Inflammatory Bowel Disease and Pregnancy (2022)

INTRODUCTION Inflammatory bowel disease (IBD) commonly affects patients during their reproductive years (1,2). It is important to arm these patients with the information they need to be able to make informed decisions and have the confidence to transition to pregnancy while maintaining good disease control. Educating patients on reproductive information in focused settings has shown to improve patient knowledge (3,4). Preconception counseling provides an opportunity to focus on the benefits of controlling disease activity before and during conception and how that outweighs the risks of medication use during pregnancy. Involving a maternal-fetal medicine specialist early in the conversation will also provide even more confidence for our patients as they make decisions about IBD management (Figure 1).Figure 1.: Decision management guide.PHYSIOLOGY DURING PREGNANCY Physiologic changes of pregnancy, including uterine expansion and anatomic compression, and the use of prenatal vitamins may precipitate gastrointestinal (GI) symptoms in all pregnant patients. In early pregnancy, increases in progesterone may delay gastric emptying and lower esophageal sphincter pressures, thereby increasing risk for reflux, nausea, early satiety, and constipation (5). Prenatal vitamins may also cause GI intolerance, which can include nausea, worsening constipation, and resultant abdominal pain. Patients should be informed that stool softeners, laxatives, and polyethylene glycol 3350 are safe for use in pregnancy. Exacerbation of hemorrhoids may be particularly challenging for pregnant patients with IBD who have preexisting large hemorrhoids or perianal Crohn's disease (CD). In pregnant patients with stomas, stretching of the abdominal wall may lead to displacement, enlargement, retraction, or prolapse of the stoma. Beyond the overlap between pregnancy-related GI symptoms that may mimic active IBD, there is a very important bidirectional relationship between IBD and pregnancy in which both conditions can be mutually beneficial. From inflammatory, immunological, and microbiological standpoints, studies suggest that pregnancy is beneficial to patients with IBD (6–8). A more recent study of mostly women pregnant people on antitumor necrosis factor (TNF) medications found that, throughout pregnancy, fecal calprotectin decreased in patients with IBD but increased in controls, suggesting a beneficial impact of pregnancy on IBD (7). Another study found that in patients with IBD, there is a decrease in pro-inflammatory cytokines and TNFα as early as the time of conception and a disappearance of IBD-associated dysbiosis during the second and third trimesters of pregnancy (8). The importance of disease remission at the time of conception cannot be overstated (9). Persistent inflammation can affect every stage of pregnancy including fertility (10,11). Beyond fertility, pregnant patients with active disease, specifically those with a high degree of clinical activity, experience higher rates of spontaneous abortion, low fetal birth weight, and preterm birth. These adverse outcomes can be particularly high for patients with ulcerative colitis (UC) whose disease is not well controlled (12–15). A systematic review and meta-analysis of 53 studies found that delivery by cesarean (odds ratio [OR] 1.79, 95% confidence interval [CI], 1.16–2.77), gestational diabetes (OR 2.96, 95% CI, 1.47–5.98), and preterm prelabor rupture of membranes were more common in patients with IBD compared with controls (16). Active disease may also result in inadequate gestational weight gain, which is associated with a 2.5-fold risk of preterm birth, 2-fold risk of small for gestational age, and risk of intrauterine growth restriction in babies born to patients with CD but not UC (17). A recent mediation analysis found evidence that some excess risk of adverse pregnancy outcomes is mediated through pregnancy complications, particularly preeclampsia (PEC) (18). In the era before the routine use of biologics, the Danish national birth cohort reported a significant risk of severe PEC, particularly in those patients managed with corticosteroids (19). Maintaining the fragile balance between pro-inflammatory and anti-inflammatory factors is crucial for successful implantation and normal pregnancy outcomes. Although TNFα levels may be important for placental architecture, it may also be associated with pregnancy loss and PEC (20). The American College of Obstetricians and Gynecologists and the National Institute for Health and Care Excellence have proposed screening for PEC based on maternal risk factors, which include autoimmune diseases (21). Early-onset PEC requiring preterm delivery is associated with a higher risk of complications in both pregnant patients and neonates. It is recommended that pregnant patients with IBD