
==== Front
Saudi J Gastroenterol
Saudi J Gastroenterol
SJG
Saudi J Gastroenterol
Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association
1319-3767
1998-4049
Wolters Kluwer - Medknow India

38099556
SJG-30-181
10.4103/sjg.sjg_318_23
Clinical Practice Guidelines
Saudi consensus guidance for the management of inflammatory bowel disease during pregnancy
Azzam Nahla A. 1https://orcid.org/0000-0002-2097-289X

Almutairdi Abdulelah 2https://orcid.org/0009-0008-7000-2905

Almudaiheem Hajer Y. 3https://orcid.org/0000-0002-0985-6193

AlAmeel Turki 4https://orcid.org/0000-0003-0147-7540

Bakkari Shakir A. 5https://orcid.org/0000-0002-9079-1437

Alharbi Othman R. 1https://orcid.org/0000-0002-1211-0157

Alenzi Khalidah A. 6https://orcid.org/0000-0003-1512-4332

AlMolaiki Maha A. 789https://orcid.org/0000-0002-4325-0515

Al-Omari Bedor A. 10https://orcid.org/0000-0002-8441-4870

Albarakati Rayan G. 11https://orcid.org/0000-0002-5729-9088

Al-Jedai Ahmed H. 312https://orcid.org/0000-0002-4730-9086

Saadah Omar I. 13https://orcid.org/0000-0002-3744-9907

Almadi Majid A. 1https://orcid.org/0000-0001-9917-2758

Al-Bawardy Badr 214https://orcid.org/0000-0002-6102-9267

Mosli Mahmoud H. 15https://orcid.org/0000-0002-6975-1297

1 Division of Gastroenterology, Department of Medicine, College of Medicine, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
2 Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
3 Deputyship of Therapeutic Affairs, Ministry of Health, Riyadh, Saudi Arabia
4 Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
5 Department of Gastroenterology, King Saud Medical City, Riyadh, Saudi Arabia
6 Executive Director of Transformation, Planning, and Business Development, Tabuk Health Cluster, Tabuk, Saudi Arabia
7 Department of Pharmaceutical Care Services, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
8 King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
9 Department of Pharmacy Practice, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
10 Department of Pharmaceutical Care Services, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
11 Department of Obstetrics and Gynecology, Majmaah University, Riyadh, Saudi Arabia
12 Professor, Colleges of Medicine and Pharmacy, Alfaisal University, Riyadh, Saudi Arabia
13 Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Inflammatory Bowel Disease Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
14 Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
15 Department of Internal Medicine, King Abdulaziz University, Inflammatory Bowel Disease Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
Address for correspondence: Dr. Mahmoud H. Mosli, King Abdulaziz University Hospital, P.O. Box 80215, Jeddah 21589, Kingdom of Saudi Arabia. E-mail: mmosli@kau.edu.sa
Jul-Aug 2024
15 12 2023
30 4 181197
03 9 2023
27 10 2023
08 11 2023
Copyright: © 2023 Saudi Journal of Gastroenterology
2023
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
The management of inflammatory bowel disease (IBD) in pregnant women is challenging and must be addressed on a patient-by-patient basis. Optimal patient management requires a multidisciplinary team and clear evidence-based recommendations that cater to this subset of patients. In this article, we provide concise guidelines and clinical care pathway for the management of IBD in pregnant women. Our recommendations were developed by a multidisciplinary working group that includes experts from the Saudi Ministry of Health in collaboration with the Saudi Gastroenterology Association and the Saudi Society of Clinical Pharmacology. All recommendations are based on up-to-date information following an extensive literature review. A total of 23 evidence-based expert opinion recommendations for the management of IBD in pregnant women are herein provided.

Crohn’s disease
guidelines
inflammatory bowel disease
management
pregnancy
Saudi Arabia
treatment
ulcerative colitis
==== Body
pmcINTRODUCTION

The prevalence of inflammatory bowel disease (IBD) is increasing in Saudi Arabia.[1234] Studies from a tertiary center in Riyadh estimated that the incidence of Crohn’s disease (CD) increased from 0.32 per 100,000 persons per year between 1983 and 1993, to 1.66 per 100,000 persons between 1994 and 2004, with a combined mean annual incidence of 0.94 per 100,000 persons per year over this 20-year period.[56] The prevalence of IBD in Saudi Arabia in 2014 was 6.3 cases per 100,000, with ulcerative colitis (UC) more common than CD.[7] In 2016, it was reported that the incidence of IBD in Saudi Arabia was 1.3 cases per 100,000, with UC being more common than CD.[8]

While IBD affects women of childbearing age, the management of pregnant IBD patients is challenging, as most regulatory trials and long-term follow-up studies exclude pregnant women. Management practices for pregnant IBD patients also lack consistency, increasing the risk of adverse maternofetal outcomes, patient anxiety, suboptimal fertility, and voluntary childlessness.[9] Although many women with IBD experience a normal pregnancy with a vaginal delivery, active CD or UC is associated with an increased risk of preterm birth, low gestation weight, and fetal loss.[10] The management of IBD in pregnant women requires close collaboration between specialists and healthcare practitioners. With proper management, most women with IBD can have an uneventful pregnancy and a healthy newborn.[811] Multiple nutritional deficiencies are common during pregnancy and must be addressed and corrected ideally before conception.[1213] Side effects of medication, venothrombotic complications, and severe dehydration represent further risk factors for expectant mothers.[14151617]

The goal of these recommendations is to provide guidance on the management and monitoring of IBD in women who are either pregnant or planning to conceive, based on a review of the current evidence and guidelines. Our recommendations were developed through a multidisciplinary working group that includes experts from the Saudi Ministry of Health (MOH) in collaboration with the Saudi Gastroenterology Association (SGA) and the Saudi Society of Clinical Pharmacology (SCCP). All recommendations are based on up-to-date information following an extensive literature review.

