Ulcerative colitis and Crohn disease are chronic inflammatory diseases with typical onset in early adulthood. These diseases, therefore, can affect a woman throughout the many stages of her life, including menstruation, sexuality, pregnancy, and menopause. Unique health issues face women during these stages and can affect the course of their inflammatory bowel disease as well as treatment strategies and health maintenance. This article covers the non–pregnancy-related issues that are important in caring for women with inflammatory bowel disease. The topics of pregnancy and fertility are covered in a separate review.
Key points
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Women with inflammatory bowel disease (IBD) consistently report lower quality of life (QOL) and sexual function than men.
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Women with IBD on immunosuppressants have an increased risk of cervical cancer and should be encouraged to undergo regular screening.
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IBD can affect the regularity of a woman’s menstrual cycle and IBD symptoms may worsen before and during menstruation.
Introduction
Ulcerative colitis (UC) and Crohn disease are chronic inflammatory diseases with typical onset in early adulthood. These diseases, therefore, can affect a woman throughout the many stages of her life, including menstruation, sexuality, pregnancy, and menopause. Unique health issues face women during these stages and can affect the course of IBD as well as treatment strategies and health maintenance. This article covers the non–pregnancy-related issues that are important in caring for women with IBD. The topics of pregnancy and fertility are covered in a separate review.
Introduction
Ulcerative colitis (UC) and Crohn disease are chronic inflammatory diseases with typical onset in early adulthood. These diseases, therefore, can affect a woman throughout the many stages of her life, including menstruation, sexuality, pregnancy, and menopause. Unique health issues face women during these stages and can affect the course of IBD as well as treatment strategies and health maintenance. This article covers the non–pregnancy-related issues that are important in caring for women with IBD. The topics of pregnancy and fertility are covered in a separate review.
Gender differences in presentation of inflammatory bowel disease
Incidence
Older data had suggested that there was a slight female predominance in developing Crohn disease and a slight male predominance in developing UC. A recent large systematic review, however, that included gender-specific incidence rates for Crohn disease (59 studies) and UC (50 studies) reported a female-to-male ratio varying from 0.51 to 1.58 for UC and 0.34 to 1.65 for Crohn disease, suggesting no true gender-specific difference in the incidence of UC or Crohn disease. Few studies are available that differentiate between the disease distribution for Crohn disease and UC between men and women. One study in children, however, evaluated for gender differences regarding clinical phenotypes, disease behavior, and treatment and found no differences between girls and boys.
Differential Diagnosis
When evaluating a patient with suspected IBD, there are several entities to consider in the differential for female patients. Endometriosis, similar to IBD, is a chronic inflammatory disorder with a typical onset in younger women and is common, affecting 5% to 10% of reproductive age women. Less commonly, it can affect the bowel (75% affecting the rectosigmoid and 25% the ileocecal/appendix) and could be confused with Crohn disease. Histology is often helpful in differentiating these diseases but occasionally can show marked inflammatory and architectural mucosal changes, making the distinction more difficult. Moreover, the diseases are not mutually exclusive and it has been reported that the risk of developing IBD is increased in patients with endometriosis (standardized incidence ratio = 1.5) and for those with both endometriosis and Crohn disease, a stricturing phenotype of Crohn disease is more common (odds ratio [OR] = 11.8).
Behçet disease is a rare chronic inflammatory disease that can be confused with IBD because they share many common features, including affecting patients in young adulthood, intestinal inflammation with diarrhea and bleeding, inflammatory arthritis, and skin manifestations like erythema nodosum. Additional features that may help set Behçet apart from IBD include genital ulcers and central nervous system and large vessel vasculidities. Although Behçet is rare in the United States, it is somewhat more common in Japanese and Korean women and Middle Eastern men.
Lastly, irritable bowel syndrome (IBS) is commonly confused with IBD and, moreover, can occur in combination with IBD. IBS is common in population-based studies, with an 11% prevalence in 1 study and more common in women than men, with a 2:1 female-to-male ratio. IBS is commonly diagnosed in patients with IBD and studies have revealed that IBS is even more common in patients with IBD than non-IBD controls, with a prevalence of 39% and an OR of close to 5 (4.89). This is an important overlap to recognize to avoid escalating immunosuppression for symptoms that are gastrointestinal (GI) but not truly from active inflammation.
