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A 30-year-old woman presented in 2011 with a six-week history of bloody diarrhoea. At presentation, she was passing six-to-eight motions per day, with nocturnal motions. There was a family history of colitis.
A colonoscopy revealed moderately severe colitis to the splenic flexure, which was suggestive of ulcerative colitis (UC), and this was subsequently confirmed histologically on biopsy. She was commenced on mesalazine (Asacolon) 1.6 grams tds and a reducing course of prednisolone, starting at 40mg and weaning by 5mg per week. She responded well initially, but she suffered a disease flare within six months, which required hospitalisation.
A flexible sigmoidoscopy showed severe left-sided colitis. She was commenced on IV steroids, but only partially responded and at day five she was given biologic therapy in the form of IV infliximab. She responded rapidly to the first, single infusion. She was switched to oral steroids and prior to discharge she was commenced on the immunosuppressant azathioprine. Initially, she was given a low dose of 50mg daily for two weeks. She was discharged home, with weekly blood monitoring of FBC and LFTs by her GP. The azathioprine was tolerated well and the dose was increased after several weeks to her target dose of 175mg daily.
Azathioprine is a relatively slow-acting medication and, like a number of immunosuppressants, it takes three-to-four months to become clinically effective. In this instance, the hope was that the infliximab could be given as so-called ‘bridging therapy’ for a few months, until such time as the azathioprine became effective, with a view to subsequent discontinuation of the infliximab therapy.
An induction course of three infliximab infusions was given over a six-week period and the patient was then reviewed. She reported feeling very well, with normal bowel movements, and was in clinical remission. However, a repeat colonoscopy showed persistent, mild, left-sided colitis, albeit significantly improved and hence it was decided not to stop the infliximab at this point. The patient also reported at this time her hope to conceive in the coming months.
She was counselled with regard to medical management and potential complications of ulcerative colitis during pregnancy. While the patient had increased risk of infection with dual immunosuppression, given the evidence of active disease, infliximab was continued at eight-week intervals, along with azathioprine and Asacolon.
A repeat colonoscopy six months later confirmed mucosal healing and complete histologic remission. The patient was clinically well and infliximab was discontinued. She remained on azathioprine and Asacolon. The patient was seen six months later and reported that she was 20 weeks pregnant. Her disease remained in remission throughout her pregnancy and she had an unremarkable pregnancy course.
She gave birth at full term to a healthy baby girl by spontaneous vaginal delivery. She was reviewed one month post-partum and reported that her colitis remained in remission. In view of her azathioprine use, she opted not to breast-feed, although current evidence indicates that this is safe (v.inf).
Unfortunately, several weeks later, the young woman’s colitis flared and two months postpartum she required admission for treatment of intravenous steroids. She responded rapidly to IV steroids on this occasion, but given the fact that her disease had flared while already on an immunosuppressant, she was commenced on another biologic.
Adalimumab was chosen, as this can be given subcutaneously and she had also had a ‘drug holiday’ from infliximab. She remained on azathioprine and Asacolon. Six months later she was in full clinical, endoscopic and histologic remission. She was maintained on dual therapy of adalimumab, a lower dose of azathioprine (100mg daily) and a low dose of Asacolon.
Over the next year, the patient remained in clinical remission and on follow-up review, the patient reported to be 18 weeks into her second pregnancy. Although clinically well, there is a risk of postpartum relapse, as previously. Subsequently, the patient was counselled on a tailored treatment plan as follows:
To continue taking azathioprine and Asacolon without interruption.
To take the last dose of adalimumab at 10 weeks before estimated due date.
To recommence adalimumab two weeks postpartum, providing there is no evidence of infection postpartum.
The patient is currently 36 weeks pregnant, clinically well and due to be reassessed at three-to-four weeks postpartum.
The prevalence of inflammatory bowel disease (IBD), both UC and Crohn’s disease (CD), in Ireland is approximately 20,000. The peak incidence is between the ages of 15-35 years old, leading to a large cohort of young women of child-bearing age who have IBD.
As a result, there are implications with regard to fertility, pregnancy and delivery, the health of the baby and lactation for young women thus affected and this is a significant concern for them. Moreover, with the increasing range of therapeutic options being used to treat patients, this brings with it the challenge of achieving a balance between optimal patient management and pregnancy outcomes on the one hand, and potential side-effects and complications of treatment on the other.
IBD presents many psychosocial challenges for young adults, including issues around body image, sexual intimacy and self-esteem. Among women of childbearing age, the worry regarding fertility and fecundity is often high up on the list and frequently comes up in consultation.
