-analysis of 14 studies found a significantly higher risk ratio of active disease during pregnancy in mothers with UC who commenced pregnancy with active disease (55%) as opposed to the mothers in remission at conception (36%) (risk ratio, 2.0; 95% confidence interval, 1.5–3; P < .001). Similar results were seen in a recent European multicenter cohort: where only 14% of patients in remission at conception relapsed during pregnancy. In contrast, 26% of those with active disease at conception remained in active disease during pregnancy [8].

Having active disease at conception is found to be associated with adverse pregnancy outcomes. In a Danish study of inflammatory bowel disease, 55% of mothers had an inactive disease and 45% had mild to moderate active disease during pregnancy. There was a twofold higher risk of preterm delivery in the active disease group when compared to the disease inactive group [15]. Several such studies have reiterated the importance of the woman being in remission or at least only having mild disease at the time of conception.

When the woman is in remission or has only mild disease activity at the time of conception, it is very likely that the pregnancy will be uncomplicated [16]. A metaanalysis by Miller et al. in more than 1300 female UC patients demonstrated that normal pregnancies are observed in 85% of women with UC (76–97% in individual studies) [17].

In a study by Mountfield et al. on fear and fertility in patients with IBD, 25.8% of patients reported fear of fertility due to ulcerative colitis. This fear was equally seen in males and females suffering from the disease. Only 15.3% have consulted for medical advice before pregnancy in this study. Fear of congenital abnormalities, fear of teratogenicity of drugs, fear of genetic transmission, and inappropriate advice negatively influenced the reproductive decisions. The impact of fertility is variable in different couples as such, it is important to use an individualized approach for prepregnancy advice [18].

Familial occurrence of inflammatory bowel disease (IBD) is well documented. In a study with over 2000 UC patients, a positive family history of IBD was confirmed in 31 patients (1.5%), and 24 (77.4%) had only first-degree relatives affected. All the affected relatives had UC [19]. Different studies have reported varying familial risks of developing ulcerative colitis depending on the study population [20].

The initial prenatal visit is very important to plan out the future pregnancy and communicate and alleviate any concerns of the couple. Discussion should focus on nutritional aspects, weight gain, disease activity, monitoring of mother and fetus, and managing a potential flareup in the future. This discussion that begins at the preconception visit should continue in a dynamic process throughout the pregnancy, further reiterating the importance of management steps.

The principle underlying the treatment of UC during pregnancy is balancing the risks associated with active disease versus any probable or actual risk associated with specific UC medications. Most mothers would feel any medication during pregnancy will be harmful to the baby and would opt not to continue with their medications. It is important this fear is acknowledged and discussed and set into context. Proper counseling of the potential adverse effects of the medications and untreated disease needs to be discussed with the mother and other relevant persons. It is important to communicate with the mother and highlight the importance of continuing the medications and being in remission throughout the pregnancy. Most drugs are considered safe in pregnancy and active disease is likely more harmful than the medication that maintains remission. Medication used by the woman should be reviewed. Medicines which are considered unsafe in pregnancy should be changed to more pregnancy friendly medication when a couple plans a pregnancy. Ideally this should be done at least 3 months prior to the pregnancy, so that there is adequate time for the new medication to take its action and the woman to be in remission at the time of conception.

#### **2.2 Ulcerative colitis and fertility**

A systematic review of 11 studies to evaluate nonsurgically treated inflammatory bowel disease found that there is no reduction in fertility in women and men with UC in remission [21]. Lower fertility rates have been reported in women with active disease [22, 23]. However, in UC patients with ileal-pouch anal anastomosis (IPAA), there is an observed reduction in fertility. In a recent meta-analysis, the relative risk of infertility is reported as 4.17 (95% CI 1.99, 8.74) compared with patients before surgery in women who had UC [24]. This is likely due to reproductive organ damage during deep pelvic dissection, formation of scar tissue and adhesions, and the increased prevalence of dyspareunia following surgery.

However, a recent Cochrane review of 16 studies concluded that the effect of surgery on female fertility is uncertain. Any differences in infertility among those undergoing open versus laparoscopic procedures were also uncertain [25].

