Updates in the management of inflammatory bowel disease during pregnancy

Inflammatory bowel disease (IBD) is a chronic disease that affects women in their childbearing years. It is known that the best pregnancy outcomes for women with IBD occur when their disease is in remission at conception and remains in remission throughout the pregnancy. The majority of women with IBD who are taking maintenance medication will require medication throughout the pregnancy to prevent relapse. Most IBD medications are thought to be safe in pregnancy, with disease flare during pregnancy being the major risk to the developing child.1

Non‐compliance with maintenance therapy during pregnancy occurs frequently and a common reason for this is the fear of medication adverse effects on the baby.2,3 While fear of adverse effects of medication on pregnancy and non‐compliance are common among women with IBD, patients often have insufficient knowledge of the adverse effect of active disease on pregnancy outcomes.4 Likewise, medical practitioners may have inadequate pregnancy‐related knowledge in IBD, including use of IBD medications.5 Patients with IBD require tailored education and pre‐conception counselling regarding the impact of disease activity on pregnancy and potential risks and benefits of medication use in pregnancy.

In this Narrative Review, we present the current evidence‐based and expert recommendations regarding the management of IBD in pregnancy — a 2018 Australian article provided a general review of the current management of IBD.6

Methods

We performed a PubMed review of original and review articles as well as specialist society guidelines (the Toronto consensus statements7 and the European Crohn's and Colitis Organisation guidelines8), from the late 1970s to the present, to formulate an evidence‐based overview of the topics as applied to clinical practice for the management of IBD in pregnancy.

Effect of inflammatory bowel disease on fertility

A significant proportion of Australian women with IBD have a fear of infertility and thoughts of voluntary childlessness.9,10 However, fertility is in fact not affected in patients with quiescent IBD, with the exception of women who have had pelvic surgery.11,12,13

Patients with IBD should be reassured that their fertility is normal when the disease is quiescent. There is no evidence that IBD medications are associated with reduced fertility in females. However, in males, sulfasalazine and methotrexate can be associated with oligospermia.14,15 Hence, sulfasalazine should be switched instead to a 5‐aminosalicylic acid (5‐ASA) agent and methotrexate should be stopped 3 months before conception in males. Methotrexate should be stopped 6 months before conception in females, as it is teratogenic.

Surgery to control active IBD has a greater beneficial effect on fertility than uncontrolled disease. For the minority of women who require colectomy for ulcerative colitis, open ileal pouch anal anastomosis surgery is associated with a two‐ to threefold increased rate of infertility.16 This is thought to be related to pelvic adhesions from open pouch surgery causing reduced fallopian tube motility and patency.17 However, the newer laparoscopic pouch surgery approach is associated with lower rates of infertility.18,19 Therefore, a minimally invasive approach for pouch surgery is preferable.

Success rates of in vitro fertilisation are similar in women after pouch surgery to women without a history of IBD and surgery.20 Early referral to a fertility specialist should be considered for patients who have had ileal pouch anal anastomosis surgery.

Effect of inflammatory bowel disease on pregnancy

IBD, especially when active, can lead to adverse pregnancy outcomes, including spontaneous abortion, pre‐term birth and low birthweight.21,22,23 A meta‐analysis assessing the risk of adverse pregnancy outcomes in women with IBD reported a 1.87‐fold increase in the incidence of pre‐term birth (< 37 weeks gestation) and, similarly, the incidence of low birthweight (< 2500 g) was over twice that of normal controls.21

Disease activity before conception and during pregnancy is the main driver of adverse pregnancy outcomes in patients with IBD. In a large Swedish cohort study, there was an increased risk of pre‐term birth and low birthweight for patients with ulcerative colitis or Crohn's disease, and these risks were greater in women with disease flares during pregnancy.24 Another Scandinavian study showed that women with ulcerative colitis had an increased risk of adverse pregnancy outcomes compared with the general population and this was associated with disease activity at pre‐conception.23

Effect of pregnancy on inflammatory bowel disease

The effect of pregnancy on IBD remains uncertain. Disease activity at the time of conception is likely to have an impact on disease activity during pregnancy.