METHODOLOGY

A literature review of current publications and international guidelines regarding the management of IBD during pregnancy was performed. Strategies were developed from guidelines from the European Crohn’s and Colitis Organisation (ECCO), the American College of Gastroenterology (ACG), the American Gastroenterology Association (AGA), the Australian IBD Consensus on Pregnancy, and the British Society of Gastroenterology (BSG).[918192021]

A total of 23 evidence-based and expert opinion-based recommendations for the management of pregnant patients with UC and CD are proposed. Guidelines were refined by a voting process and participants suggested revisions and commented on the statements, which were subsequently revised. The quality of evidence was considered “high” if further research was unlikely to change the confidence in the estimate of the effect. Guidelines were termed “moderate” if further research was likely to impact confidence in the estimate of the effect or to change the estimate. Guidelines were deemed “low” if further research was very likely to impact confidence in the estimate of the effect.

RESULTS

This consensus includes 23 statements, and a clinical care pathway focused on the management of IBD in pregnant women [Table 1].

Table 1 Summary of the 23 statements

Statement 1	Fertility rates for women with IBD in remission are like the general population. Women with active IBD or with prior surgery may have decreased fertility, which should be discussed and planned with specialists and healthcare practitioners.	
Statement 2	The genetic risk of IBD is increased in the offspring of parents with IBD particularly if both parents are affected. The risk to offspring can be discussed with parents before conception if deemed appropriate by treating physicians	
Statement 3	We recommend that women with IBD during the childbearing period should receive preconception counseling to optimize disease control and improve pregnancy outcomes.	
Statement 4	Women with IBD can consider becoming pregnant when the disease is in clinical, biochemical, and preferably in endoscopic remission to avoid unfavorable outcomes.	
Statement 5	Fecal calprotectin can be used to monitor disease activity throughout pregnancy. In contrast, C-reactive protein (CRP) is affected by pregnancy and may not be reliable.	
Statement 6	For evaluation of IBD disease activity during pregnancy, we recommend magnetic resonance imaging (MRI) without gadolinium or bowel ultrasound to minimize radiation exposure. If required, endoscopy can also be performed, ideally during the second trimester	
Statement 7	We recommend that women with active disease “or” at high risk of disease recurrence continue their medication that is proven to be safe “throughout” pregnancy. Those with inactive disease who choose to cease medication can do so at the beginning of the third trimester	
Statement 8	We recommend that pregnant women diagnosed with UC on oral and/or rectal 5-ASA as a maintenance treatment continue to take this therapy during pregnancy. Phthalate-containing 5-ASA formulations should be avoided.	
Statement 9	We recommend that pregnant women with UC suffering from mild-to-moderate flares on 5-ASA maintenance therapy modify their combination of oral and rectal 5-ASA medication to achieve symptomatic remission	
Statement 10	We recommend that pregnant women diagnosed with IBD on a thiopurine as a maintenance treatment continue to take this therapy during pregnancy.	
Statement 11	We recommend that females with IBD planning to get pregnant discontinue methotrexate at least 3 months before pregnancy and until breastfeeding is stopped to avoid detrimental effects on the infant.	
Statement 12	We recommend that women with active disease or who are at high risk of disease recurrence continue anti-TNF therapy throughout pregnancy	
Statement 13	We recommend that women with the disease in remission continue anti-TNF during pregnancy. In the presence of long-term remission and a desire to stop anti-TNF during pregnancy, it can be stopped before the third trimester	
Statement 14	We recommend that pregnant women with IBD who are controlled on vedolizumab and ustekinumab discuss the continuation of treatment with their prescriber gastroenterologist individually.	
Statement 15	We recommend that women with IBD cease tofacitinib, upadacitinib, etrasimod, and ozanimod before attempting pregnancy until further confirmatory evidence of safety is available.	
Statement 16	We recommend the use of systemic corticosteroids, anti-TNF therapy, ustekinumab, or vedolizumab to achieve symptomatic remission in pregnant women diagnosed with IBD during pregnancy or who experience a disease flare while on optimal conventional therapy	
Statement 17	Prevention of VTE is critical for hospitalized patients, particularly following a C-section or if the patient is unwell.	
Statement 18	Engaging multidisciplinary teams and patients in the decision-making process during pregnancy is recommended and should include an obstetrician with relevant experience.	
Statement 19	Excluding active perianal disease or ileoanal pouch (where a CS is usually favored), the delivery mode must be determined according to patient preference and obstetric factors	
Statement 20	We recommend that biologics can be resumed 24 h after vaginal delivery and 48 h after CS if no evidence of infection exists and dosing intervals are appropriate.	
Statement 21	For infants exposed to biologics in utero, we recommend delaying Bacillus Calmette–Guérin (BCG) immunization and avoidance of the rotavirus vaccine until at least 6 months after birth. Non-live vaccines can be administered in accordance with conventional immunization protocols.	
Statement 22	We recommend breastfeeding as a primary source of nutrition for infants of mothers with IBD.	
Statement 23	We recommend continuing the use of safe medications throughout breastfeeding.	

