Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that includes an annual national meeting, regional satellites in both official languages, www.mentoringinibd.com, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by the contributing editor at the annual national meeting, Mentoring in IBD XVIII: The Master Class, held November 3, 2017 in Toronto, Ontario.
Many patients with IBD are of child-bearing age and ask questions about fertility, conception and pregnancy. The peak age of IBD onset coincides with child-bearing years, and it is estimated that approximately one-quarter of women with IBD conceive after diagnosis.(1) This is an emotional period for prospective parents, and clinicians need to be aware that the patients’ (and their partners’) perceptions of risks and benefit may be different from those of their doctors’.
There is limited evidence available to help guide management decisions for women with IBD who are pregnant or planning a pregnancy. However, consensus recommendations do exist, based largely on the case-control and cohort studies that have been published. Gastroenterologists should be aware of these general concepts and recommendations so that they can best counsel their patients who require this education during this emotional and important period of their lives.
An emphasis needs to be on providing education proactively to help patients plan their treatment strategy when they are considering starting a family. This education, specific to the setting of IBD, should involve not only the patient, but also, whenever possible, other members of the care team who may not be knowledgeable about IBD. This might include primary-care providers, midwives and obstetricians, among others. An over-arching principle is that optimizing the mother’s health is important to optimize the health of the baby. Sometimes this is overlooked by the patient; and patients can be more preoccupied with risks of therapies. Individuals need to be aware of the risks of active disease as well as the risks of medical therapies. As new therapies become available, there is a need to collect information in this field promptly to help patients make their decisions. Well informed patients should be encouraged to actively participate in decision making. Given the potential for litigation in this sensitive area, careful documentation is also key as is communication between team members.
With respect to the provision of counseling for prospective parents, there are several ways that this information can be conveyed. Specific clinics for prospective parents with IBD can be very valuable. If resources permit, an IBD specialist nurse is an invaluable resource for providing education. Trusted web-based tools and resources are also essential components of the overall education strategy. Multidisciplinary follow-up may be desirable, particularly for higher risk patients. It should also be noted that discussion of fertility and conception should also be part of the overall counseling strategy for all patients of child-bearing age.
A key limitation in counselling patients regarding issues around fertility, conception and pregnancy in IBD is the inadequate data in this field. It is important to have a clear understanding of what is known in this area and the limitations of the available data. One must also be aware of the “known unknowns”. As gastroenterologists treating IBD patients who may be seen by other healthcare professionals, it is also important to be aware of the potential limitations in knowledge among primary care professionals in this topic area and the misinformation that patients may encounter.
Data on fertility, conception and pregnancy in IBD come predominantly from case-control or cohort studies and not randomized trials. Outcome measures are inconsistently reported in the literature and, unlike in other diseases, there are no core outcomes sets that have been defined by patients and their clinicians to guide ongoing research in the field. Meta-analyses of the available literature are limited by the heterogeneity of the sources. Registries, while important sources of information, are biased. Any guideline recommendations that exist in this area are therefore based on expert consensus.(2–6)
Research suggests that fertility is normal among both men and women with quiescent IBD,(7–9) but that fertility is reduced among women with active Crohn’s disease.(10,11) The mechanisms for this are unclear. There is also evidence suggesting that lower birth rates among women with IBD compared with the general population are mostly due to voluntary childlessness.(12)
Fertility may also be affected by some of the interventions used to treat IBD. For example, among men, sulfasalazine has been associated with a significant reduction in fertility.(13–16) Among women, ileal pouch anal anastomosis is associated with reduced fertility, although it is not clear whether this association is due to advanced maternal age (mean age of this procedure is 31 years) or if the pouch formation itself is responsible.(17) Laparoscopic pouch surgery may limit the impact on fertility. Other treatments (e.g., 5-ASA, corticosteroids, biologics) are not thought to be associated with changes in fertility (Table 1).(17)
The short answer to this question is yes, if the disease is active. Active disease has been associated with fetal loss and stillbirth; preterm delivery; low birth weight; small for gestational age; thromboembolic events; caesarean section; increased neonatal intensive care admission; and low APGAR score.(18–22) Some researchers have also suggested that active disease is associated with developmental defects/congenital anomalies (limb deficiencies and urinary malformations), but this remains a matter of debate.(18–22)
The impact of active disease on pregnancy outcomes is dependent on several factors, including the degree of activity (i.e., how active is active?), the severity of flare and its timing (i.e., first, second or third trimester). As it is difficult to the ascertain whether it is actually the disease activity itself or the treatments or some other factor that is influencing the increased risks, it is recommended that disease control be achieved prior to conception and that, during pregnancy, the goals are to keep the mother in remission and well nourished.
