Nirupama Bonthala is a gastroenterologist at Cedars-Sinai Medical Center in Los Angeles.

Nirupama Bonthala, MD

Inflammatory bowel disease (IBD) comprises ulcerative colitis and Crohn’s disease. In 2015, an estimated 1.3% of adults in the United States, or roughly 3 million people, were reported to have IBD.

 About half of those affected are female and the peak incidence of IBD is between 15 and 40 years old.

 Thus IBD in women tends to occur during their childbearing years when their most consistent health care provider is likely to be their obstetrician/gynecologist. In this article, we will review the basics of IBD and steps to optimize maternal and neonatal outcomes for women with IBD, including preconception counseling, medication management during pregnancy in conjunction with a gastroenterologist, and postpartum care.

While the exact etiology of IBD is unclear, it is widely thought to be a dysregulated host immune response to genetic, environmental, and microbial factors

. Ten to 25% of affected patients have a family history of IBD.

 Certain environmental exposures such as frequent antibiotic use in childhood, low vitamin D levels, frequent nonsteroidal anti-inflammatory drug use, and diets high in processed, sugary, or fried foods may increase risk for IBD.

 Interestingly, smoking increases risk of Crohn’s disease while smoking cessation increases risk of ulcerative colitis.

 Breastfeeding may confer a protective benefit in development of IBD.

Patients with ulcerative colitis present with acute onset of bloody diarrhea, mucus, and urgency. Ulcerative colitis affects only the colon and a colonoscopy reveals inflammation in the form of ulcers starting in the rectum and extends in a contiguous manner more proximally (Picture 1A). Ulcerative colitis is limited only to the mucosal layer of the colon wall. Despite having bloody diarrhea, patients rarely have anemia (Table 1).

TABLE 1: ULCERATIVE COLITIS VS CROHN’S DISEASE

For those with milder disease, the mainstay for therapy includes oral or rectal administration of 5-aminosalicylates. For those with more moderate to severe disease, immunomodulators (5-mercaptopurine or azathioprine) and biologic medications (Table 3) are more effective. Of note, steroids (prednisone, budesonide) are used only for flares and not for maintenance therapy.

Those with ulcerative colitis have an increased risk of colon cancer and require frequent colonoscopies, typically every 3 years, even if they are in remission, to evaluate for dysplasia. In medically refractory cases of ulcerative colitis or dysplasia, a multistage surgery that consists of complete removal of the colon and reconstruction of an ileal pouch anal anastomosis (IPAA) or “J-pouch” is recommended. Women who undergo all stages of this surgery do have a threefold decrease in fertility compared with age-matched women without this surgery because of extensive adhesions leading to tubal factor infertility.

Crohn’s disease can occur anywhere in the gastrointestinal tract from mouth to anus, although the terminal ileum is the most common site. A typical presentation is slower onset of non-bloody diarrhea, abdominal pain, weight loss, malnutrition, anemia, and vitamin deficiencies. Classic colonoscopy findings include deeper ulcers with intervening areas of normal mucosa known as “skip lesions,” a cobblestone appearance, and a relatively normal-appearing rectal area (Picture 2). While we are classically taught granulomas on biopsy are diagnostic of Crohn’s disease, less than one-third of biopsies show these findings (Table 1). Unlike in ulcerative colitis, oral 5-aminosalicylates are not found to be effective in Crohn’s disease, and biologics and/or immunomodulators are preferentially used.

TABLE 3: IBD MEDICATION SAFETY DURING PREGNANCY AND BREASTFEEDING COMPATIBILITY

Crohn’s affects all layers of the bowel wall, thus, complications like strictures, abscesses, and fistulas can occur. Of note, perianal disease occurs with Crohn’s disease and currently active perianal disease is an indication for cesarean delivery. Vulvar Crohn’s disease can occur with manifestation of linear “knife-like” vaginal fissures.

What is the difference between irritable bowel syndrome and inflammatory bowel disease?

IBD is often confused with irritable bowel syndrome (IBS) as there may be similar symptoms of abdominal pain and diarrhea but these are two very distinct entities with vastly different treatment and outcomes (Table 2). 

Irritable bowel syndrome is a functional disorder that is common in the general population with up to 10-15% affected in the United States. Risk factors include female sex, age under 50, concomitant anxiety or depression, and family history of IBS. IBS does not result in any endoscopic or imaging findings and has no increased risk of cancer. Mainstays of therapy for IBS include diet, exercise, fiber, and neuromodulating agents such as antidepressants.

