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Issue: September 2015
September 22, 2015
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Treating the Female Patient with IBD

The Unique Aspects of Health Care Maintenance in Women with Crohn's Disease and Ulcerative Colitis

Issue: September 2015

While inflammatory bowel disease occurs equally in men and women, female patients are uniquely affected throughout the course of their lives by the chronic nature of the disease. Because the majority of patients are diagnosed at a young age, with peak onset ranging from age 15 to 30 years, the gastroenterologist may be the only health care provider they see. Therefore, according to experts interviewed by Healio Gastroenterology, it is essential for gastroenterologists treating female patients with IBD to proactively discuss the issues they will face as women so they can make informed decisions about treating their disease, their sexual health and family planning.

Increased Risk for Cervical Dysplasia, Osteoporosis

Studies have demonstrated that women with IBD may have an increased risk for cervical dysplasia. A 2008 study by Kane and colleagues, for example, showed the incidence of an abnormal pap smear was 42.5% for women with IBD compared with 7% for matched controls (P < .001), and the risk for an abnormal pap smear was shown to be 50% higher among patients taking immunomodulators compared with those who were not (OR = 1.5; 95% CI, 1.2-7.1). Notably, all of the high-risk lesions detected in this study were positive for human papillomavirus (HPV). More recently, Allegretti and colleagues performed a meta-analysis of five cohort studies and three case-control studies involving a total of 77,116 IBD patients, which showed patients on immunosuppressants had an increased risk for cervical high-grade dysplasia/cancer compared with healthy controls (OR = 1.34; 95%, 1.23-1.46).

Uma Mahadevan, MD

Uma Mahadevan

According to Uma Mahadevan, MD, from the University of California San Francisco, it is imperative for gastroenterologists to educate female patients about these risks. “Women on immunosuppressive medications, particularly immunomodulators such as azathioprine and 6-mercaptopurine, may be at increased risk for cervical dysplasia. You may see it with anti-TNF agents as well, so we recommend that they have regular pap smears, particularly if they have multiple partners,” she said.

The most recent guidelines from the American Congress of Obstetricians and Gynecologists (ACOG) recommend that cervical cancer screening should begin at age 21 years and occur every 3 years until the age of 29, after which cytology and HPV co-testing every 5 years or cytology alone every 3 years is recommended until the age of 65.

“A patient who has a long-term partner can follow the general ACOG guidelines ... if things have been normal,” Mahadevan said, “but it’s particularly the younger women with multiple partners who have to be more wary — and that’s true for all populations.”

According to a 2008 clinical review, studies have shown that the increased risk for abnormal cervical cytology in women taking long-term immunosuppressants is mainly due to HPV. “Drugs like azathioprine can increase your risk of cancers from viral infections, so we think cervical dysplasia is increased in IBD patients on azathioprine because it allows the HPV to propagate,” Mahadevan said. However, a recent population-based nationwide cohort study by Rungoe and colleagues found an increased risk for cervical neoplasia among IBD patients regardless of thiopurine exposure, suggesting that the disease alone may be associated with this increased risk.

Another issue that should be emphasized in the health care maintenance of women with IBD is bone density, Mahadevan said. Exposure to corticosteroids and the disease itself “can impact bone health and raise risk for osteopenia and osteoporosis, and the patient should be aware of this and have appropriate monitoring.”

A recent review by Targownik and colleagues indicates that further research on the burden of bone disease in IBD is warranted; while reduced bone mineral density and fractures are more common among individuals with IBD, “the precise burden is not well characterized [and] the relative impact of IBD-associated factors and IBD-specific inflammation on bone health is still uncertain,” they wrote.

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Finally, women with IBD should also remember to have age-appropriate screening for other cancers, Mahadevan said. “Just because you have IBD doesn’t mean you shouldn’t get your regular mammograms, for example,” she said, and the gastroenterologist, who may be the health care provider these patients see the most, should keep in mind that their patients “may be so focused on their IBD, they neglect their routine health care.”