General considerations

It is estimated that globally, 3.9 million women live with IBD.[422] Most women carry a diagnosis of IBD during their reproductive years. Fear surrounds the impact of IBD on pregnancy and maternal health. Many expectant mothers cease therapy during pregnancy or lactation despite the significant risk of worsening IBD activity during the pregnancy.[23] The challenge of improving care for women with IBD should be met with information and shared decision-making.

Fertility

Statement 1: Fertility rates for women with IBD in remission are like the general population. Women with active IBD or with prior surgery may have decreased fertility, which should be discussed and planned with specialists and healthcare practitioners.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Fertility rates for women with CD or UC in remission do not differ from the general population, but those with active IBD may show reduced fertility. In addition to women with prior surgery, particularly open ileal pouch–anal anastomosis (IPAA) proctectomy and permanent stoma can manifest reduced fertility, which is attributed to inflammation and adhesions.[24] Data showed that 17% of women with IBD are voluntarily childless compared with 6% of women in the general population, which is largely due to inappropriate information about pregnancy and IBD.[25] Thus, preconception counseling and evaluation are the keys to overcome this misleading information.

Risk of IBD in offspring

Statement 2: The genetic risk of IBD is increased in the offspring of parents with IBD particularly if both parents are affected. The risk to offspring can be discussed with parents before conception if deemed appropriate by treating physicians.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (77% of panel strongly agreed).

Familial IBD and the future risk of IBD in children are dictated by genetic predisposition.[262728293031] A higher risk of IBD in children exists when both parents carry the illness.[32] Several genetic associations with IBD have been identified; however, no single gene is deemed responsible.[3334] Genome-wide association studies (GWAS) have identified around 240 genetic susceptibility loci for IBD with genes implicated in autophagy, T-cell responses, and pathogen infection.[3536373839] IBD shares genetic etiology with other immune-related disorders, including ankylosing spondylitis and celiac disease. IBD is, however, heterogeneous with environmental influence and genetic disposition playing key roles.[940] Although comparable disease phenotypes have been observed within families, the genetic determinants of these clinical events are largely unknown outside their role in disease susceptibility.[4142] Cohort studies highlight how the genetic risk of CD is higher than UC. The absolute risk of an offspring developing CD with maternal CD can reach up to 5%, while the risk of UC is 3%. Having both parents affected by IBD increases the risk by up to 30%.[32] Concordance rates in monozygotic twins range from 20% to 56% for CD and from 6% to 19% for UC.[43]

Preconception Disease Control

Statement 3: We recommend that women with IBD during the childbearing period should receive preconception counseling to optimize disease control and improve pregnancy outcomes.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (92% of the panel strongly agreed).

Preconception counseling improves pregnancy outcomes in patients with IBD. A period of 3–6 months of remission before conception is required to reduce the risk of disease flare during pregnancy as recommended by many international societies.[91819] Counseling patients about adherence to medication, objective disease control, smoking cessation, and up-to-date vaccinations is recommended before planning to conceive.[4445] A recent meta-analysis identified a significantly higher risk ratio of active disease during pregnancy in patients with UC and CD who conceive while the disease is active compared with those in remission at conception (risk ratio: 2.0, P < 0.001 for UC; risk ratio: 2.0; P < 0.006 for CD).[46] Adherence to therapy lowers the risk of a low-birth-weight infant.[47] All efforts should be made to achieve ideal weights and optimize nutritional status with iron and folic acid supplementation during the prenatal period.

Outcome of IBD in pregnancy and vice versa

Statement 4: Women with IBD can consider becoming pregnant when the disease is in clinical, biochemical, and preferably in endoscopic remission to avoid unfavorable outcomes.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Approximately 80% of pregnancies in females with IBD have favorable outcomes with no complications.[48495051] However, active IBD is thought to complicate 30%–35% of pregnancies with a higher rate of preterm births and low birth weights for gestational age.[52] Population studies identified an increased risk of stillbirths in women with active IBD during pregnancy in the absence of an increased risk of congenital malformations.[53] The risk of disease relapse was higher in those with UC compared with CD (48.1% vs 31.8%; P = 0.005).[54] Active perineal disease is also associated with an increased risk of perianal damage. Patients with IPAA reported a 20%–30% risk of pouch dysfunction during pregnancy.[555657585960] IBD patients in remission show no greater risk of flare during pregnancy.[616263]

Monitoring of IBD in pregnancy

Statement 5: Fecal calprotectin can be used to monitor disease activity throughout pregnancy. In contrast, C-reactive protein (CRP) is affected by pregnancy and may not be reliable.