Family history is the strongest predictor for developing IBD. If one parent is affected, risk for the child is 2–13 times higher than the general population.(23,24) However, it should be stressed that the absolute risk remains quite low in this scenario—the lifetime risk of IBD is approximately 2% for children with one parent with ulcerative colitis and approximately 5% for children with one parent with Crohn’s disease.(25) If, however, both parents have IBD, the risk is substantially higher for the offspring—a 36% lifetime risk of developing IBD, according to one study.(26)
Data suggest that development of IBD is more common when the mother has IBD compared to when the father has the disease,(27,28) and that female offspring are at higher risk of IBD development than male, with an earlier age at diagnosis,(27,28) and that maternal smoking during pregnancy is associated with increased risk of developing IBD.(29)
The primary consideration when addressing this question is to emphasize that the risk to both mother and fetus is active disease, not the medications used to treat it. As such, proactive management of disease is recommended.
With respect to providing information on benefits and risks of individual medications, unfortunately there are no published long-term data on infant outcomes.
However, the evidence that does exist suggests that most medications used to treat IBD are safe in pregnancy. The European Crohn´s and Colitis Organisation (ECCO) consensus assessment of risk of medications for use in pregnancy is shown in Table 2.(5)
Sulfasalazine, for instance, is reasonable to take in both pregnancy and breast-feeding,(30) although it does interfere with folate absorption, which necessitates higher-dose folate supplementation (2 mg) for women taking this agent.(30,31)
5-ASA medications are also reasonable to take in pregnancy, at doses up to 3 g per day, with the exception of formulations with dibutylphthalate coating, which should be avoided among pregnant women and those contemplating conception.(6)
Systemic corticosteroids do cross the placenta, but are converted to less active metabolites. Although there have been reports of a small increase in risk of cleft lip/palate when corticosteroids are used in the first trimester,(32–34) other studies did not corroborate these findings.(35,36) Case reports have also suggested neonatal adrenal suppression among infants born to women who took corticosteroids during pregnancy.(37) A small study (n=8) of pregnant women taking budesonide did not report any issues.(38) Overall, there is no compelling evidence of an increase in anomalies in humans taking corticosteroids, and the benefit of treating active disease likely outweighs the risks. Rectal preparations, it should be noted, are considered to be reasonable to take.(30)
Meta-analyses of evidence with thiopurines (azathioprine and 6-mercaptopurine) in pregnancy have not shown an association of these agents with congenital abnormalities.(39,40) There have, however, been observational/cohort studies that have reported an increase in pre-term deliveries,(41,42) while another study showed that among 28 pregnancies, 60% of infants had anemia.(43) A longer-term study of children born to mothers taking thiopurines, however, showed normal physical and mental development.(44) Among fathers, a meta-analysis concluded that there is no evidence to suggest that taking thiopurines at the time of conception is associated with congenital abnormalities in offspring.(45)
There is very little data concerning use of cyclosporine among pregnant women with IBD—most of the data are from the transplant and rheumatology literature. In those areas, higher rates of prematurity and low birth weight have been reported.(46) In a small case series in ulcerative colitis, there was no influence of cyclosporine use on fetal outcomes.(47)
Methotrexate is the exception to the general observation that IBD medications are safe during pregnancy. This agent is embryotoxic and teratogenic and is strictly contraindicated in pregnancy.(48) If methotrexate is used among women of childbearing potential, counselling on the use of contraception needs to be part of patient education. If conception accidentally occurs, obstetric assessment is required. Any prospective mother (or father) should be told to stop methotrexate for three to six months prior to trying to conceive. The drug takes approximately six weeks to wash out.
Anti-TNF biologics are considered to safe in pregnancy.(4–6) A large prospective cohort study (PIANO) demonstrated there are no differences in adverse pregnancy outcomes rates between women taking anti-TNF agents and those who were not taking these medications.(49) Similarly, population-based cohort data from Denmark and Sweden show that there is no increased risk of birth defects among women exposed to anti-TNF therapy during pregnancy taking these agents for a variety of chronic inflammatory conditions (n=683) compared to women with those diseases who were not taking anti-TNF agents (n=21,549).(50) Current consensus guidance is that these agents should be continued among women who are on maintenance therapy when they become pregnant and are safe throughout the pregnancy.(4–6)
However, the monoclonal antibodies, adalimumab and infliximab, do cross the placenta starting in the 2nd trimester.(51) Serum levels of infliximab in newborns have been detected up to 7 months later (51) and approximately 11% still have detectable infliximab at nine months.(51) The impact of this persistence is that there is may be an increased infection rate during first year of life among children born to women who are exposed to anti-TNFs during pregnancy. Consensus groups have recommended that exposure in infants can be limited by stopping the treatment during the pregnancy when the patient is well and is considered appropriate by the physician and patient.(4–6) For infliximab, research suggests that the optimal stopping time to achieve a low-risk drug level in newborns is 24.6 weeks gestation for infliximab and 36.8 weeks gestation for adalimumab.(52) Another study showed that cord blood adalimumab levels were significantly lower if adalimumab was stopped before 30 weeks compared to after 30 weeks.(53) Importantly, discontinuation of anti-TNF during pregnancy in IBD patients with quiescent disease does not increase the risk of flare during pregnancy or of the risk of allergic reactions in these women when the anti-TNF is restarted.(52,53)
There have been no long-term outcome studies published to date among offspring born to women taking anti-TNF biologics during pregnancy.
