Vedolizumab and Ustekinumab Levels in Pregnant Women With Inflammatory Bowel Disease and Infants Exposed In Utero.

BACKGROUND & AIMS: Vedolizumab and ustekinumab pharmacokinetics in pregnancy and the infant after in utero exposure remain incompletely defined. We aim to define the antenatal stability of ustekinumab and vedolizumab levels and the time at which infant drug levels become undetectable. METHODS: This multicenter prospective observational cohort study recruited pregnant or preconception women with inflammatory bowel disease receiving vedolizumab or ustekinumab. Trough drug levels, clinical data, and biochemical data were documented preconception, during each trimester of pregnancy, and postpartum. Maternal and cord blood drug levels were measured at delivery and in infants until undetectable. Infant outcomes were assessed until 2 years of age. RESULTS: A total of 102 participants (vedolizumab, n = 58) were included. The majority of mothers were, and remained, in clinical and biochemical remission. Maternal vedolizumab levels decreased over the course of pregnancy in association with increasing weight, rather than increasing gestation. Maternal ustekinumab levels remained stable. The median time to drug becoming undetectable in the infant was shorter for vedolizumab (11 wk; range, 5-19 wk; n = 32) than ustekinumab (14 wk; range, 9-36 wk; n = 17) and correlated positively with infant delivery level. Thirty-two of 41 (88%) and 17 of 30 (67%) vedolizumab- and ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age, respectively. Pregnancy and infant outcomes were favorable. Twenty infants with undetectable drug levels received the rotavirus vaccine, with no adverse reactions reported. CONCLUSIONS: Maternal vedolizumab levels decreased, whereas ustekinumab levels remained stable over the course of pregnancy. Most vedolizumab- and approximately half of ustekinumab-exposed infants had undetectable drug levels by 15 weeks of age. No concerning maternal or infant safety signals were identified.

Evaluation and management of rectal bleeding in pregnancy.

Rectal bleeding occurs in about 40% of pregnant women, and is predominantly attributed to benign perianal pathology (haemorrhoids or anal fissures). More sinister causes of rectal bleeding may be heralded by key red flag clinical and biochemical features. These features should be evaluated in all women with rectal bleeding. Imaging investigations or flexible sigmoidoscopy may be warranted. The latter can be performed safely by experienced operators in pregnant women. Women with evidence of haemodynamic compromise, elevated inflammatory markers, significant anaemia, signs of intestinal obstruction or compromise to the fetus should be evaluated urgently. Providers must be mindful of the changes in normal ranges for common haematological and biochemical parameters in pregnancy compared with the non-pregnant state. Faecal calprotectin is an established tool for identification of intestinal inflammation and is valid in pregnancy. An elevated faecal calprotectin level (≥ 50 µg/g) signifies a need for further diagnostic evaluation. Inflammatory bowel disease may present initially, or with worsening disease activity, in pregnancy. Expedient diagnosis with the use of faecal calprotectin, sigmoidoscopy with or without intestinal ultrasound, exclusion of alternative or compounding infective aetiologies, and institution of appropriate therapy are critical. Medical therapies for management of inflammatory bowel disease can be safely instituted in pregnancy. Colorectal cancer incidence is increasing in younger age groups, but fortunately remains rare. When diagnosed in pregnancy, colorectal cancer can be successfully and safely managed with a collaborative multidisciplinary team approach. Early diagnosis is key to optimising outcomes.

Managing COVID-19 in patients with inflammatory bowel disease: navigating unprecedented challenges.

The COVID-19 pandemic has demanded a rapid adaptation in healthcare provision, including patients with inflammatory bowel disease (IBD). This viewpoint discusses some of the unique challenges in managing comorbid IBD and COVID-10 experienced by our team at The Royal Melbourne Hospital, which was at the epicentre of the COVID-19 'second-wave' surge in Melbourne.

Altered bowel habit and rectal bleeding in pregnancy: the importance of recognising undiagnosed inflammatory bowel disease.

Worsening of disease activity during pregnancy in patients with known inflammatory bowel disease, especially ulcerative colitis (UC), is well recognised, but the diagnosis of new-onset or previously undiagnosed UC in pregnancy has been inadequately studied to date. Recognition of gastrointestinal symptoms in pregnancy as potentially indicating UC is of paramount importance, as this allows appropriate investigation and instigation of therapies to optimise maternal and foetal outcomes. Here, we report three cases of women with gastrointestinal symptoms in pregnancy with disparate outcomes.

Practical management of inflammatory bowel disease patients during the COVID-19 pandemic: expert commentary from the Gastroenterological Society of Australia Inflammatory Bowel Disease faculty.