Quality of evidence: Moderate.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed)

IBD patients show laboratory evidence of inflammation; however, anemia, elevated erythrocyte sedimentation rate (ESR), and serum CRP are also common during pregnancy.[20273234] Pregnancy can alter the levels of hemoglobin, albumin, and CRP, which correlate with clinical disease activity, making their use as biomarkers unreliable.[64656667] Fecal calprotectin correlated well with active disease throughout pregnancy in prospective studies unaffected by the pregnancy; thus, it can be used for effective disease monitoring.[6667]

Statement 6: For evaluation of IBD disease activity during pregnancy, we recommend magnetic resonance imaging (MRI) without gadolinium or bowel ultrasound to minimize radiation exposure. If required, endoscopy can also be performed, ideally during the second trimester.

Quality of evidence: Moderate.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

The main advantage of MRI is the ability to image deep soft tissue structures.[18] MRI does not use ionizing radiation, making it ideal for the evaluation of pregnant patients with IBD. Gadolinium is not safe during pregnancy and should only be used after discussions with the patient in select cases.[68697071]

Intestinal ultrasound (IUS) provides an objective tool to assess and monitor disease activity in pregnant patients with IBD.[72] Studies confirmed its accuracy for assessing disease activity compared with fecal calprotectin with high sensitivity and specificity (74% vs 83%, respectively).[7374] Colonic imaging is possible in the third trimester, but the terminal ileum becomes more difficult to be imaged with IUS during this period.[73] Endoscopy is the most definitive modality for the diagnosis and monitoring of IBD activity during pregnancy.[647576] However, endoscopic procedures should be avoided before the second trimester due to potential fetal damage caused by intra-procedural maternal hypotension and hypoxia.[77] If the results of gastroscopy or colonoscopy will have a major impact on the therapeutic plan for the patient, it ought to be done in the second trimester. Consideration should be given to sigmoidoscopy as it can be done without sedation or preparation at any time during gestation.[78]

Medical management of pregnancy in IBD

General therapeutic considerations

Statement 7: We recommend that women with active disease “or” at high risk of disease recurrence continue their medication that is proven to be safe “throughout” pregnancy. Those with inactive disease who choose to cease medication can do so at the beginning of the third trimester.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Women with active IBD before conception have an increased likelihood of premature birth, intrauterine growth restriction, and spontaneous abortion.[48497980818283] It is reasonable to recommend the continuation of medication during pregnancy. Most drugs used in the treatment of IBD, apart from methotrexate, JAK inhibitors, and S1P modulators, are relatively safe with no considerable adverse fetal events or pregnancy outcomes. Moreover, current evidence suggests that the adequate control of disease activity before conception is a key determinant for uncomplicated pregnancy outcomes and the maintenance of disease remission.[788485]

The discontinuation of antitumor necrosis factor (TNF) therapy during pregnancy is recommended to minimize exposure to the fetus if no significant increase in the risk of disease flare exists. However, recent studies have shown that continuing anti-TNF therapy throughout pregnancy was associated with no increase in the risk of complications or neonatal infections. As such, most international societies recommend not to interrupt TNF therapy. Plans to discontinue TNF therapy beyond week 26 should be made on an individual basis.[86]

Medical therapy

5-Aminosalicylic Acid Derivatives (5ASA)

Statement 8: We recommend that pregnant women diagnosed with UC on oral and/or rectal 5-ASA as a maintenance treatment continue to take this therapy during pregnancy. Phthalate-containing 5-ASA formulations should be avoided.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Mesalamine is a medication commonly used to treat patients with UC. When it comes to the safety of mesalamine during pregnancy, the available evidence suggests that it is generally considered safe for use. Several studies and extensive clinical experience have not found an increased risk of birth defects or adverse pregnancy outcomes associated with mesalamine use.[1377] The majority of studies that have evaluated the safety of mesalamine in pregnancy have not shown an increased risk of major malformations, spontaneous abortions, preterm birth, or low birth weight.[8788] Active disease flare-ups during pregnancy have been associated with complications, such as low birth weight, preterm birth, and maternal complications. Therefore, the potential benefits of maintaining disease remission with mesalamine often outweigh the potential risks. In pregnant patients with distal colitis, topical 5-ASA at the time of conception and its maintenance during pregnancy are safe and effective for the management of colitis.[89] Pregnant females with IBD-administered mesalamine microgranules (1–4 g/d) showed no adverse fetal outcomes or complications during pregnancy.[90] Dibutyl phthalate and 5-ASA negatively impacted the fetal skeletal system in animal models (enteric-coated mesalamine with dibutyl phthalate).[91] These drugs should be switched to other preparations during pregnancy.

Statement 9: We recommend that pregnant women with UC suffering from mild-to-moderate flares on 5-ASA maintenance therapy modify their combination of oral and rectal 5-ASA medication to achieve symptomatic remission.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

A combination of oral and rectal 5-ASA is recommended to achieve symptomatic remission for pregnant patients suffering from mild-to-moderate flares on 5-ASA maintenance therapy. Data have shown that higher doses of 5-ASA (≥2 g/day) are more efficacious than low doses (<2 g/day) during the disease flare (relative risk [RR] 0.91; 95% confidence interval [CI], 0.85-0.98). Dose escalation may be beneficial for nonresponders.[20]

Immunosuppressants

Thiopurines

Statement 10: We recommend that pregnant women diagnosed with IBD on a thiopurine as a maintenance treatment continue to take this therapy during pregnancy.

