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Meyer A, Miranda S, Drouin J, Weill A, Carbonnel F, Dray-Spira R. Safety of Vedolizumab and Ustekinumab Compared With Anti-TNF in Pregnant Women With Inflammatory Bowel Disease. Clin Gastroenterol Hepatol 2025; 23:144-153.e22. [PMID: 38199301 DOI: 10.1016/j.cgh.2023.12.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/20/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024]
Abstract
BACKGROUND & AIMS Limited data are available on the consequences of prenatal exposure to vedolizumab and ustekinumab. We aimed to compare the safety of vedolizumab and ustekinumab with that of anti-tumor necrosis factor (TNF) in pregnant women with inflammatory bowel diseases (IBD). METHODS Using nationwide, comprehensive data of the EPI-MERES registry, we identified pregnancies in women with IBD in France, exposed to anti-TNF, vedolizumab, and ustekinumab between 2014 and 2021. We compared pregnancy outcomes and complications in the offspring according to treatment exposure during pregnancy. We applied a propensity score matching for maternal, IBD, and pregnancy characteristics. RESULTS Three hundred ninety-eight pregnancies exposed to vedolizumab were compared with 1592 pregnancies exposed to anti-TNF; 464 pregnancies exposed to ustekinumab were compared with 1856 pregnancies exposed to anti-TNF. Overall, compared with anti-TNF, neither vedolizumab nor ustekinumab was associated with increased risks of abortion, caesarean section, stillbirth, preterm birth, serious infections, malignancies, or congenital abnormality in children. Women exposed to ustekinumab had an increased risk of small for gestational age births. CONCLUSIONS Overall, the safety of vedolizumab and ustekinumab compared with anti-TNF use during pregnancy is reassuring. Further studies are needed to confirm these findings.
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Affiliation(s)
- Antoine Meyer
- EPI-PHARE, Épidémiologie des produits de santé, Saint-Denis, France; Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre & Université Paris-Saclay, Le Kremlin Bicêtre, France.
| | - Sara Miranda
- EPI-PHARE, Épidémiologie des produits de santé, Saint-Denis, France
| | - Jérôme Drouin
- EPI-PHARE, Épidémiologie des produits de santé, Saint-Denis, France
| | - Alain Weill
- EPI-PHARE, Épidémiologie des produits de santé, Saint-Denis, France
| | - Franck Carbonnel
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre & Université Paris-Saclay, Le Kremlin Bicêtre, France
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Chetwood JD, Gupta S, Subramaniam K, De Cruz P, Moore G, An YK, Connor SJ, Kermeen M, Paramsothy S, Leong RW. Ustekinumab as induction and maintenance therapy for ulcerative colitis - national extended follow-up and a review of the literature. Expert Opin Drug Saf 2024; 23:449-456. [PMID: 37909484 DOI: 10.1080/14740338.2023.2278686] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 09/15/2023] [Indexed: 11/03/2023]
Abstract
INTRODUCTION Ustekinumab use in ulcerative colitis had shown low adverse event and high persistence rates to 3 years via the UNIFI long-term extension study. Outcomes beyond 3 years have not been previously described. We describe the safety signals of the entire UNIFI Australian population beyond 3 years. METHODS This retrospective multicenter observational cohort study recruited from all Australian UNIFI centers. The primary outcome was safety via adverse events. Secondary outcomes included the clinical relapse rate on ustekinumab, and the need to switch from ustekinumab to an alternate agent. RESULTS There were 14 patients [11 male, mean age 47 (±14) years], with a median diagnosis of 10.8 (±4.5) years prior to UNIFI enrollment. Median follow-up was 298 weeks (5.7 years) (Interquartile range (IQR): 220-311 weeks). Within the long-term extension, there were three serious adverse events and one minor event. 42.9% (6/14) patients had clinical relapses, of which clinical remission was recaptured in 83.3% (5/6). 85.7% (12/14) persisted on ustekinumab in the long-term, with 7.1% (1/14) electively ceasing ustekinumab and 7.1% (1/14) changed from ustekinumab due to clinical relapse. CONCLUSION For moderate-to-severe UC in Australia, ustekinumab maintained efficacy beyond 3 years with a high persistence rate and no new safety signals. TRIAL REGISTRATION The trial is registered at ANZCTR (identifier: ACTRN12622001332718).
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Affiliation(s)
- J D Chetwood
- Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney, Australia
- Concord Clinical School, University of Sydney, Sydney, Australia
| | - S Gupta
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - K Subramaniam
- Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia
- ANU Medical School, Australian National University, Canberra, Australian Capital Territory, Australia
| | - P De Cruz
- Department of Gastroenterology, Austin Hospital, Melbourne, VIC, Australia
| | - G Moore
- Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia
- School of Clinical Sciences, Monash University, Clayton, VIC, Australia
| | - Y K An
- Department of Gastroenterology, Mater Hospital, Brisbane, QLD, Australia
| | - S J Connor
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, NSW, Australia
| | - M Kermeen
- Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney, Australia
| | - S Paramsothy
- Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney, Australia
- Concord Clinical School, University of Sydney, Sydney, Australia
- Department of Gastroenterology, Macquarie University Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - R W Leong
- Department of Gastroenterology and Liver Services, Concord Repatriation General Hospital, Sydney, Australia
- Concord Clinical School, University of Sydney, Sydney, Australia
- Department of Gastroenterology, Macquarie University Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
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3
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Keating NE, Walker CJ, Lally DA, O’Brien CM, Corcoran SM, Ryan BM, Harewood GC, McAuliffe FM. Elevated cord levels of ustekinumab following its use in the treatment of Crohn's disease in pregnancy. Obstet Med 2024; 17:47-49. [PMID: 38660328 PMCID: PMC11037200 DOI: 10.1177/1753495x221135201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/05/2022] [Accepted: 10/08/2022] [Indexed: 04/26/2024] Open
Abstract
Ustekinumab (USK) was used in the treatment of two pregnant patients with Crohn's disease. It was given in the third trimester and restarted postnatally for both women. One woman remained on USK and in remission throughout pregnancy. The second woman, took a treatment break, flared, and then had remission induced with reintroduction of USK. Both women delivered healthy term infants. The interval from last dose to birth was 11 and 8 weeks respectively. Interestingly, USK levels in cord blood was observed in higher concentrations than in the maternal serum taken in third trimester. While no adverse effect in infants has been observed, clinicians should remain aware of fetal transfer when using USK in pregnancy. An evaluation of risk and benefit may favour continuing USK in pregnancy in patients with refractory disease.
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Affiliation(s)
- Niamh E Keating
- UCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin, Ireland
| | - Caroline J Walker
- Department of Gastroenterology, Tallaght University Hospital, Dublin, Ireland
| | - Damian A Lally
- Department of Laboratory Medicine, National Maternity Hospital, Dublin, Ireland
| | - Celine M O’Brien
- Department of Midwifery, National Maternity Hospital, Dublin, Ireland
| | - Siobhan M Corcoran
- UCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin, Ireland
| | - Barbara M Ryan
- Department of Gastroenterology, Tallaght University Hospital, Dublin, Ireland
| | - Gavin C Harewood
- Department of Gastroenterology, Beaumont Hospital, Dublin, Ireland
| | - Fionnuala M McAuliffe
- UCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin, Ireland
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4
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Zhang W, Zhong G, Ren X, Li M. Research progress of Ustekinumab in the treatment of inflammatory bowel disease. Front Immunol 2024; 15:1322054. [PMID: 38455044 PMCID: PMC10917885 DOI: 10.3389/fimmu.2024.1322054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 02/05/2024] [Indexed: 03/09/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic, recurrent gastrointestinal disorder with elusive etiology. Interleukin-12 (IL-12) and IL-23 have emerged as key proinflammatory mediators/cytokines in IBD pathogenesis. Ustekinumab (UST), targeting IL-12 and IL-23, has demonstrated promising efficacy and safety in the treatment of IBD. Recently, UST has become increasingly favored as a potential first-line treatment option. This review delineates UST's mechanism of action, its clinical applications in IBD, including the response rates, strategies for dose optimization for case of partial or lost response, and potential adverse events. This review aims to offer a comprehensive understanding of UST's role as a therapeutic option in IBD management.
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Affiliation(s)
| | | | - Xingxing Ren
- Inflammatory Bowel Disease Research Center, Department of Gastroenterology, Guangdong Province Key Laboratory of Major Obstetric Disease, Province Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Mingsong Li
- Inflammatory Bowel Disease Research Center, Department of Gastroenterology, Guangdong Province Key Laboratory of Major Obstetric Disease, Province Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
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5
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Wickenheisser NE, Craig AM, Kuller JA, Dotters-Katz SK. The Risks and Benefits of Monoclonal Antibody Therapy During Pregnancy and Postpartum: Maternal, Obstetric, and Neonatal Considerations. Obstet Gynecol Surv 2023; 78:429-437. [PMID: 37480293 DOI: 10.1097/ogx.0000000000001155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/24/2023]
Abstract
Importance Autoimmune and rheumatologic conditions can lead to multiple adverse maternal, obstetric, and neonatal outcomes, especially if they flare during pregnancy. Although many medications to control these conditions exist, concerns regarding their safety often unnecessarily limit their use. Objective We aim to review the current evidence available describing the use of monoclonal antibody (mAb) therapeutics in pregnancy and postpartum and understand the impact of their use on the developing fetus and neonate. Evidence Acquisition Original research articles, review articles, case series and case reports, and pregnancy guidelines were reviewed. Results Multiple retrospective (including 1924 patients) and prospective studies (including 899 patients) of anti-tumor necrosis factor (TNF) agent use in pregnancy found no significant increase in rates of miscarriage, preterm birth, or congenital anomalies compared with controls. Most societies, including American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine, recommend initiation or continuation of TNF-α inhibitors during pregnancy for patients with autoimmune diseases. An increased risk of mild infections in newborns has been reported, although infections requiring hospitalizations are rare. Data suggest that breastfeeding while taking anti-TNF agents is safe for neonates. Less data exist for the use of other mAbs including anticytokine, anti-integrin, and anti-B-cell agents during pregnancy and postpartum. Conclusions and Relevance Current evidence suggests that the use of mAbs, particularly anti-TNF agents, is safe in pregnancy and postpartum, without significant adverse effects on the pregnant patient or infant. The benefits of ongoing disease control in pregnant patients result in favorable maternal and neonatal outcomes.
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Affiliation(s)
| | | | | | - Sarah K Dotters-Katz
- Associate Professor of Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC
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Grigorescu RR, Husar-Sburlan IA, Rosulescu G, Bobirca A, Cerban R, Bobirca F, Florescu MM. Pregnancy in Patients with Inflammatory Bowel Diseases-A Literature Review. Life (Basel) 2023; 13:475. [PMID: 36836832 PMCID: PMC9961380 DOI: 10.3390/life13020475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 02/03/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023] Open
Abstract
In recent years, we have faced an increasing incidence of inflammatory bowel disease (IBD), especially among young people, affecting them during their reproductive years. The paucity of data and reduced knowledge regarding the evolution of the disease during pregnancy and the adverse effects of the therapy on the mother and infant increase voluntary childlessness in this group of patients. Depending on the type of IBD, severity and surgical or medical management, this can negatively affect the pregnancy. C-sections and the risk of low-birth-weight babies are higher in women with IBD, independent of active/inactive disease, while preterm birth, stillbirth and miscarriage are associated with disease activity. In the last period, medicinal therapy has evolved, and new molecules have been developed for better control of the lesions, but the effect on pregnancy and breastfeeding is still controversial. We conducted this review by studying the literature and recent research in order to have a better image of the practical management of IBD during pregnancy.