Assisted reproduction is safe and effective in patients with ulcerative colitis. In medically managed patients, the live birth rates are like that of the general population. However, the live births are reduced after IPAA failure [26].

#### **2.3 Contraception**

Since it is advisable to get pregnant during disease remission, contraception plays a significant role in prepregnancy management. Women with UC often present during the reproductive years [5, 7], and thus, women with this disorder need effective contraceptives to prevent unintended pregnancies or to optimally time desired pregnancies.

With regard to oral contraceptives, concerns are expressed about their absorption, increasing the risk of relapses, and increasing the risk of venous thrombosis during their use. In a systematic review on contraceptive use among patients with inflammatory bowel disease, the studies have shown that absorption of the hormones is not affected by the presence of ulcerative colitis, including the patients who had undergone surgery. The frequency or severity of relapses is also not affected compared to nonusers of oral contraceptives. There is no adequate data on the risk of venous thrombosis [27].

Long-term use of depot medroxyprogesterone acetate (DMPA) is associated with small but reversible changes in bone mineral density [28], but it is not known whether the use of DMPA modifies the risk of osteoporosis or osteopenia in women with UC.

Long-acting reversible contraceptives, such as copper or levonorgestrel intrauterine devices or levonorgestrel implants, are highly effective contraceptive methods. Center for Disease Control and Prevention (CDC) recommends the use of these methods for patients with ulcerative colitis [29].

#### **3. Effect of pregnancy on ulcerative colitis activity**

Patients with disease remission at the time of conception have 26–35% chance of flare during pregnancy, and this is comparable to the risk of flare in nonpregnant women [7, 8]. There is a significantly higher risk of disease relapse in patients with UC during pregnancy, particularly in the first and second trimesters and the postpartum period compared with nonpregnant women with UC [8, 17]. Similar results were seen in a recent European multicenter cohort: where only 26.4% of patients in remission at

*Ulcerative Colitis and Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.107268*

conception relapsed during pregnancy. In contrast, 33% of those with active disease at conception remained in active disease until delivery [8]. Most of patients with active disease went into remission during pregnancy [8, 30].

A meta-analysis of 227 women with active UC at conception identified that 24% of women continued to have active disease, 45% experienced worsening disease activity, and 27% improved during pregnancy [17, 30].

In a study with 206 women with IBD, postpartum flares occurred in 31.6% of women, out of which 60% were in patients with UC [31]. The development of postpartum flares was predicted by disease activity during the third trimester, therapy de-escalation during pregnancy, and therapy de-escalation after pregnancy [31].

#### **4. Effect of ulcerative colitis on the pregnancy and child**

Many studies have shown that women with UC have an increased risk of preterm delivery, low birth weight (LBW), small-for-gestational-age (SGA), and cesarean section (CS) delivery [30, 32–37]. It has also been shown that these complications are higher in patients with active disease requiring drug therapy [10, 32].

Having active disease at conception is found to be associated with negative pregnancy outcomes as well. In a Danish study of inflammatory bowel disease, 55% of mothers had inactive disease and 45% had mild to moderate active disease during pregnancy. There was a twofold higher risk of preterm delivery in the active disease group when compared to the inactive group [15]. Several such studies have reiterated the importance of the woman being in remission or at least only having mild disease at conception.

If the woman is in remission or has only mild disease activity at conception, it is very likely that the pregnancy will be uncomplicated [16].

Some studies have shown an increased rate of miscarriage in patients with UC compared to the normal population. However, this difference was not statistically significant [38].

Most studies have shown that there is no increased risk of congenital abnormalities in patients with UC compared to patients without the disease [32, 35, 37].

#### **5. Management of a patient with UC during pregnancy**

#### **5.1 Obstetrics care**

Once pregnant, it is recommended to refer patients with UC for consultant-led care early. An ultrasound scan to exclude an ectopic pregnancy is important, especially in patients who have undergone bowel surgery. After confirming the viability of pregnancy, arranging specialized care in a joint clinic with an experienced obstetrician and IBD physician is recommended for optimal care during pregnancy [39, 40].