Among men taking anti-TNF therapy at the time of conception, anti-TNF use has not been associated with congenital abnormalities.(54,55)
Of note, consensus recommendations also state that for thiopurine-naïve women who are starting anti-TNF therapy, monotherapy with the anti-TNF is preferred to combination thiopurine/anti-TNF, as the combination is associated with a higher risk of infection in infants.(6,53)
The evidence base for newer biologic agents in pregnancy is limited. For vedolizumab, non-human primate studies have demonstrated no adverse outcomes at dose levels 20 times greater than those given to humans.(56,57) Data from clinical trials and post-marketing data from global safety database have not shown any indication of safety concerns. Current product labelling states that vedolizumab “ …should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother and unborn child”.(58) Due to its mechanism of action, there is a theoretical risk of impact on gut-specific infections with vedolizumab. With respect to the possibility of stopping the medication, note that the half-life of vedolizumab is longer than either infliximab or adalimumab.(58)
Ustekinumab also has limited data for use in pregnancy among women with IBD. It too was found to be safe in non-human primates at supratherapeutic doses.(59) There have been two case reports of successful pregnancies (60,61) and one case report of a miscarriage among women with Crohn’s disease.(62) One other case report documented cord blood levels twice as high as those measured in the mother.(63) In the dermatologic literature, there has been a case series published documenting seven successful pregnancies among women with psoriasis taking ustekinumab, as well as one case report of miscarriage.(64,65)
Delivery decisions for women with IBD should be made in a multi-disciplinary approach, dictated primarily by obstetric necessity. In general, vaginal delivery is feasible for women with quiescent / mild disease and is usually the preferred option for women with colostomy / ileostomy. Caesarean section is typically required for women with active rectal/perianal disease, and should be considered for those with IRA/pouch. Episiotomy should be avoided among women with Crohn’s disease, but is still preferable to uncontrolled laceration.
The short answer is yes. Breastfeeding should typically be encouraged, as it may decrease risk of the children developing IBD later in life. The caveat is that some medications may have an impact on breastfeeding. The ECCO consensus recommendations for common IBD medications in lactation are shown in Table 2.(5) Notably, methotrexate is contraindicated. A delay of four hours is recommended between administration of systemic corticosteroids and breastfeeding. Concentration of thiopurines in breast milk is miniscule, and the major part is excreted in breast milk within 4 hours of dose.(5) There is no increased risk of infection or achieving developmental milestones in thiopurine exposed children.(49). The concentration of anti-TNF in breast milk is 1/100th to 1/200th maternal level.(66) Julsgaard et al studied 65 breast-fed infants and concluded that breast-feeding did not affect anti-TNF clearance from infants.(53)
The vaccination strategy with non-live vaccines in children exposed to anti-TNFs is the same as for non-exposed children. However, live vaccines (oral polio, rotavirus, BCG) should be avoided until no detectable anti-TNF levels. Alternatively, for infliximab, wait six to nine months and for adalimumab wait six months. There has been one report of a fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease.(67)
IBD often affects patients during their peak reproductive years. Patients often have important questions regarding conception, pregnancy and lactation for their gastroenterologists to answer. Although there are clear limitations to the evidence base in this area, expert groups have nonetheless provided clear guidance on how best to answer these questions. The overarching concept in discussions is that optimizing the mother’s health (i.e., achieving and maintaining control of her IBD) is critical for optimizing the health of the fetus (and the infant). Gastroenterologists are a key resource to provide reassurance and guidance during this important period of their patients’ lives.
Laura is a 25-year-old accountant with a five-year history of Crohn’s ileocolitis with perianal fistula. Max is a 24-year-old engineer with a seven-year history of ulcerative colitis. They met in your waiting room and fell in love. They are now married and want to conceive. They come to see you for counseling. Laura is on infliximab monotherapy. Max is on adalimumab and a thiopurine. Laura wishes to stop the infliximab before getting pregnant. Max is on combination therapy and is worried about the safety of these agents for conception.