Sexual Dysfunction

While many advances have been made in understanding the etiology and treatment of IBD, an area of knowledge that is “still in its infancy” is the diagnosis and treatment of sexual dysfunction, according to an editorial by Sonia Friedman, MD, from Brigham and Women’s Hospital. Sexual dysfunction in IBD can be caused by increased disease activity, surgery, medications, depression and hypogonadism, and an estimated 40% to 66% of women with IBD report sexual dysfunction when asked by their physicians, she wrote.

Sexual dysfunction is “a new hot topic” in IBD, Friedman told Healio Gastroenterology in an interview. “It’s definitely impaired, we need a disease-specific scale, and there need to be clinical trials to figure out how to treat it.”

Sonia Friedman, MD

Sonia Friedman

According to her editorial, general sexual function scales fail to address issues that affect IBD patients in particular, “such as fear of passing stool during intercourse, embarrassment due to setons, and/or severe perianal disease, inhibitions due to a stoma, and embarrassment in addressing these issues with a partner or health care provider.” Thus, she and colleagues are in the process of developing a validated IBD-specific scale, so “we can evaluate various treatment outcomes, such as the effects of pelvic floor physical therapy for dyspareunia or psychotherapy for depression in IBD, in the context of clinical trials,” she wrote.

Friedman co-authored a study that gained a lot of attention at Digestive Disease Week, which was presented by her colleague, Aoibhlinn M. O’Toole, MD, a clinical fellow in the IBD Center at Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital. The study demonstrated that men with IBD were more likely to have impaired sexual function. With no available questionnaire specific to IBD, the researchers developed a novel IBD-specific, 43-question survey called the IBD sexual dysfunction scale (IBD-SDS), and compared it to a non–IBD-specific sexual function questionnaire (the IIEF or International Index of Erectile Dysfunction) and a validated depression screening tool (PHQ-9) to see if depression correlates with sexual dysfunction.

Of 175 men with IBD, 38% reported their disease affected their desire to engage in sexual activity, 27% said their disease specifically prevented them from having sex, 18% reported their disease caused problems during sex and 20% reported their disease made them feel guilty about sex. Patients deemed to have moderate to severe depression had lower sexual satisfaction scores (P < .0001) and those with ostomies had higher scores on the depression scale compared to those who had no prior surgery (P = .0095).

Their questionnaire study in women, with colleague Punyanganie De Silva, MD, MPH, from Brigham and Women’s Hospital, is currently ongoing, Friedman said, with results expected in about 6 months. So far they have determined there is decreased sexual function in men, “especially in men of older age, with longer duration of disease, active disease, comorbid depression, ostomy and/or diabetes, although it looks like both genders have decreased sexual function.”

While O’Toole and Friedman’s study did not compare men and women, some data indicate that sexual dysfunction is worse in women compared to men. For example, a 2010 study by Muller and colleagues surveyed 347 IBD patients and showed that female gender negatively affected body image, libido, and sexual activity (all P < 0.005). A more recent review by Jedel and colleagues reported that “women typically report greater problems with desire/libido, sexual satisfaction, decreased frequency of, and lack of interest in sexual activity, and fecal incontinence during intercourse. Problems with lubrication, dyspareunia, and vaginal infections have also been frequently demonstrated in cross-sectional studies of women who have not had surgery and postoperatively in those who have had surgery.” Additionally, an estimated three-quarters of women report impaired body image compared with one half of men, they wrote.

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Notably, O’Toole and Friedman did find that depression and sexual dysfunction were correlated, which confirms findings from previous studies; a 2007 survey study by Timmer and colleagues, for instance, found depression was the most important correlating factor for impaired sexual function.

“Data have shown increased anxiety and depression among women and men with IBD, but more so in women based on available data, particularly if they have ileostomies or perianal disease, or if they’re afraid to go out because they have significant bowel symptoms,” Mahadevan said. “These are issues that impact their quality of life, their overall health and their seeking of health care, but they may not be adequately addressed. So as their gastroenterologist, you should be asking them if they have issues with anxiety and depression, referring them to appropriate counselors, and also just informing them that it’s not uncommon to have these issues. It’s very common to have those types of concerns, but they may not always be raised at the physician’s office by the patients themselves.”