should initiate low-dose aspirin (81–162 mg) before 16 weeks' gestation to reduce the rate of preterm PEC. A recent single-center analysis, however, demonstrated that daily aspirin use did not affect major clinical outcomes such as worsening disease in patients with IBD (22). Patients with IBD have higher odds for developing certain infections such as urinary tract infection and anemia during pregnancy requiring hospitalization when compared with those without IBD (23). Pregnant patients who are hospitalized with worsening disease activity are at higher risk of venous thromboembolic disease and thus should receive prophylactic anticoagulation (24). FERTILITY The reasons for infertility in patients with IBD are multifactorial with the most important factor being age, which is true for all people capable of pregnancy with or without IBD. Voluntary childlessness remains an important factor contributing to decreased rates of reported live births among patients with IBD (25). This is often driven by fears and misinformation on hereditability, infertility, congenital malformations, and medication teratogenicity (26–30). IBD therapies, in general, do not affect fertility (2,31,32). Lack of sexual desire and dyspareunia, for example, because of severe rectal or pelvic disease and possible pelvic floor dysfunction is often overlooked (33). Active disease can affect fertility and may be explained by the effect of moderate-to-severe inflammation on ovarian dysfunction and reflected as a decrease in anti-Mullerian hormone levels, a marker of ovarian reserve that naturally decreases with age (34,35). Counseling of patients on fertility reduction after ileoanal pouch anastomosis (IPAA) is very important. Patients who have undergone a colectomy with IPAA or total proctocolectomy, both involving pelvic dissection, can develop scarring of the fallopian tube secondary to pelvic adhesions (36–39). This is particularly so in the era of open surgery and may be less of an issue in the laparoscopic era (40,41). Variable rates of infertility postoperatively have been reported, and the most recent Cochrane review reports a roughly 40% reduction in fertility at 6 and 12 months postoperatively, respectively, and 54% at 24 months postoperatively. The evidence, per Cochrane, is considered low quality, and thus, recommendations based on these data are made with caution (42). This may explain why there is discrepancy as to how different providers communicate risk to patients with IBD. Bradford et al. reported that 46% and 42% of GI and colorectal surgeons, respectively, reported a 20%–50% reduction in fertility after IPAA, yet 68% of obstetricians reported no effect on fertility. More than half of GI and colorectal surgeons surveyed recommended delaying IPAA until after pregnancy (43). A recent study of patients with IBD not confounded by voluntary childlessness found that those with CD, especially those who have undergone surgery, have a significant increase in time to pregnancy compared with those without IBD (44). In general, patients with IBD who have tried unsuccessfully to conceive for 6 months should be referred for infertility evaluation, particularly if they have had pelvic surgery (45). For those older than 40 years, referral after 4 months of timed intercourse would be warranted (46). IBD medications have no effect on egg freezing or assisted reproductive therapy (ART) efficacy, and there are no data to suggest that hormones used as part of ART have an adverse effect on IBD activity. Using a Danish cohort registry, it has been reported that ART in patients with IBD is not as successful as in the general population, particularly in postoperative CD patients, but the etiology of this remains unknown (47–49). A more recent study found that infertile patients with IBD who used a single, euploid blastocyst transfer had in vitro fertilization success rates comparable with the general infertile population (50). IBD EVALUATION BEFORE AND DURING PREGNANCY Reliable, objective markers of IBD activity are particularly important in pregnancy because active disease is the greatest threat to optimal maternal and fetal outcomes. Ideally, clinical and endoscopic remission should be present for 3–6 months before conception to optimize outcomes. Laboratory evaluation Serologic changes commonly seen in pregnancy, including elevation of the sedimentation rate and decreases in hemoglobin, iron levels, and albumin, may mimic active disease and are, therefore, less accurate measures of disease activity. Iron requirements do increase during pregnancy, so it is important to monitor and supplement when deficient. Fecal calprotectin is a noninvasive, simple test that can be used to assess and screen for active disease in pregnancy. Among pregnant patients with moderate-severe IBD on anti-TNF therapy, a fecal calprotectin cutoff of 200 μg/kg