Historically, pregnancy was thought to be a state of immune suppression in order to tolerate the fetus and was hence thought to improve inflammatory disease. However, this notion has been challenged by more recent data demonstrating that women with IBD who become pregnant when their disease is active are more likely to experience ongoing active disease during pregnancy than those who become pregnant when their disease is in clinical remission.25

Disease relapse may be seen more commonly in pregnant patients with ulcerative colitis. A prospective European cohort study among pregnant women with IBD who were mostly in remission at conception showed that women with Crohn's disease had a similar disease course during pregnancy to their respective age and disease matched non‐pregnant cohort, whereas pregnant women with ulcerative colitis had a higher risk of relapse during the first and second trimesters of their pregnancy than non‐pregnant women with ulcerative colitis.26

Pre‐conception counselling and disease assessment

Opportunities exist when primary care doctors are reviewing patients with IBD to establish their wishes and beliefs regarding pregnancy and to provide subsequent education and encourage specialist review for pre‐conception counselling, as often patients do not initiate this discussion. Patients should be counselled to continue their IBD medication until review, with the exception of methotrexate, which must be stopped.

The chance of a successful pregnancy for patients with IBD is excellent if the pregnancy is planned and if women conceive when their disease is in remission. It is known that pre‐conception counselling improves pregnancy outcomes in IBD.27 In a recent prospective cohort study in the Netherlands, it was shown that a pre‐conception care clinic for patients with IBD reduced disease relapse rates during pregnancy and risk for babies with low birthweight.27

Pre‐conception counselling should be arranged with the patient's IBD specialist and will include discussions regarding the importance of optimising disease control before and during pregnancy as well as the medication management plan for pregnancy. The patient's specialist will perform a pre‐conception IBD assessment to ensure the patient is in remission. Patients should ideally undergo pre‐conception counselling and disease assessment 6 months before conception to ensure that the disease is in remission and that patients have a clear understanding of the recommendations for the management of their IBD in pregnancy.

Preparation for pregnancy should include standard health recommendations such as folate supplementation. Folate supplementation (400 μg/day) should be commenced at least one month before conception to help prevent neural tube defects; women taking sulfasalazine should start taking 2 mg folate daily, as sulfasalazine affects folate absorption, and women with a history of malabsorption (small bowel Crohn's disease) should take 5 mg folate daily.8,28

Patients often worry about heritability of IBD and, thus, should be informed that the chance of a child developing IBD is low if one parent is affected (3–8%), but higher with two affected parents (25–30%).29,30,31

Monitoring of inflammatory bowel disease during pregnancy

Monitoring of disease activity throughout pregnancy is imperative. Communication between primary care doctors, gastroenterologists and the obstetric team during pregnancy is essential. Patients should be reviewed at least once per trimester by their gastroenterologist and more regularly if they have active disease. Clinical assessment can be particularly unreliable in the setting of pregnancy‐related symptoms; therefore, IBD activity should be monitored during pregnancy using objective, non‐invasive techniques.

Serial assessment of serum markers, including haemoglobin, albumin and C‐reactive protein (CRP) should be performed pre‐conception and in each trimester, along with faecal calprotectin, to monitor disease activity. It is important to note that laboratory markers are altered in pregnancy. During normal pregnancy, CRP can be elevated up to about 22 mg/L, albumin can be as low as 30 g/L, and mild anaemia with a haemoglobin level of 110 g/L is normal in pregnancy.32 An elevated faecal calprotectin above 250 μg/g correlates with active disease in pregnancy.33 Effective monitoring of IBD during pregnancy should integrate these non‐invasive biomarkers, which should be interpreted over time on an individual patient basis.

Exposure to radiation should be avoided, and imaging, when required, should be done with intestinal ultrasound or magnetic resonance imaging without gadolinium.34 Limited endoscopy may be performed in patients with severe disease flares during pregnancy.35

Standard pregnancy monitoring should be undertaken with careful monitoring of fetal growth to identify early intrauterine growth restriction. Women with a history of previously severe IBD, including patients taking biological therapy, or with perianal Crohn's disease should be managed in a high risk obstetric clinic with more intensive monitoring of fetal growth during pregnancy.

Management of a flare during pregnancy

A flare of IBD during pregnancy poses a greater risk of harm to mother and baby than IBD therapies.

Flares in ulcerative colitis are characterised by increased frequency of loose stools, abdominal pain, rectal bleeding, urgency and, when severe, incontinence.36 Patients with colonic Crohn's disease will have similar symptoms.37 Patients with terminal ileal Crohn's disease should be asked about symptoms of subacute small bowel obstruction such as nausea, vomiting, post‐prandial colicky abdominal pain, weight loss or failure to gain weight appropriate to stage of pregnancy.37 If morning sickness does not settle by the expected time in pregnancy (usually, Week 16) or is associated with pain, this should raise the suspicion of obstruction.