The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has emerged as a public health emergency and challenged healthcare systems globally. In a minority of patients, SARS-CoV-2 manifests with a severe acute respiratory illness and currently there is insufficient data regarding the virulence of COVID-19 in inflammatory bowel disease patients taking immunosuppressive therapy. This review aims to summarise the current literature and provide guidance on the management of inflammatory bowel disease patients in the context of the COVID-19 pandemic in the Australasian setting.

Peripheral parenteral nutrition: A retrospective observational study to evaluate utility and complications.

BACKGROUND: Peripheral parenteral nutrition (PPN) provides an alternative nutrition support strategy to centrally administered PN for specific patients requiring short-term PN. Previous studies have demonstrated limited use of PPN and variable complication rates. This study aimed to evaluate PPN complications and usage at this center. METHODS: This was a single-center retrospective observational study of all adult patients who received at least 1 day of PPN from June 2018 to December 2023. Demographic and clinical data were collected, including complications, indications for PN and reason for PPN, duration of therapy, reason for cessation of PPN, nutrition status, energy and protein provision, and central line insertion rates. RESULTS: 381 patients were included, the median age was 62 (interquartile range = 28-74) years, and 235 were men (61.7%). The most common indication for PN was ileus (n = 153, 40%) followed by gastrointestinal obstruction (n = 93, 24%). The median time receiving PPN was 3 (2-4) days. Patients received a median of 65% (55%-75%) of energy and 58% (50%-69%) of protein requirements with PPN. Malnutrition was diagnosed in 47.5% (n = 181) of this cohort. Total complication rates were 8.7% (n = 33), with cannula infiltration being the most common complication (6.6%, n = 25). 213 (56%) patients proceeded to central line insertion. CONCLUSION: PPN proved to be a safe and effective therapy for short-term PN when managed by a nutrition support team. PPN has the potential to attenuate short-term nutrition deficits and prevent central venous access device insertion in selected patients, making it a valuable nutrition support therapy.

Feasibility of transperineal intestinal ultrasound in assessing ulcerative proctitis during pregnancy.

This study explored the use of transperineal intestinal ultrasound (TPIUS) for assessment of ulcerative colitis (UC) in pregnancy. 8 pregnant women with UC underwent TP-US, clinical assessment and fecal calprotectin. TP-IUS was well tolerated and feasible with adequate rectal views obtained in all trimesters of pregnancy. No correlation between TP-IUS, clinical, or biochemical rectal disease activity assessment was found in this small cohort. Further studies are required to define the optimal technique and references ranges in the pregnant population.

Thrombocytosis and Transaminitis in Infants Born to Women With Inflammatory Bowel Disease Is Associated With Exposure to Maternal Inflammation In Utero.

BACKGROUND: Despite reassuring clinical safety data, thrombocytosis, anemia, lymphopenia, and liver function derangements have been observed in infants born to women with inflammatory bowel disease (IBD) treated with thiopurines and biologics. We aimed to define the prevalence, course, associations, and clinical impact of hematological and biochemical abnormalities in such infants. METHODS: This multicenter prospective cohort study assessed clinical, hematologic, and biochemical outcomes of infants exposed to thiopurines or biologics in utero for management of maternal IBD. Liver transaminases, full blood examination, and infant thiopurine metabolites (where exposed) were taken at delivery and 6 weeks of age. Abnormal results were repeated until normalization. Infants were followed clinically by a pediatric gastroenterologist up to 2 years of age. RESULTS: A total of 130 infants were included. Thrombocytosis and elevated alanine transaminase (ALT) were seen in over half of infants up to 6 months of age with no significant clinical impact. Elevated ALT was associated with increasing maternal C-reactive protein in second trimester, while thrombocytosis was associated with increasing maternal C-reactive protein and fecal calprotectin in third trimester. Preceding infection and vaccination were associated with an increased risk of elevated alkaline phosphatase at 3 months. In those exposed to thiopurines, increasing maternal 6-methylmercaptopurine at delivery was associated with increased ALT to 6 months. CONCLUSIONS: Infants born to women with IBD commonly developed thrombocytosis, elevated alkaline phosphatase, and elevated ALT. These findings were associated with exposure to maternal inflammation, elevated 6-methylmercaptopurine at delivery, and infant vaccinations and infections, and had minimal clinical consequence.

Hematological and biochemical abnormalities have been observed in infants born to women with inflammatory bowel disease. This prospective study shows that thrombocytosis and elevated alanine transaminase are common in infants to 6 months of age and are associated with maternal inflammation, rather than with in utero medication exposures.