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Affiliation(s)
| | | | - Georgiana Rosulescu
- Gastroenterology Department, “Sfanta Maria” Hospital, 011172 Bucharest, Romania
| | - Anca Bobirca
- Department of Internal Medicine and Rheumatology, Dr. I. Cantacuzino Clinical Hospital, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Razvan Cerban
- Center for Digestive Disease and Liver Transplantation, Fundeni Clinical Institute, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Florin Bobirca
- Surgery Department, Dr. Ion Cantacuzino Clinical Hospital, 011437 Bucharest, Romania
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Torres J, Chaparro M, Julsgaard M, Katsanos K, Zelinkova Z, Agrawal M, Ardizzone S, Campmans-Kuijpers M, Dragoni G, Ferrante M, Fiorino G, Flanagan E, Gomes CF, Hart A, Hedin CR, Juillerat P, Mulders A, Myrelid P, O'Toole A, Rivière P, Scharl M, Selinger CP, Sonnenberg E, Toruner M, Wieringa J, Van der Woude CJ. European Crohn's and Colitis Guidelines on Sexuality, Fertility, Pregnancy, and Lactation. J Crohns Colitis 2023; 17:1-27. [PMID: 36005814 DOI: 10.1093/ecco-jcc/jjac115] [Citation(s) in RCA: 111] [Impact Index Per Article: 55.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Indexed: 02/02/2023]
Affiliation(s)
- Joana Torres
- Division of Gastroenterology, Hospital Beatriz Ângelo, Loures, Portugal
- Division of Gastroenterology, Hospital da Luz, Lisboa, Portugal
- Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - María Chaparro
- Department of Gastroenterology, Hospital Universitario de La Princesa, IIS-Princesa, UAM, CIBEREHD, Madrid, Spain
| | - Mette Julsgaard
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Center for Molecular Prediction of Inflammatory Bowel Disease [PREDICT], Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Zuzana Zelinkova
- Department of Internal Medicine, Svet zdravia, Nemocnica Dunajska Streda, Slovakia
- Firstst Department of Internal Medicine of University Hospital and Slovak Medical University in Bratislava, Bratislava, Slovakia
| | - Manasi Agrawal
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Molecular Prediction of Inflammatory Bowel Disease [PREDICT], Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Sandro Ardizzone
- Gastrointestinal Unit, Department of Biomedical and Clinical Sciences. University of Milan, Milan, Italy
| | - Marjo Campmans-Kuijpers
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Florence, Florence, Italy
- Gastroenterology Department, Careggi University Hospital, Florence, Italy
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
- Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium
| | - Gionata Fiorino
- Department of Gastroenterology and Digestive Endoscopy, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Emma Flanagan
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Fitzroy, VIC, Australia
| | | | - Ailsa Hart
- Inflammatory Bowel Diseases Unit, St Mark's Hospital, Harrow, UK
| | - Charlotte Rose Hedin
- Karolinska Institutet, Department of Medicine Solna, Stockholm, Sweden
- Karolinska University Hospital, Department of Gastroenterology, Dermatovenereology and Rheumatology, Stockholm, Sweden
| | - Pascal Juillerat
- Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland
- Crohn's and Colitis Center, Gastroenterology Beaulieu SA, Lausanne, Switzerland
| | - Annemarie Mulders
- Department of Obstetrics and Gynaecology, Division of Obstetrics and Fetal Medicine Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands
| | - Pär Myrelid
- Department of Surgery, Linköping University Hospital, Linköping, Sweden
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Aoibhlinn O'Toole
- Beaumont Hospital, Department of Gastroenterology, Royal College of Surgeons, Dublin, Ireland
| | - Pauline Rivière
- Gastroenterology Unit, Bordeaux University Hospital, Pessac, France
| | - Michael Scharl
- Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | | | - Elena Sonnenberg
- Charité-Universitätsmedizin Berlin, Department of Gastroenterology, Infectious Diseases and Rheumatology, Germany
| | - Murat Toruner
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Jantien Wieringa
- Department of Paediatrics, Haaglanden Medical Center, The Hague, The Netherlands
- Department of Paediatrics, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - C Janneke Van der Woude
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Di Cesare A, Ricceri F, Rosi E, Fastame MT, Prignano F. Therapy of PsO in Special Subsets of Patients. Biomedicines 2022; 10:2879. [PMID: 36359399 PMCID: PMC9687729 DOI: 10.3390/biomedicines10112879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/17/2022] [Accepted: 10/27/2022] [Indexed: 01/02/2024] Open
Abstract
Psoriasis is a chronic, inflammatory skin disease that may occur at any age, with a bimodal peak of incidence around the age of 16-20 years of age (early onset) and 57-60 years (late-onset). It is estimated that roughly 70% of patients develop the disease before the age of 40, which coincides with the reproductive years. Moreover, psoriasis is a chronic disease, meaning that, with increased life-duration expectancy, the number of patients affected with psoriasis aged over 65 years is going to increase and represent a big therapeutic challenge. Actually, no specific drug recommendation is available, based only on the age of the patients, while therapeutic prescription should take into account that elderly patients have more comorbidities than younger patients, with polypharmacy and an increased risk of drug interactions. Women with psoriasis are more likely to report a worse influence of the disease on their quality of life, and they are more susceptible to the development of depression. Furthermore, pregnancy and lactation represent a major contraindication to several systemic agents, and only a few studies exist providing the safety of certain drugs during these periods of life of a woman, such as certolizumab pegol. In this paper, we discuss systemic therapeutic strategies, including conventional and biological therapies, in a special subset of patients affected with moderate-to-severe psoriasis focusing on elderly patients and on female patients in fertile age, pregnancy, and lactation.
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Affiliation(s)
| | | | | | | | - Francesca Prignano
- Department of Health Sciences, Section of Dermatology, University of Florence, 50125 Florence, Italy
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9
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Chowdhury R, Kane SV. Pregnancy and Crohn's disease: concerns and assurance of medical therapy. Gastroenterol Rep (Oxf) 2022; 10:goac055. [PMID: 36225722 PMCID: PMC9550230 DOI: 10.1093/gastro/goac055] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 09/19/2022] [Accepted: 09/20/2022] [Indexed: 11/04/2022] Open
Abstract
Approximately 50% of patients with inflammatory bowel disease including both Crohn’s disease and ulcerative colitis are female with many being diagnosed and treated during their reproductive years. It is important for women to be in remission prior to and during pregnancy. There have been many advances in the treatment of inflammatory bowel disease, including new therapies. In this review, we summarize the currently approved medications for Crohn’s disease and their safety in pregnancy and postpartum. The totality of evidence suggests that the majority of therapies are low-risk before and during pregnancy, and should be continued to control maternal disease.
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Affiliation(s)
- Reezwana Chowdhury
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Sunanda V Kane
- Corresponding author. Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, 200 First Street St SW, Rochester, MN 55905, USA; Tel: +1-507-284-0959;
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10
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Mahadevan U, Naureckas S, Tikhonov I, Wang Y, Lin CB, Geldhof A, van der Woude CJ. Pregnancy outcomes following periconceptional or gestational exposure to ustekinumab: Review of cases reported to the manufacturer's global safety database. Aliment Pharmacol Ther 2022; 56:477-490. [PMID: 35560249 DOI: 10.1111/apt.16960] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/17/2022] [Accepted: 04/22/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND Ustekinumab, a human immunoglobulin G1 monoclonal antibody that binds to and inhibits interleukin (IL)-12/IL-23, is indicated for multiple immune-mediated diseases. Ustekinumab is actively transported across the placenta and theoretically could impact pregnancy outcomes. Limited data on pregnancy outcomes with ustekinumab exposure are available. AIM To assess pregnancy outcomes in patients exposed to ustekinumab during pregnancy METHODS: Cumulative data on medically confirmed ustekinumab-exposed pregnancies from the manufacturer's Global Safety Database were summarised. Descriptive data for pregnancy outcomes were presented overall and by patient subgroups. RESULTS As of 31 August 2020, 408 medically confirmed, prospective, maternal ustekinumab-exposed pregnancies with reported outcomes were identified. The mean maternal age was 31 years. Of the 420 pregnancy outcomes (including 4 sets of twins),a , b 340 (81%) were live births, 51 (12.1%) spontaneous abortions, 25 (6%) elective/induced abortions, 3 (0.7%) stillbirths and 1 (0.2%) ongoing pregnancy with foetal congenital anomaly (CA). Among 340 live births, 33 (9.7%) were born pre-term. The rate of major CAs was similar by indication (Crohn's disease vs psoriasis), ustekinumab dose (45 mg vs 90 mg) and timing and duration of maternal exposure to ustekinumab. Prospective outcomes of pregnancies with paternal periconceptional ustekinumab exposure (n = 87) included 92% live births (1.2% major CA), 5.7% spontaneous abortions and 2.3% elective/induced abortions. CONCLUSIONS Rates of adverse pregnancy outcomes or CAs with ustekinumab exposure were consistent with rates reported for the US general population and do not suggest a higher risk associated with maternal or paternal exposure to ustekinumab.
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Affiliation(s)
- Uma Mahadevan
- University of California San Francisco, San Francisco, California, USA
| | - Saule Naureckas
- Janssen Research and Development, LLC, Raritan, New Jersey, USA
| | - Ilia Tikhonov
- Janssen Research and Development, LLC, Raritan, New Jersey, USA
| | - Yiting Wang
- Janssen Research and Development, LLC, Spring House, Pennsylvania, USA
| | - Connie B Lin
- Janssen Research and Development, LLC, Horsham, Pennsylvania, USA
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11
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Saito J, Kaneko K, Kawasaki H, Hayakawa T, Yakuwa N, Suzuki T, Sago H, Yamatani A, Murashima A. Ustekinumab during pregnancy and lactation: drug levels in maternal serum, cord blood, breast milk, and infant serum. J Pharm Health Care Sci 2022; 8:18. [PMID: 35773736 PMCID: PMC9248188 DOI: 10.1186/s40780-022-00249-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/06/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Patients with ulcerative colitis (UC) may be concerned about medication safety during preconception, pregnancy, and lactation, and they should be closely followed up to ensure that UC activity is controlled during the perinatal period. Reported information on the safety of ustekinumab during pregnancy and lactation is limited. In this case report, we examined the safety of ustekinumab in a fetus and breastfed infant with reference to drug concentrations in maternal serum, cord blood, breast milk, and infant serum. CASE PRESENTATION A 36-year-old female who developed hematochezia and was diagnosed with ulcerative colitis at age 24 was pregnant with her first child. During pregnancy she was treated with subcutaneous bimonthly ustekinumab, at a dose of 90 mg, until 29 weeks of gestation. Her ulcerative colitis symptoms remained in remission. At 38 weeks of gestation she underwent cesarean section and delivered a healthy female infant weighing 3043 g and with no congenital malformations. The infant received routine vaccinations with no adverse events. Ustekinumab treatment was resumed at 7 weeks postpartum. The ustekinumab concentration in maternal serum at 12 days after injection (30.7 weeks of gestation) was 7968.5 ng/mL, and it decreased to 106.1 ng/mL at 114 days after the last dose. In cord blood, the ustekinumab concentration was 1131.2 ng/mL at 65 days after the last dose; this was 2.5 times higher than that in the maternal serum, which was consistent with a previous report. Ustekinumab was detected in infant serum collected at 71 days after the last maternal dose (299.0 ng/mL), with rapid elimination from the infant's body. In breast milk, the maximum ustekinumab concentrations were 13.6 ng/mL at 9 days after the last maternal dose, respectively. The ratio of the calculated areas under the time-concentration curves of ustekinumab in breast milk and maternal serum was 0.0008 (257.1/327632.7), which was comparable with a previous human study. CONCLUSION The placental transfer and breast milk secretion of ustekinumab in our case were comparable with previous reports. Use of ustekinumab during pregnancy and lactation was feasible in this case. Further research is needed to clarify the safety of ustekinumab during pregnancy and lactation.