If a patient has a suspected flare of IBD during pregnancy, standard investigations such as faecal microscopy, faecal calprotectin, full blood examination and CRP should be performed. Patients with ulcerative colitis treated with 5‐ASA drugs should be taking full dose therapy (4–4.8 g daily). Rectal 5‐ASA or rectal steroid therapy can be safely used in pregnancy. Patients with moderately severe disease (more than four to six bowel movements daily or nocturnal symptoms) should start a course of prednisolone, and the gastroenterologist should be promptly notified and a review arranged. Patients with obstructive symptoms should commence steroids and a low fibre diet and they should obtain an urgent review.

Disease flares that fail to settle on steroids (prednisolone 40–50 mg daily and tapered over 6–8 weeks) may require the introduction of thiopurines (azathioprine or 6‐mercaptopurine) and anti‐tumour necrosis factor‐α (anti‐TNF‐α) antibodies by the patient's gastroenterologist. These drugs are safe in pregnancy and breastfeeding (see below). Patients with active disease during pregnancy require obstetric follow‐up in a high risk clinic, including additional antenatal scans to monitor for intrauterine growth restriction.

Medication safety in pregnancy and lactation

Most IBD medications are safe to continue during pregnancy and breastfeeding.1 Stopping IBD medications before or during pregnancy may result in higher rates of spontaneous abortion, intrauterine growth restriction and prematurity due to active disease.24 Women should be encouraged to continue their maintenance IBD medications in order to maintain disease remission.

Patients should be educated regarding the risk of birth defects in the general population, which is around 3%,38 and informed that current evidence does not suggest an increase in birth defects from IBD medications (with the exception of methotrexate and thalidomide, which are teratogenic).

Electronic prescribing programs may show warnings when IBD medications are prescribed. These pop‐up warnings are based on outdated data and do not take into consideration the negative effect of disease activity during pregnancy. The categorisation system for prescribing medications in pregnancy of the Australian Therapeutic Goods Administration, while simple and accessible, can be misleading. The alphabetical structure of the system implies that it is hierarchical. However, a “Category B” medication, for example, does not mean a medication is of lower risk than a “Category C” medication. The categories system is not able to take into account the clinical indication for the medication and the labelling is often not updated when new evidence emerges regarding the safety of medications in pregnancy. In the United States, the Food and Drug Administration is no longer using categories A, B, C, D and X in product labelling in recognition of this problem.

All patients should have an agreed IBD medication plan for the pregnancy from their gastroenterologist and this plan should be communicated to the treating team, including primary care physicians, obstetricians and midwives. Primary care physicians are encouraged to liaise with the gastroenterologist if there are any queries regarding a patient's medication plan in pregnancy in order to ensure a clear and consistent message for the patient.

5‐Aminosalicylic acid drugs

Sulfasalazine and 5‐aminosalicylates, including mesalasine, are considered safe in pregnancy. A meta‐analysis demonstrated no significant increase in risk of congenital anomalies, spontaneous abortion, pre‐term delivery or low birthweight.39 Women taking sulfasalazine should take high dose folate supplementation (2 mg daily).8

Corticosteroids

Short courses of corticosteroids may be required to treat disease flares during pregnancy. Hence, in available studies regarding corticosteroid use in pregnancy, it is difficult to interpret the confounding effect of active disease. An older meta‐analysis showed a small increased risk of oral cleft with first trimester corticosteroid exposure.40 However, a recent large Danish cohort study showed no increased risk of cleft lip or palate with exposure to corticosteroids in the first trimester.41 The data from the ongoing prospective multicentre Pregnancy in Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry, which have been adjusted for disease activity, indicated that corticosteroids were associated with gestational diabetes and low birthweight.42 Thus, steroids must not be an alternative to maintenance therapy for IBD during pregnancy, but should be prescribed as a weaning course when necessary to treat active disease.