Quality of evidence: Moderate.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Azathioprine (AZA) is relatively safe during pregnancy.[9293] No significant congenital anomalies, failure of conception, abortions, infections, or neoplasms were found in pregnant ladies exposed to 6-mercaptopurine in comparison with control groups (RR = 0.85, CI: 0.47–1.55, P = 0.59).[94]

During pregnancy, the active metabolite 6-thioguanine (6-TG) crosses the placenta, but prodrugs AZA and 6-MP do not.[4895] Recent studies suggest no increased risk of adverse pregnancy outcomes in those administered thiopurine during pregnancy.[9697] Flanagan and his colleague reported that up to 12.5% of pregnant women with IBD on AZA had elevated 6-MMP concentrations and that was associated with increased risk of hepatotoxicity; furthermore, 9.5% of the study population developed intrahepatic cholestasis of pregnancy. Thus, the authors recommended close monitoring of thiopurine metabolites during pregnancy, in particular during the second trimester.[98] However, most societies and experts still recommend AZA as a maintenance therapy during pregnancy.[489599100101102103] This being said, we recommend against initiating these agents during pregnancy due to the potential of serious adverse events, such as pancreatitis and severe leukopenia.[18]

Methotrexate

Statement 11: We recommend that females with IBD planning to get pregnant discontinue methotrexate at least 3 months before pregnancy and until breastfeeding is stopped to avoid detrimental effects on the infant.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Methotrexate is contraindicated in pregnancy as it is an abortifacient with teratogenic effects, including craniofacial abnormalities, and limb and central nervous system (CNS) defects, including anencephaly, hydrocephaly, and meningomyelopathy, particularly following exposure during the first trimester.[104] As its active metabolites have a long half-life, methotrexate must be discontinued at least 3 months before conception.

Biologics

Statement 12: We recommend that women with active disease or who are at high risk of disease recurrence continue anti-TNF therapy throughout pregnancy.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Statement 13: We recommend that women with the disease in remission continue anti-TNF during pregnancy. In the presence of long-term remission and a desire to stop anti-TNF during pregnancy, it can be stopped before the third trimester.

Quality of evidence: Moderate.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Anti-TNF medication

TNF inhibitors are the most widely prescribed drugs for the treatment of IBD during pregnancy.[95105106107108109110111] Infliximab, golimumab, and adalimumab can cross the placenta during the third trimester.[106112113114] Higher levels of both biologics have been detected in infants and cord blood compared with their respective maternal levels. However, longitudinal studies that followed children exposed to anti-TNF therapy during pregnancy observed no differences in the overall rate of infections, milestone developments, or other negative outcomes.[115]

A recent systematic review and meta-analysis showed that anti-TNF therapy does not increase the risk of unfavorable pregnancy outcomes among women with IBD.[116] In four women who continued infliximab during pregnancy (weeks 21 to 30), therapeutic levels in cord blood ranged from 5.5 to 13.7 μg/mL, which was two- to threefold higher than the maternal blood levels.[117118] No negative pregnancy outcomes, infections, or signs of allergy were observed. The long-term effects of in utero exposure to anti-TNF therapies have not been extensively investigated. Normal health outcomes and development during the first year in children exposed to anti-TNF were recently reported.[9899100101102] In a study of 493 children and adolescents exposed to anti-TNF in utero in Denmark, the adjusted HR for infections ranged from 1.34 to 2.36 and did not differ from 728,055 non-exposed controls.[119] Similarly, the European multicenter The Environmental Determinants of Diabetes in the Young (TEDDY) study showed no significant differences in severe infections in children exposed (n = 388) or non-exposed (n = 503) to anti-TNF agents during pregnancy, when followed up for 68 months.[120]

Statement 14: We recommend that pregnant women with IBD who are controlled on vedolizumab and ustekinumab discuss the continuation of treatment with their prescriber gastroenterologist individually.

Quality of evidence: Moderate.

Strength of recommendation: (92% of the panel strongly agreed).

Anti-adhesion molecules

Vedolizumab

A systematic review highlighted possible concerns over the safety of vedolizumab during pregnancy. An increase in premature births and early loss was reported.[121] Vedolizumab at supraphysiological levels had no negative impact on prenatal or postnatal development in animal studies[122] or small clinical cohorts.[123] In the recently published Pregnancy Inflammatory Bowel Disease and Neonatal Outcomes (PIANO) registry data, 41 pregnant women exposed to vedolizumab showed no increase in complications, congenital malformations, or neonatal infections.[121122124125126127] The Groupe d’Étude Thérapeutique des Affections Inflammatoires du Tube Digestif (GETAID) group also reported 44 pregnancies in patients receiving vedolizumab without negative effects on maternal or neonatal outcomes. In contrast, an increased risk of early pregnancy loss and preterm birth in vedolizumab users compared with anti-TNF therapy was observed in two recent meta-analyses.[83128129] While no differences in stillbirths between vedolizumab and anti-TNF were observed, the occurrence of low birth weights and congenital malformations did differ.[83123126127128129] These findings may be confounded by disease activity. Further prospective cohort studies of vedolizumab and pregnancy outcomes are required before affirmative recommendations.