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Affiliation(s)
- Jumpei Saito
- Department of Pharmacy, National Center for Child Health and Development, Okura 2-10-1, Setagaya-ku, Tokyo, 157-8535, Japan.
| | - Kayoko Kaneko
- Division of Maternal Medicine, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Hiroyo Kawasaki
- Department of Pharmacy, National Center for Child Health and Development, Okura 2-10-1, Setagaya-ku, Tokyo, 157-8535, Japan
| | | | - Naho Yakuwa
- Japan Drug Information Institute in Pregnancy, National Center for Child Health and Development, Tokyo, Japan
| | - Tomo Suzuki
- Division of Obstetrics, Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Haruhiko Sago
- Division of Obstetrics, Center for Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan
| | - Akimasa Yamatani
- Department of Pharmacy, National Center for Child Health and Development, Okura 2-10-1, Setagaya-ku, Tokyo, 157-8535, Japan
| | - Atsuko Murashima
- Division of Maternal Medicine, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.,Japan Drug Information Institute in Pregnancy, National Center for Child Health and Development, Tokyo, Japan
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12
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Balakirski G, Gerdes S, Beissert S, Ochsendorf F, von Kiedrowski R, Wilsmann-Theis D. Psoriasis-Therapie während Schwangerschaft und Stillzeit. J Dtsch Dermatol Ges 2022; 20:653-685. [PMID: 35578434 DOI: 10.1111/ddg.14789_g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 03/09/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Galina Balakirski
- Zentrum für Dermatologie, Allergologie und Dermatochirurgie, HELIOS Universitätsklinikum Wuppertal, Universität Witten/Herdecke, Wuppertal
| | - Sascha Gerdes
- Psoriasis-Zentrum, Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Schleswig- Holstein - Campus Kiel
| | - Stefan Beissert
- Klinik und Poliklinik für Dermatologie, Universitätsklinikum Carl Gustav Carus Dresden
| | - Falk Ochsendorf
- Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Frankfurt am Main
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13
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Balakirski G, Gerdes S, Beissert S, Ochsendorf F, von Kiedrowski R, Wilsmann-Theis D. Therapy of psoriasis during pregnancy and breast-feeding. J Dtsch Dermatol Ges 2022; 20:653-683. [PMID: 35578438 DOI: 10.1111/ddg.14789] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 03/09/2022] [Indexed: 12/21/2022]
Abstract
There have been multiple systemic drugs approved for the therapy of psoriasis vulgaris and psoriasis arthritis (PsA) in the last decade. However, treatment decisions are difficult to make in women planning a pregnancy and in pregnant and lactating women due to the paucity of data for such cases. The strongest evidence for psoriasis therapy during pregnancy exists for topical corticosteroids. Medically controlled use of UVB-therapy is also considered safe. The best evidence regarding systemic therapy during pregnancy and lactation is available for the group of TNF-alpha inhibitors, which is also reflected in the respective medical product information. This is especially important in cases of psoriatic arthritis. Among traditional systemic therapeutics, the largest clinical experience exists for ciclosporin, which, if medically necessary, may be continued during gestation. However, TNF-alpha inhibitors, especially the pegylated form, should be preferred in case of pregnancy. Furthermore, an elective pregnancy termination is not necessary due to systemic therapy of psoriasis with many further substances during the first pregnancy weeks. The current work provides a comprehensive review of the scientific literature on treatment of psoriasis during pregnancy and lactation. Based on the available scientific information, severity of psoriasis and patient's comorbidities, the best possible therapeutic approach can be found in consensus with the patient.
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Affiliation(s)
- Galina Balakirski
- Center for Dermatology, Allergology and Dermatosurgery, HELIOS University Hospital Wuppertal, Witten/Herdecke University, Wuppertal, Germany
| | - Sascha Gerdes
- Psoriasis Center, Department of Dermatology, Venereology and Allergology, University Hospital Schleswig- Holstein - Campus Kiel, Germany
| | - Stefan Beissert
- Department and Clinic for Dermatology, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Falk Ochsendorf
- Department of Dermatology, Venereology and Allergology, University Hospital Frankfurt am Main, Frankfurt, Germany
| | | | - Dagmar Wilsmann-Theis
- Department and Clinic for Dermatology and Allergology, University Hospital Bonn, Germany
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14
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Honap S, Meade S, Ibraheim H, Irving PM, Jones MP, Samaan MA. Effectiveness and Safety of Ustekinumab in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. Dig Dis Sci 2022; 67:1018-1035. [PMID: 33723700 DOI: 10.1007/s10620-021-06932-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 02/26/2021] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Ustekinumab, an interleukin-12 and interleukin-23 antagonist, is licensed for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) after the phase III trial programs demonstrated efficacy over placebo. However, these findings may not be directly transferable to the real-world due to the stringent inclusion criteria of clinical trials. METHODS We conducted a systematic review and meta-analysis of the safety and effectiveness of ustekinumab in inflammatory bowel disease (IBD). A systematic literature search was conducted via Medline and Embase from inception to April 21, 2020. Observational studies assessing ustekinumab's safety and effectiveness by reporting response, remission and/or adverse events (AE) in either CD or UC were included. Two reviewers independently assessed risk of bias and extracted study data. Random-effects meta-analysis was performed to pool rates of clinical response, remission, and safety data. RESULTS Following deduplication, 2147 records were identified of which 41 studies (38 CD, 3 UC) comprising 4400 patients were included for quantitative analysis. Pooled clinical remission rates for CD were 34% (95% CI, 26%-42%) following induction and 31% (95% CI, 25%-38%) at one year. For UC, post-induction clinical remission rates were 39% (95% CI, 23%-56%). Serious AEs were reported in 5.6% of patients. Pregnancy outcomes were similar to the general population. One-third of patients with active baseline perianal disease responded or had fistula healing with ustekinumab. CONCLUSIONS In the most comprehensive systematic review and meta-analysis to date, and the first to include UC, ustekinumab was shown to be effective and safe in the real-world treatment of IBD.
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Affiliation(s)
- Sailish Honap
- IBD Centre, 1st Floor IBD Centre, Westminster Bridge Road, St Thomas Hospital, Guys and St Thomas NHS Foundation Trust, London, SE1 7EH, UK. .,School of Immunology and Microbial Sciences, Kings College London, London, UK.
| | - Susanna Meade
- IBD Centre, 1st Floor IBD Centre, Westminster Bridge Road, St Thomas Hospital, Guys and St Thomas NHS Foundation Trust, London, SE1 7EH, UK
| | - Hajir Ibraheim
- Department of Metabolism, Digestion and Reproduction, Norfolk Place, St Marys Campus, Imperial College London, London, W2 1PG, UK
| | - Peter M Irving
- IBD Centre, 1st Floor IBD Centre, Westminster Bridge Road, St Thomas Hospital, Guys and St Thomas NHS Foundation Trust, London, SE1 7EH, UK.,School of Immunology and Microbial Sciences, Kings College London, London, UK
| | - Michael P Jones
- Center for Emotional Health, Department of Psychology, Macquarie University, New South Wales, NSW, 2109, Australia
| | - Mark A Samaan
- IBD Centre, 1st Floor IBD Centre, Westminster Bridge Road, St Thomas Hospital, Guys and St Thomas NHS Foundation Trust, London, SE1 7EH, UK
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15
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Armuzzi A, Bortoli A, Castiglione F, Contaldo A, Daperno M, D'Incà R, Labarile N, Mazzuoli S, Onali S, Milla M, Orlando A, Principi M, Pugliese D, Renna S, Rizzello F, Scribano ML, Todeschini A. Female reproductive health and inflammatory bowel disease: A practice-based review. Dig Liver Dis 2022; 54:19-29. [PMID: 34120858 DOI: 10.1016/j.dld.2021.05.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/08/2021] [Accepted: 05/16/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases, namely ulcerative colitis and Crohn's disease, occur worldwide and affect people of all ages, with a high impact on their quality of life. Sex differences in incidence and prevalence have been reported, and there are also gender-specific issues that physicians should recognize. For women, there are multiple, important concerns regarding issues of body image and sexuality, menstruation, contraception, fertility, pregnancy, breastfeeding and menopause. This practice-based review focuses on the main themes that run through the life of women with inflammatory bowel diseases from puberty to menopause. Gastroenterologists who specialize in inflammatory bowel diseases and other physicians who see female patients with inflammatory bowel diseases should provide support for these problems and offer adequate therapy to ensure that their patients achieve the same overall well-being and health as do women without inflammatory bowel diseases.
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Affiliation(s)
| | - Alessandro Armuzzi
- CEMAD - IBD Unit, Department of Medical and Surgical Sciences, A Gemelli University Hospital, Rome, Italy
| | | | - Fabiana Castiglione
- Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine Federico II of Naples, Naples, Italy
| | - Antonella Contaldo
- Emergency and Organ Transplantation Department, Section of Gastroenterology, AOU Policlinico, Bari, Italy
| | - Marco Daperno
- Gastroenterology and Endoscopic Unit, Umberto I Mauriziano Hospital, Turin, Italy
| | - Renata D'Incà
- Gastroenterology Unit, Padua University Hospital, Padua, Italy
| | - Nunzia Labarile
- Gastroenterology Unit, Ospedale Santissima Annunziata, Taranto, Italy
| | - Silvia Mazzuoli
- Gastroenterology and Artificial Nutrition Department, "Mons. Dimiccoli " Barletta, Italy
| | - Sara Onali
- Gastroenterology Unit, Department of Science and Public Health, University Hospital of Cagliari, Italy
| | - Monica Milla
- IBD Referral Center, Gastroenterology Clinic, Careggi University Hospital, Florence, Italy
| | - Ambrogio Orlando
- Inflammatory Bowel Disease Unit, A.O.O.R. Villa Sofia-Cervello, Palermo, Italy
| | - Mariabeatrice Principi
- Emergency and Organ Transplantation Department, Section of Gastroenterology, AOU Policlinico, Bari, Italy.
| | - Daniela Pugliese
- CEMAD - IBD Unit, Department of Medical and Surgical Sciences, A Gemelli University Hospital, Rome, Italy
| | - Sara Renna
- Inflammatory Bowel Disease Unit, A.O.O.R. Villa Sofia-Cervello, Palermo, Italy
| | - Fernando Rizzello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Alessia Todeschini
- Emergency and Organ Transplantation Department, Section of Gastroenterology, AOU Policlinico, Bari, Italy
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16
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Simionescu AA, Danciu BM, Stanescu AMA. State-of-the-Art Review of Pregnancy-Related Psoriasis. ACTA ACUST UNITED AC 2021; 57:medicina57080804. [PMID: 34441010 PMCID: PMC8402069 DOI: 10.3390/medicina57080804] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 08/02/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022]
Abstract
Psoriasis is a chronic immunologic disease involving inflammation that can target internal organs, the skin, and joints. The peak incidence occurs between the age of 30 and 40 years, which overlaps with the typical reproductive period of women. Because of comorbidities that can accompany psoriasis, including metabolic syndrome, cardiovascular involvement, and major depressive disorders, the condition is a complex one. The role of hormones during pregnancy in the lesion dynamics of psoriasis is unclear, and it is important to resolve the implications of this pathology during pregnancy are. Furthermore, treating pregnant women who have psoriasis represents a challenge as most drugs generally prescribed for this pathology are contraindicated in pregnancy because of teratogenic effects. This review covers the state of the art in psoriasis associated with pregnancy. Careful pregnancy monitoring in moderate-to-severe psoriasis vulgaris is required given the high risk of related complications in pregnancy, including pregnancy-induced hypertensive disorders, low birth weight for gestational age, and gestational diabetes. Topical corticosteroids are safe during pregnancy but effective only for localised forms of psoriasis. Monoclonal antibodies targeting cytokines specifically upregulated in psoriasis, such as ustekinumab (IL-12/23 inhibitor), secukinumab (IL-17 inhibitor) can be effective for the severe form of psoriasis during pregnancy. A multidisciplinary team must choose optimal treatment, taking into account fetal and maternal risks and benefits.