This is in contrast to IBD, which has visual endoscopic inflammation and can be seen on imaging studies. If IBD is left untreated there is a risk for colon cancer and complications such as strictures, abscess, and fistulas, as above. Medications for IBD include immunosuppressants.

Adverse pregnancy outcomes with active IBD

Women with active IBD at conception or those who flare during pregnancy are at increased risk for adverse outcomes including miscarriages, poor maternal weight gain, preterm birth, low birth weight infants, preeclampsia, and increased risk of cesarean delivery.

 Data have shown that these risks are far lower in women who are in endoscopic remission prior to pregnancy and an updated colonoscopy should be performed in those contemplating pregnancy.

For those women with IBD who are not yet optimized, we advocate counseling patients on safe and effective contraception. Intrauterine devices and implants are the preferred over combined hormonal contraceptives as women with IBD are higher risk for thromboembolic disease.

 Women with IBD are also higher risk for osteoporosis, thus, depot medroxyprogesterone acetate injections should be used with caution.

Team approach with obstetrician, gastroenterologist, maternal fetal medicine specialist

Because of these increased risks, preconception counseling is of utmost importance and, in fact, has been shown to improve outcomes by improving adherence with medications and decreasing flares during pregnancy.

 We advocate for a team approach with an obstetrician and/or maternal fetal medicine (MFM) along with a gastroenterologist for all patients with IBD as there are data that even those in remission can have some increased risk of flares and adverse outcomes.

 Discussion of safety of medications is often the focus for patients but providers should also counsel on the risks of flares and adverse outcomes of active inflammation if medications are decreased or discontinued. A consistent message to the patient is critical

During preconception counseling, obtain baseline labs including inflammatory markers (sedimentation rate, C-reactive protein), a commonly utilized stool inflammatory marker (fecal calprotectin) and recent colonoscopy to ensure endoscopic remission.

Nearly all IBD medications with few exceptions can be continued during pregnancy and breastfeeding (Table 3). The exceptions include methotrexate and thalidomide for their well-known teratogenic effects. Tofacitinib, a newer medication that was recently approved for ulcerative colitis, does not have enough data for comment on safety during pregnancy. These three medications should be avoided and patients who are on these and are contemplating pregnancy should be switched to a safer alternative that achieves endoscopic remission before conceiving.

These medications come in the form of oral tablets or rectal suppositories/enemas. They are commonly used for mild to moderate ulcerative colitis and less commonly for Crohn’s disease. They are low risk and can be continued during pregnancy. Pregnant women on sulfasalazine need increased folic acid supplementation of 2 mg daily. Reversible infant diarrhea has been reported in a few cases but these medications are considered compatible with breastfeeding.

IMMUNOMODULATORS: 6-MERCAPTOPURINE (6MP), AZATHIOPRINE

These oral medications are used for moderate to severe ulcerative colitis and Crohn’s disease either as monotherapy or in combination with biologics. Recent data do not show any increased risk of congenital anomalies. Recommendations are to continue with these medications during pregnancy if used for monotherapy. In patients with combination therapy with biologics who are in deep remission, we can consider stopping these medications while continuing biologic monotherapy on a case-by-case basis in conjunction with the gastroenterologist. They are both compatible with breastfeeding.

These medications, which are either infusions or injections, are used for moderate to severe ulcerative colitis and Crohn’s disease. Three broad categories exist at this time: 1) tumor necrosis factor (TNF) inhibitors such as infliximab, adalimumab, certolizumab, golimumab; 2) anti-integrins (vedolizumab, natalizumab); and 3) anti-interleukins (ustekinumab).

These are highly effective medications that should be continued in pregnancy. If doses are missed or an extended gap exists between doses, patients may develop antibodies to these medications that not only render them ineffective but also may actually cause a life-threatening allergic reaction on reexposure. Thus, it is imperative to be mindful of these medications and plan each dose during pregnancy and postpartum period.

Biologic medications used in IBD are monoclonal antibodies and are actively transferred across the placenta, with the highest levels in the second and third trimester.