The genetics and heredity aspect of IBD pathogenesis is not fully understood. Issues to discuss include:
For Max, apart from some case reports of oligospermia with sulfasalazine, there are no evidence-based recommendations to stop either the thiopurine or the adalimumab prior to trying to conceive.(74)
Laura has been well since her diagnosis five years prior. Her perianal fistula is inactive. She feels well but reports two to four soft bowel movements per day with occasional abdominal cramps. Her complete blood count (CBC) and C-reactive protein (CRP) are normal. Her last colonoscopy and magnetic resonance enterography (MRE) were three years ago while on infliximab and her disease was in remission.
Laura has mild gastrointestinal symptoms that may reflect ongoing disease activity. This would be important to determine prior to conception in view of optimizing therapy if needed. Fecal calprotectin and endoscopy are recommended.
The Selecting Therapeutic Targets in Inflammatory Bowel Disease group (STRIDE, 2015), recommends that patients with CD be treated to achieve a composite target including both clinical/patient-reported and endoscopic outcomes.(75) The endoscopic component specifies achieving endoscopic remission, defined as resolution of ulceration at ileocolonoscopy (or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy). They recommend monitoring the endoscopic aspect every six to nine months.
You perform a colonoscopy, which reveals a normal colon, apart from scattered small pseudopolyps and a normal ileum. Fecal calprotectin is normal. You inform Laura that the IBD is in remission and that this is a good time to try to conceive.
Apart from the heredity aspect, importance of disease being in remission and the safety of medications as discussed above, the preconception counseling could also touch on other issues, including:
Laura returns several months later to inform you of the good news that she is eight weeks pregnant. She has decided to remain on infliximab. You see her again in follow-up at 17 weeks gestation. Her 1st trimester was uneventful. Her last infliximab dose was at 10 weeks pregnancy. She now complains of a three-week history of abdominal cramping and diarrhea with five to six loose bowel movements per day. There is no history of fever. She has not gained optimal weight. An ultrasound by her obstetrician at 12 weeks showed a normal developing fetus.
Ultrasound is the preferred imaging method to evaluate the small bowel.(76) Magnetic resonance imaging is also a safe option, although it is considered wise to avoid the use of gadolinium in the first trimester (possible teratogenicity).(76)
For endoscopic evaluation, flexible sigmoidoscopy with the patient unsedated is reasonable.(77)
Standard laboratory evaluation is also appropriate for pregnant women (e.g., blood work, fecal calprotectin). Hemoglobin, albumin and ESR are not reliable to assess disease activity during pregnancy.
Her CRP is 14 mg/L, Hb 99 g/L, white blood cells normal, fecal calprotectin 475 mcg/g. Abdominal ultrasound shows thickened ileum wall consistent with active disease.
Management of pregnant women with CD is largely similar to what you would do were she not pregnant.
Laura has experienced a flare despite maintenance therapy with infliximab. One might therefore consider typical courses of action to this clinical scenario, including dose optimization. You might also consider checking her infliximab drug level and testing for anti-drug antibodies.
You decide to increase the infliximab to 10 mg/kg empirically and do an anti-TNF level prior to the next infusion at week 18 of Laura’s pregnancy. The level of Infliximab is 2.1 mcg/mL. There are no antibodies. She has a significant improvement. You see her at week 28 of gestation. She is doing well in clinical remission after her second dose of 10 mg/kg infliximab. CRP and fecal calprotectin have normalized.
Her last infliximab dose was at week 26. One might consider having a discussion with the patient about discontinuing infliximab at this time to minimize fetal exposure to the drug. This is the approach suggested by expert consensus groups.(6)
John K. Marshall, MD MSc FRCPC AGAF, Director, Division of Gastroenterology, Professor, Department of Medicine, McMaster University, Hamilton, ON
Richard N. Fedorak, MD FRCPC FRCP (London) FRCP (Edinburgh) FRCS, Dean, Faculty of Medicine and Dentistry, Professor of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB
Ailsa Hart, BA(Hons) BMBCh FRCP PhD, Director, IBD Research and Sub-Dean, St Mark’s Hospital and Academic Institute, Department of Surgery and Cancer, Imperial College, London, UK
Sonia Bouri, MBBS BSc, IBD Research Fellow, St Mark’s Hospital, London, UK
Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Brian Bressler, MD MS FRCPC, University of British Columbia, Vancouver, BC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Steven E. Gruchy, MD MSc FRCPC, Dalhousie University, Halifax, NS
Remo Panaccione, MD FRCPC, University of Calgary, Calgary, AB
Craig Render, MD FRPCP, University of British Columbia, University of Alberta, Kelowna, BC
Hillary Steinhart, MD MSc FRCPC, University of Toronto, Toronto, ON
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
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