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Affiliation(s)
- Anca Angela Simionescu
- Department of Obstetrics and Gynecology, Filantropia Clinical Hospital, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Correspondence: (A.A.S.); (A.M.A.S.)
| | - Bianca Mihaela Danciu
- Department of Obstetrics, Gynecology and Neonatology, “Dr. Alfred Rusescu” National Institute for Maternal and Child Health, 127715 Bucharest, Romania;
| | - Ana Maria Alexandra Stanescu
- Department of Family Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Correspondence: (A.A.S.); (A.M.A.S.)
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17
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Fischer-Betz R, Østensen M. Biologics and small molecules in the management of psoriatic arthritis: Reproduction related issues in female and male patients. Expert Rev Clin Pharmacol 2021; 14:979-989. [PMID: 33982647 DOI: 10.1080/17512433.2021.1925536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
STRACTBackground: Psoriatic arthritis (PsA) is the musculoskeletal manifestation of psoriatic disease, an inflammatory systemic disease with a high incidence in the reproductive years. Biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) as well as 'small molecules', are increasingly used to treat subtypes of PsA. Safety concerns exist in the field of fertility for PsA patients since the literature shows discordant results toward the influence of anti-psoriatic drugs.Areas covered: This comprehensive review critically reviews the available data on the safety of biologics and small molecules in PsA including pregnancy and lactation and men who want to father a child. TNF inhibitors (TNFi) are best studied in relation to reproduction. For other biologics and small molecules, no prospective, controlled studies are available.Expert opinion: No contraindications appear for TNFi in pregnancy, lactation, and paternal exposure. For biologics other than TNFi and small molecules, prospective controlled studies on outcomes after exposure in early and late pregnancy are urgently needed. Potential effects of all biologics on immune function, infection rates, and vaccine responses in prenatally exposed children need to be expanded. Until more data become available, small molecules should be avoided during pregnancy and breastfeeding. More reproduction-related data are expected from various national and international registries in the future.
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Affiliation(s)
- Rebecca Fischer-Betz
- Department for Rheumatology and Hiller Research Institute, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Monika Østensen
- Department of Rheumatology, Sorlandet Hospital, Kristiansand, Norway
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18
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Gisbert JP, Chaparro M. Safety of New Biologics (Vedolizumab and Ustekinumab) and Small Molecules (Tofacitinib) During Pregnancy: A Review. Drugs 2021; 80:1085-1100. [PMID: 32562207 DOI: 10.1007/s40265-020-01346-4] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Two new biological drugs (vedolizumab and ustekinumab) and one small molecule (tofacitinib) have been recently approved for the treatment of inflammatory bowel disease. Therefore, we must be familiar with the safety of these "new" drugs during pregnancy and breastfeeding. In the present article, we critically review available data on the safety of new biologics (vedolizumab and ustekinumab) and small molecules (tofacitinib) during pregnancy and breastfeeding, with special focus on women with inflammatory bowel disease. Bibliographical searches (MEDLINE) up to April 2020 were performed. The timing and mechanisms of placental transfer of vedolizumab and ustekinumab are expected to be similar to anti-TNF agents. Animal studies show no evidence of adverse effects on pre- or post-natal development after administration of vedolizumab and ustekinumab. Just a few studies including patients treated with vedolizumab or ustekinumab during pregnancy have been published, reporting uneventful pregnancies in most cases. The clinical programme of both drugs and post-marketing studies showed no new safety concerns. Due to the expected safety of vedolizumab and ustekinumab during pregnancy, it may be recommended to plan the final pregnancy dose approximately 8 or 12 weeks, respectively, before the estimated date of delivery. Live vaccines should be avoided for up to a year in children exposed in utero to vedolizumab or ustekinumab unless drug elimination has been documented. Miniscule amounts of vedolizumab and ustekinumab are transferred to breast milk, so breastfeeding is probably safe. There is no evidence of adverse effect of vedolizumab or ustekinumab paternal exposure. Regarding tofacitinib, it is reasonable to assume that this molecule crosses the placenta from the beginning of pregnancy. In animal studies, tofacitinib was feticidal and teratogenic in rats and rabbits, although at exposures many times greater than the standard human dose. Reported outcomes of pregnancy cases identified from tofacitinib randomised controlled trials, post-approval and non-interventional studies, and spontaneous adverse-event reporting appear similar to those observed in the general population. Nevertheless, at present, the use of tofacitinib during pregnancy should be avoided. Although no human studies have reported outcomes of breastfeeding with small molecules such as tofacitinib, this drug is present in lactating rat milk so, at present, breastfeeding should be avoided. Pregnancy among patients with paternal exposure to tofacitinib appears to be safe. In summary, we can conclude that new biologic agents (vedolizumab and ustekinumab) and small molecules (tofacitinib) should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother and unborn child.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Diego de León, 62, 28006, Madrid, Spain.
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Diego de León, 62, 28006, Madrid, Spain
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19
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Laube R, Paramsothy S, Leong RW. Use of medications during pregnancy and breastfeeding for Crohn's disease and ulcerative colitis. Expert Opin Drug Saf 2021; 20:275-292. [PMID: 33412078 DOI: 10.1080/14740338.2021.1873948] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Introduction: The peak age of diagnosis of inflammatory bowel disease (IBD) occurs during childbearing years, therefore management of IBD during pregnancy is a frequent occurrence. Maintenance of disease remission is crucial to optimize pregnancy outcomes, and potential maternal or fetal toxicity from medications must be balanced against the risks of untreated IBD.Areas covered: This review summarizes the literature on safety and use of medications for IBD during pregnancy and lactation.Expert opinion: 5-aminosalicylates, corticosteroids and thiopurines are safe for use during pregnancy, while methotrexate and tofacitinib should only be used with extreme caution. Anti-TNF agents (except certolizumab), vedolizumab, ustekinumab and tofacitinib readily traverse the placenta via active transport, therefore theoretically may affect fetal development. Certolizumab only undergoes passive transfer across the placenta, thus has markedly lower cord blood levels making it likely the safest biologic agent for infants. There is reasonable evidence to support the safety of anti-TNF monotherapy and combination therapy during pregnancy and lactation. Vedolizumab and ustekinumab are also thought to be safe in pregnancy and lactation, while tofacitinib is generally avoided due to teratogenic effects in animal studies.
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Affiliation(s)
- Robyn Laube
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.,Department of Gastroenterology, Macquarie University Hospital, Sydney, Australia
| | - Sudarshan Paramsothy
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.,Department of Gastroenterology, Macquarie University Hospital, Sydney, Australia.,Department of Gastroenterology and Hepatology, Concord Repatriation General Hospital, Sydney, Australia
| | - Rupert W Leong
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia.,Department of Gastroenterology, Macquarie University Hospital, Sydney, Australia.,Department of Gastroenterology and Hepatology, Concord Repatriation General Hospital, Sydney, Australia
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20
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Nakase H, Uchino M, Shinzaki S, Matsuura M, Matsuoka K, Kobayashi T, Saruta M, Hirai F, Hata K, Hiraoka S, Esaki M, Sugimoto K, Fuji T, Watanabe K, Nakamura S, Inoue N, Itoh T, Naganuma M, Hisamatsu T, Watanabe M, Miwa H, Enomoto N, Shimosegawa T, Koike K. Evidence-based clinical practice guidelines for inflammatory bowel disease 2020. J Gastroenterol 2021; 56:489-526. [PMID: 33885977 PMCID: PMC8137635 DOI: 10.1007/s00535-021-01784-1] [Citation(s) in RCA: 251] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 03/25/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a general term for chronic or remitting/relapsing inflammatory diseases of the intestinal tract and generally refers to ulcerative colitis (UC) and Crohn's disease (CD). Since 1950, the number of patients with IBD in Japan has been increasing. The etiology of IBD remains unclear; however, recent research data indicate that the pathophysiology of IBD involves abnormalities in disease susceptibility genes, environmental factors and intestinal bacteria. The elucidation of the mechanism of IBD has facilitated therapeutic development. UC and CD display heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management depends on the understanding and tailoring of evidence-based interventions by physicians. In 2020, seventeen IBD experts of the Japanese Society of Gastroenterology revised the previous guidelines for IBD management published in 2016. This English version was produced and modified based on the existing updated guidelines in Japanese. The Clinical Questions (CQs) of the previous guidelines were completely revised and categorized as follows: Background Questions (BQs), CQs, and Future Research Questions (FRQs). The guideline was composed of a total of 69 questions: 39 BQs, 15 CQs, and 15 FRQs. The overall quality of the evidence for each CQ was determined by assessing it with reference to the Grading of Recommendations Assessment, Development and Evaluation approach, and the strength of the recommendation was determined by the Delphi consensus process. Comprehensive up-to-date guidance for on-site physicians is provided regarding indications for proceeding with the diagnosis and treatment.
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Affiliation(s)
- Hiroshi Nakase
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan ,grid.263171.00000 0001 0691 0855Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, S-1, W-16, Chuoku, Sapporo, Hokkaido 060-8543 Japan
| | - Motoi Uchino
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Shinichiro Shinzaki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Minoru Matsuura
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Katsuyoshi Matsuoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Taku Kobayashi
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Masayuki Saruta
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Fumihito Hirai
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Keisuke Hata
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Sakiko Hiraoka
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Motohiro Esaki
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Ken Sugimoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Toshimitsu Fuji
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Kenji Watanabe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Shiro Nakamura
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Nagamu Inoue
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Toshiyuki Itoh
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Makoto Naganuma
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Tadakazu Hisamatsu
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Mamoru Watanabe
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the “Evidence-Based Clinical Practice Guidelines for Inflammatory Bowel Disease”, The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004 Japan
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21
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Clark-Snustad K, Butnariu M, Afzali A. Women's Health and Ulcerative Colitis. Gastroenterol Clin North Am 2020; 49:769-789. [PMID: 33121695 DOI: 10.1016/j.gtc.2020.07.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Although ulcerative colitis affects males and females at similar rates, certain sex-specific differences influence the disease-related risks and experiences of females with ulcerative colitis. This article reviews topics that affect females with ulcerative colitis, including the impact of disease on the menstrual cycle, fertility, child bearing, sexual health, and recommendations for health care maintenance.