Anti-cytokines

Ustekinumab

Ustekinumab exposure has no negative impact on fetal or postnatal development in animal studies. Ustekinumab is, however, associated with early pregnancy loss and congenital malformations in trials with small patient numbers.[83126128] In the PIANO study, 18 pregnant women exposed to ustekinumab showed no increase in pregnancy complications, congenital malformations, or neonatal infections.[96] In a retrospective cohort of 29 pregnancies on Ustekinumab, no patients showed adverse maternal or neonatal outcomes.[128] A recently published prospective multicenter study of 54 ustekinumab-exposed pregnancies reported congenital anomalies consistent with those occurring within the general population.[129] The summary of these data is that ustekinumab shows no negative effects on pregnancy outcomes, but risks and advantages should be carefully assessed on a patient-by-patient basis before recommendations on therapy.

Statement 15: We recommend that women with IBD cease tofacitinib, upadacitinib, etrasimod, and ozanimod before attempting pregnancy until further confirmatory evidence of safety is available.

Quality of evidence: Moderate

Strength of recommendation: (85% of the panel strongly agreed).

Small molecules

Janis Kinase Inhibitors

Tofacitinib

Tofacitinib was the first oral small-molecule Janus kinase (JAK) inhibitor licensed and approved for use in moderate-to-severe UC after failure or intolerance to biologic therapy.[130] Tofacitinib is a small molecule and is assumed to cross the placenta,[126131] as shown in animal models where it was feticidal and teratogenic, although at exposures exceeding standard human doses.[126] Tofacitinib was also present in rat milk. Upon assessment of the maternal exposure to tofacitinib in five UC interventional studies, pregnancy and newborn outcomes were unaffected.[130] Reported outcomes of pregnancy from tofacitinib randomized controlled clinical trials (RCTs) and non-interventional studies were also comparable to those of the general population.[126130132133134] Despite these data, the use of tofacitinib during pregnancy should be limited to situations in which the benefits to the mother outweigh the risks to the mother and child. The use of contraception is also advised for 4–6 weeks following tofacitinib use, as its suppressive effects on natural killer cells can last up to 6 weeks.[126131135136137]

Upadacitinib

Upadacitinib is recommended for the treatment of moderate-to-severely active UC and CD in adults. Upadacitinib is not recommended during pregnancy.[138139] In animal studies, upadacitinib caused severe fetal malformations during early pregnancy. Its use is therefore prohibited in pregnant UC patients.[140141142143]

Sphingosine-1-Phosphate Receptor Modulator (S1P1) Inhibitors

Ozanimod

Ozanimod is a S1P1-5 agonist that is Food and Drug Administration (FDA) approved for moderate-to-severe UC in the USA and Europe.[144] While data regarding the safety of ozanimod during pregnancy are sparse, its use in pregnant mothers with UC and CD has been documented.[145] Within these studies, the incidence of spontaneous abortions and preterm births in pregnant women was comparable to the general population.[146] No teratogenicity was observed. The paucity of available data, however, fails to advocate its use during pregnancy according to the recent ECCO guideline.[9]

Management during acute flares

Statement 16: We recommend the use of systemic corticosteroids, anti-TNF therapy, ustekinumab, or vedolizumab to achieve symptomatic remission in pregnant women diagnosed with IBD during pregnancy or who experience a disease flare while on optimal conventional therapy.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

General guidelines support the use of systemic corticosteroids or anti-TNF therapy in pregnant women.[147] Both can be used to achieve symptomatic remission in those with IBD or who experience a disease flare while on 5-ASA or thiopurine maintenance therapy.[148] Data regarding the safety of biological drugs in pregnancy have mostly been performed with infliximab and adalimumab and to a lesser extent on ustekinumab or vedolizumab. Their use in the third trimester results in fetal exposure and concentrations that can exceed maternal levels at birth. No negative impact on pregnancy or newborn outcomes has been documented.[20107149150] During pregnancy, corticosteroids cross the placenta, but short-acting steroids, such as prednisone and prednisolone, are rapidly metabolized by placental 11-hydroxylase and inactivated.[151] This leads to fetal exposures of ~ 10% of the maternal dose, likely explaining their low impact on pregnancy outcomes.

Peripartum

Venous thromboembolism (VTE)

Statement 17: Prevention of VTE is critical for hospitalized patients, particularly following a C-section or if the patient is unwell.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (92% of the panel strongly agreed).

The risk of VTE in pregnant IBD patients is twofold higher than during postpartum.[152153] A meta-analysis confirmed that IBD flares during pregnancy were associated with an increased risk of VTE (RR: 2.64, 95% CI: 1.69–4.14).[154] VTE prophylaxis is now mandatory following a cesarean section (CS) and for pregnant patients with reduced mobility.[155156] Fondaparinux is the most widely used anticoagulant anti-VTE agent.[157158]

Multidisciplinary approaches

Statement 18: Engaging multidisciplinary teams and patients in the decision-making process during pregnancy is recommended and should include an obstetrician with relevant experience.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

A multidisciplinary team provides the optimal approach for the individualized management of pregnant patients diagnosed with IBD. During pregnancy, an experienced obstetrician should monitor the well-being of the mother and fetus and advise on the appropriate mode of delivery.[159]

Mode of delivery

Statement 19: Excluding active perianal disease or ileoanal pouch (where a CS is usually favored), the delivery mode must be determined according to patient preference and obstetric factors.