Dating the pregnancy with an ultrasound scan between 12 and 14 weeks should be done as there is an increased risk of preterm delivery in a patient with UC. Aneuploidy screening should be performed in line with local guidelines. An anomaly scan to screen for congenital anomalies should be offered to all patients with UC.

Serial growth scans in the third trimester are recommended as there is an increased risk of small for gestational age and fetal growth restriction [30, 32–37].

Vaccinations during pregnancy should be offered as routine, including vaccination against COVID-19, although very limited data is available regarding its safety.

Preliminary studies have shown no significant increased risk with COVID-19 mRNA vaccines during pregnancy [41].

#### **5.2 Nutrition**

During pregnancy, the fetus derives all its nutrition from the mother via the placenta. Therefore, the mother's nutrition should be optimal to ensure a healthy baby. IBD patients are at increased risk of macro and micronutrient deficiencies due to mucosal loss and impaired absorption [42]. Zinc, Vitamin D and B12, Calcium, folic acid, iron, and protein deficiencies are known to occur in IBD patients and should be actively suspected and treated as indicated [40, 43, 44].

There are studies that have shown that a diet rich in vegetable oils, fruits, grains, and fish has protective effects on adverse pregnancy outcomes [44].

#### **5.3 Drug therapy and safety during pregnancy**

Most medications used in UC are considered safe during pregnancy (**Table 1**). But an honest discussion with the mother is important to ensure compliance.

#### *5.3.1 5 Aminosalicylates (5 ASA)*

Aminosalicylates are used in the treatment of mild to moderate UC. Aminosalicylates are generally considered safe for use in pregnancy as per the European Crohn's and colitis guidelines (ECCO) [45]. Several case series, populationbased cohort studies, and two meta-analyses did not demonstrate an increased risk for early pregnancy adverse outcomes such as miscarriage and ectopic pregnancy in mothers continuing with 5 ASA during pregnancy [46]. Few trials have demonstrated premature birth and low birth weight with 5 ASA use, but whether active disease during pregnancy was considered a confounding factor cannot be ascertained [46]. Reassuringly, animal and human data, including recent meta-analysis, did not demonstrate any teratogenic effects with 5 ASA and therefore is recommended to be continued during pregnancy [47]. Sulfasalazine can potentially interfere with folate


#### **Table 1.**

*Summary of medications used in ulcerative colitis.*

absorption, which is essential for neural tube development. Folic acid supplementation is therefore always required if not already given.

#### *5.3.2 Corticosteroids*

Steroids are needed in the management of most acute flares of UC and are recommended for use in the ECCO guidelines [45]. Corticosteroid may increase the risk of pregnancy-related adverse outcomes and gestational diabetes. Although most studies have not shown an increased risk of congenital malformations associated with the use of steroids, there seems to be an increased risk of orofacial malformations if steroids are used in the first trimester [48]. However, a large population-based study, including 51,973 pregnancies, did not show any adverse events from using steroids during pregnancy [49].

#### *5.3.3 Ciclosporin and tacrolimus*

Both ciclosporin and tacrolimus are widely used for the treatment of solid organ transplantation, and most data on pregnancy outcomes are derived from such patients. In a meta-analysis of 15 studies with 410 pregnant patients, ciclosporin did not cause an increased rate of congenital malformations [50]. Data on pregnant women with IBD are minimal.

#### *5.3.4 Thiopurine*

Thiopurines, both azathioprine and 6-mercaptopurine, are used in the maintenance of remission of UC and are considered low risk and well tolerated during pregnancy [45].

Thiopurine use in pregnancy has been evaluated in several studies. Initial studies showed an increased risk of preterm delivery, small for gestational age and low birth weight, [51, 52] but these studies overall failed to consider disease activity, which is commonly associated with these pregnancy outcomes. On the contrary, several recent studies revealed thiopurines did not cause any negative pregnancy outcomes [53, 54]. With respect to congenital anomalies, studies have revealed an association with thiopurine use in pregnancy, but again several long-term studies have refuted these findings, adding up to the debate on the safety of thiopurines in pregnancy [55–57]. In a Spanish study, interestingly, patients on thiopurines had better pregnancy-related outcomes than those not exposed to thiopurines, further emphasizing the importance of controlling the disease throughout pregnancy [53, 58].