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Affiliation(s)
- Kindra Clark-Snustad
- Inflammatory Bowel Disease Program, Division of Gastroenterology, University of Washington, 1959 Northeast Pacific Street, Box 356424, Seattle, WA 98195, USA
| | - Madalina Butnariu
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, 410 W. 10(th) Ave. 2(nd) floor, Columbus, OH 43210, USA
| | - Anita Afzali
- Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, 395 West 12(th) Avenue, Room 280, Columbus, OH 43210, USA.
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22
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Son YW, Choi HN, Che JH, Kang BC, Yun JW. Advances in selecting appropriate non-rodent species for regulatory toxicology research: Policy, ethical, and experimental considerations. Regul Toxicol Pharmacol 2020; 116:104757. [PMID: 32758521 DOI: 10.1016/j.yrtph.2020.104757] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 07/27/2020] [Accepted: 07/31/2020] [Indexed: 12/20/2022]
Abstract
In vivo animal studies are required by regulatory agencies to investigate drug safety before clinical trials. In this review, we summarize the process of selecting a relevant non-rodent species for preclinical studies. The dog is the primary, default non-rodent used in toxicology studies with multiple scientific advantages, including adequate background data and availability. Rabbit has many regulatory advantages as the first non-rodent for the evaluation of reproductive and developmental as well as local toxicity. Recently, minipigs have increasingly replaced dogs and rabbits in toxicology studies due to ethical and scientific advantages including similarity to humans and breeding habits. When these species are not relevant, nonhuman primates (NHPs) can be used as the available animal models, especially in toxicology studies investigating biotherapeutics. Particularly, based on the phylogenetic relationships, the use of New-World marmosets can be considered before Old-World monkeys, especially cynomolgus with robust historical data. Importantly, the use of NHPs should be justified in terms of scientific benefits considering target affinity, expression pattern, and pharmacological cross-reactivity. Strict standards are required for the use of animals. Therefore, this review is helpful for the selection of appropriate non-rodent in regulatory toxicology studies by providing sufficient regulatory, ethical, and scientific data for each species.
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Affiliation(s)
- Yong-Wook Son
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, South Korea
| | - Ha-Ni Choi
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, South Korea
| | - Jeong-Hwan Che
- Biomedical Center for Animal Resource and Development, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Byeong-Cheol Kang
- Graduate School of Translational Medicine, Seoul National University College of Medicine, Seoul, 03080, South Korea
| | - Jun-Won Yun
- Department of Biotechnology, The Catholic University of Korea, Bucheon, 14662, South Korea.
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23
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Cacciapuoti S, Scala E, Megna M, Gallo L, Fontanella G, Ruggiero A, Savastano S, Fabbrocini G. Impact of current antipsoriatic systemic treatments on male and female fertility: what endocrinologists need to know. Minerva Endocrinol (Torino) 2020; 46:350-362. [PMID: 32720503 DOI: 10.23736/s2724-6507.20.03236-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Fertility is a function of the body that is often overlooked as a site for the expression of the side effects of certain drugs. With the approval of new drugs with a totally innovative mechanism of action, the risk assessment on fertility both in male and female is more difficult. This is particularly true in psoriasis, an invalidating inflammatory skin disease. The estimated prevalence of psoriasis in adults ranged from 0.51% to 11.43%, and in children from 0% to 1.37%, with frequent diagnosis in young patients of childbearing age. With the increasing use of new, predominantly immunosuppressive or biologic drugs for psoriasis, questions frequently arise in clinical practice as to their safety in men and women wishing to procreate. Both psoriatic patients and their physicians are concerned about adverse effects of the disease and its treatment on their future fertility, causing additional concerns in the therapeutic management of these patients. Among antipsoriatic drugs, conventional therapies are mainly involved in the onset of infertility in both sexes, exerting in some cases toxic effects against reproductive organs. Conversely, biologic agents appear to improve male and female fertility especially when gonadal impairment is related to inflammatory phenomena. There is a lack of review articles of commonly used medications in psoriasis with respect to their potential effects on fertility. The aim of this paper was to provide a practical guide for both dermatologist and endocrinologist in therapeutic management of psoriatic patients of childbearing age, considering the impact of prescribed drugs on their current and future fertility.
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Affiliation(s)
- Sara Cacciapuoti
- Section of Dermatology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy -
| | - Emanuele Scala
- Section of Dermatology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Matteo Megna
- Section of Dermatology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Lucia Gallo
- Section of Dermatology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Giuseppina Fontanella
- Section of Dermatology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Angelo Ruggiero
- Section of Dermatology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Silvia Savastano
- Unit of Endocrinology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - Gabriella Fabbrocini
- Section of Dermatology, Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
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24
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Selinger CP, Nelson-Piercy C, Fraser A, Hall V, Limdi J, Smith L, Smith M, Nasur R, Gunn M, King A, Mohan A, Mulgabal K, Kent A, Kok KB, Glanville T. IBD in pregnancy: recent advances, practical management. Frontline Gastroenterol 2020; 12:214-224. [PMID: 33912333 PMCID: PMC8040511 DOI: 10.1136/flgastro-2019-101371] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 04/27/2020] [Accepted: 05/04/2020] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) poses complex issues in pregnancy, but with high-quality care excellent pregnancy outcomes are achievable. In this article, we review the current evidence and recommendations for pregnant women with IBD and aim to provide guidance for clinicians involved in their care. Many women with IBD have poor knowledge about pregnancy-related issues and a substantial minority remains voluntarily childless. Active IBD is associated with an increased risk of preterm birth, low for gestation weight and fetal loss. With the exception of methotrexate and tofacitinib the risk of a flare outweighs the risk of IBD medication and maintenance of remission from IBD should be the main of care. Most women with IBD will experience a normal pregnancy and can have a vaginal delivery. Active perianal Crohn's disease is an absolute and ileal pouch surgery a relative indication for a caesarean section. Breast feeding is beneficial to the infant and the risk from most IBD medications is negligible.
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Affiliation(s)
| | | | - Aileen Fraser
- Gastroenterology, United Hospitals Bristol, Bristol, Avon, UK
| | - Veronica Hall
- Gastroenterology, Royal Bolton Foundation NHS Trust, Bolton, UK
| | - Jimmy Limdi
- Section of iBD- Division of Gastroenterology, The Pennine Acute Hospitals NHS Trust, Manchester, UK,Gastroenterology, Manchester Academic Health Science Centre, Manchester, UK
| | - Lyn Smith
- Gastroenterology, NHS Greater Glasgow and Clyde North Glasgow University Hospitals Division, Glasgow, UK
| | - Marie Smith
- Obstetrics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Reem Nasur
- Obstetrics, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
| | - Melanie Gunn
- Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, UK
| | - Andrew King
- Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, Tyne and Wear, UK
| | - Aarthi Mohan
- Obstetrics, United Hospitals Bristol, Bristol, Avon, UK
| | | | - Alexandra Kent
- Gastroenterology, King's College Hospital NHS Foundation Trust, London, UK
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25
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Wieringa JW, van der Woude CJ. Effect of biologicals and JAK inhibitors during pregnancy on health-related outcomes in children of women with inflammatory bowel disease. Best Pract Res Clin Gastroenterol 2019; 44-45:101665. [PMID: 32359679 DOI: 10.1016/j.bpg.2019.101665] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/14/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023]
Abstract
Current guidelines advise to maintain immunomodulators and biologicals in pregnant patients because relapse of inflammatory bowel is associated with unfavourable pregnancy outcome. With the exception of Methotrexate, IBD therapy seems not to be related to an increase of congenital malformations or infections requiring hospitalisation of the babies, although the effect the on the developing immune system of the exposed infants remains unknown. In this review we will focus on the effect of IBD drugs on health-related outcomes in children taking into account possible long-term effects of biologicals and immunomodulators, which are transferred across the placenta.
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Affiliation(s)
- J W Wieringa
- Department of Pediatrics, Haaglanden Medical Center and Department of Pediatrics, Subdivision of Infectious Diseases and Immunology, Erasmus MC University Medical Center-Sophia Children's Hospital, Rotterdam, Lijnbaan 32, CK The Hague, 2501, the Netherlands.
| | - C J van der Woude
- Department of Gastroenterology, Erasmus MC University Medical Center, 's Gravendijkwal 230, 3015, CE, Rotterdam, the Netherlands.
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26
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Abstract
PURPOSE OF REVIEW Roughly half of the nearly 1.6 million people with inflammatory bowel disease (IBD) are women of reproductive age. Caring for women with IBD who are also pregnant can be challenging, particularly if with a disease flare or in remission, as there are special considerations needed. RECENT FINDINGS Despite older studies concluding potential risks associated with IBD medical therapies, more recent literature reports healthier maternal and birth outcomes associated with disease control and reduction in the inflammatory burden. Most IBD therapies should generally be continued throughout all three trimesters without interruption as this is associated with better outcomes. SUMMARY Active IBD increases risk of pregnancy complications and adverse pregnancy outcomes. Most medications have a favorable safety profile for use during pregnancy, regardless if in disease flare or remission. Short course corticosteroids for induction and management of flare is permitted. Thiopurines should not be started during pregnancy for a disease flare, but may be continued during pregnancy if previously on monotherapy. Biologics should be continued throughout pregnancy without interruption and timing of third trimester dosing made based on drug levels and estimated date of delivery. Risks/benefit assessment of therapies and disease control is important and should be individualized.
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27
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Klenske E, Osaba L, Nagore D, Rath T, Neurath MF, Atreya R. Drug Levels in the Maternal Serum, Cord Blood and Breast Milk of a Ustekinumab-Treated Patient with Crohn's Disease. J Crohns Colitis 2019; 13:267-269. [PMID: 30388211 DOI: 10.1093/ecco-jcc/jjy153] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Ustekinumab [UST] therapy during pregnancy has not yet been extensively evaluated in patients with Crohn's disease. Here, we present the case of a 24-year-old woman with therapy-refractory Crohn's disease, who was treated with UST until Week 30 of pregnancy and successfully delivered a healthy baby boy, who had normal development in the follow-up period of one year. The cord blood UST level was markedly higher than the measured maternal serum drug level. The trough level in the breast milk after re-initiating postpartum UST therapy was initially in the same range as the corresponding serum trough level, and then decreased during maintenance therapy. This is one of the first reports describing the drug levels in the breast milk after re-initiating UST treatment in a Crohn's disease patient.
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Affiliation(s)
- Entcho Klenske
- Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | | | | | - Timo Rath
- Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
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28
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Puchner A, Gröchenig HP, Sautner J, Helmy-Bader Y, Juch H, Reinisch S, Högenauer C, Koch R, Hermann J, Studnicka-Benke A, Weger W, Puchner R, Dejaco C. Immunosuppressives and biologics during pregnancy and lactation : A consensus report issued by the Austrian Societies of Gastroenterology and Hepatology and Rheumatology and Rehabilitation. Wien Klin Wochenschr 2019; 131:29-44. [PMID: 30643992 PMCID: PMC6342891 DOI: 10.1007/s00508-019-1448-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 12/06/2018] [Indexed: 12/14/2022]
Abstract
An increasing and early-onset use of immunosuppressives and biologics has become more frequently seen among patients with inflammatory bowel diseases (IBD) and rheumatic disorders. Many women in their childbearing years currently receive such medications, and some of them in an interdisciplinary setting. Many questions arise in women already pregnant or wishing to conceive with respect to continuing or discontinuing treatment, the risks borne by the newborns and their mothers and long-term safety. Together with the Austrian Society of Rheumatology and Rehabilitation, the IBD working group of the Austrian Society of Gastroenterology and Hepatology has elaborated consensus statements on the use of immunosuppressives and biologics in pregnancy and lactation. This is the first Austrian interdisciplinary consensus on this topic. It is intended to serve as a basis and support for providing advice to our patients and their treating physicians.