According to Friedman’s editorial, no gastroenterology society guidelines currently provide recommendations for evaluating sexual function in patients with IBD. “Given this lack of guidance, it is not surprising that we often do not ask our patients about their sexual functioning,” she wrote. “But whether we are unaware, reluctant to ask because we do not know how to treat, or are embarrassed, it should be our responsibility to discuss sexual function with our patients.”

Contraception, Fertility and Pregnancy

Lori Gawron, MD

Lori M. Gawron

In addition to the adverse outcomes associated with unintended pregnancy in the general population, women with active IBD at the time of conception have increased risk for recurrent flares during pregnancy, miscarriage, preterm delivery and low birth weight, according to Lori M. Gawron, MD, MPH, assistant professor in the department of obstetrics and gynecology at the University of Utah. During her presentation at the Advances in IBD Meeting in Orlando, Fla., in December 2014, she said that because of these risks, gastroenterologists should routinely initiate reproductive counseling with female patients.

There are two important questions gastroenterologists should ask every woman they treat with IBD, she said. “The first question is, ‘Would you like to become pregnant in the next year?’” For women with IBD, it is imperative that pregnancy is planned, she said, so gastroenterologists should understand and discuss the benefits and risks of different contraceptive options. The second question gastroenterologists should be asking women is if their disease-related symptoms coincide with their menstrual cycles, she said, as patients may have lower quality of life if they have these symptoms, and hormonal contraception and keeping a menstrual diary can improve them.

“Women with IBD are able to take standard contraception measures,” Mahadevan said, but “one issue is that most contraception measures increase the risk of blood clots, and women with IBD already have an increased risk, so if I am going to put my patient on an oral contraceptive, I make it very clear that they cannot smoke, because when you add tobacco into the mix they have a very significant increase in thromboembolic events.” While contraception should be effective in patients with IBD, certain medications can make them less effective, she added, “particularly certain antibiotics, and the patient should be aware of this risk.” Many patients with IBD therefore use IUDs, she said. “If they have a history of a rectovaginal fistula, I may avoid it, but in general, IUDs are safe to use in patients with IBD.”

For clarification, according to Gawron, only the estrogen-based contraceptive methods of combined pills, transdermal patches and vaginal rings increase blood clot risks, while IUDs, implants, progestin-only pills and progesterone-only injectables do not. Furthermore, “the antibiotics typically used in IBD (metronidazole and ciprofloxacin) do not affect pill efficacy, but if there is concern for absorption or other interactions, an IUD should be considered as first-line contraception,” she told Healio Gastroenterology.

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Another important aspect of reproductive counseling for patients with IBD is addressing their concerns with fertility. A meta-analysis by Waljee and colleagues showed that women who undergo surgery and have an ileoanal pouch anastomosis have a threefold increased risk for infertility (increased from 15% to 48%). According to a review article by Nee and colleagues, the exact cause is unknown, but “it is speculated that either it is related to the surgical manipulation in the pelvic area or secondary to adhesions resulting in damage to the reproductive organs. Therefore, while not an ideal surgery, some may consider either a temporary diverting ileostomy or temporary ileorectal anastomosis until after childbearing is completed.”

However, two recent retrospective studies performed by Friedman and colleagues at Brigham and Women’s and Beth Israel Deaconess Hospitals showed that in vitro fertilization is equally successful in women with IBD compared with the general infertile population, and IVF has similar success in women with ulcerative colitis and ileal pouch anal anastomosis compared to women with ulcerative colitis who do not have an ileal pouch anal anastomosis and women without IBD.