#### *5.3.5 Biologics*

Although there is substantial evidence of its safety in pregnancy, some mothers may insist on stopping biologics during pregnancy. Discontinuation of biological therapy early during pregnancy poses several problems. There is a potential risk of flares during pregnancy and postpartum period, increased risk of developing antibodies against the biologics, and possible loss of response if restarting is needed. Therefore, discontinuation of biologics during pregnancy should only be considered under certain circumstances in patients who are at a very low risk of relapse. Studies have shown patients may be considered low risk if objective sustained endoscopic remission is seen for 6 months before conception, appropriate therapeutic levels

before conception, no hospitalization in the last 3 years, no prior bowel resection, no previous loss of response to anti-TNFs, or need for dose optimization [59].

#### *5.3.5.1 Anti-TNF agents*

Anti-TNF agents used for IBD include infliximab (IFX), adalimumab, golimumab, and in some countries certolizumab (CZP). Anti-TNF agents do not cross the placenta passively as they are large molecules. However, as their structure resembles maternal immunoglobulins that are transported actively from the end of the second trimester, they too can be actively transported across the placenta. Therefore, not only is the fetus potentially exposed to these agents, but they can have blood levels exceeding maternal levels [60]. In contrast to the other anti-TNF agents, certolizumab has a pegylated molecular structure and is not transferred across or has very low or no detectable fetal drug levels at birth [61]. As organogenesis occurs before this transplacental anti-TNF drug transfer, there are no reported congenital malformations with the use of biological agents. In the PIANO (Pregnancy Inflammatory bowel disease And Neonatal Outcomes) registry, more than 500 women were exposed to the anti-TNF medications during pregnancy, and no increased risk of adverse pregnancy outcomes was reported [62]. Several studies have shown anti-TNF agents do not increase pregnancy-related outcomes [53, 63] and are therefore considered low risk and recommended for being used in pregnancy in the ECCO guidelines [45]. It is important to delay the scheduled dose of anti-TNF agents as late as possible during the second trimester (around 24–26 weeks of gestation), to maintain remission during the third trimester and to limit its transport to the fetus [64].

Infliximab has been detected at 6 months after birth in the child; therefore, there have been concerns about its implications on neonatal vaccinations. No adverse outcomes have been reported for non-live vaccines [65]. It s recommended to only institute live vaccines after 6 months of age when no detectable anti-TNF medication is seen in the child's blood. Levels of other immune suppressants used in pregnancy are probably not elevated in neonates, and routine vaccination schedules can be followed, although reliable data are lacking.

#### *5.3.5.2 Anti-integrin agents – Vedolizumab*

Vedolizumab (VDZ) is unique as it is a gut-selective IgG-1 monoclonal antibody against the integrin α4β7. There is limited data on the effects of VDZ in pregnancy. A small case series consisting of 24 and 73 pregnancies exposed to VDZ had no safety concerns reported [66, 67].

In a European retrospective study, no difference in miscarriages was seen with VDZ exposed and a control group on IFX (16 vs. 13%, p = 0.71) or a control group not exposed to any biologics (16 vs. 10%, p = 0.236). Similar number of miscarriages were seen once patients with active disease were excluded from the analysis [68]. It is recommended to use VDZ in pregnancy if indicated. But, if the childbearing age woman is naïve to biologics, as most data are available with anti-TNF agents, anti-TNFs, especially CZP, are most appropriate as a first-line treatment option for use of biologics in pregnancy.

#### *5.3.5.3 Ustekinumab*

Ustekinumab is increasingly used in pregnancy, and like the other anti-TNF agents, it is an actively transported IgG1 antibody across the placenta via neonatal Fc receptors. It appears to have stable drug levels during pregnancy, with a similar infant: maternal ratio of the older anti-TNFs. It is completely cleared from the infant's blood by 20 weeks. But like with other biologics, live vaccination needs to be avoided at least till 12 months of age until further clearance data are obtained [69].

