IBD in women of reproductive age: where do novel therapies fit in?

KEYWORDS:

• Inflammatory Bowel Disease
• Biological therapy
• small molecule therapy
• Tofacitinib
• Filgotinib
• Upadactininb
• Ozanimod

1. Introduction

The landscape of medical therapies for the management of inflammatory bowel disease (IBD) is rapidly changing. Biologic drugs and novel therapies in the form of small molecule drugs (SMDs) are positively bolstering our ability to control the disease. Here, we will consider the implications for women of reproductive age, through discussion of the critical goal of pre-conception disease control and what role the novel therapies play.

2. The challenge facing women of reproductive age with a diagnosis of IBD

The peak incidence of IBD coincides with the age of peak fertility and desire to family plan for young adults, largely between the ages of 20 and 30 years [1]. This overlays a myriad of uncertainty and concern onto the already emotional prospect of starting or extending a family. Active disease is associated with many adverse pregnancy outcomes such as: premature rupture of membranes, preterm birth, low birthweight, intrauterine growth restriction, miscarriage and stillbirth, cesarean section, and admission to the neonatal intensive care unit [2–4]. Conversely, quiescent IBD confers pregnancy outcomes similar to those without the disease. Decision making is further complicated by the impact of pregnancy upon the disease course, for example, patients with ulcerative colitis carry a propensity for relapse during pregnancy and post-partum periods over those with Crohn’s disease, precipitated by interactions of the immunological, hormonal and microbial changes inherent in pregnancy [5].

It is important to aim for disease remission prior to conception and maintain it throughout pregnancy. In women with IBD wishing to conceive it is recommended to confirm remission by assessing the clinical picture, fecal and blood biomarkers, alongside endoscopic and cross-sectional imaging evaluation where indicated [4].

In an ideal world, all women of childbearing age with IBD should receive counseling about IBD and pregnancy shortly after diagnosis for a discussion in principal and more detailed counseling prior to any planned pregnancy [6]. Pre-pregnancy counseling is associated with better knowledge of pregnancy-related issues in IBD, and better maternal and fetal outcomes [7,8]. Many pregnancies are however unplanned (up to 45% in the United Kingdom), and IBD care should consider this fact when making therapeutic choices for women of childbearing age.

3. Biologics in pregnancy – friend or foe?

Biologics have become a cornerstone of medical treatment for IBD. While the greatest experience in pregnancy relates to Infliximab and Adalimumab, more data have emerged for Vedolizumab and Ustekinumab recently. There are few data for Golimumab, and the recently licensed Risankizumab and Mirikizumab have not been evaluated in real-world clinical practice yet. The large immunoglobulin structure of biologics means that these molecules do not cross the placental barrier in the 1st trimester but are actively transported during the 2nd and 3rd trimester. Outcomes of large-scale observational studies looking at their perinatal safety have been reassuring for both mother and fetus, with no demonstrable increased risk of gestational or postpartum complications for Infliximab, Adalimumab, Vedolizumab and Ustekinumab [9]. Regarding breastfeeding, there is only low level of transmission of biologic drugs in breastmilk, with no apparent negative impact for the infant, and the benefits of breastfeeding outweigh the potential risks [4].

There remains concern that in utero biologic exposure could increase the risk of child infections due to drug levels persisting in the infant for months, or longer-term immunological dysfunction. The majority of studies show no increased risk of serious infection in children exposed to anti-TNF drugs in utero, whilst early discontinuation of anti-TNF drugs prior to the 3rd trimester has been shown to increase the risk of relapse, with one study showing relapse rates as high as 10% in the pre-partum period, and 15% in the postpartum period [9]. The significant fetal exposure to biologics in the 2nd and 3rd trimesters may still affect infection risk especially when combined with immunomodulators. Most importantly live vaccinations should be avoided for the first 6–12 months or postponed, allowing for sufficient clearing of drug in the infant [4].

While the numbers of patients exposed to Vedolizumab or Ustekinumab throughout pregnancy is lower than those exposed to anti-TNFs, the reports show no signals of concern for maternal or infant health [9]. Current ECCO guidance suggests individualized decision making as to whether the medication should be discontinued during the third trimester [4]. As further reassuring evidence has arisen since the authors would suggest that most patients should continue Vedolizumab throughout pregnancy. Evolving data in Ustekinumab and infant clearance of drug are also reassuring [10].

Based on the available evidence Infliximab, Adalimumab, Vedolizumab and Ustekinumab have been classed as low risk during pregnancy. ‘Accidental’ exposure in unplanned pregnancies is therefore not a concern making these biologics a good choice for women of childbearing age.

4. Where do SMDs fit in?

In contrast with the biologic drugs, SMDs including Tofacitinib, Filgotinib, Upadacitinib and Ozanimod passively cross the placenta at all stages of pregnancy. Animal studies in rodents and rabbits have revealed that in utero exposure to Tofacitinib, Filgotinib, Upadacitinib and Ozanimod leads to loss of pregnancy and was associated with significant teratogenicity [11]. Malformations in major organ systems including cardiac and skeletal systems have been reported often at doses comparable to those licensed in human use [11]. This raises significant concern for any unplanned or planned pregnancies in females exposed to SMDs. A systematic review summarizing their safety profiles has shown SMD exposure in human pregnancy gave outcomes largely similar to what can be expected in the IBD cohort, with available human data suggesting that approximately 40% of pregnancies exposed to SMDs resulted in a healthy live birth [11]. However there were many miscarriages and terminations of pregnancy limiting the number of pregnancies to term. Furthermore, the outcome for a significant proportion of pregnancies was unknown. It must be stressed however that the human data are limited to accounts of accidental SMD exposure in clinical trial settings and a very limited number of real-world clinical experiences, whereby the drugs were immediately discontinued. This can be considered minimal SMD exposure in contrast to the biologics real-world evidence where most patients continue throughout pregnancy or at least until trimester three. The 10 studies evaluated by the review were also associated with significant risks of bias, with 8 of the 10 studies deemed to have high risk of bias, with a moderate risk of bias in the remaining 2 [11].