“Especially after J pouch surgery for ulcerative colitis, there’s an increased risk of infertility, and a lot of these women don’t want to get the surgery because they’re afraid they won’t be able to have babies,” Friedman said. “This is a reassurance that IVF works very well after the surgery, just as well as if you didn’t have IBD at all. It works very well in Crohn’s and ulcerative colitis, and surgeries don’t matter. We are still looking to see if medications and disease activity matter. So [these results] are really positive for women who have IBD surgery and are worried about fertility.”

Finally, many IBD-related factors may affect pregnancy outcomes and thus, according to Friedman and colleagues, managing an IBD patient’s pregnancy should be a multidisciplinary effort. Patients should be provided with accurate information, especially the safety of medications and modes of delivery, to combat the misinformation they may encounter on the Internet or from other health care providers, they wrote.

Marla C. Dubinsky, MD, from Mount Sinai Hospital in New York, agreed there is a lot of discussion on the internet about risk to fetuses in this patient population, and they subsequently have a lot of questions about the impact on their child or their future fertility.

Marla C. Dubinsky

“I’m very sensitive about how I communicate risks with therapies these days,” she said in an interview. “We’re lucky the therapies we use are now enabling women to actually get pregnant because they feel better,” but voluntary childlessness remains a major reason why infertility rates are higher in IBD patients, she said.

This voluntary childlessness (18% in American women with Crohn’s disease and 14% with ulcerative colitis, according to a survey study) is likely due to concerns regarding the impact their disease will have on their pregnancy. According to Friedman and colleagues, these concerns include the potential for pregnancy to worsen the disease or cause recurrence, the possibility of genetically passing on the disease to a child (a 1.6%-5.2% chance with one IBD parent, according to one study), concern about being able to care for a child, and concern about the added stress.

“I don’t think you can start preconception early enough,” Dubinsky said. “Obviously the discussion is framed differently as you get closer to wanting to have a baby. That’s when you need these women to actually be referred to physicians who have expertise in this, and start the conversation early so there’s no anxiety surrounding it.”

“I tell my patients when they’re ready to consider conception to come talk to me first, because it’s very important to have a plan and to be comfortable with your medical management during pregnancy,” Mahadevan said. “I think the worst thing that happens is that patients are doing well, they get pregnant and they see an obstetrician who says they need to stop all of their medication because it’s a category D or category C. That is not in the best interest of the patient in most cases. There are certain medications we do want them to stop; for example, if they’re on methotrexate, which is category X and is a known abortifacient and teratogen, they should stop that at least 3 months, ideally 6 months, before considering conception. If they’re on a drug that has dibutyl phthalate in the coating, like Asacol HD [mesalamine, Actavis], that is a concern and I would switch them to a different 5-ASA agent.”

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Experts agreed that most IBD medications are safe during pregnancy, and that a larger problem is discontinuation of long-term medications before or during pregnancy.

It is important for physicians to have an open dialogue with patients about the safety of these therapies, Dubinsky said. “It’s safe, you can conceive on it, you can carry a full-term child on it, you can breastfeed on it. ... At the end of the day, there are very few therapies you can’t use in pregnancy, and most people think it’s the other way around.”

“Gastroenterologists should be even more meticulous and aggressive than usual in caring for pregnant patients, as disease activity and medication cessation are probably the two most important factors causing adverse pregnancy outcomes,” Friedman and colleagues wrote. “Most IBD medications are safe during pregnancy, but patients frequently require reassurance from both the gastroenterologist and the obstetrician.”

In response to a meta-analysis by Schulze and colleagues, in which they recommend that anti-TNF agents should be stopped at the beginning of the third trimester to prevent immunosuppression caused by persistent antibody levels in the newborn, Mahadevan and colleagues wrote an editorial in which they disagreed with this recommendation and argued that anti-TNF therapy should be continued throughout the pregnancy, citing data from the PIANO registry.