had a positive predictive value of 67%–74% (51). We recommend screening for active disease in all pregnant patients with IBD by checking the fecal calprotectin level at preconception, every trimester, and postpartum. Endoscopy Lower GI endoscopy (flexible sigmoidoscopy or colonoscopy) can be safely performed and should not be avoided in pregnant patients with IBD who have a strong indication for the procedure (52). An unsedated flexible sigmoidoscopy is favored; however, a colonoscopy may be performed if needed. Bowel preparation with a polyethylene glycol solution and tap water enemas is safe. Sodium phosphate solutions should be avoided given risk of electrolyte abnormalities. Intrauterine exposure to anesthetic and sedative drugs are deemed safe (53). Avoid external compression at all gestational time points and the supine position in the second and third trimester to decrease risk of compression of the aorta and inferior vena cava by the gravid uterus. The decision to use fetal monitoring should be individualized in the setting of resource availability, gestational age, and overall risks of the procedure (53). Imaging If imaging is indicated for the evaluation of disease, ultrasound and magnetic resonance imaging are preferred. Gadolinium contrast should be avoided, in general, but absolutely avoided in the first trimester. If computed tomography is needed, this may be performed because radiation exposure from this modality is at a dose lower than that associated with fetal harm and should be used only when necessary (54). Iodinated contrast media can cross the placenta, but clinical harm has not been reported in limited animal and human studies. MEDICATIONS The safety of IBD medications during pregnancy is a major concern shared by many patients with IBD. Many patients receive negative information regarding the safety of IBD medications and, therefore, stop treatment, which can lead to poor health outcomes because of uncontrolled, active disease. Organogenesis is complete by 10 weeks' gestation, and this is particularly important information for discussions with patients who are on biologics because they will be relieved to know that biologics do not cross the placenta until closer to week 27. Corticosteroids Previously, a few small studies reported an association between in utero exposure to corticosteroids in the first trimester and orofacial clefts in infants (55–57). The PIANO study failed to demonstrate this association, although definite conclusions cannot be made because the very low incidence of oral facial clefts makes it challenging to study with adequate statistical power (58). However, there was a positive association between corticosteroid use and risk of preterm birth (13% vs 8%, P = 0.008), small for gestational age (6% vs 4%, P = 0.03), low birth weight (10% vs 6%, P = 0.008), intrauterine growth restriction (3% vs 2%, P = 0.03), and neonatal intensive care unit admission (13% vs 9%, P = 0.03). In addition, maternal corticosteroid use in the second and/or third trimesters was associated with serious infections at the age of 9 months (OR 2.9 [CI 1.2–6.8]) and 12 months (OR 2.9 [CI 1.2–6.8]). A similar finding was previously reported by Plauborg et al. (59). Aminosalicylates Aminosalicylates include sulfasalazine and mesalamine-based formulations. Overall, these medications are safe in pregnancy. Of note, all mesalamine formulations are now free of dibutyl phthalate, which had been associated with neurodevelopmental abnormalities in animal studies. Sulfasalazine may inhibit folic acid absorption, so increased folate supplementation (2 mg daily) is recommended. Immunomodulators Thiopurines cross the placenta as early as the first trimester; however, risks of congenital malformations, long-term development issues, or immune dysfunction are not increased (60,61). A recent large French nationwide study reported an association between thiopurine monotherapy and stillbirth, preterm births, and large for gestational age compared with pregnancies exposed to anti-TNF or no medications (62). Thiopurine exposure in the setting of combination therapy with an anti-TNF therapy was also associated with preterm births and large for gestational age (62). This association with adverse fetal outcomes, albeit a different study design, was not seen in the PIANO study (61). Therefore, if a patient with IBD is in deep remission, then de-escalating to biologic monotherapy may be warranted in preparation for conception. However, if a patient's disease course merits combination therapy or they are on combination therapy at the time of conception, their regimen can be continued through pregnancy. Initiating a thiopurine in pregnancy is discouraged because of risk of short-term side effects and intolerance in the pregnant patient, in particular, idiosyncratic acute pancreatitis. Methotrexate is teratogenic