The temptation is to wonder, for those patients with previously difficult to control disease who have poorly responded to biologics, but have gone on to achieve disease remission with SMD therapy – should we be seeking ways to continue these drugs and maintain disease control in the hopes of avoiding adverse pregnancy outcomes associated with active disease? Unfortunately, the animal data are clear and alarming. Combined with a lack of robust human data and the ethical challenges to advancing this area of knowledge, the use of SMDs must remain contraindicated in pregnancy. If emerging data provide more reassurance, the current strict stance could possibly be revised but in the current era clinicians should avoid pregnancy exposure.

5. The roles of SMDs in women of childbearing age

It is important to not exclude women of childbearing age per se from treatment with SMDs. We need to provide counseling on the potential adverse events from accidental SMD exposure in unplanned pregnancies for all women of childbearing age and advise on safe contraception. In our opinion, SMDs are probably not appropriate for women wishing to conceive in the next 12 months especially when alternative options with biologics are available. For those women who may not plan to have children, have completed their family, or may wish to have children in the more distant future, SMDs are appropriate treatment options when effective contraception is used. As clinicians, we need to proactively hold these conversations with patients and asking about family planning should become routine in the care of women of childbearing age. Those women established on SMDs planning for pregnancy should cease therapy for a minimum of 4 weeks and discuss a switch to a more suitable alternative or, when in prolonged remission, a period of observation. It is important to ensure that the new strategy by switch or observation of therapy maintains remission for 3–6 months before trying to conceive in order to reduce the risk of intra partum flares.

6. A holistic strategy

Naturally the clinician’s focus for IBD management in women of child bearing and especially during pregnancy centers on the therapeutic drug options and the often-challenging discussions required to serve shared decision making. We must also promote the importance of the non-pharmacological interventions and wider considerations for physical and mental health in addition to medical treatment of IBD. For those already pregnant or planning pregnancy, nutritional optimization, anemia prevention or management, vaccinations, smoking cessation, psychological support and the management of social vulnerabilities are key. Folic acid supplementation should be offered to all patients and those with significant small-bowel disease should be offered higher doses up to 5 mg daily. Detailed counseling regarding the risks and benefits of drug cessation versus continuation in pregnancy is imperative, and multidisciplinary specialist care remains paramount.

7. Expert opinion

With increasing choices in the therapeutic landscape of IBD, clinicians and patients face more difficult decisions. While safety and efficacy of any chosen treatment probably play a key role, other factors are also coming into play. Patients may prefer an oral over a subcutaneous or intravenous application method. Clinicians need to factor in infusion unit capacity, cost of treatments and time to treatment initiations. These factors apply to all patients. Safety concerns may however restrict the choice of treatments for older or comorbid patients.

As biologics have been found to have a favorable fetal and maternal safety profile, medication choices for women of childbearing age were previously only curtailed for methotrexate. As significant concerns over animal studies on SMDs and reproduction have arisen, we need to carefully consider the role of SMDs in women of childbearing age. Clinicians should not assume that women of childbearing age may or may not wish to have children. Consultations require tactful exploration of a woman’s wishes and counseling whether SMDs are an appropriate treatment option.

The current advice regarding SMDs and pregnancy is largely based on animal data. While these show significant concern, we must acknowledge that although very limited the human evidence has so far not shown these worrying safety signals. Two phenomena are responsible for this. Firstly, most data have arisen from clinical trails where drug exposure during any pregnancy will be very limited due to strict monitoring for any unplanned pregnancy. Secondly, the number of pregnancies reported is small with a high level of missing data, miscarriages of pregnancy or planned pregnancy terminations.

It is conceivable that future studies will alleviate some of the current concerns and treatment with SMDs may even be seen as acceptable in the future. This will however require data on pregnancies with significant exposure during the first two trimesters. These data will arise from unplanned pregnancies mainly. As such we can not expect reassuring studies in the near future. We must also refrain from comparing the current data on SMD pregnancies with biologics, where most studies reported on exposure for at least two trimesters. Clinicians should report outcomes of any pregnancies exposed to SMDs to the manufacturers, national medication licensing bodies and/or observational studies (such as the PIANO registry; https://gastroenterology.ucsf.edu/research/piano).

In the meantime, clinicians should ensure that any patient planning for pregnancies is on therapies that are compatible. Those on SMD treatment should be switched to a better alternative prior to any planned pregnancy and continued remission should be ensured.

Declaration of interest

CP Selinger has received unrestricted research grants from Warner Chilcott, Janssen, Galapagos and AbbVie, has provided consultancy to Warner Chilcott, Dr Falk, AbbVie, Takeda, Fresenius Kabi, Eli Lilly, Galapagos, Ferring, Arena and Janssen, and had speaker arrangements with Warner Chilcott, Dr Falk, Galapagos, AbbVie, MSD, Pfizer, Eli Lilly, BMS, UCB, Fresenius Kabi, Celltrion and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One reviewer has received payments in the last five years for services like fees for consulting, lectures, speaker’s bureau from AbbVie, Ferring, Falk, Yansen, Takeda, Pfizer, Tillots. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Author contributions

M Cuffe and CP Selinger developed the manuscript outline. M Cuffe wrote the draft, which was critically reviewed by CP Selinger.

Institutional review board statement

Not applicable.

Additional information

Funding

This paper was not funded.