While studies suggest fertility rates amongst IBD patients are comparable to the general population, other factors related to IBD may make conceiving potentially more challenging, which include:
Dyspareunia related to perianal disease.
Pelvic adhesions secondary to inflammation/ previous surgery.
Ileal pouch anal anastomosis.
Ileal pouch anal anastomoses have been linked with reduced rates of fecundity in women and pelvic surgery in male patients can potentially lead to postoperative impotence and ejaculatory problems.
Ideally, these surgeries should be deferred as a surgical option until patients have completed their family, if possible.
Medications used in IBD, such as sulfasalazine and methotrexate (MTX), can also affect the sperm count in male patients, causing oligospermia, prompting the need for pre-conception counselling in both male and female patients considering conceiving.
Literature now supports the concept that the better the disease control prior to conception, the better the likelihood of a successful pregnancy.
If conception occurs when the disease is quiescent, then the risk of relapse is about 30 per cent. If the disease is active at the time of conception, this increases the risk of persistent/worsening disease activity during pregnancy to about 60 per cent and this is more likely in the first two trimesters or post partum.
The effect of pregnancy on UC and CD differs: there is an increased risk of disease relapse postpartum in patients with UC, but not with CD.
With increasing numbers of early diagnoses of IBD and a trend towards deferring pregnancy to later years, some patients will have been diagnosed with IBD for a considerable amount of time before becoming pregnant. Accordingly, many patients may have failed initial therapies and escalated to second- or third-line therapies, such as immunomodulator and biologic therapies by the time they become pregnant.
What are the implications of these medications in the pre-pregnancy period, during pregnancy and postpartum for the baby and with regard to lactation? This is an important issue, which should be addressed in pre-conception counselling to ensure medications that can affect fertility or potentially effect the pregnancy are discontinued, but also to ensure that beneficial medications are not unnecessarily discontinued, potentially leading to adverse pregnancy outcomes.
The majority of medications used for treatment of IBD are safe to continue at the time of conception. The important exception is MTX (in addition to thalidomide). This is not a first-line treatment for IBD, and the numbers of young women of child-bearing age receiving this medication are low.
However, if a patient is on MTX, this should always be discontinued at least three months prior to attempts to conceive. In male patients, while there is no evidence of birth defects, it is generally advised to also discontinue three months prior to conception. MTX can cause oligospermia, which is fully reversible within a few months of drug cessation. Anti-TNF agents such as infliximab and adalimumab have been reported to reduce sperm motility, but the results are conflicting.
Along with the general population, folate supplementation is advised in all patients pre-conception. IBD patients may also be more prone to iron deficiency, vitamin D deficiency and in the case of patients with small-bowel CD, vitamin B12 deficiency. All of these should be measured and supplemented as necessary, before and during pregnancy.
Most common medications used in IBD
Recently, the European Crohn’s and Colitis Organisation (ECCO) published a position statement and consensus document regarding the treatment of IBD during pregnancy and lactation.
Table 1 (taken from the ECCO guidelines) shows a list of the most commonly-used medications in the treatment of IBD and summarises their safety profiles during pregnancy and lactation. These medications include:
Sulfasalazine and 5-aminosalicylic acid, 5-ASA, agents.
Immunomodulators — Azathioprine, 6-mercaptopurine (6-MP), MTX.
Anti-TNF agents — infliximab, adalimumab, golimumab.
Other monoclonal antibodies — vedolizumab, ustekinumab.
Antibiotics — metronidazole and ciprofloxacin.
Sulfasalazine and 5-ASA agents
Sulfasalazine and 5-ASA agents are often the first-line agents used in IBD. In general, these medications are safe to use during both pregnancy and lactation, with complication rates comparable to the general population.
The use of glucocorticosteroids for maintenance of disease remission is no longer common practice but they still remain a key component in the management of acute relapses.
There has been an associated increased risk of cleft palate in infants with the use glucocorticosteroids during the first trimester of pregnancy. However, the overall risk is low, approximately 0.2-0.4 per cent.
It is advised to use steroid therapy but at the lowest dose necessary to achieve remission and if possible, to avoid during the first trimester. Patients who do receive steroids during pregnancy may be at greater risk of gestational diabetes, hypertension and pre-term delivery.
Although rare, adrenal insufficiency can occur with long-term steroid use, both in the mother and infant, requiring monitoring and potentially, stress-dose therapy. Lactation while on steroids is not contraindicated, as although steroids can be detected in breast milk, the levels are not clinically significant.