and should not be taken for 3–6 months before conception or at any time during or after pregnancy to avoid potential chromosomal damage. Cyclosporine and tacrolimus are calcineurin inhibitors that may be used in specific cases of IBD, but patients will need close monitoring for hypertension, PE, and gestational diabetes (63). Kidney function and electrolytes should be monitored in infants with in utero exposure to tacrolimus because hyperkalemia and renal impairment have been reported (64). Biologics All biologic agents for IBD, except for certolizumab pegol, cross the placental barrier starting at around 27 weeks when maternal immunoglobulins naturally cross. Although this is beyond the period of organogenesis, which is complete by 10 weeks' gestation, there were concerns about their safety in pregnancy when they were first introduced. However, decades of real-world experience and large registry studies have not negatively affected drug exposure in children up to the age of 4 years who had in utero exposure to biologics (65). As noted above, the safety of anti-TNF may be reduced when used in combination with thiopurines, although this was not seen in the PIANO study (61). Most biologics result in higher concentrations in the newborn than in the pregnant patient, with increased transfer during the third trimester (66). It is recommended that all biologics should be continued in pregnancy because interruption increases risk of flare and continuation is considered safe (61,67,68). A recent meta-analysis confirmed that adverse pregnancy outcomes among pregnant patients with IBD using biologics are comparable with that of the general population (69). Therapeutic drug monitoring Owing to significant fluid shifts and increased renal clearance during pregnancy, therapeutic drug monitoring of biologics and thiopurine metabolite testing may be particularly important in pregnancy. Dosing schedule modifications are best done well in advance when pregnancy is first confirmed. This way, small scheduling changes can be made throughout pregnancy without having to make any significant changes in the third trimester. For example, a biologic that is given every 8 weeks can be given every 7–9 weeks, with the last dose at 31–33 weeks of gestation; a biologic that is given every 4 weeks can be given every 3–5 weeks so that the last dose is at 35–37 weeks of gestation; and a biologic that is given every 1 or 2 weeks can be given every 1–3 weeks so that the last dose is at 37–39 weeks of gestation. Small molecules Tofacitinib, a Janus kinase (JAK) 1 and 3 inhibitor; upadacitinib, a selective JAK-1 inhibitor; and ozanimod, a sphingosine-1-phosphate receptor 1 and receptor 5 agonist, are approved for the treatment of UC. Animal studies for all medications have demonstrated fetal anomalies at doses significantly higher than what is approved (70). Human data are very limited regarding the safety of these medications in pregnancy (71). Patients who get pregnant in a clinical trial must stop the trial, which contributes to the lack of longer term exposure outcome data. The long half-life of ozanimod results in the label warning to stop therapy at least 3 months earlier from the anticipated time of conception. The JAK inhibitors do have a relatively short half-life. Therefore, until more robust human data are obtained, patients should be counseled to avoid these medications in pregnancy. LACTATION AND IBD Most IBD medications are safe to continue uninterrupted while lactating (Table 1). Maintaining healthy nutrition is particularly important in lactating people with IBD. Patients with an ostomy or active disease may have difficulty staying hydrated and nutritionally optimized because of malabsorption of nutrients and fluid. If there is concern, referral to a nutritionist may be beneficial. If a galactagogue is needed, fenugreek should be used with caution because side effects include nausea, vomiting, and hypoglycemia in the lactating person and diarrhea in the infant, which could be unnecessarily alarming in the context of IBD. In patients with IBD who undergo sedation for endoscopic procedures, lactation and feeding of the milk can continue (72) as long as the patient is alert enough to safely perform this task. Lactating people who receive gadolinium or iodinated contrast for imaging studies can resume feeding without interruption (54).Table 1.: Medication safety during pregnancy and lactation in IBDVACCINATIONS All pregnant people are recommended to receive the influenza nonlive vaccine during flu season. Pregnant patients with IBD should also be up to date on their pneumococcal series and hepatitis B. The nonlive tetanus, diphtheria, pertussis vaccine is ideally given between 27 and 36 weeks of pregnancy and is safe to give while on immunosuppression (73). Rubella immunity is very important and should be checked in anyone