Thiopurines

Thiopurines comprising 6‐mercaptopurine and its pro‐drug azathioprine are widely used as maintenance therapy for IBD and have been shown to be safe during pregnancy in a number of studies, including a recent meta‐analysis incorporating some prospective cohort studies.43,44,45 The large PIANO registry has not shown an association between thiopurine use and congenital anomalies or pregnancy complications.45 A recent prospective study found no association between maternal thiopurine use and adverse birth outcomes or number of infections in infants out to 12 months.46

Anti‐tumour necrosis factor‐α agents: infliximab and adalimumab

Infliximab and adalimumab are anti‐TNF‐α monoclonal antibodies, which are used both to induce and maintain remission in IBD. Available data, including a recent meta‐analysis, have shown that patients with IBD who are exposed to anti‐TNF‐α therapy during pregnancy do not have increased rates of adverse pregnancy outcomes or congenital anomalies.45,47,48 These agents are transferred across the placenta in the second and third trimesters.49 Levels in infants at birth usually exceed maternal levels and can take between 3 and 12 months to clear.50 Therefore, infants exposed to anti‐TNF‐α agents in utero should not be administered live vaccinations, including rotavirus, until 12 months of age.50 A systematic review did not reveal an increased risk of infections in the first year of life in infants exposed to anti‐TNF‐α agents in utero.51 Babies exposed to both thiopurines and anti‐TNF‐α agents in utero have been shown to have a higher risk of childhood infections (eg, chickenpox) out to 12 months, but there is no link to serious infections or need for antibiotics.50 There is no current evidence of harm from continuing anti‐TNF‐α therapy into the third trimester and in women whose disease has been recently active, anti‐TNF‐α agents should continue throughout pregnancy.1,7 For women in remission, dosing may be adjusted in the third trimester to both reduce placental transfer and also minimise the break in therapy, with the last anti‐TNF‐α dose administered at around 32–34 weeks’ gestation.

Vedolizumab

Vedolizumab is a monoclonal antibody that modulates gut lymphocyte trafficking and is increasingly used for moderate to severely active IBD.52 Initial data relating to vedolizumab in pregnancy are very limited; no new concerns for pregnancy outcomes have been identified; however, the evidence is restricted by follow‐up and sample size.52 Current use of vedolizumab in pregnancy is limited to women with no other therapeutic options and is undertaken on a case by case basis.

Ustekinumab

Ustekinumab is a monoclonal antibody that is commonly used in psoriasis and has recently been approved for use in moderate to severely active Crohn's disease.53 Data relating to ustekinumab in pregnancy for patients with IBD are extremely limited. The use of this agent in pregnancy is not currently recommended.

Mode of delivery

There are insufficient long term data regarding the impact of vaginal delivery compared with caesarean delivery on long term continence in women with IBD. The majority of women with IBD can have a vaginal delivery and the mode of delivery should be determined by obstetric need.7,8 However, caesarean delivery is preferred for women with a history of ileal pouch anal anastomosis surgery or active perianal Crohn's disease in order to reduce the risk of anal sphincter and perianal injury, respectively.7,8 A recent systematic review reported no significantly increased risk of developing perianal Crohn's disease with vaginal delivery compared with caesarean delivery in patients who did not have a history of perianal Crohn's disease.54

Breastfeeding

Breastfeeding should be encouraged in all patients, given the known beneficial effects for mother and child. It is considered safe with most IBD medications (Box), including prednisolone, 5‐ASAs, thiopurines and anti‐TNF‐α medications. Low levels of these medications may be found in breast milk, but this is not thought to be clinically significant.8

Post partum management of inflammatory bowel disease

Patients should be closely monitored for a flare in the post partum period, especially in patients with ulcerative colitis when there is an increased risk of disease flare post partum.26 In the prospective European cohort study that compared pregnant and non‐pregnant women with IBD, only 60% of women with ulcerative colitis maintained remission during the 6 months after pregnancy compared with 81% of controls.26

Conclusion

The peak incidence of IBD overlaps with the prime childbearing years; thus, the issue of medication use and disease control in pregnancy is of particular relevance for both patient wellbeing and all treating physicians.

The most important factor in optimising pregnancy outcomes for women with IBD is to ensure their disease is in remission before and during pregnancy. Patients should be encouraged to continue their IBD medications in order to maintain disease remission. Patients with IBD require clinician‐initiated pre‐conception counselling and a consistent message regarding these factors. It is recommended that patients are reviewed regularly by their gastroenterologist during pregnancy and assessment of disease activity is performed in the form of objective, non‐invasive markers, such as faecal calprotectin. In the event of a disease flare during pregnancy, the patient's gastroenterologist should be contacted promptly and appropriate escalation of therapy should be arranged.