Thiopurine Metabolite Shunting in Late Pregnancy Increases the Risk of Intrahepatic Cholestasis of Pregnancy in Women With Inflammatory Bowel Disease, and Can be Managed With Split Dosing.

BACKGROUND AND AIMS: The risk of intrahepatic cholestasis of pregnancy [ICP] is increased in thiopurine-exposed pregnancies. Thiopurine 'shunting', with a 6-methylmercaptopurine [MMP] to 6-thioguanine [TGN] ratio of >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesised impact of thiopurine shunting, and identify risk minimisation strategies. METHODS: This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician. RESULTS: Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. MMP/TGN ratio increased from preconception to third trimester [p <0.01], with approximately 25% of participants shunting in pregnancy. Second trimester split dosing led to a decrease in the median MMP/TGN ratio from 18 (interquartile range [IQR] 6-57) to 3 [IQR 2-3.5] at delivery [p = 0.04]. The risk of ICP was increased in thiopurine-exposed pregnancies (6.7% [7/105] vs 0% [0/112], p <0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (risk ratio [RR] 8.10, 95% confidence interval [CI] 1.88-34.85, p = 0.005) and shunting in third trimester [6.20, 1.21-30.73, p = 0.028] and at delivery [14.18, 1.62-123.9, p = 0.016] were associated with an increased risk of ICP. CONCLUSIONS: Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted.

Well controlled maternal inflammatory bowel disease does not increase the risk of abnormal neurocognitive outcome screening in offspring.

Background: Exposure to maternal inflammation is associated with an increased risk of neurocognitive and developmental disorders in offspring. Early diagnosis and intervention improves childhood motor and cognitive functioning. Neonatal cerebral MRI and remote app-based generalised movement assessments (GMAs) are both predictive of adverse neurocognitive outcomes but have only been used in infants at significantly increased risk for these outcomes, rather than following in utero exposure to maternal inflammatory disorders. Methods: Pregnant women with inflammatory bowel disease were assessed clinically and biochemically in each trimester of pregnancy in this single centre prospective study. Neonatal cerebral MRIs were performed at 6-12 weeks post-corrected term. Two GMA videos were filmed using the 'BabyMoves' app from 12 to 16 weeks of age. MRIs and GMAs were assessed by a blinded highly qualified practitioner using validated scoring systems. Results: 40/53 of invited maternal-infant dyads were recruited. C-reactive protein was elevated antenatally in less than 13%. 5/37 neonatal MRIs had incidental or obstetric trauma related gross anatomical abnormalities, with none abnormal on validated gross abnormality scoring. 3/35 GMAs were abnormal, with one GMA abnormality being clinically significant. Of those with abnormal GMAs, 2/3 were in exposed to severely active IBD in-utero. Conclusion: Neonatal cerebral MRI and GMA for neurocognitive screening is feasible in the setting of maternal inflammatory bowel disease, where the risk of cerebral palsy is poorly defined and thus burdensome screening interventions are less appealing to parents. Larger studies are required to stratify adverse neurocognitive outcome risk in infants born to women with maternal inflammatory disorders, but these data are reassuring for women with IBD in remission antenatally.

Evaluation and management of ileal pouch-anal anastamosis (IPAA) complications in pregnancy, and the impacts of an IPAA on fertility.

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) remains the preferred surgical option for medically refractory ulcerative colitis. Management of individuals with an IPAA prior to and during pregnancy presents challenges that can have serious consequences. Infertility, mechanical obstructive and inflammatory pouch complications are frequently encountered in pregnant women with an IPAA. Mechanical obstructions occur due to a variety of underlying aetiologies, including stricturing disease, adhesions and pouch twists. Conservative management of such obstructions often results in resolution of symptoms without a need for endoscopic or surgical intervention, although endoscopic decompression may be attempted in isolation or as a bridge to definitive surgical intervention. Parenteral nutrition, and early delivery, may also be necessary. Faecal calprotectin and intestinal ultrasound, both of which are accurate in pregnancy, are useful in the setting of suspected inflammatory pouch complications, in some circumstances allowing for avoidance of pouchoscopy. Penicillin-based antimicrobials can be considered first line in pregnancy for the management of pouchitis and pre-pouch ileitis, and biologics can be safely instituted in the setting of refractory disease or suspected Crohn's disease-like inflammation of the pouch or pre-pouch ileum. Pragmatism, clear patient communication and multidisciplinary discussion are essential in approaching pregnant women with complications of an IPAA, particularly given the lack of definitive evidence to guide therapeutic decisions.

The Effect of In Utero Exposure to Maternal Inflammatory Bowel Disease and Immunomodulators on Infant Immune System Development and Function.