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Affiliation(s)
- Antonia Puchner
- Division of Rheumatology, Third Medical Department, Medical University of Vienna/Vienna General Hospital, Vienna, Austria
| | - Hans Peter Gröchenig
- Medical Department, Hospital of the Brothers of Mercy, St. Veit an der Glan, Austria
| | - Judith Sautner
- Second Medical Department, Korneuburg-Stockerau Hospital/Lower Austrian Center for Rheumatology, Stockerau, Austria
| | - Yvonne Helmy-Bader
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Herbert Juch
- Department of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria
| | - Sieglinde Reinisch
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christoph Högenauer
- Division of Gastroenterology and Hepatology, Medical Department, Medical University of Graz, Graz, Austria
| | - Robert Koch
- Division of Gastroenterology, First Medical Department, Medical University of Innsbruck, Innsbruck, Austria
| | - Josef Hermann
- Division of Rheumatology and Immunology, Medical Department, Medical University of Graz, Graz, Austria
| | | | - Wolfgang Weger
- Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria
| | - Rudolf Puchner
- Division of Rheumatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Clemens Dejaco
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
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29
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Balbi GGM, Domingues V, Balbi GGM, De Jesús GR, Levy RA. Use of synthetic and biologic DMARDs during pregnancy. Expert Rev Clin Immunol 2018; 15:27-39. [PMID: 30365902 DOI: 10.1080/1744666x.2019.1541739] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction: Since most of the autoimmune diseases (AID) affect mostly women in their fertile years, and fertility is in general preserved, the use of disease-modifying antirheumatic drugs (DMARDs) during conception, pregnancy, and lactation has been a matter of concern in the treatment of women affected by AID. Areas covered: We performed a comprehensive review of the latest and most relevant research papers published in the field and discussed different aspects related to the use of synthetic and biologic DMARDs and immunosuppressants in the preconceptional period, during pregnancy and lactation in AID patients, both in males and females. Expert commentary: Active AID impose an increased risk for adverse maternal and fetal outcomes, such as preeclampsia, miscarriage, intrauterine growth restriction, prematurity, low birth weight, and stillbirth. Family planning with proper contraception and shared decision-making on the ideal time to conceive with treatment adjustment must be a rule. One of the main challenges when counseling and/or adjusting treatment of patients that are planning a pregnancy is to provide a medication that is at the same time efficacious and safe at the conceptional period and to developing the fetus.
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Affiliation(s)
| | - Vinicius Domingues
- b College of Medicine , Florida State University , Daytona Beach , FL , USA
| | | | - Guilherme Ramires De Jesús
- d Department of Obstetrics , Hospital Universitário Pedro Ernesto (HUPE), Universidade do Estado do Rio de Janeiro (UERJ) , Rio de Janeiro , RJ , Brazil
| | - Roger Abramino Levy
- e Global Medical Expert , GlaxoSmithKline (GSK) , Upper Providence , PA , USA
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30
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Shim HH, Chan PW, Chuah SW, Schwender BJ, Kong SC, Ling KL. A review of vedolizumab and ustekinumab for the treatment of inflammatory bowel diseases. JGH Open 2018; 2:223-234. [PMID: 30483594 PMCID: PMC6207060 DOI: 10.1002/jgh3.12065] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/26/2018] [Accepted: 05/07/2018] [Indexed: 12/11/2022]
Abstract
Recent advancement in the understanding of the pathophysiology of inflammatory bowel disease has seen an expansion in therapeutic options. Vedolizumab, a selective α4β7 inhibitor, and ustekinumab, an IL 12/23 p40 inhibitor, have provided the much-awaited out-of-class alternatives for patients who have failed or who are intolerant to anti-Tumor Necrosis Factor (TNF) therapy. However, questions remain as to how we may best use these novel therapeutic agents. We evaluate the evidence available from randomized controlled trials and postmarketing cohort studies and discuss their safety, efficacy, and limitations, in relation to anti-TNF therapy, in optimizing the treatment outcomes.
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Affiliation(s)
- Hang Hock Shim
- Department of Gastroenterology and HepatologySingapore General HospitalSingapore
| | - Pak Wo Chan
- Department of Gastroenterology and HepatologySingapore General HospitalSingapore
| | - Sai Wei Chuah
- Department of Gastroenterology and HepatologySingapore General HospitalSingapore
| | - Brian J Schwender
- Department of Gastroenterology and HepatologySingapore General HospitalSingapore
| | - San Choon Kong
- Department of Gastroenterology and HepatologySingapore General HospitalSingapore
| | - Khoon Lin Ling
- Department of Gastroenterology and HepatologySingapore General HospitalSingapore
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31
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Gerosa M, Argolini LM, Artusi C, Chighizola CB. The use of biologics and small molecules in pregnant patients with rheumatic diseases. Expert Rev Clin Pharmacol 2018; 11:987-998. [PMID: 30227748 DOI: 10.1080/17512433.2018.1525293] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
INTRODUCTION Biological agents have radically changed the prognosis of rheumatic patients. Current evidence demonstrates that tight disease control during pregnancy is mandatory to minimize adverse outcome risk. As the new therapeutic tools are pivotal to maintain appropriate disease activity, it is timely to review available evidence about the safety of biologics and small molecules in pregnancy. Areas covered: A comprehensive literature review has been performed, reporting available data about the passage into breast milk, rate of pregnancy loss and fetal malformations, and long-term complications due to in utero exposure to biological agents and small molecules. Expert commentary: Data about the safety of agents against tumor necrosis factor in pregnancy are reassuring. Even rituximab, tocilizumab, belimumab, ustekinumab, secukinumab, and abatacept have not been associated with an increased rate of fetal abnormalities or adverse pregnancy outcome. Experience with small molecules is too small to draw any conclusion. Even if further data are warranted to define the possible long-term effects of in utero biologic exposure on the infant immune system development, it is reasonable to speculate that in the next future the use of biologics during pregnancy will continue to expand, at least when maternal benefit justifies the potential risk to the fetus.
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Affiliation(s)
- Maria Gerosa
- a Department of Clinical Sciences and Community Health , University of Milan, Division of Clinical Rheumatology, ASST Istituto Gaetano Pini - CTO , Milan , Italy
| | - Lorenza Maria Argolini
- a Department of Clinical Sciences and Community Health , University of Milan, Division of Clinical Rheumatology, ASST Istituto Gaetano Pini - CTO , Milan , Italy
| | - Carolina Artusi
- b Division of Clinical Rheumatology , ASST Istituto Gaetano Pini - CTO , Milan , Italy
| | - Cecilia Beatrice Chighizola
- c Department of Clinical Sciences and Community Health , University of Milan, Milan, Italy; Experimental Laboratory of Immunorheumatological Researches, Istituto Auxologico Italiano , Milan , Italy
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32
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Aggeletopoulou I, Assimakopoulos SF, Konstantakis C, Triantos C. Interleukin 12/interleukin 23 pathway: Biological basis and therapeutic effect in patients with Crohn's disease. World J Gastroenterol 2018; 24:4093-4103. [PMID: 30271076 PMCID: PMC6158482 DOI: 10.3748/wjg.v24.i36.4093] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 08/02/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
Considering that both innate and adaptive immune responses are involved in the pathogenesis of Crohn’s disease (CD), novel therapeutic options have significantly been developed. Biological agents represent an important addition to the conventional treatments for immuno-inflammatory conditions, acting as antagonists of adhesion molecules or various inflammatory cytokines. The interleukin 12 (IL-12)/IL-23 common pathway has been found to play a determinant role in the induction of inflammation in adaptive immune responses. In particular, IL-23 promotes the differentiation of naïve T helper cells into Th17 phenotype with the concomitant secretion of several inflammatory cytokines such as IL-17 and IL-22, whereas IL-12 induces the Th1 polarization and production of critical cytokines such as interferon-γ and tumor necrosis factor. Nowadays, there is increased interest regarding the role of IL-23 as a therapeutic target of CD through the blockage of IL-23 mediated pathways. In this editorial, we focus on the role of IL-12/IL-23 pathway in the regulation of mucosal immunity and in the induction and maintenance of chronic inflammation. In parallel, we critically discuss the available data regarding the therapeutic effect of the IL-12/IL-23 inhibitors and especially of ustekinumab, a human monoclonal antibody which has been recently approved by the United States Food and Drug Administration for the management of moderate-to-severe CD and its potential to be used as first-line therapy in everyday clinical practice.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | | | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
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33
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Brown SM, Aljefri K, Waas R, Hampton P. Systemic medications used in treatment of common dermatological conditions: safety profile with respect to pregnancy, breast feeding and content in seminal fluid. J DERMATOL TREAT 2018; 30:2-18. [PMID: 28092212 DOI: 10.1080/09546634.2016.1202402] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Prescribing for pregnant or lactating patients and male patients wishing to father children can be a difficult area for dermatologists. There is a lack of review articles of commonly used systemic medications in dermatology with respect to their effects on developing embryogenesis and their potential transfer across the placenta, in breast milk and in seminal fluid. This paper aims to provide an up to date summary of evidence to better equip dermatologists to inform patients about the effects of systemic medications commonly used in dermatology to treat conditions such as atopic dermatitis, psoriasis and acne, on current and future embryogenesis and fertility.
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Affiliation(s)
| | - Khadija Aljefri
- a Dermatology Department , Royal Victoria Infirmary , Newcastle Upon Tyne , UK
| | - Rachel Waas
- a Dermatology Department , Royal Victoria Infirmary , Newcastle Upon Tyne , UK
| | - Philip Hampton
- a Dermatology Department , Royal Victoria Infirmary , Newcastle Upon Tyne , UK
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34
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Targeted drugs in spondyloarthritis during pregnancy and lactation. Pharmacol Res 2018; 136:21-28. [PMID: 30125669 DOI: 10.1016/j.phrs.2018.08.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 07/29/2018] [Accepted: 08/13/2018] [Indexed: 12/16/2022]
Abstract
Spondyloarthritis (SpA) are a heterogeneous group of chronic inflammatory joint diseases that includes several clinical subgroups. SpA can affect women in the reproductive stage so pregnancy can influence the course of the disease and SpA can affect the maternal-fetal outcome. The treatment of SpA has changed dramatically in recent years and the use of targeted drugs is part of therapeutic armamentarium. The use of targeted drugs during pregnancy is controversial because the information available on safety during this period is still limited. Several cytokines have an important role in the normal development of pregnancy or other cytokines may play a role in certain maternal-fetal complications. Potentially targeted drugs can affect the function of these cytokines during pregnancy. The aim of this study is to review the interrelationship between SpA during pregnancy and lactation, the role of some cytokines during normal pregnancy and the development of maternal-fetal complications as well as to review recent information on targeted drugs during pregnancy and breastfeeding in these patients in order to maximize their use in these critical periods of life.