considering pregnancy. If the patient is not immune to rubella and receiving small molecules, immunomodulators, and/or biologics, the patient and the obstetric team need to be reminded that the mother cannot receive the MMR vaccine or any live vaccine, varicella included, unless they have treatment interruption. Coronavirus disease 2019 (COVID-19) vaccines are strongly recommended during pregnancy and lactation, regardless of immunosuppression status. Pregnancy increases risk for severe illness and adverse neonatal outcomes in people with COVID-19 (74,75). Receipt of the messenger RNA COVID-19 during preconception and pregnancy has not been associated with adverse pregnancy and neonatal outcomes (76,77). Vaccination during pregnancy promotes an immune response similar to that in the nonpregnant state, and there is efficient maternal-to-neonatal transfer of antibodies after the vaccine in utero and in breastmilk (78,79). Therefore, it is very important to counsel patients regarding the benefits and reassuring the safety of vaccination against COVID-19. MODE OF DELIVERY Mode of delivery, although often driven by personal preference and obstetrical indications, does merit careful planning and discussion either during preconception or early on in pregnancy. Perhaps as important is the need for all providers to be on the same page to avoid confusion and uncertainty as to when a cesarean may be preferred over vaginal delivery in certain clinical scenarios (80). Cesarean delivery is more common in patients with IBD compared with the general population, specifically in patients with UC, severe disease, and those on biologic therapy (16,80). A patient may undergo vaginal delivery in most settings of IBD unless there is active perineal disease present around the time of However, a of disease should also be considered as an indication for The of these recommendations is to avoid perineal by obstetrical or to to the and sphincter function and The same can be to those who have undergone IPAA Although vaginal delivery has not affected longer term continued pelvic floor and sphincter can affect which may be present before pregnancy It should be noted that many patients experience a 1 or 2 especially on their first delivery, but the risk of a remains less than the potential impact of perineal assisted vaginal delivery should be considered and, if to a cesarean may be a in some patients. A should include these to the obstetrical A colorectal should be on to adhesions or the bowel if during a cesarean A discussion around the risk of cesarean must be had with the obstetric team because there is an increased risk of placenta and with delivery, which can result in severe vaginal that can have complications uninterrupted IBD therapy is to disease CD, disease activity, and of biologics during pregnancy and after delivery are associated with disease activity planning to the delivery patients would be able to get their at the at the time of specifically of delivery did not increase the risk of poor after cesarean or vaginal delivery for to the is often preferred and should be before IBD, cesarean delivery, and are risk factors for venous thromboembolic disease. All patients with IBD should receive in the hospitalized Patients who undergo cesarean delivery may be considered for prophylactic anticoagulation during the hospitalized and may be continued for up to 6 weeks after delivery in those with a of should be monitored and anti-inflammatory drugs can be used safely because they have been demonstrated to reduce and use after cesarean without increasing risk of flare If short of may be used as necessary to pain. Of note, use during lactation can cause and therefore, it is not recommended as the first for is a side effect of and should be anticipated and managed with an More than of patients with IBD experience including and use Most selective inhibitors and and inhibitors are safe in pregnancy and except which may be associated with an increased risk for fetal All pregnant and patients should be for and those who are on should continue these medications through the All patients with IBD capable of pregnancy should receive preconception which ideally would a between the and the medicine improve pregnancy outcomes, clinical and endoscopic remission should be before conception. Fecal calprotectin should be checked at preconception, every trimester, and to screen for active disease. Most of the IBD medications in pregnancy are with Biologics should be continued throughout pregnancy, and if a schedule should be made so that the biologic is given after Methotrexate and ozanimod must be at least 3 months before conception. more human data are obtained, JAK inhibitors should be avoided in pregnancy and Most patients can safely undergo a vaginal delivery unless there is active perineal disease. medications after delivery to disease