Quality of evidence: Moderate.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

CS deliveries are recommended in situations where a maternal indication to avoid vaginal delivery exists, such as in patients with perianal disease and ileoanal anastomosis.[160161162163] In all other cases, the mode of delivery is dictated by obstetrical factors, such as acute fetal distress, fetal dystocia, and placental abnormalities.[164] The recommendation for CS is based on a systematic review of 18 articles comparing the complication rates of patients undergoing vaginal or CS delivery.[165] At least half of the CS deliveries in these patients are unplanned.[166] The decision for CS is complex and should involve IBD-related and obstetric factors made by a gastroenterologist and obstetrician.

Postpartum management

Statement 20: We recommend that biologics can be resumed 24 h after vaginal delivery and 48 h after CS if no evidence of infection exists and dosing intervals are appropriate.

Quality of evidence: Strong.

Strength of recommendation: (100% of the panel strongly agreed).

Analgesics can be used during the postpartum period for pregnant IBD patients.[167168] These include short courses of nonsteroidal anti-inflammatory drugs (NSAIDs) and select opioids with the avoidance of tramadol and codeine.[169170171] As opioids cause constipation, concurrent treatment with osmotic agents to maintain physiological stool consistency should be considered.[66] Excluding methotrexate, tofacitinib, upadacitinib, and ozanimod, IBD medications can be resumed during the postpartum period. Biologics can be resumed within 24–48 hours if no infections and when dosing intervals are appropriate.[1517126171172173174] The postpartum dose of biologics should be calculated based on the preconception weight of the mother.[175176177178]

In pregnant IBD patients, early feeding and supportive measures are required to minimize post-CS ileus. It is considered a major factor influencing the length of hospital stay.[165] Stoma-related concerns, such as displacement, enlargement, retraction, stenosis, and prolapse, can occur during pregnancy due to stretching of the abdominal wall.[179] Coordination between the patient, stoma nurse, and colorectal surgery team is key for the postpartum care of mothers with stoma. Other general aspects, such as a balanced diet, hydration, weight maintenance, and discussion of contraceptive options, are encouraged, before discharging patients.[21174180181]

Infant vaccinations

Statement 21: For infants exposed to biologics in utero, we recommend delaying Bacillus Calmette–Guérin (BCG) immunization and avoidance of the rotavirus vaccine until at least 6 months after birth. Non-live vaccines can be administered in accordance with conventional immunization protocols.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Patients with IBD should not be vaccinated at the same rate as healthy patients. The use of inactivated vaccines for the immunization of newborns exposed to anti-TNF therapies, vedolizumab, and ustekinumab in utero is supported. Studies assessing the safety of live-attenuated vaccines administered to infants exposed to biologics in utero are scanty. A recently published review suggested that live vaccines should be administered after 6 months of age for infants exposed in utero to anti-TNF, vedolizumab, and ustekinumab.[182]

Although no severe complications have been reported with the rotavirus live vaccination, a fatal disseminated tuberculosis infection following administration of the BCG live vaccine in infants exposed to anti-TNFs in utero was reported. Therefore, both vaccines should be deferred until at least 6 months of age.[183] The BCG vaccine was recently deferred to 6 months of age as per the new vaccination guidelines by the Saudi MOH.[184]

Breastfeeding

Statement 22: We recommend breastfeeding as a primary source of nutrition for infants of mothers with IBD.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

Statement 23: We recommend continuing the use of safe medications throughout breastfeeding.

Quality of evidence: High.

Strength of recommendation: Strongly recommended (100% of the panel strongly agreed).

The benefits of natural breastfeeding should be discussed with parents and encouraged.[185186] Breastfed infants of mothers receiving biologics, immunosuppressants, or combination therapy show similar risks of infection and milestone achievements at 12 months when compared to non-breastfed infants.[187188189190] Only low levels of infliximab, adalimumab, certolizumab, natalizumab, and ustekinumab can be detected in breast milk.[108169]

Although a risk of adverse effects exists, 5-ASA derivatives, thiopurines, and anti-TNF agents can be used for the treatment of IBD during pregnancy and breastfeeding.[108147169182185186187188189190] The administration of these agents to the mother should be supported by an experienced obstetrician. The consensus recommendation regarding the IBD medications during pregnancy and breastfeeding are summarized in Table 2.

Table 2 Recommendations for IBD therapy during pregnancy and breastfeeding

Medication	During pregnancy	During breastfeeding	
Aminosalicylates	Low risk (continue)	Low risk (continue)	
Azathioprine	Low risk (continue)	Low risk (continue)	
Methotrexate	Avoid	Avoid	
Anti-TNF: infliximab, adalimumab, golimumab, certolizumab	Low risk (continue)	Low risk (continue)	
Vedolizumab	Assumed low risk (consider continue or individualize)	Low risk (continue)	
Ustekinumab	Assumed low risk (consider continue or individualize)	Low risk (continue)	
Tofacitinib	Avoid	Avoid	
Upadacitinib	Avoid	Avoid	
Ozanimod	Avoid	Avoid	
Etrasimod	Avoid	Avoid	

Clinical care pathway

The working group proposes the following clinical care pathway to guide clinicians and care providers in the management of pregnant women with IBD [Figure 1].