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Wieringa JW, Driessen GJ, Van Der Woude CJ. Pregnant women with inflammatory bowel disease: the effects of biologicals on pregnancy, outcome of infants, and the developing immune system. Expert Rev Gastroenterol Hepatol 2018; 12:811-818. [PMID: 29972674 DOI: 10.1080/17474124.2018.1496820] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Relapse of inflammatory bowel disease (IBD) during conception and pregnancy has been associated with a negative pregnancy outcome. Therefore, it is advised to maintain drugs in order to prevent relapse. The effect of drugs, which cross the placenta, on children who have been exposed during pregnancy will be discussed in this review. Areas covered: A literature search was performed using the following search terms: inflammatory bowel disease, pregnancy, infant, antitumor necrosis factor alpha, infliximab, adalimumab, golimumab, certolizumab, anti-integrins, vedolizumab, anti-interleukin (IL)-12/23 ustekinumab, placenta, vaccination. Other studies were identified by using references from articles identified through our original literature search. The occurrence of unfavorable pregnancy outcome and congenital malformations does not seem to be increased after exposure to anti-TNFα, but the effects on the developing immune system are largely unknown. For anti-integrins and anti IL-12/23, the numbers of exposed pregnancies are too small to draw any conclusions. Expert commentary: Follow-up of the developing immune system in children exposed to these drugs seems warranted, preferably in a prospective study design.
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Affiliation(s)
- Jantien W Wieringa
- a Department or Pediatrics , Haaglanden Medical Center , The Hague , The Netherlands.,b Department of Pediatric Infectious Diseases and Immunology , Erasmus Medical Centre-Sophia Children's Hospital , Rotterdam , The Netherlands
| | - Gertjan J Driessen
- c Department of Pediatrics , Haga Teaching Hospital, Juliana Children's Hospital , The Hague , The Netherlands
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36
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Galluzzo M, D'Adamio S, Bianchi L, Talamonti M. Psoriasis in pregnancy: case series and literature review of data concerning exposure during pregnancy to ustekinumab. J DERMATOL TREAT 2018; 30:40-44. [PMID: 29676599 DOI: 10.1080/09546634.2018.1468066] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Psoriasis tends to improve for approximately half of patients during pregnancy, but an equal number of patients report no change or worsening during this period, when lots of medications, like biologics, are not indicated. The aim of our study was to review data of patient that had been pregnant during ustekinumab treatment, analyzing data of our data set between September 2010 and February 2018. We found data of three patients that had been pregnant during ustekinumab treatment. All three patients successfully completed the pregnancy without complications. One of the three patients was pregnant even twice during treatment with ustekinumab, with also a successful birth of two perfectly healthy twins. Biologic agents approved for the treatment of moderate-to-severe psoriasis are currently classified as pregnancy category B, even if, particularly for ustekinumab, there are several case reports regarding exposure during pregnancy in humans related to a healthy pregnancy, both for women and children. Although further studies are required to find real indication of biological treatment in pregnant patients, according to our and to the reviewed experience, ustekinumab does not interfere with gestation.
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Affiliation(s)
- Marco Galluzzo
- a Division of Dermatology, Department of "Medicina dei Sistemi" , University of Rome "Tor Vergata" , Rome , Italy
| | - Simone D'Adamio
- a Division of Dermatology, Department of "Medicina dei Sistemi" , University of Rome "Tor Vergata" , Rome , Italy
| | - Luca Bianchi
- a Division of Dermatology, Department of "Medicina dei Sistemi" , University of Rome "Tor Vergata" , Rome , Italy
| | - Marina Talamonti
- a Division of Dermatology, Department of "Medicina dei Sistemi" , University of Rome "Tor Vergata" , Rome , Italy
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37
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Rowan CR, Cullen G, Mulcahy HE, Keegan D, Byrne K, Murphy DJ, Sheridan J, Doherty GA. Ustekinumab Drug Levels in Maternal and Cord Blood in a Woman With Crohn's Disease Treated Until 33 Weeks of Gestation. J Crohns Colitis 2018; 12:376-378. [PMID: 29045603 DOI: 10.1093/ecco-jcc/jjx141] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 10/13/2017] [Indexed: 02/08/2023]
Abstract
A 35-year old woman with ileocolonic, perianal, and vulval Crohn's disease was treated with subcutaneous ustekinuamb [USK] throughout pregnancy. Dose intervals were shortened from 6-weekly to 4-weekly to maintain clinical remission. The last dose of USK was administered at 33 weeks of gestation, and a healthy baby boy was delivered by caesarean section at 37 weeks. Maternal trough USK levels remained stable during pregnancy. Cord blood USK levels were nearly 2-fold higher than contemporaneous maternal serum levels. To our knowledge, this is the first report of maternal and cord USK levels in a patient with Crohn's disease.
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Affiliation(s)
- Catherine R Rowan
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
| | - Garret Cullen
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
| | - Hugh E Mulcahy
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
| | - Denise Keegan
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
| | - Kathryn Byrne
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
| | - Deirdre J Murphy
- Academic Department of Obstetrics and Gynaecology, Coombe Women and Infants University Hospital and Trinity College, University of Dublin, Dublin, Ireland
| | - Juliette Sheridan
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
| | - Glen A Doherty
- Centre for Colorectal Disease, St Vincent's University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
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38
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Danese S, Bonovas S, Peyrin-Biroulet L. Positioning Ustekinumab in Crohn's Disease: From Clinical Evidence to Clinical Practice. J Crohns Colitis 2017; 11:1258-1266. [PMID: 28575273 DOI: 10.1093/ecco-jcc/jjx079] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 06/02/2017] [Indexed: 02/08/2023]
Abstract
Biological medicines have revolutionised the treatment of Crohn's disease [CD]. Yet, the management of patients not responding to tumour necrosis factor [TNF] antagonists remains a clinical challenge. Ustekinumab is a human monoclonal antibody blocking the biological activity of interleukins 12 and 23, which regulate the immune system and immune-mediated inflammatory disorders. Ustekinumab has recently been approved for the treatment of adult patients with moderately to severely active CD, who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF antagonist, or have medical contraindications to such therapies. Herein, we review the new biological drug's efficacy and safety data reported from randomised controlled trials and real-world observational studies conducted in populations with CD, in order to identify the patient groups most likely to benefit, and to appropriately place ustekinumab into treatment algorithms for CD.
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Affiliation(s)
- Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy
| | - Stefanos Bonovas
- Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Hepato-Gastroenterology and Inserm U954, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France
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Abstract
This article reviews the available data regarding the efficacy of ustekinumab across published randomized clinical trials and open-label experience from tertiary medical centers, safety data, including in pregnancy, and its use in patients who have failed tumor necrosis factor (TNF) antagonists as well as patients who have not failed TNF antagonists. We have proposed an algorithm for positioning the use of ustekinumab among other agents (TNF antagonists, vedolizumab) in moderate-severe Crohn's disease. The article also enumerates drugs that are specific interleukin-23 blockers, including brazikumab (MEDI2070), risankizumab, LY3074828, tildrakizumab, and guselkumab, and the current status of their clinical trials.
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40
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Venturin C, Nancey S, Danion P, Uzzan M, Chauvenet M, Bergoin C, Roblin X, Flourié B, Boschetti G. Fetal death in utero and miscarriage in a patient with Crohn's disease under therapy with ustekinumab: case-report and review of the literature. BMC Gastroenterol 2017. [PMID: 28629323 PMCID: PMC5477379 DOI: 10.1186/s12876-017-0633-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Ustekinumab is a fully human monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 which is involved in the pathogenesis of several inflammatory diseases. Ustekinumab is approved for psoriasis and psoriatic arthritis treatment and has been successfully evaluated in phase II and III trials for patients with Crohn’s disease (CD). Case presentation We report here the case of a patient who became pregnant during treatment with ustekinumab for a refractory CD and which ended in miscarriage. Conclusion Ustekinumab is a relatively new pharmacotherapy and in addition to this clinical case, we reviewed the published literature concerning the use of this treatment during pregnancy and its consequences on pregnancy and fetus outcome.
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Affiliation(s)
- C Venturin
- Department of Gastroenterology, Lyon-Sud hospital, Hospices Civils de Lyon, Université Lyon1, Lyon, France
| | - S Nancey
- Department of Gastroenterology, Lyon-Sud hospital, Hospices Civils de Lyon, Université Lyon1, Lyon, France.,INSERM U1111, Centre International de Recherche en Infectiologie, Lyon, France
| | - P Danion
- Department of Gastroenterology, Lyon-Sud hospital, Hospices Civils de Lyon, Université Lyon1, Lyon, France
| | - M Uzzan
- Department of Gastroenterology and Nutritional Support, Beaujon Hospital, Assistance Publique des Hôpitaux de Paris, Université Paris VII, Clichy, France
| | - M Chauvenet
- Department of Gastroenterology, Lyon-Sud hospital, Hospices Civils de Lyon, Université Lyon1, Lyon, France
| | - C Bergoin
- Department of Gastroenterology, Lyon-Sud hospital, Hospices Civils de Lyon, Université Lyon1, Lyon, France
| | - X Roblin
- Department of Gastroenterology, Saint-Etienne hospital, Saint-Etienne, France
| | - B Flourié
- Department of Gastroenterology, Lyon-Sud hospital, Hospices Civils de Lyon, Université Lyon1, Lyon, France.,INSERM U1111, Centre International de Recherche en Infectiologie, Lyon, France
| | - G Boschetti
- Department of Gastroenterology, Lyon-Sud hospital, Hospices Civils de Lyon, Université Lyon1, Lyon, France. .,INSERM U1111, Centre International de Recherche en Infectiologie, Lyon, France. .,Service d'Hépato-Gastroentérologie, Centre Hospitalier Lyon-Sud, 165 Chemin du Grand Revoyet, 69495, Pierre Benite, France.
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41
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Verstockt B, Deleenheer B, Van Assche G, Vermeire S, Ferrante M. A safety assessment of biological therapies targeting the IL-23/IL-17 axis in inflammatory bowel diseases. Expert Opin Drug Saf 2017; 16:809-821. [DOI: 10.1080/14740338.2017.1338273] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Bram Verstockt
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Barbara Deleenheer
- Department of Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Gert Van Assche
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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Abstract
INTRODUCTION An increasing number of female patients with autoimmune diseases are treated with biologic drugs. Concerns in regard to safety of biologics during pregnancy arise in patients who have not completed their families. Areas covered: A review of the literature dealing with child outcomes of pregnancies exposed to biologics shows that TNF inhibitors (TNFi) are the best studied in regard to human pregnancy. In studies comparing exposed pregnancies to disease-matched controls no increased risk of spontaneous abortion, low birth weight, prematurity or congenital malformations has been observed. For rituximab, tocilizumab, anakinra, belimumab and ustekinumab no prospective, controlled studies are available, and firm conclusions about their safety during pregnancy cannot be drawn. Expert commentary: TNFi appear fairly safe when given in early pregnancy. For biologics other than TNFi prospective, controlled studies on outcomes after early and late pregnancy exposure are urgently needed. Possible effects of TNFi and all other biologics on children's immune function, infection rate and vaccination responses are either limited or absent and need to be extended. Development of laboratory tests to measure concentrations of biologics routinely in children exposed in utero would facilitate decisions in regard to the time point of vaccination with live vaccines.