Extraintestinal Manifestations of Inflammatory Bowel Disease
IBD can affect many systems outside the GI tract, including the eyes, skin, joints, and bile ducts. These manifestations, overall, are more commonly seen in women than in men. A study of approximately 400 patients with IBD found that cutaneous manifestations (namely, erythema nodosum and pyoderma gangrenosum) were more common in women than men (15% vs 4%). Moreover, in women, skin manifestations of Crohn disease rarely may present as vulvar lesions. Although perianal disease with fistulas are common in Crohn disease, it is important to remember metastatic Crohn disease of the skin in the differential for vulvar lesions because perianal disease rarely extends to the genital area. A biopsy revealing noncaseating epithelioid cell granuloma establishes the diagnosis; however, it is not always seen on all biopsies of metastatic Crohn disease and clinical suspicion must remain high. Moreover, some women may present with vulvar involvement with Crohn disease as their initial presentation before having bowel symptoms. Two features that should raise concern for metastatic Crohn disease of the vulva include painless vulvar swelling and concomitant perianal lesions (like skin tags, anorectal strictures, and fissures).
Treatment differences between men and women
Several reasons exist why men and women may respond to medical therapies differently. From a pharmacokinetic standpoint, drug distribution is different simply based on differences in weight (men are generally heavier), body composition (women have a higher percentage of body fat), glomerular filtration rate (women have lower glomerular filtration rate than men even after adjusting for weight), and differences in metabolism of various drugs. The data assessing these differences between men and women, specifically for the drugs used to treat IBD, are sparse. A pharmacokinetic analysis was done for the UC patients treated with infliximab who participated in the large Active Ulcerative Colitis Trials 1 and 2 trials. Drug clearance was found 33% lower in women than men and the central volume of drug distribution was 16% lower for men. Because men have both higher weight and increased drug clearance, however, it is difficult to completely separate these changes from differences in weight. Another study that specifically looked at inflammatory patients (IBD, rheumatoid arthritis, and psoriasis) started on biologics conversely suggested that at the same extent of disease, women had more subjective complaints regarding disease activity, possibly indicating undertreatment or simply greater disease effect. Another study evaluated adverse events in patients with Crohn disease who used thiopurines and found that women over age 40 had a higher risk of adverse event, leading to discontinuation of their thiopurine. Lastly, a recent meta-analysis reported that the most reliable predictor for nonadherence to anti–tumor necrosis factor use was female gender but without convincing rationale.
When planning surgery for women with UC, consideration must be given to their plans for future childbearing. It has been clearly shown that fertility is reduced after ileoanal pouch anastomosis (IPAA). A meta-analysis revealed that infertility was increased 3-fold after IPAA, from baseline 15% to 48%. This reduction in fertility seems related, however, to the dissection into the pelvis that accompanies proctectomy, because fertility is preserved in patients who undergo other surgeries without removal of the rectum. Physicians need to discuss the options of a conventional IPAA, performing only the first stage of the IPAA with completion after childbearing and ileorectal anastomosis in context of disease control and fertility. Moreover, when counseling women prior to surgery, it is important to relay that there have been differences observed between men and women after surgery. A large study of more than 3400 patients from the Cleveland Clinic showed higher rates of long-term complications after IPAA for women. They reported female patients were significantly more likely to experience bowel obstruction (21% vs 17%) and pouch-related fistulas (11% vs 8%); had more daily bowel movements, urgency, and seepage after surgery; and reported more dietary and work restrictions after surgery compared with men. Although the reasons for these differences remain incompletely understood, some experts hypothesize that estrogens may affect the formation of abdominal adhesions and potentially explain the increased risk for bowel obstruction. Moreover, in the Cleveland Clinic study, baseline anal manometry prior to surgery revealed lower resting and squeeze pressures for women and it was postulated this may be representative of physiologic differences between men and women and may account for the difference in bowel movements, urgency, and seepage after surgery. Lastly, for women with Crohn disease, several older studies have shown that the risk of disease recurrence after intestinal resection is higher for women than men (OR = 1.2) and occurs earlier (4.8 years vs 6.5 years). Possible explanations for this finding may be the effect of tobacco smoke or hormones on bowel, because surgical technique was not different and these studies were done in the era of laparoscopic procedures.