“The PIANO (pregnancy in IBD and neonatal outcomes) registry, which is supported by the [Crohn’s and Colitis Foundation of America], is in its seventh year, and it recruits women across the U.S. at major IBD centers who have IBD and who are pregnant,” Mahadevan said. “We enroll women who are pregnant with IBD and follow them through pregnancy and the first 4 years of the child’s life. What’s novel about this is that it’s large scale, it’s prospective, and it follows the kids out until 4 years to look at developmental milestones. We have about 1,500 patients enrolled and about 350 have been exposed to azathioprine, about half have been exposed to biologics, and then some patients have been exposed to neither, and we found that there is no increase in the rate of birth defects based on exposure to medication, which is important because people are always concerned about azathioprine.”

We did find that biologics cross the placenta, Mahadevan said, though certolizumab crosses at “trivial” levels (less than 2 µg/mL) “regardless of maternal dose. So that’s an important distinguishing factor for certolizumab. The other agents do cross more robustly because they are full antibodies as opposed to fragments,” she said.

Recent data from the PIANO study presented at DDW reported on breast milk transfer of biologic agents, all of which “seem to cross into breast milk but at a very low level — at the nanogram level — and that transfer into breastmilk was not associated with infections or with growth and development in the infant,” Mahadevan said. “So we feel that the use of these biologic agents or immunomodulators in pregnancy is low risk, and ... the downside of not using them is that these women can flare, and that actually is a bigger risk to the pregnancy.” Furthermore, if patients discontinue medication and flare in the post-partum period, they may not be able to return to the same agent because they can become immunized, according to Mahadevan. “We do want to be cognizant of how much is transferring into the infant, so we may try to manipulate the dose in the third trimester to have less cross,” she said.

Another issue of concern for many women with IBD is the impact of the mode of delivery, particularly for patients with perianal Crohn’s disease. In the previously mentioned review article, Friedman and colleagues recommended that women with active perianal fistulas should opt for cesarean delivery, as should women with ileoanal pouches, unless they desire multiple children. “Moderate to severely active patients with IBD, patients on biologics, immunomodulators and steroids, and patients with active perianal fistulas or pouches should be delivered in a tertiary care facility by an experienced high-risk obstetrician,” they added.

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More recently, Friedman participated in a retrospective chart review study of patients with perianal Crohn’s disease, which found no difference in the risk for symptomatic perianal flares with vaginal or cesarean delivery. “The growing, albeit limited, data suggest that in women with inactive perianal [Crohn’s disease], vaginal delivery is unlikely to result in exacerbation of disease, though more rigorous high-quality data are needed,” they wrote.

Knowledge Gaps

While many advances in fertility, medications and surgery have improved health care maintenance for women with IBD, many knowledge gaps persist and require further research, Friedman said.

“We don’t know the impact of disease activity on fertility. We don’t know the rates of pregnancy loss, [or] the rates of ectopic pregnancies, [and] we don’t have a good way to reliably look at disease activity during pregnancies, because all of the scales were [developed with] women who weren’t pregnant.” A study to validate such scales to measure disease activity during pregnancy is currently underway, she said.

It is also uncertain whether an immunomodulator should be stopped in the context of combination immunomodulator and anti-TNF therapy during pregnancy, she added. “We also don’t really know the effect of pregnancy on the course of IBD, and we don’t know the long-term outcomes in children whose mothers take these medications during pregnancy.”

In the meantime, experts agreed that maintaining an open dialogue with patients about these issues and the available information is essential. “Recognizing that — for both men and women — fears of stoma and surgery and [the impact] on sexuality, intimacy, mood, [are all] a huge part of our discussion,” Dubinsky said. “It’s all about preparing the individual to be out there, to be dating, to be able to engage in intimate relationships, and then progress through the transition of getting married and wanting to have a baby. It’s a full gamut, and it starts early.” – by Adam Leitenberger

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Disclosures: Dubinsky reports consulting relationships with AbbVie, Janssen, Prometheus Laboratories and UCB. Gawron and Friedman report no relevant financial disclosures. Mahadevan reports she is a consultant for AbbVie, Janssen, Takeda and UCB, and has received research support from Prometheus Labs, Millenium and UCB.