#### *5.3.5.4 Tofacitinib*

Animal studies clearly show congenital malformations with tofacitinib in supra therapeutic doses. Although no reliable human studies are available, it is recommended to avoid this drug, especially in the first trimester. As the half-life of the drug is short, a washout period of approximately 1 week is adequate before conception [67].

#### **5.4 Disease assessment and monitoring of UC**

As IBD may adversely affect pregnancy and vice versa, it is important that the activity of the disease is objectively monitored before pregnancy and during a flair within the duration of the pregnancy. Various modalities are used to assess disease activity in IBD.

Along with histology, direct visualization with endoscopy is the definitive method to assess disease activity in IBD. But procedure-related hazards to the mother and fetus, including fetal hypoxia and demise, maternal positioning for the endoscopy and maternal hypotension, and sedation during pregnancy, are a concern [70].

Due to physiological changes in pregnancy haeamoglobin, albumin are lower and erythrocyte sedimentation rate (ESR) is higher than normal, therefore these should not be used to monitor disease activity. Fecal calprotectin that measures gastrointestinal mucosal inflammation is detected before clinical symptoms and is a useful noninvasive indicator of disease activity, although its use specifically in pregnancy has not been studied. Fecal calprotectin of lower than 50 ug/g has been shown to be predictive of quiescent disease in UC [71].

#### **5.5 Management of flare and acute severe ulcerative colitis in pregnancy**

Management of flares in UC would be like a nonpregnant patient. Serum biomarkers used traditionally to assess severity of UC may be physiologically abnormal during pregnancy.

Steroid therapy: The steroid regime is IV methylprednisolone 40 mg BD or IV hydrocortisone 100 mg QDS and rectal Hydrocortisone 100 mg in 100 ml normal saline BD given through soft rectal cannula (Foley catheter) over 30 minutes, via IV giving set.

Dehydration: Administer IV fluids to correct dehydration, with at least 60 mmol potassium per day. Patients are highly prone to hypokalemia due to diarrhea and steroid therapy, and this requires close attention.

Anti-coagulation: Prophylactic doses of LMW heparin should be considered in all pregnant females with acute relapse, as pregnancy and acute severe UC greatly predisposes a patient to venous thrombosis.

Antibiotics: Metronidazole and ciprofloxacin can be considered for patients suspected of infection after recent hospital admission, visit to an endemic area for amoebiasis, the first attack of UC, or when surgery is considered. In the absence of these features and especially in pregnancy, antibiotics are not routinely indicated [72].

Rescue therapy: Both infliximab and cyclosporine are equally effective and can be considered as rescue therapy in patients who do not respond to first-line therapy.

#### **5.6 Endoscopy during pregnancy**

Endoscopy during pregnancy is considered safe if indicated, except in states of placental abruption, ruptured membranes, or eclampsia. It should be performed by an experienced endoscopist and, if possible, should be postponed until after the first trimester. While performing the lower gastrointestinal endoscopy, mothers need to be lying in a left lateral position or what is known as "left pelvic tilt" to avoid compression to the major vessels supplying the placenta. Unsedated flexible sigmoidoscopy is preferred following an enema and would give the necessary information in a patient with UC [73].

If strongly indicated, colonoscopy can be done with obstetric anesthesia monitoring, but colonoscopy is generally avoided due to the difficulties in bowel preparation, technical difficulties, and negative effects on pregnancy. Sedation needs to be discussed with anesthetists, and benzodiazepines are best avoided during pregnancy. It is recommended to document the fetal heartbeat before and after endoscopy and to always have obstetric support available.

#### **5.7 Timing, planning, and management of the delivery of the fetus**

In the majority of patients with UC, the mode and timing of delivery can be decided according to the obstetric indications. There is no contraindication for vaginal delivery in a patient with UC without fetal or maternal complications. Episiotomy should be given, if necessary. Vacuum or forceps deliveries should be done for usual obstetrics indications.