Quality of life
QOL is important for all people, but even more so for patients who are diagnosed with a chronic disease, often at a young age, that will affect them for their entire lives. Multiple studies have shown that women with IBD have overall lower health-related QOL (HRQL) compared with men with IBD. A study from Croatia found that women have a lower HRQL and more emotional disturbances related to their disease compared with men, and this was especially true in women with higher levels of depression and anxiety. Moreover, in a Swedish population-based cohort, Crohn disease had a greater negative impact on HRQL than did UC, and this was more pronounced for women. It is unclear if these differences between men and women are due to perceived differences in disease symptoms or if this is a gender-related difference caused by the disease itself. The good news however, is that a large European cohort of patients reported that a majority of patients had improvements in QOL with specific treatment of their disease.
Comorbid depression and anxiety are diseases that can greatly affect QOL for patients with IBD, similar to patients with other chronic diseases. Multiple studies have evaluated the presence of anxiety and depression in patients with IBD and have found that the rate of depression is at least 2-fold higher than in the general population. Therefore, gastroenterologists should be aware of this and include screening for depression and anxiety in clinics and, when identified, refer for or begin appropriate treatment.
Sexual health
Sexual health is defined by the World Health Organization as a state of physical, emotional, mental, and social well-being in relation to sexuality, not merely the absence of disease, dysfunction, or infirmity. Gastroenterologists, when addressing sexual health (if they even do), focus more on sexual dysfunction, which encompasses predominantly the physical aspects of sexuality, and often neglect to address the other areas of sexual health. The impact that IBD, however, can have on sexual health when caring for women with IBD, who are often young and in the midst of their reproductive years, is important.
Sexual Dysfunction
Sexual function can be influenced by several factors, including increasing age, psychological problems like depression or anxiety, relationship problems, body image, and chronic medical problems. Similar to HRQL, women report a greater negative impact of IBD on multiple aspects of sexuality than do men. A German study reported strikingly low levels of sexual interest and activity in a cohort of 336 women with IBD. In this study, 80% of women reported no activity or only low activity during the 4 weeks preceding the survey. In an Australian cohort with IBD, women reported a greater disease-related decrease in sexual activity and decrease in libido than men. Another group found that women with Crohn disease had more concerns with sexual performance and intimacy than men with Crohn disease. Moreover, several studies have shown that a poorer body image and depression both contribute greatly to reduced sexual function in women.
For chronic medical problems like IBD, medications, surgery, and, in particular, disease activity can all contribute to sexual dysfunction. There are few data regarding the impact of medical therapy for IBD on sexual function. In a questionnaire study, patients associated steroid use with low pleasure and orgasm scores ; however, it is difficult to separate the use of steroids from the impact from presumably active disease as the indication for steroids. Other studies have reported that although a majority of patients did not believe that their IBD medications affected their sexual function, a small portion (9.7%) did stop their medications for this reason. The specific medications that patients attributed to negative effects on sexual function in this study, however, were not reported. Surgery can affect sexual function by disturbing the innervation to the genitalia or by distorting anatomy in the pelvis. Dyspareunia, a frequent complaint, can occur after surgery due to altered anatomy or sympathetic nerve injury, which may cause decreased lubrication or decreased vaginal proprioception. Fecal incontinence during intercourse has also been reported and is obviously distressing to patients. On the other hand, a study of patients undergoing IPAA found that although male sexual function did not change after surgery, for women, sexual function improved within 12 months of surgery. Disease activity is likely the most important component of IBD that affects sexual function with associated depression worsening symptoms. Active disease symptoms, whether diarrhea, pain, or even active perianal disease, affects feelings of sexual attractiveness and desire and can cause associated discomfort during intercourse.
Body Image
Body image is an important factor that plays into QOL and sexual function. Body image is a person’s own sense of how he or she appears physically in addition to the impression of how other people see his or her body. A negative body image has been associated with low self-esteem and depression. Moreover, chronic illness has been found a predictor of body image dissatisfaction.
For women with IBD, studies report higher rates of body image dissatisfaction than men. Furthermore, dissatisfaction with body image has been associated with active disease and with being treated with steroids (but not other immunosuppressives). Moreover, body image dissatisfaction in patients with IBD was also linked to lower self-esteem, higher rates of anxiety and depression, and less sexual satisfaction.