 While there are no known fetal adverse effects, it is ideal to time the final pregnancy dose more remote from the estimated delivery date to minimize the neonatal levels. The last dose of a biologic medication in pregnancy should be given roughly so that the next dose is a few days after delivery. For example, a standard infliximab dosing interval is every 8 weeks, therefore the last dose should be given around 32 weeks’ gestation and the subsequent dose 1-2 days postpartum assuming a 40-week delivery. While this is the ideal scenario for remission, if a patient is flaring during pregnancy, these medications are often increased and continued through the time of delivery.

Breastfeeding is compatible with all of the biologics as levels in the breast milk are exceedingly low or undetectable. Finally, infants exposed to these biologics should avoid live virus vaccines in the first 6 months of life.

The exception to the above is certolizumab pegol, which is an injectable anti-TNF biologic approved for treatment of Crohn’s disease. Because it lacks a fragment crystallizable (Fc) region, it is the only biologic that does not cross the placenta, so fetal and neonatal exposure is negligible. Therefore dosing does not need to be timed with delivery and infant vaccine schedules are not altered. While the lack of transplacental transfer is a favorable characteristic of certolizumab, efficacy, cost, and other potential factors should be considered as well when choosing any biologic to find the best individualized options for patients.

Prednisone or budesonide (a gastrointestinal tract–targeting oral steroid equivalent used for milder flares in IBD) are often used for flares in both ulcerative colitis and Crohn’s disease but should not be used for maintenance therapy. If patient is early in their pregnancy and requires steroids, escalation of maintenance therapy including initiation of a fast-acting biologic such as infliximab should be considered. Steroids during pregnancy come with well-known adverse effects but are effective in quickly controlling IBD flares. They are compatible with breastfeeding. 

For those IBD patients who are in endoscopic remission prior to pregnancy, are on stable medications, and do not flare, routine antepartum care is appropriate. We recommend a GI visit and a complete blood count with liver enzymes every trimester in conjunction with the routine OB labs and visits. The obstetrician can consider growth ultrasounds as necessary if pregnancy is progressing as planned. An examination of the perineum in those with Crohn’s disease is recommended to ensure no active disease is seen in the third trimester. 

For those IBD patients who flare during pregnancy, close OB, GI, and MFM follow-ups are essential. The GI physician can obtain more specialized labs including stool tests for infections and stool inflammatory marker of calprotectin and adjust or start medications as needed to control the flare. From an OB and MFM standpoint, consider more frequent growth scans and if on steroids, closer glucose monitoring.12

If there is a concern for a new diagnosis of IBD or a severe flare that requires initiation of biologics during pregnancy, an endoscopic procedure can be considered with strong preference for a shorter flexible sigmoidoscopy rather than a full colonoscopy. Flexible sigmoidoscopies can be done quickly without sedation or a preparation and be performed in the hospital GI lab setting rather than outpatient clinic office. However, routine GI procedures such as screening colonoscopies or nonurgent upper endoscopies should be deferred to the postpartum period. Any GI procedure during pregnancy should be done in coordination with the obstetrician to ensure an adequate fetal monitoring plan is in place prior to procedure.

Despite higher rates of cesarean delivery in women with IBD compared with the general population, the only absolute contraindication to vaginal delivery is active perianal disease in women with Crohn’s disease.

 In women who have undergone J-pouch surgery and have done well, recent studies have shown no worsening of pouch function after a vaginal delivery, thus this decision can be individualized. The concern for vaginal delivery in women with IBD is the perceived increased risk of adverse outcomes with perineal lacerations, especially 3rd or 4th degrees, but thus far this has not been shown.

 Women with ileostomy or colostomy may also attempt a vaginal delivery if they have not had complications with their ostomies. Therefore, for the vast majority of women with IBD, there is no reason to recommend a planned cesarean delivery because of the IBD.

NSAIDS have been shown in IBD patients to cause ulcerations and flares.

 NSAIDS are also the most commonly used pain medication after delivery. Alternate forms of pain medications in IBD patients are preferred but if NSAIDS are required to control pain, we recommend using the lowest dose and shortest duration.

Fenugreek is a common lactation supplement but should be avoided as it can cause bloody diarrhea and may precipitate postpartum flares in women with IBD.

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Articles

The authors offer guidance on how to optimize maternal and neonatal health outcomes for women with IBD.  

Nirupama Bonthala, MD

Articles

Inflammatory bowel disease and pregnancy