When deciding the mode of delivery, the AGA guideline would be a good reference (**Figure 1**) [40]. Patients without perineal disease should be encouraged for vaginal delivery. However, for patients with active disease or with perineal disease (anorectal fistula, anal abscess, rectovaginal fistula, anal fissures, and anal stenosis), cesarean

#### **Figure 1.**

*Guide to decide the mode of delivery in patients with UC. VTE, venous thromboembolism.*

delivery should be offered [74]. IPAA is a relative contraindication for vaginal delivery. One should consider the possible protection of anal sphincter by performing an elective cesarean delivery. An experienced obstetrician should perform the cesarean section to minimize the risk of intraoperative organ injury with the possible involvement of the surgical team if required.

Nevertheless, women with UC have a higher risk of cesarean deliveries compared to women in the general population [75]. Most of the time, a cesarean section is suggested or requested because of unjustified fears on the part of patients or care providers.

#### **6. Breast feeding, postpartum management, and follow up including family planning**

#### **6.1 Thromboprophylaxis**

Patients with UC have an increased risk of developing venous thromboembolism (VTE), especially during the postpartum period [76]. The need for thromboprophylaxis should be assessed in each patient according to AGA guideline [40] (**Figure 1**). Thromboembolic deterrent stockings and low molecular weight heparin (LMWH) should be offered to all women who have undergone cesarean delivery. UC patients with other risk factors for VTE regardless of the mode of delivery should be offered with both mechanical and LMWH as thromboprophylaxis. Some may need anticoagulation for an extended period. LMWH and warfarin can be used in these circumstances. UC patients who have been successful in vaginal delivery with no other risk factors for VTE can be offered mechanical thromboprophylaxis only.

#### **6.2 Postpartum**

The risk of relapse is higher during the postpartum period. Discontinuation of drug therapy during pregnancy and fear of drug therapy during breastfeeding are the main reasons. In one study, 75% of cases experienced a relapse during the postpartum period in patients who discontinued the drug treatment before 30 weeks of gestation. In contrast, only 26% of cases had a relapse in patients who continued the drug therapy throughout pregnancy [77].

Biological treatment can be restarted 24 hours after vaginal delivery and 48 hours after cesarean delivery [78]. However, exclusion of possible infection is mandatory before recommencing treatment. Methotrexate can be restarted during the postpartum period if the mother is not breastfeeding [79]. Most of the other drug therapies can be safely continued in the postpartum period (**Figure 2**).

Patients with IPAA are at a higher risk of developing paralytic ileus during the postpartum period, especially the ones who undergo cesarean deliveries. Early feeding and mobilization, proper hydration, and other supportive measures can reduce this risk significantly [80].

The risk of stoma complications is higher during the postpartum period. Liaising with a stoma specialist nurse and colorectal surgeon will help to minimize complications with stoma [79]. Covering the ostomy with a gauze towel is recommended to protect the operative field during cesarean section [76].

**Figure 2.** *Postpartum care for women with UC.*

#### **6.3 Lactation**

In most instances, a woman with UC can breastfeed the child without any major issues. Exclusive breastfeeding for 6 months, with the continuation of breastfeeding for 1 year or longer as mutually desired by mother and infant is recommended. However, a significant number of women with UC defer breastfeeding due to fear of drugs in breast milk or discontinuing medication during the postpartum period, equally harmful to both the mother and baby. In the PIANO registry, the breastfeeding rate was significantly lower in women on immunomodulators and biologic treatments [81].

Breastfeeding has a protective effect on the development of UC in offspring. A systematic review has shown that ever being breastfed was associated with a lower risk of UC (OR 0.78, 95% CI 0.67–0.91) [82].

When deciding the drug therapy during the postpartum period and lactation, the AGA guideline will be very helpful [40].

5-ASA agents (mesalamine, basaloid, and olsalazine) can be continued when breastfeeding. Although they are excreted in breastmilk, only a few isolated cases of diarrhea are reported in infants who are exposed. Compared to sulfasalazine, which is excreted into milk and known to have hemolytic and antimicrobial properties, mesalamine derivatives are safer during lactation [83].