In addition to medication side effects and active disease, scars and ostomies left after surgery can affect body image and thus sexual function. An Australian study of approximately 350 IBD patients found that more patients who had undergone surgery reported an impaired body image compared with patients who had not undergone surgery (81% vs 51%). Patients with Crohn disease who underwent laparoscopic surgery as opposed to open surgery reported a better body image after surgery as well as QOL. On the other hand, in a group of men and women who underwent IPAA, there was no significant difference found in body image between those who underwent open versus laparoscopic IPAA, although there was a trend toward lower self-esteem postoperatively for women compared with men. Moreover, they also found a trend toward better body image in the women who underwent laparoscopic compared with open IPAA.
Active disease
Weight loss
Hair loss
Cutaneous manifestations of IBD (pyoderma gangrenosum and erythema nodosum)
Fistulas to skin or perineum
Arthritis
Medication side effects
Weight gain, lipodystrophy, hair growth, acne, skin thinning (corticosteroids)
Hair loss, photosensitivity (6-mercaptopurine/azathioprine)
Hair loss (methotrexate)
Psoriasis (anti–tumor necrosis factor)
Surgery
Stomas
Surgical scars
Cervical cancer risk, screening, and prevention
The most widely accepted risk factor for cervical cancer is chronic infection with high-risk oncogenic types of human papilloma virus (HPV). Although many HPV infections are cleared spontaneously, others become chronic and may progress to cancer. It remains unclear, however, why some people spontaneously clear and others progress. In addition to HPV infections, other risk factors for the development of cervical cancer include early onset of sexual activity, multiple sexual partners, a history of sexually transmitted diseases (ie, early and/or higher probability for HPV exposure), and impaired ability to clear HPV infections (ie, immunosuppression). For the authors’ patients with IBD, the frequent use of immunosuppressants to treat their disease or even the immunologic changes that occur in the disease itself may be risk factors for an increased risk of cervical cancer in this population. Initial studies reported an increased risk of abnormal cytology (Papanicolaou smears) in women with IBD (42.5% in women with IBD vs 7% in controls) and this risk was increased more so in women with a history of immunosuppressant use. Other studies did not find any increased risk for cervical dysplasia in women with IBD on immunosuppressants but did find that the risk was increased if they were current smokers, exposed to oral contraceptive use, or used combinations of corticosteroids and immunosuppressants. Most recently, a meta-analysis of the available studies (5 cohort studies and 3 case-control studies) revealed that IBD patients on immunosuppressive medications did have an increased risk of cervical high-grade dysplasia and cancer compared with healthy controls (OR = 1.34; 95% CI, 1.23–1.46).
Current guidelines for women in general recommend screening for cervical cancer with cytology every 3 years beginning at age 21. For women aged 30 to 65, cotesting with cervical cytology and HPV testing every 5 years is preferred. Over age 65, provided women have been adequately screened previously, no further screening is recommended. Several studies have assessed rates of screening for cervical cancer specifically in women with IBD. One US study of a large insurance claims database found that 70% of women with IBD received cervical testing every 3 years whereas a large population-based study in Canada found that only 54% of their women with IBD had regular cervical cancer screening. Predictors for lower utilization of cervical cancer screening included immunosuppressant use in both groups. Improved adherence to current guidelines for screening would improve prevention and early detection of cervical cancer for women with IBD and should be stressed as a part of routine IBD health maintenance. The American College of Obstetricians and Gynecologists recommends more frequent screening for patients with HIV and women who are immunocompromised (specifically solid organ transplant recipients) and, although there is no specific societal guidance for IBD, many experts advocate increased screening for women with IBD who are on immunosuppressants.
Lastly, it is important for gastroenterologists to be aware of the recommendations for HPV vaccines, which have the potential to significantly reduce the burden of cervical dysplasia and cancer. Current vaccines for HPV include Gardasil (covers HPV types 6, 11, 16, and 18) and Cervarix (covers HPV 16 and 18) and the newly approved Gardasil 9 (covers HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58). Any of these is recommended as an option by the Advisory Committee on Immunization Practices for girls by age 11 or 12. They can be given, however, as early as 9 and the Gardasil and Gardasil 9 are also recommended for boys of the same age. For young women up to the age of 26 (or boys up to age 21) who were not previously vaccinated or did not receive the complete 3-shot series, a catch-up series of immunizations is recommended.
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