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Affiliation(s)
- Monika Østensen
- a Norwegian National Advisory Unit on Pregnancy and Rheumatic Diseases, Department of Rheumatology , St. Olavs Hospital - Trondheim University Hospital , Norway
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43
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Abstract
OPINION STATEMENT Inflammatory bowel disease is frequently diagnosed before or during key childbearing years. One of the most important factors for a healthy pregnancy is having quiescent disease prior to conception and maintaining disease remission for the duration of the pregnancy. In order to achieve that, most women will need to continue their inflammatory bowel disease (IBD) treatment during pregnancy. One of the main concerns these women have is whether these medications will have adverse effects on their growing fetus. Aminosalicylates, antibiotics, and steroids are all relatively low risk for use during pregnancy and breastfeeding. Recent studies also support the safety of continuing immunomodulators and anti-tumor necrosis factor agents during pregnancy and with breastfeeding. There seems to be an increased risk for infection, however, with use of combination therapy including both a biologic agent and an immunomodulator. Less evidence is available on the use of anti-integrins in pregnancy; however, the current data suggest they may be safe as well. Conversations about a patient's desire for pregnancy should occur between the patient and provider on a regular basis prior to conception and particularly with any change in disease activity or change in the treatment regimen. This chapter will review the current evidence on the safety of IBD medications during pregnancy and lactation so that providers can more easily discuss the importance of medication adherence for disease remission with their patients who are contemplating conception.
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Cortes X, Borrás-Blasco J, Antequera B, Fernandez-Martinez S, Casterá E, Martin S, Molés JR. Ustekinumab therapy for Crohn's disease during pregnancy: a case report and review of the literature. J Clin Pharm Ther 2016; 42:234-236. [PMID: 28004853 DOI: 10.1111/jcpt.12492] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 10/31/2016] [Indexed: 12/13/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVES The safety of continued ustekinumab (UST) therapy during pregnancy remains unclear in patients with Crohn's disease (CD). There are no meta-analysis reports of exposure to UST during pregnancy. The objective was to describe a case of a pregnant patient with CD who was successfully treated with UST maintenance therapy throughout the pregnancy and delivered a baby boy without any congenital malformations, neurological abnormalities or birth defects. CASE SUMMARY A 37-year-old patient with CD treated with UST became pregnant. She had been receiving UST for 8 months at the time. After discussion with the patient and the obstetric team, the UST therapy was continued. The result of treatment was an uneventful pregnancy with delivery, at term, of a healthy boy and the maintenance of clinical, biological and endoscopic remission of CD during and after pregnancy. WHAT IS NEW AND CONCLUSION To our knowledge, this is the first reported use of continued UST therapy for CD throughout a pregnancy. The result of treatment was an uncomplicated pregnancy with the mother giving birth to a healthy boy at term and the maintenance of clinical biological and endoscopic remission of CD during and after pregnancy.
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Affiliation(s)
- X Cortes
- Gastroenterology Section, Internal Medicine, Hospital de Sagunto, Sagunt, Spain
| | | | - B Antequera
- Internal Medicine, Hospital de Sagunto, Sagunt, Spain
| | | | - E Casterá
- Pharmacy Service, Hospital de Sagunto, Sagunt, Spain
| | - S Martin
- Pediatric Service, Hospital de Sagunto, Sagunt, Spain
| | - J R Molés
- Gastroenterology Section, Internal Medicine, Hospital de Sagunto, Sagunt, Spain
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45
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Deepak P, Loftus EV. Ustekinumab in treatment of Crohn's disease: design, development, and potential place in therapy. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:3685-3698. [PMID: 27956825 PMCID: PMC5113936 DOI: 10.2147/dddt.s102141] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Crohn’s disease is characterized by a dysregulation of both innate and adaptive immunity responses. Interleukin-12/23 (IL-12/23) pathway has been found to be a major driver of inflammation in adaptive immune responses. Ustekinumab is a fully human immunoglobulin G1 kappa monoclonal antibody that blocks the p40 subunit of IL-12 and IL-23 and prevents their interaction with their cell surface receptor and further cytokine activation. It is currently approved in the management of plaque psoriasis and psoriatic arthritis. Very promising data have emerged through phase II and phase III trials (UNITI-1, UNITI-2, and IM-UNITI) for both induction and maintenance of clinical response and remission in moderate-to-severe Crohn’s disease, resulting in approval by the Food and Drug Administration for this condition. This article reviews the immunology of the IL-12/23 pathway, available data regarding the initial designing of ustekinumab, drug development through clinical trials including pharmacokinetics, efficacy, and safety, and its potential place in the treatment of Crohn’s disease.
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Affiliation(s)
- Parakkal Deepak
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA
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46
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Armstrong AW, Aldredge L, Yamauchi PS. Managing Patients With Psoriasis in the Busy Clinic: Practical Tips for Health Care Practitioners. J Cutan Med Surg 2016; 20:196-206. [PMID: 26712930 PMCID: PMC4834511 DOI: 10.1177/1203475415623508] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Psoriasis is a common inflammatory disease with significant comorbidities, whose management can be challenging given the variety of treatment options. It is critical for nurse practitioners, physician assistants, general practitioners, and dermatology trainees to have useful information about the treatment and monitoring of patients with psoriasis. Although certain aspects of care apply to all patients, each therapeutic agent has its own nuances in terms of assessments, dosing, and monitoring. The most appropriate treatment is based not only on disease severity but also on comorbid conditions and concomitant medications. These practitioners are vital in facilitating patient care by thorough understanding of systemic agents, selection criteria, dosing, and recommended monitoring. This article provides high-yield practical pearls on managing patients with moderate to severe psoriasis. It includes case-based discussions illustrating considerations for special populations, such as pregnant women, children, and patients with comorbidities (eg, human immunodeficiency virus infection, hepatitis C, hepatitis B, and history of malignancy).
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Affiliation(s)
- April W Armstrong
- Department of Dermatology, University of Colorado Denver, Aurora, CO, USA
| | - Lakshi Aldredge
- Department of Dermatology, Portland Veterans Affairs Medical Center, Portland, OR, USA
| | - Paul S Yamauchi
- Dermatology Institute and Skin Care Center, Santa Monica, CA, USA Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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47
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Simon EG, Ghosh S, Iacucci M, Moran GW. Ustekinumab for the treatment of Crohn's disease: can it find its niche? Therap Adv Gastroenterol 2016; 9:26-36. [PMID: 26770265 PMCID: PMC4699281 DOI: 10.1177/1756283x15618130] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Crohn's disease is an immune-mediated disease that results in panenteric chronic inflammation in genetically predisposed individuals exposed to an appropriate environment. The past two decades have witnessed the emergence of an important class of drugs known as anti-tumour necrosis factor (TNF) agents in the treatment of Crohn's disease. Unfortunately, the utility of these agents have been hampered by primary and secondary nonresponse in a significant proportion of patients. Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin (IL) 12 and 23, is a novel pharmacotherapy for this patient cohort that offers an out-of-class option. It is approved for use in psoriasis and psoriatic arthritis, and has now been evaluated in phase II trials for moderate-to-severe Crohn's disease. We here review the published literature and describe a potential clinical role for its use in this disease cohort.
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Affiliation(s)
- Ebby G. Simon
- Department of Gastroenterology, Christian Medical College, Vellore, India NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases, Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, UK
| | - Subrata Ghosh
- Department of Medicine and IBD Clinic, University of Calgary, Calgary, Alberta, Canada
| | - Marietta Iacucci
- Department of Medicine and IBD Clinic, University of Calgary, Calgary, Alberta, Canada
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48
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Galli-Novak E, Mook SC, Büning J, Schmidt E, Zillikens D, Thaci D, Ludwig RJ. Successful pregnancy outcome under prolonged ustekinumab treatment in a patient with Crohn's disease and paradoxical psoriasis. J Eur Acad Dermatol Venereol 2015; 30:e191-e192. [PMID: 26559393 DOI: 10.1111/jdv.13499] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- E Galli-Novak
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - S-C Mook
- Department of Dermatology, University of Lübeck, Lübeck, Germany.,Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany
| | - J Büning
- Gastroenterology, Medical Department I, University Hospital of Schleswig-Holstein, Lübeck, Germany
| | - E Schmidt
- Department of Dermatology, University of Lübeck, Lübeck, Germany.,Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
| | - D Zillikens
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - D Thaci
- Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany
| | - R J Ludwig
- Department of Dermatology, University of Lübeck, Lübeck, Germany.,Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany.,Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
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49
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Bangsgaard N, Rørbye C, Skov L. Treating Psoriasis During Pregnancy: Safety and Efficacy of Treatments. Am J Clin Dermatol 2015; 16:389-98. [PMID: 26149091 DOI: 10.1007/s40257-015-0137-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Psoriasis is a chronic inflammatory disease with a well-documented negative effect on the quality of life of affected patients. Psoriasis often occurs in the reproductive years, during which the issue of pregnancy needs to be addressed. The course of psoriasis during pregnancy is unpredictable, and many patients face the challenge of needing treatment during pregnancy. In this review we provide an overview of the key considerations for managing psoriasis in pregnant women, covering the potential effects of active psoriasis and co-morbid conditions on the health of the mother and fetus, as well as the effects of psoriasis treatment options on the developing fetus. Although there are no robust data on the safety of systemic treatment of pregnant women, increasing evidence regarding the safety of cyclosporine (ciclosporin) treatment as well as anti-tumor necrosis factor-α is available and should be considered in pregnant women with moderate to severe psoriasis unresponsive to local corticosteroids and UVB light treatment.
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Affiliation(s)
- Nannie Bangsgaard
- Herlev and Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, 2900, Hellerup, Denmark.
| | - Christina Rørbye
- Department of Obstetrics and Gynecology, Hvidovre Hospital, University of Copenhagen, 2650, Hvidovre, Denmark
| | - Lone Skov
- Herlev and Gentofte Hospital, University of Copenhagen, Kildegårdsvej 28, 2900, Hellerup, Denmark
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50
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Vena GA, Cassano N, Bellia G, Colombo D. Psoriasis in pregnancy: challenges and solutions. PSORIASIS-TARGETS AND THERAPY 2015; 5:83-95. [PMID: 29387585 PMCID: PMC5683115 DOI: 10.2147/ptt.s82975] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The available information about the effects of pregnancy on psoriasis and those of psoriasis on pregnancy is almost limited, despite the high frequency of the disease in the general population, as well as in women in reproductive years. Considering the existing evidence, pregnancy does not tend to have a negative influence on psoriasis, as in most women who experience a change in the severity and course of their psoriasis during pregnancy, the change is more likely to be reported as an improvement. This assumption can be applied more convincingly to plaque-type psoriasis, while an exception may be represented by generalized pustular psoriasis, which has been somehow linked to impetigo herpetiformis. Conflicting findings emerged from the few available studies that explored the effect of psoriasis on pregnancy outcomes. Recent studies found an association between moderate-to-severe psoriasis and some pregnancy complications, including pregnancy-induced hypertensive diseases, and have emphasized a trend toward a newborn with low birth weight in patients with psoriasis, especially in those suffering from severe forms. The safety profile during pregnancy is not completely known for many drugs used to treat psoriasis. Moisturizers and low- to moderate-potency topical steroids or ultraviolet B phototherapy represent the first-line therapy for pregnant patients. Many dermatologists may, however, recommend discontinuing all drugs during pregnancy, in consideration of medico-legal issues, and also taking into account that common forms of psoriasis do not compromise the maternal and fetal health. Anyway, for those women whose psoriasis improves during pregnancy, the interruption of any therapy for psoriasis can be a reasonable strategy. The objective of this paper was to review the most relevant literature data on psoriasis in pregnancy, trying to give concurrently practical information about clinical and prognostic aspects, as well as counseling and management.
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