Autoimmune and inflammatory disorders, including inflammatory bowel disease (IBD), commonly affect women of childbearing age, warranting the use of immunomodulatory agents at a time where pregnancy may be desired. In utero exposure to pro-inflammatory mediators from maternal IBD, IBD-associated intestinal dysbiosis, and immunomodulatory drug use may impact neonatal immune system development during what is considered to be a critical period, with potential long-lasting impacts on susceptibility to disease. Both the innate and adaptative immune systems of the neonatal differ to that of the adult in terms of both cellular composition and sensitivity to antigenic and innate stimulation. The infant immune system gradually develops to more closely resemble that of the adult. Exposure to maternal inflammation in utero may aberrantly impact this period of infant immune system development, with maternal autoimmune and inflammatory disorders shown to affect the physiologic changes in serum cytokine abundance observed during pregnancy. The maternal and neonatal intestinal microbiome greatly influence infant mucosal and peripheral immune system development, and thereby impact the susceptibility to short-term inflammatory diseases, the adequacy of vaccine response, and later life risk of atopic and inflammatory disorders. Maternal disease, mode of delivery, method of feeding, time of weaning to include solid foods in the diet, and neonatal antibiotic exposure all influence the composition of the infant microbiome, and thereby infant immune system maturation. How exposure to specific immunosuppressive medications in utero alters infant immune cell phenotype and response to stimulation has been explored, but with existing studies limited by the time at which samples are performed, heterogenicity in methods, and small sample size. Furthermore, the impact of more recently introduced biologic agents have not been explored. Evolving knowledge in this field may influence therapeutic preferences for individuals with IBD planning to conceive, particularly if substantive differences in the risk of infant infection and childhood immune disease are identified.

Preconception, antenatal and postpartum management of inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn's disease, commonly affects individuals of childbearing age. Pregnancy in women with IBD presents an anxiety-provoking prospect for practitioners and patients alike, with disease flares occurring in between 20% and 55% of patients antenatally. OBJECTIVE: The aim of this review is to provide an overview of antenatal IBD management principles and therapeutic goals, with a specific focus on the role of general practitioners. DISCUSSION: A collaborative approach is favoured in managing pregnancy and IBD. Preconception counselling should be prioritised, with emphasis on the importance of achieving three months of preconception corticosteroid-free remission. Close monitoring of disease activity in pregnancy is crucial, warranting the careful interpretation of both clinical and biochemical parameters. Reassurance regarding the safety of IBD medications in pregnancy and vaginal delivery can be provided in the majority of cases. Specialist support should be sought expeditiously in the setting of disease flare, particularly where symptoms and biochemical parameters are refractory to escalation of 5-aminosalicylates or topical therapies, corticosteroids or biologic agents are required, or an emergent IBD complication is suspected.

Ustekinumab levels in pregnant women with inflammatory bowel disease and infants exposed in utero.

BACKGROUND: Ustekinumab is increasingly used in pregnant women with inflammatory bowel disease (IBD). Existing safety data are reassuring, but the stability of ustekinumab levels in pregnancy, degree of transfer to the infant and time to infant clearance are unknown. METHODS: In this prospective observational study, ustekinumab-exposed women with IBD had trough levels measured in each trimester of pregnancy and at delivery. Infant ustekinumab levels were measured at delivery and ongoing until clearance was achieved. Trough ustekinumab level stability in individuals across pregnancy was compared by Skillings-Mack test. Spearman coefficients were used to correlate maternal and infant delivery levels, and median time to infant ustekinumab clearance was defined. RESULTS: 19 pregnant women receiving ustekinumab were included. There was no difference in ustekinumab levels across pregnancy in those with two or more representative trough levels (P = 0.83, n = 11). Infant delivery ustekinumab levels were higher than maternal levels, with a median infant:maternal ratio of 1.79 (IQR 1.26-3.1). There was a positive correlation between maternal and infant delivery ustekinumab levels (r = 0.75, P = 0.001) and an inverse correlation between the number of days from final antenatal dose and delivery infant ustekinumab level (r = -0.65, P = 0.006). Median time of infant ustekinumab clearance was 9 (range 6-19) weeks (n = 9). CONCLUSION: Ustekinumab drug levels appear stable in pregnancy, with a delivery infant:maternal ratio similar to that of anti-TNFs. Infant ustekinumab clearance was complete by 20 weeks post-partum, however, infants exposed in utero should avoid live vaccination before 12 months of age until further clearance data are obtained.

SARS-CoV-2 vaccination in patients with inflammatory bowel disease.