Thiopurines and corticosteroids are secreted in minute amounts in breast milk. Some studies have shown when corticosteroid dose is higher than 20 mg per day, significant levels are detected in breast milk [84]. They can also reduce breast milk production. Some advice avoiding breastfeeding for 3 to 4 hours after taking thiopurines as the drug is not detected in breast milk after 4 hours of dosing. Most of the biological agents are found in minute amounts in breast milk and are degraded in the stomach of the infant, and no significant adverse effects are reported, thus can continue during breastfeeding [85].

Anti-interleukin 12–23 and anti-integrin are considered safe during lactation, as only minute amount is secreted in breastmilk. Nevertheless, limited safety data are available for these relatively new therapies [86].

Due to lack of data, lactation is contraindicated in women who are on tofacitinib.

#### **6.4 Postpartum contraception**

Effective, safe, and reliable contraception should be offered to all women with UC after delivery. Long-acting reversible contraceptives are the safest and most effective. These include hormonal or nonhormonal intrauterine devices or hormonal implants. Estrogen-containing contraceptive methods may increase the risk of venous thromboembolism, hence should be offered only if no personnel or family history of DVT or no other risk factors. Estrogen patches or low-dose estrogen contraceptive pills are safer.

#### **7. Long-term effects of ulcerative colitis on the Fetus**

#### **7.1 Ulcerative colitis and genetics**

Genetic studies have shown an increased risk of developing UC in the offspring, although the risk is somewhat less than Crohn's disease. Family history with multiple members having the disease increases the risk further for the offspring. In monozygotic twins, there is a 6–19% concordance for UC [87]. The incidence rate ratio is 3.7 for UC in an offspring if the mother is having UC and the absolute risk of an offspring developing UC is 1.6% [88]. The risk of developing IBD rises to 30% if both parents have UC [89]. There are no genetic tests available currently to predict the probability of a child developing the disease.

#### **7.2 Infection and vaccination**

There is a significant risk of neonatal infection postdelivery due to immunosuppressive treatment during pregnancy. Neonates and infants should be monitored for possible infections, especially if they are exposed to a combination of thiopurines and biologics [79].

It is recommended to avoid live vaccinations until 6 months postdelivery in infants exposed to biological therapy during the third trimester [39]. This is because of possible immunosuppression in the infant due to clinically significant drug levels detected up to 6 months after birth.

#### **7.3 Mental development**

PIANO registry data and other studies indicate that there is no significant effect on the neurodevelopment of babies regardless of exposure to the antenatal medication. In fact, some studies have shown better achievement of neurodevelopment milestones in infants with higher drug levels compared to infants with lower drug levels at birth. Therefore, good disease control with proper medication should be encouraged when counseling women with UC [90].

#### **8. Conclusion**

Ulcerative colitis affects women during their reproductive years and many of them are likely to plan pregnancy after the diagnosis of the disease. Fertility is reduced in women with active disease and in patients who have undergone surgical management. Development of advanced fertility management has improved the chances of pregnancy in these women. Prepregnancy assessment of the disease activity, counseling regarding the fetal and maternal outcome, and safety and importance of continuation of medication are important aspects of management of patients affected by ulcerative colitis. Because the pregnancy outcome is adversely affected by disease activity, adequate attention should be given to the continuation of treatment during pregnancy. Most of the drugs used in the management of ulcerative colitis are safe in pregnancy with a few exceptions. Multidisciplinary team management, including gastroenterologist, obstetrician, and neonatologist will help to reduce complications and improve maternal and neonatal outcomes.

### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

Athula Kaluarachchi1 \*, Nilesh Fernandopulle1 , Probhodana Ranaweera1 , Dinindu Kaluarachchi<sup>2</sup> , Indumini Kaluarachchi3 and Sanupa Kumarasiri Jayawardena4

1 Faculty of Medicine, University of Colombo, Sri Lanka

2 Colombo North Teaching Hospital, Ragama, Sri Lanka

3 Faculty of Medical Sciences, University of Sri Jayewardenepura, Sri Lanka

4 Colombo South Teaching Hospital, Kalubowila, Sri Lanka

\*Address all correspondence to: athula.kal@gmail.com

© 2022 The Author(s). Licensee IntechOpen. 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.

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