Figure 1 Clinical care pathway for women with IBD planning pregnancy

DISCUSSION

When IBD is active at the time of conception, the risk of miscarriage, preterm birth, and low birth weight increases.[191192] IBD patients who plan to become, or who are pregnant, should be adequately treated and advised.[135561106193] In this study, we describe a series of guidelines designed to improve the management of IBD in pregnant women in Saudi Arabia. A series of consensus statements were developed by the MOH in collaboration with the SGA and SCCP following a detailed evaluation of the responses and remission rates of pregnant IBD sufferers using real-world data.[17667788171172187194195196197198] Guidelines were adapted from the ECCO, ACG, AGA, and BSG and agreed upon using a voting process. In total, 23 evidence-based and expert opinion-based consensus recommendations for the diagnosis, treatment, and management of IBD in pregnant women are provided. These have been designed to maximize safety for both the mother and fetus.

Fertility rates in women with IBD in remission are equivalent to those of the general population.[199] However, women with active IBD or with prior surgery have decreased fertility and this must be discussed and managed. The genetic risk of IBD is high in the offspring of parents with IBD, and it is significantly increased if both parents are affected.[18200201202] In our guidelines, we recommend that risks to offspring should be discussed with parents before conception. We recommend that women with IBD during childbearing periods should receive preconception counseling aimed to optimize disease control and improve pregnancy outcomes.[55185203] While most pregnancies in IBD patients have favorable outcomes, adverse events can occur in pregnant women with active disease. Fecal calprotectin can be used to monitor disease activity throughout pregnancy, but CRP is affected by pregnancy and may not be reliable.[6667204205] We recommend an MRI or bowel ultrasound for disease assessment as required during pregnancy as a method of minimizing radiation exposure. Endoscopy can also be performed, ideally during the second trimester.[7677206] We recommend that women with active disease at high risk of recurrence continue their medication during pregnancy. In contrast, those with inactive disease, who choose to cease medication, should do so at the beginning of the third trimester. Throughout pregnancy, we recommend the use of phthalate-free 5-ASA, thiopurines, and anti-TNF to maintain remission.[95101169207208209] We advise that corticosteroids should be reserved for the treatment of flares.[93210] We recommend that pregnant women diagnosed with IBD on oral and/or rectal 5-ASA as a maintenance treatment continue this therapy during pregnancy.[137788] Phthalate-containing 5-ASA formulations should be avoided. We recommend that pregnant women diagnosed with IBD on thiopurine as a maintenance treatment continue to take this therapy during pregnancy.[4895969899211212213214215] Pregnant women with UC suffering from mild-to-moderate flares while on 5-ASA maintenance therapy must modify oral and rectal 5-ASA medications to achieve symptomatic remission.

We recommend the cessation of methotrexate at least 3 months before pregnancy and until breastfeeding is stopped to avoid detrimental effects on the infant. Women with active disease at high risk of disease recurrence should continue anti-TNF therapy during pregnancy. Those with inactive disease who choose to cease medication, should do so at the beginning of the third trimester. We recommend that pregnant women with IBD controlled on vedolizumab and ustekinumab should hold discussions with their prescriber gastroenterologist on a case-by-case basis to decide on the continuation of therapy.[78104117119120122] We recommend that women with IBD cease JAK inhibitors 4–6 weeks before attempting pregnancy and avoid their use until further confirmatory evidence of their safety becomes available.[126] We further recommend the use of systemic corticosteroids or anti-TNF therapy to achieve symptomatic remission in pregnant women diagnosed with IBD or who experience a disease flare while on optimal 5-ASA or thiopurine maintenance therapy.

The prevention of VTE is critical for hospitalized patients, particularly following CS or when patients are unwell. Engaging multidisciplinary teams and patients in the decision-making process during pregnancy is recommended and should include an obstetrician with relevant experience. Excluding active perianal disease and ileocecal anastomosis or ileoanal pouch (where CS is usually favored), the delivery mode must be determined according to patient preference and obstetric factors.[164165] We recommend that biologics are resumed 24 h after vaginal delivery and 48 h after CS if no infections are evident and dosing intervals are appropriate. For infants exposed to biologics in utero, the BCG immunization and other live vaccines should be delayed until at least 6 months after birth and after the avoidance of the rotavirus vaccine.[182216] Non-live vaccines should be administered. We advocate breastfeeding as a source of nutrition for the infants of mothers with IBD, which should be combined with conventional immunization protocols.[18108169182185186187188189217]

CONCLUSIONS

The current consensus statements were developed after an extensive review of available data. It aimed to help clinicians caring for pregnant women with IBD in daily practice. The 23 statements and the care pathway cover aspects related to disease monitoring and management of pregnant IBD patients in Saudi Arabia. Multidisciplinary team (MDT) management is critical to maximize the likelihood of successful delivery and healthy offspring.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
==== Refs
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