BACKGROUND: The current COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), has drastically impacted societies worldwide. Vaccination against SARS-CoV-2 is expected to play a key role in the management of this pandemic. Inflammatory conditions such as inflammatory bowel disease (IBD) often require chronic immunosuppression, which can influence vaccination decisions. AIM: This review article aims to describe the most commonly available SARS-CoV-2 vaccination vectors globally, assess the potential benefits and concerns of vaccination in the setting of immunosuppression and provide medical practitioners with guidance regarding SARS-CoV-2 vaccination in patients with IBD. METHODS: All published Phase 1/2 and/or Phase 3 and 4 studies of SARS-CoV-2 vaccinations were reviewed. IBD international society position papers, safety registry data and media releases from pharmaceutical companies as well as administrative and medicines regulatory bodies were included. General vaccine evidence and recommendations in immunosuppressed patients were reviewed for context. Society position papers regarding special populations, including immunosuppressed, pregnant and breast-feeding individuals were also evaluated. Literature was critically analysed and summarised. RESULTS: Vaccination against SARS-CoV-2 is supported in all adult, non-pregnant individuals with IBD without contraindication. There is the potential that vaccine efficacy may be reduced in those who are immunosuppressed; however, medical therapies should not be withheld in order to undertake vaccination. SARS-CoV-2 vaccines are safe, but data specific to immunosuppressed patients remain limited. CONCLUSIONS: SARS-CoV-2 vaccination is essential from both an individual patient and community perspective and should be encouraged in patients with IBD. Recommendations must be continually updated as real-world and trial-based evidence emerges.

Review article: investigation and management of internal fistulae in Crohn's disease.

BACKGROUND: Crohn's disease is an inflammatory, penetrating intestinal disease associated with fistula formation. Fistulae in Crohn's disease can be classified into external and internal fistulae. Internal fistulae form between the gastrointestinal tract and another internal organ and include enteroenteric, enterocolic, enterovesical and rectovaginal fistulae. They are associated with significant morbidity and a decreased quality of life. AIM: To review the classification, diagnosis, medical and surgical management of internal fistulae in Crohn's disease, and propose a treatment algorithm. METHODS: A literature review on internal fistulae in Crohn's disease in the adult population was undertaken, synthesised and summarised. RESULTS: Internal fistulae occur in up to 15% of patients with Crohn's disease. Multi-modal assessment including a combination of endoscopy and cross-sectional imaging, usually magnetic resonance, is required to diagnose fistulae and determine extent of disease. Determining optimal treatment strategies for these complex fistulae remains a challenge due to limited and generally low-quality data. Most studies to date have focussed on luminal disease, with (usually post hoc) outcomes more often reported for external fistulae, particularly perianal fistulae, than internal fistulae. Anti-tumour necrosis factor therapies have emerged as the mainstay of medical therapy, with particularly promising data for enterovesical fistulae, but many patients will still require surgical intervention. The indications and optimal timing of surgery vs medical therapy remains uncertain; thus multi-disciplinary input when making such decisions is important. CONCLUSIONS: Internal fistulae result in significantly increased morbidity in Crohn's disease, and further studies to determine optimal multi-modality management strategies incorporating medical and surgical therapy are required.

Review article: prevention, diagnosis and management of COVID-19 in the IBD patient.

BACKGROUND: The current COVID-19 pandemic, caused by SARS-CoV-2, has emerged as a public health emergency. All nations are seriously challenged as the virus spreads rapidly across the globe with no regard for borders. The primary management of IBD involves treating uncontrolled inflammation with most patients requiring immune-based therapies. However, these therapies may weaken the immune system and potentially place IBD patients at increased risk of infections and infectious complications including those from COVID-19. AIM: To summarise the scale of the COVID-19 pandemic, review unique concerns regarding IBD management and infection risk during the pandemic and assess COVID-19 management options and drug interactions in the IBD population. METHODS: A literature review on IBD, SARS-CoV-2 and COVID-19 was undertaken and relevant literature was summarised and critically examined. RESULTS: IBD patients do not appear to be more susceptible to SARS-CoV-2 infection and there is no evidence of an association between IBD therapies and increased risk of COVID-19. IBD medication adherence should be encouraged to prevent disease flare but where possible high-dose systemic corticosteroids should be avoided. Patients should exercise social distancing, optimise co-morbidities and be up to date with influenza and pneumococcal vaccines. If a patient develops COVID-19, immune suppressing medications should be withheld until infection resolution and if trial medications for COVID-19 are being considered, potential drug interactions should be checked. CONCLUSIONS: IBD patient management presents a challenge in the current COVID-19 pandemic. The primary focus should remain on keeping bowel inflammation controlled and encouraging medication adherence.