Azathioprine and 6-MP treatment are used more commonly and earlier in the disease course in IBD patients. It is recommended that patients remain on immunomodulator therapy during pregnancy.
There has been some association with increased risk of pre-term delivery in patients on azathioprine and 6-MP compared to the general population. However, being on immunomodulator therapy itself is a refection of the severity of IBD activity, which may contribute to preterm delivery. Adverse outcomes of pregnancy after a relapse of IBD during pregnancy are thought to be more significant than the risk of the medication itself.
Advice regarding lactation from the World Health Organisation and drug manufacturers remains to avoid breast-feeding while on azathioprine/6-MP therapy, as levels are detectable in breast milk.
However, recent studies have shown that only nanomolar levels of these drugs are found in breast milk, rendering them highly unlikely to cause immunosuppression in the breast-fed babies. A number of prospective studies have shown these drugs are safe during lactation and do not increase the risk of infection in the newborn infant.
Hence the current consensus statement from ECCO recommends that these medications can be used in mothers who wish to breast-feed. Moreover, there is evidence to suggest that breast-feeding reduces the risk of a post-partum disease flare and possibly improves the disease course over the following few years.
Hence, breast feeding should be encouraged, where possible, in young mothers with IBD.
Based on current evidence, patients are advised to continue with anti-TNF therapy up to the third trimester and to stop treatment in or around 30 weeks, although individual practice can differ slightly.
While adverse pregnancy and birth defects are comparable to the general population, increased drug levels have been detected in the cord blood at birth of babies exposed to anti-TNF in utero.
During the third trimester, there is active transport of antibodies across the placenta from the mother to the foetus and levels in the foetus at birth can exceed those in the mother. Adalimumab persists for an average of four months in newborn babies, but infliximab persists for an average of seven months, with one baby having detectable levels 12 months after birth (although these levels were negligible and not thought to be clinically significant).
This has very important implications for neonatal vaccinations, as these infants will have some degree of immunosuppression. One case of fatal TB infection following a BCG vaccination was reported some years ago in a young infant.
Several cases of chicken pox were also reported in one study between three and 12 months of age: these were mild infections and all babies recovered fully. The current recommendation is to defer all live vaccines until after six months of age in infants exposed to anti-TNF agents in utero. In Ireland, this affects the dosing schedule of the MMR and BCG.
It is possible that this period might be prolonged in the future, but vaccination is important and unnecessary delays should also be avoided.
Recent studies show that the risk of infection in babies exposed to an anti-TNF agent alone in utero does not appear to be increased. However, if the mother was on both an anti-TNF and an immunosuppressant such as azathioprine or 6-MP, then the risk of infection in increased almost three-fold, although none of these infections were serious.
Golimumab has recently been approved for the use in moderate-to-severe UC. At present, there is no specific guideline for use in pregnancy.
However, it is thought to have a similar bioavailability to other anti-TNF agents. The manufacturer advises avoiding lactation for six months after treatment.
Other monoclonal antibodies
A number of other biologic agents, both approved and non-approved, are now being increasingly used in patients with refractory IBD.
This patient cohort is likely to have more disease activity and less complete remission rates both before and during pregnancy because of the refractory nature of their disease. These drugs include vedolizumab (Entyvio) and ustekinumab (Stelara) and should be used only by specialists with close supervision of the patients.
While the manufacturers’ guidelines are that they are not approved for use during pregnancy, this must be balanced by the clinical needs of the patient and an individual, tailored approach to treatment should be used.
Complication rates in pregnancy
Pregnancy in IBD patients carries the same risk of congenital or birth defects as the general population.
However, there is an increased risk of preterm birth, low birth rate and haemorrhage. Risk of complicated IBD during pregnancy has been related to degree of disease active at time of conception.
Typically, patients may report relatively good IBD control during pregnancy. However, there is an increased risk of relapse in the postpartum period, particularly in UC patients, and short-interval clinical review following delivery is advisable. IBD patients should be considered high-risk and patients with perianal disease should be considered for elective Caesarean section at time of delivery.
Pregnancy in the setting of immunosuppressant and biologic therapy can be a daunting prospect for young mothers. Close cooperation between the IBD specialist, GP and obstetrician is desirable to ensure the best outcome for both mother and baby.
Current management of IBD in young women has improved pregnancy outcomes for both the mother and child.
Most drugs are safe during pregnancy and breast-feeding, with the exception of those outlined in Table 1.
Vaccination schedules for new-born infants exposed to anti-TNF agents in utero must be altered: Live vaccines must not be given in the first six months, whereas other vaccines can be given as normal.